Methods of treating cancer by sustained infusion of coenzyme Q10

Abstract

The present invention provides regimens and methods for treating cancer, including continuous infusion of coenzyme Q10. Coenzyme Q10 can be administered as a monotherapy or in combination with other agents, such as anti-cancer agents, chemotherapeutic agents, or anti-angiogenic agents. Coenzyme Q10 can be administered at two or more different rates.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201480060063.4, filed on September 4, 2014, entitled "Method for Treating Cancer by Continuous Infusion of Coenzyme Q10". Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 61 / 873,510, filed September 4, 2013; U.S. Provisional Patent Application No. 61 / 901,351, filed November 7, 2013; and U.S. Provisional Patent Application No. 61 / 912,770, filed December 6, 2013, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention generally relates to methods for treating tumor diseases, including administering coenzyme Q10 by continuous infusion. Background Technology

[0004] Cancer is one of the leading causes of death in developed countries. The diagnosis of cancer has traditionally involved serious health complications. Cancer can cause disfigurement, chronic or acute pain, injury, organ failure, or even death. Commonly diagnosed cancers include pancreatic cancer, breast cancer, lung cancer, melanoma, lymphoma, carcinoma, sarcoma, non-Hodgkin's lymphoma, leukemia, endometrial cancer, colon and rectal cancer, prostate cancer, and bladder cancer. Traditionally, many cancers (e.g., breast cancer, leukemia, lung cancer, etc.) are treated with surgery, chemotherapy, radiation therapy, or a combination thereof. Chemotherapy agents used in cancer treatment are known to produce several serious and unpleasant side effects in patients. For example, some chemotherapy agents can cause neuropathy, nephrotoxicity (e.g., hyperlipidemia, proteinuria, hypoalbuminemia, etc.), stomatitis, mucositis, vomiting, hair loss, anorexia, esophagitis, amenorrhea, weakened immunity, anemia, high-pitched hearing loss, cardiotoxicity, fatigue, neuropathy, myelosuppression, or a combination thereof. Often, chemotherapy is ineffective during treatment or shortly after the treatment regimen ends, or it loses its effectiveness after a period of effectiveness (i.e., the treatment regimen does not lead to a cure). There remains a need for improved methods for treating oncological diseases (including cancer) and compositions capable of delivering bioactive agents to aid in the treatment of the disease and other conditions. Summary of the Invention

[0005] The present invention provides a method for treating cancer by continuous intravenous administration of coenzyme Q10, said cancer being, for example, a solid tumor or a non-solid tumor (e.g., leukemia).

[0006] The present invention provides a method for treating cancer in a subject, comprising administering a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours.

[0007] The present invention also provides a method of treating cancer in a subject, comprising administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein the coenzyme Q10 is administered at two or more different rates.

[0008] In a particular implementation, coenzyme Q10 is administered sequentially at a first rate and a second rate, wherein the first rate is higher than the second rate.

[0009] In a particular embodiment, the method further includes administering coenzyme Q10 at a third rate after the second rate.

[0010] In a particular implementation, the third rate is slower than the first rate but faster than the second rate.

[0011] In a particular implementation, coenzyme Q10 is administered at a first rate for about 0.5 hours to about 3 hours.

[0012] In a particular implementation, coenzyme Q10 is administered at a first rate for about 0.5 hours to about 2 hours.

[0013] In a particular implementation, coenzyme Q10 is administered at a first rate for approximately 1 hour.

[0014] In a particular implementation, the total infusion time at the first rate plus the infusion time at the second rate is approximately 24 hours.

[0015] In a particular implementation, the total infusion time at the first rate plus the infusion time at the second rate is approximately 48 hours.

[0016] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion for at least 48 hours.

[0017] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion for at least 72 hours.

[0018] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion for at least 96 hours.

[0019] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion for no more than 120 hours.

[0020] In a specific implementation, continuous intravenous infusion is administered once a week.

[0021] In a particular implementation, one or more doses are administered via continuous intravenous infusion.

[0022] In a particular implementation, continuous intravenous infusion is administered for two or more weeks, three or more weeks, four or more weeks, five or more weeks, six or more weeks, seven or more weeks, or eight or more weeks.

[0023] In a specific implementation, coenzyme Q10 is administered via continuous intravenous infusion for at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, at least 216 hours, at least 240 hours, at least 288 hours, at least 312 hours, at least 336 hours, at least 360 hours, at least 384 hours, at least 408 hours, at least 432 hours, at least 456 hours, or at least 480 hours.

[0024] In a specific embodiment, coenzyme Q10 is administered via continuous intravenous infusion for no more than 480 hours. In a specific embodiment, coenzyme Q10 is administered via continuous intravenous infusion for no more than 456 hours.

[0025] In certain implementations, the medication is administered intravenously every two weeks, every three weeks, or every four weeks.

[0026] In a particular implementation, continuous intravenous infusion is administered once or more, twice or more, or three or more times.

[0027] In certain implementations, coenzyme Q10 is administered together with other medications.

[0028] In a particular implementation, the administration of other agents begins on the same day that coenzyme Q10 is started.

[0029] In a specific implementation, the administration of other agents may be initiated one week or more, two weeks or more, three weeks or more, four weeks or more, five weeks or more, six weeks or more, seven weeks or more, or eight weeks or more after the initiation of coenzyme Q10 administration.

[0030] In certain implementation schemes, the other agents are anticancer agents.

[0031] In certain implementation schemes, the other agents are chemotherapeutic agents.

[0032] In certain embodiments, other agents are selected from gemcitabine, 5-fluorouracil, leucovorin, and docetaxel. In certain embodiments, other agents are selected from fludarabine and cytarabine. In certain embodiments, other agents are selected from cyclophosphamide, paclitaxel, docetaxel, busulfan, methotrexate, doxorubicin, melphalan, cladribine, vincristine, vinblastine, chlorambucil, tamoxifen, paclitaxel, camptothecin, actinomycin D, mitomycin C, cobustatin, cisplatin, etoposide, pentamethasone, podophyllotoxin, and 5-fluorouracil.

[0033] In certain implementations, the other agents are anti-angiogenic agents.

[0034] In certain embodiments, during treatment with coenzyme Q10, other agents are administered when the cancer progresses. In certain embodiments, during treatment with coenzyme Q10, other agents are administered when the cancer stabilizes or regresses.

[0035] In certain implementations, the adverse effects of other drugs are limited or reduced in subjects who receive coenzyme Q10 via continuous infusion along with other drugs, compared to subjects who do not receive coenzyme Q10 along with other drugs.

[0036] In a specific implementation, the adverse event is bone marrow suppression. In a specific implementation, the adverse event is cardiotoxicity.

[0037] In a specific embodiment, the first rate of response does not exceed 4.2 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 5.5 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 7.4 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 8.3 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 9.2 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 11 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 14.5 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 18.4 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 19.6 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 22.9 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 26.0 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 28.7 mg / kg / hour. In a specific embodiment, the first rate of response does not exceed 35.8 mg / kg / hour.

[0038] This invention provides a method for treating cancer in a subject, including... (a) Administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein coenzyme Q10 is administered at two or more different rates; (b) Monitor subjects for decreased coagulation; and (c) Discontinue Coenzyme Q10 treatment in subjects identified as having reduced clotting ability.

[0039] This invention provides a method for treating cancer in a subject, including... (a) Administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein coenzyme Q10 is administered at two or more different rates; (b) Monitor subjects for decreased coagulation; (c) Administering a drug to improve coagulation in subjects identified as having a reduced coagulation effect; (d) Confirm that the subject has normal coagulation function; and (e) Continue treatment with Coenzyme Q10.

[0040] In certain implementations, agents used to improve blood clotting include vitamin K.

[0041] This invention provides a method for treating cancer in a subject, including... (a) Administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein coenzyme Q10 is administered at two or more different rates; (b) Monitor subjects for decreased coagulation; and (c) Continue treatment with coenzyme Q10 in subjects identified as having normal coagulation.

[0042] This invention provides a method for treating cancer in a subject, including... (a) Administer the composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) Monitor subjects for decreased coagulation; and (c) Discontinue Coenzyme Q10 treatment in subjects identified as having reduced coagulation.

[0043] This invention provides a method for treating cancer in a subject, including... (a) Administer the composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) Monitor subjects for decreased coagulation; and (c) Administering a drug to improve coagulation in subjects identified as having a reduced coagulation effect; (d) Confirm that the subject has normal coagulation function; and (e) Continue treatment with Coenzyme Q10.

[0044] In certain implementations, agents used to improve blood clotting include vitamin K.

[0045] This invention provides a method for treating cancer in a subject, including... (a) Administer the composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) Monitor subjects for decreased coagulation; and (c) Continue treatment with coenzyme Q10 in subjects identified as having normal coagulation.

[0046] In a particular implementation, reduced clotting includes an INR higher than 2, while normal clotting includes an INR of 2 or lower.

[0047] In a particular implementation, reduced clotting includes an INR higher than 3, while normal clotting includes an INR of 3 or lower.

[0048] In a particular implementation, reduced coagulation includes a platelet threshold of less than 50,000 / uL.

[0049] In a particular implementation, normal coagulation includes a platelet threshold of at least 50,000 / uL.

[0050] The present invention provides a method for preventing or limiting the severity of adverse events related to cancer treatment using intravenously administered coenzyme Q10, comprising administering a composition containing coenzyme Q10 to a subject with cancer by continuous intravenous infusion for at least 48 hours, wherein the severity of adverse events in the subject is reduced compared to intravenous administration of the same dose of coenzyme Q10 over a period of 6 hours or less.

[0051] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion for at least 72 hours.

[0052] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion for at least 96 hours.

[0053] In a specific implementation, coenzyme Q10 is administered via continuous infusion for no more than 120 hours.

[0054] In a particular implementation, the continuous intravenous infusion dose is administered twice a week.

[0055] In a particular implementation, the continuous intravenous infusion dose is administered once a week.

[0056] In certain embodiments, the continuous intravenous infusion dose is administered once or multiple times. In certain embodiments, the continuous intravenous infusion dose is administered for two or more weeks, three or more weeks, four or more weeks, five or more weeks, six or more weeks, seven or more weeks, or eight or more weeks.

[0057] In a particular implementation, coenzyme Q10 is administered by continuous intravenous infusion for at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, at least 216 hours, at least 240 hours, at least 264 hours, at least 288 hours, at least 312 hours, at least 336 hours, at least 360 hours, at least 384 hours, at least 408 hours, at least 432 hours, at least 456 hours, or at least 480 hours.

[0058] In a specific implementation, coenzyme Q10 is administered via continuous infusion for no more than 456 hours. In a specific implementation, coenzyme Q10 is administered via continuous infusion for no more than 480 hours.

[0059] In certain implementation schemes, continuous intravenous infusion is administered every two weeks, every three weeks, or every four weeks.

[0060] In a particular implementation, continuous intravenous infusion is administered once or more, twice or more, or three or more times.

[0061] In certain implementations, adverse events include coagulopathy.

[0062] In a specific implementation, coagulopathy includes grade 1 coagulopathy.

[0063] In a specific implementation, coagulopathy includes grade 2 coagulopathy.

[0064] In a specific implementation, coagulopathy includes grade 3 coagulopathy.

[0065] In a specific implementation, coagulopathy includes grade 4 coagulopathy.

[0066] In a particular implementation, adverse events include serious adverse events.

[0067] In certain implementations, adverse events include bleeding events.

[0068] In a particular implementation, adverse events include at least two INRs.

[0069] In a particular implementation, adverse events include at least 3 INRs.

[0070] This invention provides a method for treating cancer, comprising administering a composition containing coenzyme Q10 by continuous intravenous infusion for at least 96 hours, wherein the composition is administered sequentially at a first rate, a second rate, and a third rate, wherein: (a) The first rate is the highest rate administered during the first hour of continuous intravenous infusion; (b) The second rate is the lowest rate administered during continuous intravenous infusion from hour 2 to hour 48; and (c) The third rate is an intermediate rate between the first and second rates and is administered during the 49th to 96th hour of continuous intravenous infusion.

[0071] In a preferred embodiment, the amount of coenzyme Q10 administered during the first to 48 hours of continuous intravenous infusion is equivalent to the amount of coenzyme Q10 administered during the 49th to 96th hours of continuous intravenous infusion.

[0072] In a particular embodiment, the first rate is selected from not more than 4.2 mg / kg / hour, not more than 5.5 mg / kg / hour, not more than 7.4 mg / kg / hour, not more than 8.3 mg / kg / hour, not more than 9.2 mg / kg / hour, not more than 11.0 mg / kg / hour, not more than 14.5 mg / kg / hour, not more than 18.4 mg / kg / hour, not more than 19.6 mg / kg / hour, not more than 22.9 mg / kg / hour, not more than 26.0 mg / kg / hour, not more than 28.7 mg / kg / hour, and not more than 35.8 mg / kg / hour.

[0073] In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 50 mg / kg / 96 hours, with a first rate of approximately 4.2 mg / kg / hour, a second rate of approximately 0.98 mg / kg / hour, and a third rate of approximately 1.05 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 66 mg / kg / 96 hours, with a first rate of approximately 5.5 mg / kg / hour, a second rate of approximately 1.29 mg / kg / hour, and a third rate of approximately 1.38 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 88 mg / kg / 96 hours, with a first rate of approximately 7.4 mg / kg / hour, a second rate of approximately 1.71 mg / kg / hour, and a third rate of approximately 1.83 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 110 mg / kg / 96 hours, with a first rate of approximately 9.2 mg / kg / hour, a second rate of approximately 2.14 mg / kg / hour, and a third rate of approximately 2.29 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 137 mg / kg / 96 hours, with a first rate of approximately 11 mg / kg / hour, a second rate of approximately 2.68 mg / kg / hour, and a third rate of approximately 2.85 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 171 mg / kg / 96 hours, with a first rate of approximately 14 mg / kg / hour, a second rate of approximately 3.34 mg / kg / hour, and a third rate of approximately 3.56 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of about 215 mg / kg / 96 hours, with a first rate of about 18 mg / kg / hour, a second rate of about 4.19 mg / kg / hour, and a third rate of about 4.48 mg / kg / hour.

[0074] In a particular embodiment, coenzyme Q10 is administered at a dose of about 40 mg / kg / 96 hours to about 250 mg / kg / 96 hours, with a first rate of about 3.4 mg / kg / hour to about 21 mg / kg / hour, a second rate of about 0.8 mg / kg / hour to about 4.8 mg / kg / hour, and a third rate of about 0.84 mg / kg / hour to about 5.25 mg / kg / hour.

[0075] In a particular implementation, approximately 3-5% of the total coenzyme Q10 administered during the first hour of the continuous intravenous infusion over the 96-hour period is given.

[0076] This invention provides a method for treating cancer, comprising administering a composition containing coenzyme Q10 by continuous intravenous infusion for about 18 days, wherein the composition is administered sequentially at a first rate, a second rate, and a third rate, wherein: (a) The first rate is the highest rate administered during the first hour of the first day of continuous infusion; (b) The second rate is the lowest rate administered during the second to 24 hours of continuous infusion on day 1; and (c) The third rate includes an intermediate administration rate between the first and second rates administered during the continuous infusion period from day 2 to day 17.

[0077] In a preferred embodiment, the amount of coenzyme Q10 administered during each 24-hour period of continuous intravenous infusion is equal.

[0078] In a particular embodiment, the first rate is selected from not more than 4.2 mg / kg / hour, not more than 5.5 mg / kg / hour, not more than 7.4 mg / kg / hour, not more than 8.3 mg / kg / hour, not more than 9.2 mg / kg / hour, not more than 11.0 mg / kg / hour, not more than 14.5 mg / kg / hour, not more than 18.4 mg / kg / hour, not more than 19.6 mg / kg / hour, not more than 22.9 mg / kg / hour, not more than 26.0 mg / kg / hour, not more than 28.7 mg / kg / hour, and not more than 35.8 mg / kg / hour.

[0079] In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 33 mg / kg / 24 hours via infusion, with a first rate of approximately 8.3 mg / kg / hour, a second rate of approximately 1.07 mg / kg / hour, and a third rate of approximately 1.38 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 44 mg / kg / 24 hours via infusion, with a first rate of approximately 11 mg / kg / hour, a second rate of approximately 1.43 mg / kg / hour, and a third rate of approximately 1.83 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 58.7 mg / kg / 24 hours via infusion, with a first rate of approximately 14.7 mg / kg / hour, a second rate of approximately 1.91 mg / kg / hour, and a third rate of approximately 2.44 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 73.4 mg / kg / 24 hours via infusion, with a first rate of approximately 18.4 mg / kg / hour, a second rate of approximately 2.39 mg / kg / hour, and a third rate of approximately 3.06 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 91.7 mg / kg / 24 hours via infusion, with a first rate of approximately 22.9 mg / kg / hour, a second rate of approximately 2.99 mg / kg / hour, and a third rate of approximately 3.82 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 114.6 mg / kg / 24 hours via infusion, with a first rate of approximately 28.7 mg / kg / hour, a second rate of approximately 3.73 mg / kg / hour, and a third rate of approximately 4.78 mg / kg / hour. In a particular embodiment, coenzyme Q10 is administered at a dose of approximately 143.3 mg / kg / 24 hours, with a first rate of approximately 35.8 mg / kg / hour, a second rate of approximately 4.67 mg / kg / hour, and a third rate of approximately 5.97 mg / kg / hour.

[0080] In a particular embodiment, coenzyme Q10 is administered at a dose of about 30 mg / kg / 24 hours to about 170 mg / kg / 24 hours, and at a first rate of about 7.5 mg / kg / hour to about 42.5 mg / kg / hour, a second rate of about 0.98 mg / kg / hour to about 5.54 mg / kg / hour, and a third rate of about 1.25 mg / kg / hour to about 7.08 mg / kg / hour.

[0081] In a particular implementation, approximately 20-30% of the total coenzyme Q10 administered during the first hour of continuous infusion is given during the first 48 hours of continuous infusion.

[0082] In certain implementations, coenzyme Q10 is administered together with other medications.

[0083] In one specific embodiment, the other agents are administered before the administration of coenzyme Q10. In another specific embodiment, the other agents are not administered before the administration of coenzyme Q10.

[0084] In a particular implementation, the administration of other medications begins on the same day that coenzyme Q10 administration is initiated.

[0085] In a particular implementation, the administration of other agents may begin one or more weeks after the initiation of coenzyme Q10 administration.

[0086] In a particular implementation, the administration of other medications may begin two weeks or more after the start of coenzyme Q10 administration.

[0087] In a particular implementation, the administration of other agents may begin three weeks or more after the initiation of coenzyme Q10 administration.

[0088] In a particular implementation, the administration of other medications may begin four weeks or more after the initiation of coenzyme Q10 administration.

[0089] In a particular implementation, the administration of other agents may begin five weeks or more after the initiation of coenzyme Q10 administration.

[0090] In a particular implementation, the administration of other agents may begin six weeks or more after the initiation of coenzyme Q10 administration.

[0091] In a particular implementation, administration of other agents may begin seven weeks or more after the start of coenzyme Q10 administration.

[0092] In a particular implementation, administration of other medications may begin eight weeks or more after the start of coenzyme Q10 administration.

[0093] In a particular embodiment, the invention further includes monitoring bone marrow suppression in the subject.

[0094] In a specific implementation, no bone marrow suppression was observed.

[0095] In certain implementation schemes, the other agents are anticancer agents.

[0096] In certain implementation schemes, the other agents are chemotherapeutic agents.

[0097] In a particular implementation, the other agents are selected from gemcitabine, 5-fluorouracil, folate, and docetaxel.

[0098] In a particular implementation, the other agents are selected from fludarabine and acytidine.

[0099] In certain embodiments, other agents are selected from cyclophosphamide, paclitaxel, docetaxel, busulfan, methotrexate, doxorubicin, melphalan, cladribine, vincristine, vinblastine, chlorambucil, tamoxifen, paclitaxel, camptothecin, actinomycin-D, mitomycin C, cobustatin, cisplatin, etoposide, pentamethasone, podophyllotoxin, and 5-fluorouracil.

[0100] In certain implementations, other agents are administered when cancer progresses during treatment with coenzyme Q10.

[0101] In certain implementations, other agents are administered when there is no cancer progression during treatment with coenzyme Q10.

[0102] In certain implementations, the adverse effects of other drugs are limited or reduced in subjects who receive coenzyme Q10 via continuous infusion along with other drugs, compared to subjects who do not receive coenzyme Q10 along with other drugs.

[0103] In a specific implementation, the adverse event is bone marrow suppression.

[0104] In a specific implementation, the adverse event is cardiotoxicity.

[0105] In certain implementations, cancer includes solid tumors.

[0106] In a specific implementation, the solid tumor is selected from carcinoma, melanoma, sarcoma, and lymphoma.

[0107] In a specific embodiment, the solid tumor is selected from breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney (renal cell) cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, bone cancer, brain cancer, cervical cancer, liver cancer, stomach cancer, oral and oral cavity cancer, neuroblastoma, testicular cancer, uterine cancer, thyroid cancer, and vulvar cancer. In a preferred embodiment, the coenzyme Q10 composition is used to treat various types of solid tumors, such as breast cancer, bladder cancer, colon and rectal cancer, endometrial cancer, kidney (renal cell) cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, bone cancer, brain cancer, cervical cancer, liver cancer, stomach cancer, oral and oral cavity cancer, neuroblastoma, testicular cancer, uterine cancer, thyroid cancer, and vulvar cancer. In a specific embodiment, the solid tumor includes breast cancer, including triple-negative breast cancer. In a specific embodiment, skin cancer includes melanoma, squamous cell carcinoma, and cutaneous T-cell lymphoma (CTCL).

[0108] In certain implementations, cancer includes leukemia.

[0109] In a specific implementation, leukemia is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (or myeloid or non-lymphocytic) leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). Further types of leukemia include hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, and adult T-cell leukemia.

[0110] In a specific implementation plan, leukemia is acute leukemia.

[0111] In a specific implementation, leukemia is selected from ALL and AML.

[0112] In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 12.5 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 16.5 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 22 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 27.5 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 33 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 34.2 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 42.8 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 44 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 53.8 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 58.7 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 73.4 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 91.7 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 114.6 mg / kg / day (24 hours). In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 143.3 mg / kg / day (24 hours).

[0113] In a particular implementation, coenzyme Q10 is administered at a dose of approximately 33 mg / kg / day (24 hours) to approximately 143.3 mg / kg / day (24 hours).

[0114] In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 50 mg / kg / week. In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 66 mg / kg / week. In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 88 mg / kg / week. In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 110 mg / kg / week. In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 137 mg / kg / week. In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 171 mg / kg / week. In a specific embodiment, coenzyme Q10 is administered at a dose of approximately 215 mg / kg / week.

[0115] In a particular implementation, coenzyme Q10 is administered at a dose of about 50 mg / kg / week to about 215 mg / kg / week.

[0116] In a specific implementation, coenzyme Q10 is administered at a dose of approximately 50 mg / kg / week.

[0117] In a particular implementation, continuous intravenous infusion of coenzyme Q10 is administered at a higher rate during the first hour of infusion.

[0118] In a particular embodiment, at least 5% of the total dose of coenzyme Q10 administered over the previous 48 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 6% of the total dose of coenzyme Q10 administered over the previous 48 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 7% of the total dose of coenzyme Q10 administered over the previous 48 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 8% of the total dose of coenzyme Q10 administered over the previous 48 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 9% of the total dose of coenzyme Q10 administered over the previous 48 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 10% of the total dose of coenzyme Q10 administered over the previous 48 hours is administered during the first hour of continuous intravenous infusion.

[0119] In a particular implementation, no more than 10% of the total dose of coenzyme Q10 administered during the first hour of continuous intravenous infusion is given.

[0120] In a particular embodiment, at least 20% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 21% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 22% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 23% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 24% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 25% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 26% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 27% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion. In a particular embodiment, at least 28% of the total dose of coenzyme Q10 administered over the previous 24 hours is administered during the first hour of continuous intravenous infusion.

[0121] In a particular implementation, no more than 28% of the total dose of coenzyme Q10 administered during the first hour of continuous intravenous infusion is given.

[0122] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion at a constant rate.

[0123] In a particular embodiment, the composition contains 0.1% to 10% w / v of coenzyme Q10.

[0124] In a particular implementation, it contains 1% to 10% w / v of coenzyme Q10.

[0125] In a particular embodiment, the composition contains 1% to 5% w / v coenzyme Q10.

[0126] In a particular embodiment, the composition contains 2% to 6% w / v coenzyme Q10.

[0127] In a particular embodiment, the composition contains 3% to 5% w / v coenzyme Q10.

[0128] In a particular implementation, the method further includes selecting subjects with cancer for treatment with coenzyme Q10, wherein the subjects have sufficient clotting ability.

[0129] In a specific implementation, adequate coagulation includes a platelet threshold of 50,000 / mcL, prothrombin time (PT) within normal limits, partial thromboplastin time (PTT), and international normalized ratio (INR).

[0130] In a particular embodiment, the method further includes selecting subjects with cancer for treatment with coenzyme Q10, wherein the subjects exhibit at least one condition or characteristic selected from: (a) The subject was taking an HMG-CoA reductase inhibitor; (b) The subject was taking digoxin, digitoxin, digitoxin C or any type of digitalis alkaloid.

[0131] (c) The subject has a history of uncontrolled or severe coagulopathy or clinically significant bleeding within the past 6 months; (d) The subject suffers from at least one of hemoptysis, epistaxis, hematochezia, hematuria, or gastrointestinal bleeding; (e) The subject has a bleeding tendency; (f) The subject has been given an anticoagulant; (g) The subject has grade 3 thrombocytopenia, accompanied by clinically significant bleeding; (h) The subject experienced ≥ grade 4 hematologic toxicity; (i) Subjects with grade 2 elevated INR / PTT, accompanied by clinically significant bleeding; and (j) The subject had grade 3 INR / PTT abnormalities.

[0132] In a specific embodiment of the above method, the tendency to bleed includes von Willebrand's disease. In a specific embodiment of the above method, ≥ grade 4 hematologic toxicity is selected from death, grade 4 anemia, grade 4 thrombocytopenia, grade 4 neutropenia lasting more than 5 days, and grade 4 neutropenia of any duration accompanied by fever or definite infection.

[0133] The present invention provides a method for improving the therapeutic index of intravenously administered coenzyme Q10 by increasing the infusion time of the coenzyme Q10 dose from at least 6 hours to at least 48 hours of continuous intravenous infusion.

[0134] In a specific embodiment, the subject's response to coenzyme Q10 is assessed at the end of a four-week cycle. In a specific embodiment, if no tumor progression is observed by RECIST criteria, the subject continues coenzyme Q10 treatment. In a specific embodiment, if no tumor progression is observed by RECIST criteria, the subject continues coenzyme Q10 treatment alone. In a specific embodiment, the coenzyme Q10 dose is increased compared to the dose administered during the first 28 days of treatment. In a specific embodiment, the increased dose is administered for 21 days. In a specific embodiment, the increased dose is administered weekly in a continuous 96-hour infusion once a week. In a specific embodiment, the dose is continuously increased until the subject's maximum tolerated dose is identified.

[0135] In a specific implementation, if tumor progression is observed according to RECIST criteria, the subject continues coenzyme Q10 supplementation with standard chemotherapy. In a specific implementation, the standard chemotherapy is selected from gemcitabine, 5-fluorouracil and leucovorin, and docetaxel. In a specific implementation, at 600 mg / m²... 2 The initial dose of gemcitabine is administered intravenously once weekly. In a specific regimen, it is 350 mg / m². 2 The starting dose is 5-fluorouracil (5-FU) administered once weekly via IV, plus 100 mg / m². 2 Formyltetrahydrofolate (LV). In a specific implementation, at 20 mg / m² 2 The starting dose is docetaxel administered once weekly via IV.

[0136] In a specific embodiment, coenzyme Q10 is administered as a continuous infusion over 18 days. In a specific embodiment, the cancer is leukemia. In a specific embodiment, if no disease progression is observed according to standard guidelines, the subject continues treatment with coenzyme Q10. In a specific embodiment, if disease progression is observed according to standard guidelines, the subject continues treatment with coenzyme Q10 alone. In a specific embodiment, if tumor progression is observed according to standard guidelines, the subject continues treatment with coenzyme Q10 supplemented with standard chemotherapy. In a specific embodiment, standard treatment... For example, preferred coenzyme Q10 compositions and dosages for intravenous administration are provided in WO2011112900.

[0137] In a specific embodiment of the present invention, the coenzyme Q10 compound is formulated into a nanodispersion.

[0138] In a specific embodiment of the invention, a coenzyme Q10 compound is provided in a coenzyme Q10 formulation for intravenous administration, the formulation comprising: Aqueous solution; Coenzyme Q10 dispersed into particulate nanoparticles; and At least one of a dispersion stabilizer and an opsonization reducer; The coenzyme Q10 nanodispersion is dispersed in nanoparticles with an average particle size of less than 200 nm. In a particular embodiment, the dispersion stabilizer is selected from PEGylated castor oil, Cremophor® EL, Cremophor® RH 40, PEGylated vitamin E, vitamin E TPGS, and myristoylphosphatidylcholine (DMPC). In a particular embodiment, the dispersion stabilizer is DMPC. In a particular embodiment, the opsonizing agent is selected from poloxamer and poloxamine. In a particular embodiment, the opsonizing agent is poloxamer 188. In a particular embodiment, the opsonizing agent is poloxamer 188, and the dispersion stabilizer is DMPC.

[0139] In a specific embodiment of the invention, the coenzyme Q10 formulation has weight / volume ratios of 4%, 3%, and 1.5% for coenzyme Q10, DMPC, and poloxamer 188, respectively.

[0140] In a particular embodiment of the invention, the CoQ10 compound is administered to the subject together with other pharmaceutical agents. In a particular embodiment, the other pharmaceutical agents are chemotherapeutic agents.

[0141] In a preferred embodiment of the present invention, the CoQ10 compound is coenzyme Q10.

[0142] This invention provides intravenous coenzyme Q10 for use in any of the methods provided herein.

[0143] This invention provides the use of intravenously administered coenzyme Q10 in any of the methods provided herein.

[0144] The present invention provides pharmaceutical compositions comprising coenzyme Q10 for use in any of the methods provided herein.

[0145] The present invention provides compositions comprising a CoQ10 compound for carrying out any of the methods provided herein.

[0146] In a specific embodiment of the invention, the CoQ10 compound is applied at least once a week. In a specific embodiment, the CoQ10 compound is applied at least twice a week. In a specific embodiment, the CoQ10 compound is applied at least three times a week. In a specific embodiment, the CoQ10 compound is applied once a week. In a specific embodiment, the CoQ10 compound is applied twice a week. In a specific embodiment, the CoQ10 compound is applied three times a week.

[0147] In specific embodiments of the invention, the CoQ10 compound is administered at a 24-hour dose selected from at least 5.6 mg / kg / dose, at least 11.2 mg / kg / dose, at least 22.5 mg / kg / dose, at least 33 mg / kg / dose, at least 44 mg / kg / dose, at least 58.7 mg / kg / dose, at least 73.4 mg / kg / dose, at least 78.2 mg / kg / dose, at least 91.7 mg / kg / dose, at least 104.3 mg / kg / dose, at least 114.6 mg / kg / dose, at least 139 mg / kg / dose, and at least 78.2 mg / kg / dose. In specific embodiments, the CoQ10 compound is administered at a 24-hour dose selected from at least 50 mg / kg / dose, at least 75 mg / kg / dose, at least 100 mg / kg / dose, at least 125 mg / kg / dose, at least 150 mg / kg / dose, and at least 200 mg / kg / dose. In a particular embodiment, the dose is administered for four (4) consecutive 24-hour periods (i.e., 96-hour continuous infusion). In a particular embodiment, the dose is administered for eighteen (18) consecutive 24-hour periods (i.e., 432-hour continuous infusion).

[0148] In a specific embodiment of the invention, the CoQ compound is administered at a 24-hour dose not exceeding 500 mg / kg / dose, 400 mg / kg / dose, 300 mg / kg / dose, 250 mg / kg / dose, 200 mg / kg / dose, 150 mg / kg / dose, or 100 mg / kg / dose.

[0149] In a specific embodiment of the invention, the CoQ10 compound is administered at a 96-hour dose selected from at least 50 mg / kg / dose, at least 66 mg / kg / dose, at least 88 mg / kg / dose, at least 110 mg / kg / dose, at least 137 mg / kg / dose, at least 171 mg / kg / dose, and at least 215 mg / kg / dose. In a specific embodiment of the invention, the CoQ10 compound is administered at a 96-hour dose selected from about 50 mg / kg / dose, about 66 mg / kg / dose, about 88 mg / kg / dose, about 110 mg / kg / dose, about 137 mg / kg / dose, about 171 mg / kg / dose, and about 215 mg / kg / dose.

[0150] In a particular embodiment, the CoQ10 compound is administered at a dose that does not cause Grade III toxicity in the subject. In a particular embodiment, the CoQ10 compound is administered at a dose that does not cause Grade IV toxicity in the subject.

[0151] In a specific embodiment of the invention, at least 12 doses of the CoQ10 compound are administered to a subject. That is, in a specific embodiment, at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 62, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more doses are administered to a subject.

[0152] In a specific implementation, subjects are treated with CoQ10 for at least 4 weeks. In a specific implementation, subjects are treated with CoQ10 for at least 8 weeks. That is, in a specific implementation, subjects are treated with CoQ10 for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 62, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more weeks.

[0153] In a preferred embodiment, coenzyme Q10 is prepared in a solution of about 3% to about 5% coenzyme Q10 (e.g., about 4%) prior to application. In a particular embodiment, the coenzyme Q10 prepared in a solution of about 3% to about 5% coenzyme Q10 is diluted in a suitable carrier prior to application.

[0154] In certain embodiments, treatment of a subject is analyzed or monitored by detecting one or more biomarkers. Biomarkers used in this method may include protein biomarkers, nucleic acid biomarkers, and lipid biomarkers. Biomarkers can be analyzed or monitored in any subject sample, including but not limited to blood, urine, or tissue. In certain embodiments, one or more biomarkers are at least one cancer biomarker. In certain embodiments, one or more biomarkers are at least one metabolic biomarker.

[0155] The present invention also provides a method for treating cancer in a subject, comprising administering a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours.

[0156] The present invention also provides a method of treating cancer in a subject, comprising administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein the coenzyme Q10 is administered at two or more different rates.

[0157] In a particular implementation, coenzyme Q10 is administered sequentially at a first rate and a second rate, wherein the first rate is higher than the second rate.

[0158] In a particular embodiment, the method further includes administering coenzyme Q10 at a third rate after the second rate. In a particular embodiment, the third rate is lower than the first rate but higher than the second rate.

[0159] In a particular embodiment, coenzyme Q10 is administered at a first rate for about 0.5 hours to about 3 hours, or about 0.5 hours to about 2 hours. In a particular embodiment, coenzyme Q10 is administered at a first rate for about 1 hour.

[0160] In a particular implementation, the total time for infusion at the first rate plus the time for infusion at the second rate is approximately 24 hours, approximately 48 hours, or approximately 72 hours.

[0161] In a particular embodiment, coenzyme Q10 is administered by continuous intravenous infusion for at least 48 hours. In a particular embodiment, coenzyme Q10 is administered by continuous intravenous infusion for at least 72 hours. In a particular embodiment, coenzyme Q10 is administered by continuous intravenous infusion for at least 96 hours. In a particular embodiment, coenzyme Q10 is administered by continuous intravenous infusion for at least 144 hours.

[0162] In one embodiment, continuous intravenous infusion is administered once weekly. In another embodiment, continuous infusion is administered twice weekly.

[0163] In a specific implementation, coenzyme Q10 is administered by continuous intravenous infusion for at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, at least 216 hours, at least 240 hours, at least 288 hours, at least 312 hours, at least 336 hours, at least 360 hours, at least 384 hours, at least 408 hours, at least 432 hours, at least 456 hours, or at least 480 hours.

[0164] In certain implementations, continuous intravenous infusion is administered every two weeks, every three weeks, or every four weeks.

[0165] In a specific implementation, the first rate does not exceed 3.1 mg / kg / hr, 4.2 mg / kg / hour, 5.5 mg / kg / hour, 7.4 mg / kg / hour, 8.3 mg / kg / hour, 9.2 mg / kg / hour, 11.0 mg / kg / hour, 11.2 mg / kg / hour, 14 mg / kg / hour, 14.5 mg / kg / hour, 18.0 mg / kg / hour, 18.4 mg / kg / hour, 19.6 mg / kg / hour, 22.9 mg / kg / hour, 26.0 mg / kg / hour, 28.7 mg / kg / hour, or 35.8 mg / kg / hour.

[0166] The present invention also provides a method of treating a subject with cancer, comprising: (a) administering a composition comprising coenzyme Q10 by continuous intravenous infusion, wherein the coenzyme Q10 is administered at two or more different rates; (b) monitoring the subject for reduced clotting; and (c) discontinuing treatment with coenzyme Q10 in subjects identified as having reduced clotting.

[0167] The present invention also provides a method of treating a subject with cancer, comprising: (a) administering a composition comprising coenzyme Q10 by continuous intravenous infusion, wherein the coenzyme Q10 is administered at two or more different rates; (b) monitoring the subject for reduced clotting; (c) administering an agent to improve clotting in subjects identified as having reduced clotting; (d) confirming that the subject has normal clotting; and (e) continuing treatment with coenzyme Q10.

[0168] In certain implementations, agents used to improve blood clotting include vitamin K.

[0169] The present invention also provides a method of treating a subject with cancer, comprising: (a) administering a composition comprising coenzyme Q10 by continuous intravenous infusion, wherein the coenzyme Q10 is administered at two or more different rates; (b) monitoring the subject for reduced clotting; and (c) continuing treatment with coenzyme Q10 in subjects identified as having normal clotting.

[0170] The present invention also provides a method of treating a subject with cancer, comprising (a) administering a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) monitoring the subject for reduced clotting; and (c) discontinuing treatment with coenzyme Q10 in subjects identified as having reduced clotting.

[0171] The present invention also provides a method of treating a subject with cancer, comprising (a) administering a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) monitoring the subject for reduced clotting; and (c) administering an agent to improve clotting in subjects identified as having reduced clotting; (d) confirming that the subject has normal clotting; and (e) continuing treatment with coenzyme Q10.

[0172] In certain implementations, agents used to improve blood clotting include vitamin K.

[0173] The present invention also provides a method of treating cancer in a subject, comprising (a) administering a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) monitoring the subject for reduced clotting; and (c) continuing treatment with coenzyme Q10 in subjects identified as having normal clotting.

[0174] In certain embodiments, reduced clotting includes an INR greater than 2, while normal clotting includes an INR of 2 or lower. In certain embodiments, reduced clotting includes an INR greater than 3, while normal clotting includes an INR of 3 or lower. In certain embodiments, reduced clotting includes a platelet threshold of less than 50,000 / µL. In certain embodiments, normal clotting includes a platelet threshold of at least 50,000 / µL.

[0175] The present invention also provides a method for preventing or limiting the severity of adverse events associated with the use of intravenously administered coenzyme Q10 to treat cancer, comprising administering a composition containing coenzyme Q10 to a subject with cancer by continuous intravenous infusion for at least 48 hours, wherein the severity of adverse events in the subject is reduced compared to intravenous administration of the same dose of coenzyme Q10 over a period of 6 hours or less.

[0176] In a particular embodiment, coenzyme Q10 is administered by continuous intravenous infusion for at least 72 hours. In a particular embodiment, coenzyme Q10 is administered by continuous intravenous infusion for at least 96 hours. In a particular embodiment, coenzyme Q10 is administered by continuous intravenous infusion for at least 144 hours.

[0177] In one embodiment, the continuous intravenous infusion dose is administered twice weekly. In another embodiment, the continuous intravenous infusion dose is administered once weekly.

[0178] In a particular implementation, coenzyme Q10 is administered by continuous intravenous infusion for at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, at least 216 hours, at least 240 hours, at least 264 hours, at least 288 hours, at least 312 hours, at least 336 hours, at least 360 hours, at least 384 hours, at least 408 hours, at least 432 hours, at least 456 hours, or at least 480 hours.

[0179] In certain implementations, continuous intravenous infusion is administered every two weeks, every three weeks, or every four weeks.

[0180] In a particular embodiment, adverse events include coagulopathy. In a particular embodiment, adverse events include bleeding events. In a particular embodiment, adverse events include an INR of at least 2 or an INR of at least 3.

[0181] The present invention also provides a method of treating cancer, comprising administering a composition comprising coenzyme Q10 by continuous intravenous infusion for about 96 hours, wherein the composition is administered in sequence at a first rate, a second rate and a third rate, wherein: (a) the first rate is the highest rate administered during the first hour of continuous intravenous infusion; (b) the second rate is the lowest rate administered during the second to 48 hours of continuous intravenous infusion; and (c) the third rate is an intermediate rate between the first and second rates and is administered during the 49th to 96th hours of continuous intravenous infusion.

[0182] In a particular implementation, the amount of coenzyme Q10 administered during the first to 48 hours of continuous intravenous infusion is equal to the amount of coenzyme Q10 administered during the 49th to 96th hours of continuous intravenous infusion.

[0183] The present invention also provides a method of treating cancer, comprising administering a composition comprising coenzyme Q10 by continuous intravenous infusion for about 144 hours, wherein the composition is administered in sequence at a first rate, a second rate and a third rate, wherein: (a) the first rate is the highest rate administered during the first hour of continuous intravenous infusion; (b) the second rate is the lowest rate administered during the second to 72 hours of continuous intravenous infusion; and (c) the third rate is an intermediate rate between the first and second rates and is administered during the 73rd to 144th hours of continuous intravenous infusion.

[0184] In a particular implementation, the amount of coenzyme Q10 administered during the first to 72 hours of continuous intravenous infusion is equal to the amount of coenzyme Q10 administered during the 73rd to 144th hours of continuous intravenous infusion.

[0185] In a specific embodiment, the first rate is selected from not more than 3.1 mg / kg / hour, not more than 4.2 mg / kg / hour, not more than 5.5 mg / kg / hour, not more than 7.4 mg / kg / hour, not more than 8.3 mg / kg / hour, not more than 9.2 mg / kg / hour, not more than 11.0 mg / kg / hour, not more than 11.2 mg / kg / hour, not more than 14.0 mg / kg / hour, not more than 14.5 mg / kg / hour, not more than 18.0 mg / kg / hour, not more than 18.4 mg / kg / hour, not more than 19.6 mg / kg / hour, not more than 22.9 mg / kg / hour, not more than 26.0 mg / kg / hour, not more than 28.7 mg / kg / hour, and not more than 35.8 mg / kg / hour.

[0186] In a specific embodiment, the infusion dose is selected from approximately 50 mg / kg / 48 hours and the first infusion rate is approximately 4.2 mg / kg / hour, approximately 66 mg / kg / 48 hours and the first infusion rate is approximately 5.5 mg / kg / hour, approximately 88 mg / kg / 48 hours and the first infusion rate is approximately 7.4 mg / kg / hour, approximately 110 mg / kg / 48 hours and the first infusion rate is approximately 9.2 mg / kg / hour, and approximately 137 mg / kg / 48 hours. Coenzyme Q10 is administered at a dose and first rate of approximately 11 mg / kg / hour, approximately 171 mg / kg / 48 hours at a dose and first rate of approximately 14 mg / kg / hour, approximately 215 mg / kg / 48 hours at a dose and first rate of approximately 18 mg / kg / hour, and approximately 40 mg / kg / 48 hours at a dose and first rate of approximately 250 mg / kg / 48 hours at a dose and first rate of approximately 3.4 mg / kg / hour to approximately 21 mg / kg / hour.

[0187] In a specific embodiment, the infusion dose is selected from approximately 38 mg / kg / 72 hours with a first rate of approximately 3.1 mg / kg, approximately 50 mg / kg / 72 hours with a first rate of approximately 4.1 mg / kg / hour, approximately 66 mg / kg / 72 hours with a first rate of approximately 5.4 mg / kg / hour, approximately 88 mg / kg / 72 hours with a first rate of 7.2 mg / kg / hour, and approximately 110 mg / kg / 72 hours with a first rate of approximately 9.0 mg / kg / hour. Coenzyme Q10 was administered at a dose of approximately 137 mg / kg / 72 hours with a first rate of approximately 11.2 mg / kg / hour, a dose of approximately 171 mg / kg / 72 hours with a first rate of approximately 14.0 mg / kg / hour, a dose of approximately 215 mg / kg / 72 hours with a first rate of approximately 17.6 mg / kg / hour, and a dose of approximately 38 mg / kg / 72 hours to approximately 250 mg / kg / 72 hours with a first rate of approximately 3.1 mg / kg / hour to approximately 21 mg / kg / hour.

[0188] In a particular embodiment, 3-5% of the total coenzyme Q10 administered during the first hour of continuous intravenous infusion is given during the 96-hour continuous intravenous infusion. In a particular embodiment, 3-5% of the total coenzyme Q10 administered during the first hour of continuous intravenous infusion is given during the 144-hour continuous intravenous infusion.

[0189] The present invention also provides a method of treating cancer, comprising administering a composition comprising coenzyme Q10 by continuous intravenous infusion for about 18 days, wherein the composition is administered in sequence at a first rate, a second rate and a third rate, wherein: (a) the first rate is the highest rate administered during the first hour of the first day of continuous infusion; (b) the second rate is the lowest rate administered during the second to 24 hours of the first day of continuous infusion; and (c) the third rate comprises an intermediate rate administered between the first and second rates administered during the second to 17 days of continuous infusion.

[0190] In a particular implementation, the amount of coenzyme Q10 administered during each 24-hour period of continuous intravenous infusion is equal.

[0191] In a particular embodiment, the first rate is selected from rates not exceeding 4.2 mg / kg / hour, not exceeding 5.5 mg / kg / hour, not exceeding 7.4 mg / kg / hour, not exceeding 8.3 mg / kg / hour, not exceeding 9.2 mg / kg / hour, not exceeding 11.0 mg / kg / hour, not exceeding 14.5 mg / kg / hour, not exceeding 18.4 mg / kg / hour, not exceeding 19.6 mg / kg / hour, not exceeding 22.9 mg / kg / hour, not exceeding 26.0 mg / kg / hour, not exceeding 28.7 mg / kg / hour, and not exceeding 35.8 mg / kg / hour.

[0192] In a specific embodiment, the infusion dose is selected from approximately 33 mg / kg / 24 hours and the first infusion rate is approximately 8.3 mg / kg / hour, approximately 44 mg / kg / 24 hours and the first infusion rate is approximately 11 mg / kg / hour, approximately 58.7 mg / kg / 24 hours and the first infusion rate is approximately 14.7 mg / kg / hour, approximately 73.4 mg / kg / 24 hours and the first infusion rate is approximately 18.4 mg / kg / hour, and approximately 91.7 mg / kg / 24 hours. Coenzyme Q10 is administered at a dose and first rate of approximately 22.9 mg / kg / hour, approximately 114.6 mg / kg / 24 hours, approximately 28.7 mg / kg / hour, approximately 143.3 mg / kg / 24 hours, approximately 35.8 mg / kg / hour, approximately 30 mg / kg / 24 hours, approximately 170 mg / kg / 24 hours, and approximately 7.5 mg / kg / hour to approximately 42.5 mg / kg / hour.

[0193] In a particular implementation, 20-30% of the total coenzyme Q10 administered during the first hour of continuous infusion is given during the first 48 hours of continuous infusion.

[0194] In certain embodiments, coenzyme Q10 is administered together with other agents. In certain embodiments, administration of the other agents begins on the same day as the commencement of coenzyme Q10 administration. In certain embodiments, administration of the other agents begins one week or more, two weeks or more, three weeks or more, four weeks or more, five weeks or more, six weeks or more, seven weeks or more, or eight weeks or more after the commencement of coenzyme Q10 administration.

[0195] In a particular implementation, the method further includes monitoring bone marrow suppression in the subject.

[0196] In a specific embodiment, the other agents are anticancer agents. In a specific embodiment, the other agents are chemotherapeutic agents. In a specific embodiment, the other agents are selected from gemcitabine, 5-fluorouracil, leucovorin, docetaxel, fludarabine, cytarabine, cyclophosphamide, paclitaxel, docetaxel, busulfan, methotrexate, doxorubicin, melphalan, cladribine, vincristine, vinblastine, chlorambucil, tamoxifen, paclitaxel, camptothecin, actinomycin D, mitomycin C, cobustatin, cisplatin, etoposide, pentamethasone, podophyllotoxin, and 5-fluorouracil. In a specific embodiment, the other agents are antiangiogenic agents.

[0197] In a particular embodiment, during treatment with coenzyme Q10, other agents are administered when cancer progresses. In a particular embodiment, during treatment with coenzyme Q10, other agents are administered when there is no cancer progression.

[0198] In certain implementations, the adverse effects of other drugs are limited or reduced in subjects who receive coenzyme Q10 via continuous infusion along with other drugs, compared to subjects who do not receive coenzyme Q10 along with other drugs.

[0199] In a specific implementation, the adverse effect is bone marrow suppression. In a specific implementation, the adverse effect is cardiotoxicity.

[0200] In certain implementations, cancer includes solid tumors.

[0201] In a specific implementation, the solid tumor is selected from carcinoma, melanoma, sarcoma, and lymphoma.

[0202] In certain embodiments, solid tumors are selected from breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney (renal cell) carcinoma, lung cancer, melanoma, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, bone cancer, brain cancer, cervical cancer, liver cancer, stomach cancer, oral and oral cavity cancer, neuroblastoma, testicular cancer, uterine cancer, thyroid cancer, and vulvar cancer. In certain embodiments, solid tumors include triple-negative breast cancer. In certain embodiments, skin cancers include melanoma, squamous cell carcinoma, and cutaneous T-cell lymphoma (CTCL).

[0203] In a specific implementation, cancer includes leukemia. In a specific implementation, leukemia is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphoblastic leukemia, and adult T-cell leukemia.

[0204] In a specific implementation plan, leukemia is acute leukemia.

[0205] In a specific embodiment, coenzyme Q10 is administered at a dose ranging from approximately 10 mg / kg / day (24 hours) to approximately 150 mg / kg / day. In a specific embodiment, coenzyme Q10 is administered at a dose selected from approximately 11.8 mg / kg / day (24 hours), approximately 12.5 mg / kg / day (24 hours), approximately 14.4 mg / kg / day (24 hours), approximately 15.6 mg / kg / day (24 hours), approximately 16.5 mg / kg / day (24 hours), approximately 19 mg / kg / day (24 hours), approximately 20.4 mg / kg / day (24 hours), approximately 22 mg / kg / day (24 hours), and approximately 25 mg / kg / day. g / kg / day (24 hours), approximately 27.5 mg / kg / day (24 hours), approximately 29.3 mg / kg / day (24 hours), approximately 33 mg / kg / day (24 hours), approximately 34.2 mg / kg / day (24 hours), approximately 36.7 mg / kg / day (24 hours), approximately 41.7 mg / kg / day (24 hours), approximately 42.8 mg / kg / day (24 hours), approximately 44 mg / kg / day (24 hours), approximately 45 mg / kg / day (24 hours). 7 mg / kg / day (24 hours), approximately 51.9 mg / kg / day (24 hours), approximately 53.8 mg / kg / day (24 hours), approximately 55 mg / kg / day (24 hours), approximately 57 mg / kg / day (24 hours), approximately 58.7 mg / kg / day (24 hours), approximately 64.8 mg / kg / day (24 hours), approximately 66.7 mg / kg / day (24 hours), approximately 68.5 mg / kg / day (24 hours), approximately Coenzyme Q10 was administered at doses of approximately 71.7 mg / kg / day (24 hours), approximately 73.4 mg / kg / day (24 hours), approximately 81.5 mg / kg / day (24 hours), approximately 85.5 mg / kg / day (24 hours), approximately 91.7 mg / kg / day (24 hours), approximately 107.5 mg / kg / day (24 hours), approximately 114.6 mg / kg / day (24 hours), and approximately 143.3 mg / kg / day (24 hours).

[0206] In a specific implementation, coenzyme Q10 is administered at a dose selected from about 38 mg / kg / week, about 50 mg / kg / week, about 66 mg / kg / week, about 76 mg / kg / week, about 88 mg / kg / week, about 100 mg / kg / week, about 110 mg / kg / week, about 132 mg / kg / week, about 137 mg / kg / week, about 171 mg / kg / week, about 176 mg / kg / week, about 215 mg / kg / week, about 220 mg / kg / week, about 274 mg / kg / week, about 342 mg / kg / week, and about 430 mg / kg / week.

[0207] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion at a faster rate during the first hour of infusion.

[0208] In a particular implementation, at least 5%, 6%, 7%, 8%, 9%, or 10% of the total dose of coenzyme Q10 administered over the preceding 48 hours is administered during the first hour of continuous intravenous infusion.

[0209] In a particular implementation, at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, or 28% of the total dose of coenzyme Q10 administered over the preceding 24 hours is administered during the first hour of continuous intravenous infusion.

[0210] In a particular implementation, coenzyme Q10 is administered via continuous intravenous infusion at a constant rate.

[0211] In a particular embodiment, the composition contains 0.1% to 20% w / v coenzyme Q10. In a particular embodiment, the composition contains 1% to 10% w / v coenzyme Q10. In a particular embodiment, the composition contains 1% to 5% w / v coenzyme Q10.

[0212] In a particular implementation, the method further includes selecting cancer subjects for treatment with coenzyme Q10, wherein the subjects have sufficient clotting ability.

[0213] In a specific implementation, adequate coagulation includes a platelet threshold of 50,000 / mcL, prothrombin time (PT) within normal limits, partial thromboplastin time (PTT), and international normalized ratio (INR).

[0214] In a particular embodiment, the method further includes selecting cancer subjects for treatment with coenzyme Q10, wherein the subject presents at least one of the following conditions or characteristics: (a) the subject is taking an HMG-CoA reductase inhibitor; (b) the subject is taking digoxin, digitoxin, digitoxin C, or any type of digitalis alkaloid; (c) the subject has an uncontrolled or severe coagulopathy or a history of clinically significant bleeding within the past 6 months; (d) the subject has at least one of hemoptysis, epistaxis, hematochezia, hematuria, or gastrointestinal bleeding; (e) the subject has a bleeding tendency; (f) the subject has been given an anticoagulant; (g) the subject has grade 3 thrombocytopenia with clinically significant bleeding; (h) the subject has grade 4 hematologic toxicity; (i) the subject has grade 2 elevated INR / PTT with clinically significant bleeding; and (j) the subject has grade 3 abnormal INR / PTT.

[0215] In a particular embodiment, the method includes improving the therapeutic index of intravenously administered coenzyme Q10 by increasing the infusion time of the coenzyme Q10 dose from no more than 6 hours to a continuous intravenous infusion of at least 48 hours.

[0216] The present invention also provides a method for improving the therapeutic index of intravenously administered coenzyme Q10 by increasing the infusion time of the coenzyme Q10 dose from no more than 6 hours to at least 48 hours of continuous intravenous infusion.

[0217] In a specific implementation, coenzyme Q10 is administered for at least two cycles.

[0218] The present invention also provides coenzyme Q10 for intravenous administration in any of the above methods.

[0219] The present invention also provides the use of intravenously administered coenzyme Q10 in any of the above methods.

[0220] The present invention also provides a pharmaceutical composition comprising coenzyme Q10 for use in any of the above methods.

[0221] Other implementation schemes are provided below. Attached Figure Description

[0222] Figure 1 A flowchart of a clinical trial treatment method for subjects with solid tumors using coenzyme Q10 in combination with other drugs is shown.

[0223] Figure 2 A flowchart is shown of a treatment method in a clinical trial in which Coenzyme Q10 was optionally combined with other drugs to treat subjects with leukemia.

[0224] Figure 3 A flowchart of the clinical trial protocol is shown.

[0225] Figure 4 The results show the survival outcomes from a mouse study of acute myeloid leukemia. The x-axis represents the number of days since the start of treatment, where day 1 is the first day of treatment, while the y-axis represents the number of surviving animals.

[0226] Figure 5 The survival results from a mouse study of acute erythroleukemia are shown. The x-axis represents the number of days since the start of treatment, where day 1 is the first day of treatment, while the y-axis represents the number of surviving animals.

[0227] Figure 6 The effect of coenzyme Q10 on the viability of cancer cell lines was demonstrated. Each cell line was treated with a fixed dose (100 μM) of coenzyme Q10. Data represent cell viability in the presence and absence of coenzyme Q10 at 48 or 72 hours of exposure.

[0228] Figure 7 Three regimens are shown for evaluating the effect of coenzyme Q10, alone or in combination with gemcitabine, on overall survival in preclinical animal models of pancreatic cancer. The study included coenzyme Q10 administered alone or in combination with gemcitabine (150 mg / kg body weight) once, twice, or three times daily at a dose of 50 mg / kg body weight (Rule 1 and Rule 2), or coenzyme Q10 at a dose of 50 mg / kg or 75 mg / kg body weight (Rule 3).

[0229] Figures 8A-8C The effects of gemcitabine, coenzyme Q10 (at a dose of 50 mg / kg body weight), and the combination of gemcitabine and coenzyme Q10 on survival in animal models of pancreatic cancer were demonstrated. The effects of once-daily coenzyme Q10, alone or in combination with gemcitabine, were also demonstrated. Figure 8A Coenzyme Q10 twice daily ( Figure 8B ) and Coenzyme Q10 three times daily ( Figure 8C Animal survival spectrum after treatment. The x-axis represents the number of days since treatment began, while the y-axis represents the number of surviving animals.

[0230] Figure 9 This study demonstrates the effect of continuous infusion of various concentrations of coenzyme Q10 on survival duration in an animal model of pancreatic cancer. Infusion pumps were surgically implanted in the animals to facilitate continuous infusion of coenzyme Q10 at doses of 25 mg / kg, 50 mg / kg, or 100 mg / kg body weight / day. The x-axis represents the number of days from the start of treatment, while the y-axis represents the number of surviving animals.

[0231] Figure 10 This study demonstrates the effect of continuous infusion of various concentrations of coenzyme Q10 on survival in an animal model of prostate cancer. Coenzyme Q10 was administered using two different dosing regimens: 75 mg / kg body weight / day (as a dose of 25 mg / kg body weight every 8 hours) or continuous infusion of 75 mg / kg body weight / day. Treatment continued throughout the study period. The x-axis represents the number of days from the start of treatment, while the y-axis represents the number of surviving animals.

[0232] Figure 11 The PET scan showed an early response to a dose of 66 mg / kg / week of coenzyme Q10 in patients with recurrent, heavily pretreated gastric cancer.

[0233] Figure 12 The effects of three-times daily treatment with coenzyme Q10 and continuous infusion of coenzyme Q10 are shown in rats injected with pulmonary chloroma. The x-axis represents the number of days from the start of treatment, while the y-axis represents the number of surviving animals.

[0234] Figure 13The effects of three-times daily treatment with coenzyme Q10 and continuous infusion of coenzyme Q10 are shown in rats injected with hepatic chloroma. The x-axis represents the number of days from the start of treatment, while the y-axis represents the number of surviving animals.

[0235] Figure 14 The effects of continuous infusion of coenzyme Q10 alone, chemotherapy alone, or a combination of chemotherapy and continuous infusion of coenzyme Q10 were shown in rats injected with human lung cancer cells. The dose of coenzyme Q10 was 50 mg / kg at a concentration of 4%. Chemotherapy was repeated in three-week cycles as follows: Week 1: IV cyclophosphamide, 35 mg / kg, 1x / week and IV doxorubicin 2.5 mg / kg, 3x / week; Weeks 2–3: no treatment. The x-axis represents the number of days from the start of treatment, while the y-axis represents the number of surviving animals. Detailed Implementation

[0236] I. Definition The terms “cancer” or “tumor” are well known in the art and refer to, for example, cells in a subject that have typical characteristics of cancer-causing cells (such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rates, reduced cell death / apoptosis, and specific characteristic morphological features).

[0237] As used herein, “cancer” means all types of cancer or growths or malignant tumors found in humans, including, but not limited to: leukemia, lymphoma, melanoma, carcinoma, and sarcoma. As used herein, the terms or language “cancer,” “growth,” and “tumor” are used interchangeably and, in the singular or plural form, refer to cells that have undergone a malignant transformation that makes them pathological to the host organism. Primary cancer cells (i.e., cells obtained from the vicinity of the site of malignant transformation) can be easily distinguished from non-cancer cells by well-established techniques, particularly histological examination. As used herein, the definition of cancer cells includes not only primary cancer cells but also cancer stem cells, as well as cancer progenitor cells or any cells derived from the ancestors of cancer cells. This includes metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. In a particular embodiment, cancer is not a central nervous system (CNS) cancer, i.e., not a cancer of a tumor present in at least one of the spinal cord, brain, and eye. In a particular embodiment, primary cancer is not a CNS cancer. In a particular embodiment, cancer is a solid tumor. In a particular embodiment, cancer is a hematologic malignancy (i.e., a non-solid tumor).

[0238] "Solid tumors" are tumors that are detectable based on the size of the tumor mass; for example, they are detectable by procedures such as CAT scans, MR imaging, X-rays, ultrasound, or palpation, and / or by the expression of one or more cancer-specific antigens in a sample available from the patient. The tumor does not need to have a measurable size.

[0239] The specific criteria used for cancer staging are based on tumor size, histological features, tumor markers, and other criteria known to those skilled in the art, depending on the specific cancer type. Generally, cancer stages can be described as follows: Stage 0 - Carcinoma in situ Stages I, II, and III – Higher numbers indicate a wider range of disease: larger tumor size and / or cancer spreading beyond its primary organ to adjacent lymph nodes and / or tissues or organs near the site of the primary tumor. Stage IV - The cancer has spread to distant tissues or organs.

[0240] As used herein, the terms “treat,” “treating,” or “treatment” preferably refer to actions that achieve beneficial or desired clinical outcomes, including relief or improvement (e.g., resolution, partial or complete) of one or more signs or symptoms of a disease or condition, reduction in the severity of the disease, stabilization of the condition (i.e., no worsening, achieving stable disease), a reduced rate of progression or time to progression, and a reduction (whether partial or overall). “Treatment” for cancer can also mean prolonged survival compared to expected survival without treatment. Treatment is not necessarily curative. In certain embodiments, treatment includes one or more of pain relief or improved quality of life (QOL), as determined by a qualified individual (e.g., a treating physician), for example, using recognized pain and QOL assessment tools. In certain embodiments, pain relief or improved quality of life (QOL) determined by a qualified individual (e.g., a treating physician) using, for example, recognized pain and QOL assessment tools is not considered “treatment” for cancer.

[0241] The RECIST criteria are clinically recognized standard methods for providing measurements of solid tumors and defining objective evaluation criteria for changes in tumor size during clinical trials. Such criteria can be used to monitor the response of individuals undergoing treatment for solid tumors. The RECIST 1.1 criteria are found in Eisenhauer et al.'s (New response evaluation criteria in solid tumors: Revised RECIST guideline) (version 1.1). Eur. J. CancerThe following is a detailed discussion in (45:228-247, 2009), the entire contents of which are incorporated herein by reference. The criteria for response to target lesions include: Complete response (CR): All target lesions disappear. Any pathological lymph nodes (whether target or non-target) must have their short axis reduced to <10 mm.

[0242] Partial response (PR): The total diameter of the target lesions is reduced by at least 30%, with the baseline total diameter as a reference.

[0243] Progressive disease (PD): The sum of the diameters of target lesions must increase by at least 20%, using the minimum sum at the time of study as a reference (this includes the baseline sum if it is the minimum sum at the time of study). In addition to a relative increase of 20%, the sum must also show an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression).

[0244] Stable disease (SD): There is not enough contraction to be considered PR, nor enough improvement to be considered PD, with the minimum total diameter at the time of study as the reference.

[0245] The RECIST 1.1 criteria also consider non-target lesions defined as lesions that may be measurable but do not need to be measured, and should only be quantitatively assessed at the required time points. Response criteria for non-target lesions include: Complete response (CR): All non-target lesions disappear and tumor marker levels normalize. All lymph nodes must be non-pathological in size (<10 mm short axis).

[0246] Non-CR / Non-PD: Persistent and / or tumor marker levels in one or more non-target lesions remain above normal limits.

[0247] Progressive disease (PD): existing non-target lesions Clear progress (Emphasis on initial). The appearance of one or more new lesions is also considered progression. For a "clear progression" based on non-target disease, there must be substantial exacerbation of the overall non-target disease, such that even with SD or PR in the target disease, the overall tumor burden is sufficiently increased to warrant discontinuation of treatment. A modest "increase" in the size of one or more non-target lesions is generally insufficient to constitute a clear progression. Therefore, designations of overall progression based solely on changes in non-target disease in the face of SD or PR in the target disease would be very rare.

[0248] The clinically acceptable criteria for treatment response in acute leukemia are as follows: Complete remission (CR): The patient must be free of all symptoms associated with leukemia and have an absolute neutrophil count ≥1.0 × 10⁻⁶. 9 / L, platelet count ≥100×10 9 / L, and has <5% blast cells and normal bone marrow without Auer bars.

[0249] Complete remission with incomplete recovery of blood cell count (Cri): meets CE criteria, but has residual thrombocytopenia (platelet count <100×10⁻⁶). 9 ( / L) or residual neutropenia (absolute neutrophil count <1.0×10⁻⁶). 9 / L).

[0250] Partial remission (PR): ≥50% reduction in bone marrow blasts to 5 to 25% of abnormal cells in the bone marrow; or CR with ≤5% blasts if Auer rod is present.

[0251] Treatment failure: Treatment failed to achieve CR, Cri, or PR. Relapse.

[0252] Relapse confirmed after CR: the reappearance of leukemia blasts in peripheral blood or ≥5% of blasts in the bone marrow or new developmental abnormalities not due to any other cause (e.g., bone marrow regeneration after consolidation therapy).

[0253] "Chemotherapy agents" refers to drugs used to treat cancer. Chemotherapy agents include, but are not limited to, small molecules, hormones and hormone analogs, and biological agents (e.g., antibodies, peptide drugs, nucleic acid drugs). In certain implementations, chemotherapy does not include hormones and hormone drugs.

[0254] A "chemotherapy regimen" is a clinically recognized administration regimen for treating cancer, which involves administering one or more chemotherapeutic agents to a subject at specific times and in specific amounts. In a particular implementation plan, the chemotherapeutic agent may be a drug used in a clinical trial.

[0255] Chemotherapy regimens may include administering medication according to predetermined “cycles,” which consist of intervals between administration and non-administration of one or more agents used to treat cancer. For example, an agent may be administered once or more weekly for three consecutive weeks, followed by a week without administration, thus providing a four-week cycle. The cycles may be repeated, such that the subject will experience three weeks of treatment, one week without treatment, three weeks of treatment, one week without treatment, and so on, for the required number of cycles. In a particular implementation, treatment efficacy and laboratory values ​​(e.g., liver enzymes, blood cell counts, kidney function) are evaluated at the end of each cycle or every other cycle.

[0256] "Subjects who have failed chemotherapy regimens" are subjects with cancer who, according to RECIST 1.1 criteria (see Eisenhauer et al., 2009 and discussed above), do not respond to or have stopped responding to a chemotherapy regimen, i.e., do not achieve at least stable disease at the target lesion (i.e., stable disease, partial response, or complete response); or do not achieve at least non-CR / non-PD at a non-target lesion (i.e., non-CR / non-PD or complete response), whether during or after the chemotherapy regimen, whether alone or in combination with surgery and / or radiotherapy (which is often used clinically in conjunction with chemotherapy where possible). Failed chemotherapy regimens result in, for example, tumor growth, increased tumor burden, and / or tumor metastasis. In some implementations, as used herein, failed chemotherapy regimens include treatment regimens terminated due to dose-limiting toxicities, such as Grade III or IV toxicities that cannot be resolved to allow continued or resumed treatment with the toxic chemotherapeutic agent or regimen. In some embodiments, a “failed chemotherapy regimen” includes a treatment regimen that does not result in at least stable disease for all targeted and non-target lesions over an extended period of time, such extended period being, for example, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 12 months, at least 18 months, or less than any period of clinically defined cure. In some embodiments, a failed chemotherapy regimen includes a treatment regimen that produces progressive disease in at least one target lesion during treatment with chemotherapy agents, or a treatment regimen that produces progressive disease in less than 2 weeks, less than 1 month, less than 2 months, less than 3 months, less than 4 months, less than 5 months, less than 6 months, less than 12 months, or less than 18 months after the end of the treatment regimen, or less than any period of clinically defined cure.

[0257] A failed chemotherapy regimen does not include treatment regimens in which the subject receiving cancer treatment achieved a clinically defined cure (e.g., a complete response 5 years after the end of the treatment regimen), or treatment regimens in which the subject was subsequently diagnosed with a different cancer, for example, more than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 years after the end of the treatment regimen. For example, a subject who had childhood cancer may later develop cancer in life after being cured of childhood cancer. In such subjects, the chemotherapy regimen used to treat childhood cancer is considered successful.

[0258] "Intractable cancer" refers to malignant tumors that are unresponsive to surgery, that initially do not respond to chemotherapy or radiation therapy, or that become unresponsive to chemotherapy or radiation therapy over time.

[0259] "Therapeutic effective dose" is an amount sufficient to treat the subject's disease. Therapeutic effective doses can be administered in one or more applications.

[0260] The terms "administer," "administering," or "administration" encompass any method of delivering a pharmaceutical composition or agent to a subject's system or a specific area within the subject's body. In certain embodiments, the agent is delivered orally. In certain embodiments, the agent is administered parenterally. In certain embodiments, the agent is delivered locally, including via a mucosa. In certain embodiments, the agent is delivered by inhalation. In certain embodiments of the invention, the agent is administered via parenteral delivery, including intravenous, intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intracardiac, intraperitoneal, intranasal, or intraocular injection. In one embodiment, the composition provided herein can be administered by direct injection into a tumor. In a preferred embodiment, the agent is delivered by injection or infusion.

[0261] In a preferred embodiment, the formulation of the present invention can be administered by intravenous injection or intravenous infusion. In a more preferred embodiment, the formulation of the present invention can be administered by continuous infusion.

[0262] In certain embodiments, administration is not oral. In certain implementations, administration is systemic. In certain embodiments, administration is local. In some embodiments, administration is not intravenous administration over less than 8, 6, or 4 hours. In some embodiments, one or more routes of administration may be combined, such as, for example, intravenous and intratumoral, or intravenous and oral, or intravenous and oral, intravenous and local, or intravenous and percutaneous or mucosal. Administration of the drug may be performed by multiple collaborating personnel. Administration of the drug includes, for example, prescribing the drug to be administered to the subject and / or providing instructions for taking the specific drug directly or through another person, via self-administration (e.g., via oral delivery, subcutaneous delivery, intravenous delivery via the central line, etc.) or via delivery by a trained professional (e.g., intravenous delivery, intramuscular delivery, intratumoral delivery, etc.).

[0263] As used herein, “continuous infusion” means the continuous administration of a dosage form for at least 24 hours. Continuous administration is typically aided by the use of a pump, which may be implantable or external. The dosage form may be administered via multiple separate continuous infusions, with one or more interruptions between continuous infusions.

[0264] It should be understood that continuous infusion may include short administration interruptions, such as to change the reservoir of the administered coenzyme Q10. For example, two sequentially administered 48-hour continuous infusions or four 24-hour continuous infusions, administered without an intentional, obvious pause (less than 4 hours, preferably less than 2 hours, preferably less than 1 hour, preferably about 30 minutes) between the end of one infusion and the beginning of the next, are considered equivalent to a 96-hour continuous administration. Similarly, two sequentially administered 72-hour continuous infusions, administered without an obvious pause (e.g., less than 4 hours, preferably less than 2 hours, preferably less than 1 hour, preferably about 30 minutes) between the end of one infusion and the beginning of the next, are considered equivalent to a 144-hour (6-day) continuous infusion. In a particular embodiment, a subject treated with a 96-hour or 144-hour continuous infusion of coenzyme Q10 has a solid tumor. In a particular embodiment, a subject treated with a 96-hour or 144-hour continuous infusion of coenzyme Q10 has leukemia.

[0265] A 18-day continuous infusion will similarly include short interruptions during administration and will be considered a continuous infusion, provided that the dose is administered without any intentional, obvious pause (less than 4 hours, preferably less than 2 hours, preferably less than 1 hour, preferably about 30 minutes) between the end of one infusion and the beginning of the next. In a particular embodiment, the subject treated with a 18-day continuous infusion of Coenzyme Q10 has leukemia. In a particular embodiment, the subject treated with a 18-day continuous infusion of Coenzyme Q10 has a solid tumor. It should be understood that one day in a multi-day continuous infusion is one of a series of sequential 24-hour periods during the continuous infusion process, which does not necessarily or even usually do not correspond to a calendar day. For example, day 1 of continuous infusion includes hours 1-24 of continuous infusion, day 2 of continuous infusion includes hours 25-48 of continuous infusion, day 3 of continuous infusion includes hours 49-72 of continuous infusion, and so on.

[0266] Continuous administration is typically assisted by the use of a pump. Continuous administration may include administration at a single rate. Continuous administration may include administration at more than one rate (e.g., two rates, three rates). Continuous administration may include a loading dose at a higher rate, followed by a lower administration rate for the remaining dose. Continuous infusion is performed without any intentional, obvious interruption of administration. As used herein, interruptions for assessing vital signs and / or performing laboratory evaluations to ensure patient safety and the absence of unacceptable adverse events are not considered obvious interruptions. Interruptions due to equipment malfunction (e.g., pump failure) are not intentional interruptions.

[0267] As used herein, continuous administration does not include intravenous administration of two or more doses in which the end of the first dose and the start of the second dose are intentionally separated from each other by at least four hours, preferably at least eight, twelve, or twenty-four hours. When two intravenous administrations are intentionally separated by at least four hours, they are separate doses.

[0268] In certain embodiments, continuous infusion is designed to be administered at a single rate. In certain embodiments, continuous infusion is designed to be administered at a higher rate at the start of infusion to provide a loading dose. For example, the dose administered during the first 24 hours of continuous infusion may be administered at two rates, such that at least 5% of the dose is administered in the first hour, and the remainder (95% of the dose) of the dose used for the first 24 hours is administered over the remaining 23 hours. In certain embodiments, the dose administered during the first 24 hours of continuous infusion may be administered at two rates, such that at least 6% of the dose is administered in the first hour, and the remainder (94% of the dose) of the dose used for the first 24 hours is administered over the remaining 23 hours. For example, the dose administered during the first 24 hours of continuous infusion may be administered at two rates, such that at least 7% of the dose is administered in the first hour, and the remainder (93% of the dose) of the dose used for the first 24 hours is administered over the remaining 23 hours. For example, the dose administered during the first 24 hours of continuous infusion can be given at two rates, such that at least 8% of the dose is administered in the first hour, and the remainder of the dose used for the first 24 hours (92% of the dose) is administered over the remaining 23 hours. Alternatively, the dose administered during the first 24 hours of continuous infusion can be given at two rates, such that at least 9% of the dose is administered in the first hour, and the remainder of the dose used for the first 24 hours (91% of the dose) is administered over the remaining 23 hours. Alternatively, the dose administered during the first 24 hours of continuous infusion can be given at two rates, such that at least 10% of the dose is administered in the first hour, and the remainder of the dose used for the first 24 hours (90% of the dose) is administered over the remaining 23 hours. Alternatively, the dose administered during the first 24 hours of continuous infusion can be given at two rates, such that at least 11% of the dose is administered in the first hour, and the remainder of the dose used for the first 24 hours (89% of the dose) is administered over the remaining 23 hours. For example, the dose administered during the first 24 hours of continuous infusion can be given at two rates, such that at least 12% of the dose is administered in the first hour, and the remainder of the dose used for the first 24 hours (88% of the dose) is administered over the remaining 23 hours. Alternatively, the dose administered during the first 24 hours of continuous infusion can be given at two rates, such that at least 13% of the dose is administered in the first hour, and the remainder of the dose used for the first 24 hours (87% of the dose) is administered over the remaining 23 hours. Or, the dose administered during the first 24 hours of continuous infusion can be given at two rates, such that at least 14% of the dose is administered in the first hour, and the remainder of the dose used for the first 24 hours (86% of the dose) is administered over the remaining 23 hours.The dose administered during the first 24 hours of continuous infusion can be given at two rates, such that at least 15% of the dose is administered in the first hour, and the remaining portion (85%) of the dose used for the first 24 hours is administered over the remaining 23 hours. In a particular embodiment, at least 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the dose is administered in the first hour, with the remainder administered over the subsequent 23 hours.

[0269] In a particular embodiment, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 8.1%, approximately 8.2%, approximately 8.3%, approximately 8.4%, approximately 8.5%, approximately 8.6%, approximately 8.7%, approximately 8.8%, approximately 8.9%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, or approximately 25% of the dose is administered during the first 24 hours, and the remaining portion of the dose used for the first 24 hours is administered during the subsequent 23 hours, for example, approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, or approximately 75%. Any of these values ​​can be used to define the range of the percentage of dose administered in the first hour and the percentage of dose administered in the subsequent 23 hours. For example, the percentage of dose administered in the first hour could be 5% to 25%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 25%, 15% to 20%, 20% to 25%, 8% to 25%, 8% to 15%, 6% to 9%, or 7% to 9%. The remaining dose is administered in the subsequent 23 hours. For example, the percentage of dose administered in the subsequent 23 hours can range from 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 95%, 85% to 90%, 90% to 95%, 91% to 94%, 91% to 93%, 75% to 92%, or 85% to 92%.

[0270] In a particular embodiment, the administration dose during the first 48 hours of continuous infusion can be administered at two rates, such that at least 5% of the dose is administered in the first hour, and the remainder of the first 48-hour dose (95% of the dose) is administered over the remaining 47 hours. In another particular embodiment, the administration dose during the first 48 hours of continuous infusion can be administered at two rates, such that at least 6% of the dose is administered in the first hour, and the remainder of the first 48-hour dose (94% of the dose) is administered over the remaining 47 hours. For example, the administration dose during the first 48 hours of continuous infusion can be administered at two rates, such that at least 7% of the dose is administered in the first hour, and the remainder of the first 48-hour dose (93% of the dose) is administered over the remaining 47 hours. For example, the administration dose during the first 48 hours of continuous infusion can be administered at two rates, such that at least 8% of the dose is administered in the first hour, and the remainder of the first 48-hour dose (92% of the dose) is administered over the remaining 47 hours. For example, the administration dose during a continuous infusion of the first 48 hours can be administered at two rates, such that at least 9% of the dose is administered in the first hour, and the remainder of the first 48-hour dose (91% of the dose) is administered in the remaining 47 hours. Alternatively, the administration dose during a continuous infusion of the first 48 hours can be administered at two rates, such that at least 10% of the dose is administered in the first hour, and the remainder of the first 48-hour dose (90% of the dose) is administered in the remaining 47 hours. Alternatively, the administration dose during a continuous infusion of the first 48 hours can be administered at two rates, such that at least 11% of the dose is administered in the first hour, and the remainder of the first 48-hour dose (89% of the dose) is administered in the remaining 47 hours. Alternatively, the administration dose during a continuous infusion of the first 48 hours can be administered at two rates, such that at least 12% of the dose is administered in the first hour, and the remainder of the first 48-hour dose (88% of the dose) is administered in the remaining 47 hours. For example, the administration dose during the first 48 hours of continuous infusion can be administered at two rates, such that at least 13% of the dose is administered in the first hour, and the remaining portion (87% of the dose) of the first 48 hours' dose is administered over the remaining 47 hours. Alternatively, the administration dose during the first 48 hours of continuous infusion can be administered at two rates, such that at least 14% of the dose is administered in the first hour, and the remaining portion (86% of the dose) of the first 48 hours' dose is administered over the remaining 47 hours. Or, the administration dose during the first 48 hours of continuous infusion can be administered at two rates, such that at least 15% of the dose is administered in the first hour, and the remaining portion (85% of the dose) of the first 48 hours' dose is administered over the remaining 47 hours.In a particular implementation, at least 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the dose is administered in the first hour, with the remainder administered in the subsequent 47 hours.

[0271] In a particular embodiment, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 8.1%, approximately 8.2%, approximately 8.3%, approximately 8.4%, approximately 8.5%, approximately 8.6%, approximately 8.7%, approximately 8.8%, approximately 8.9%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, or approximately 25% of the dose is administered during the first hour, and the remaining portion of the dose used for the first 48 hours is administered during the subsequent 47 hours, for example, approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, or approximately 75%. Any of these values ​​can be used to define the range of the percentage of dose administered in the first hour and the percentage of dose administered in the subsequent 47 hours. For example, the percentage of dose administered in the first hour could be 5% to 25%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 25%, 15% to 20%, 20% to 25%, 8% to 25%, 8% to 15%, 6% to 9%, or 7% to 9%. The remaining dose is administered in the subsequent 47 hours. For example, the percentage of dose administered in the subsequent 47 hours can range from 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 95%, 85% to 90%, 90% to 95%, 91% to 94%, 91% to 93%, 75% to 92%, or 85% to 92%.

[0272] In a particular embodiment, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 5% of the dose is administered in the first hour, and the remainder of the first 72-hour dose (95% of the dose) is administered in the remaining 71 hours. In another particular embodiment, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 6% of the dose is administered in the first hour, and the remainder of the first 72-hour dose (94% of the dose) is administered in the remaining 71 hours. For example, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 7% of the dose is administered in the first hour, and the remainder of the first 72-hour dose (93% of the dose) is administered in the remaining 71 hours. For example, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 8% of the dose is administered in the first hour, and the remainder of the first 72-hour dose (92% of the dose) is administered in the remaining 71 hours. For example, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 9% of the dose is administered in the first hour, and the remainder of the first 72 hours' dose (91% of the dose) is administered over the remaining 71 hours. Alternatively, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 10% of the dose is administered in the first hour, and the remainder of the first 72 hours' dose (90% of the dose) is administered over the remaining 71 hours. Alternatively, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 11% of the dose is administered in the first hour, and the remainder of the first 72 hours' dose (89% of the dose) is administered over the remaining 71 hours. Alternatively, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 12% of the dose is administered in the first hour, and the remainder of the first 72 hours' dose (88% of the dose) is administered over the remaining 71 hours. For example, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 13% of the dose is administered in the first hour, and the remaining portion (87% of the dose) of the first 72 hours' dose is administered over the remaining 71 hours. Alternatively, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 14% of the dose is administered in the first hour, and the remaining portion (86% of the dose) of the first 72 hours' dose is administered over the remaining 71 hours. Or, the administration dose during the first 72 hours of continuous infusion can be administered at two rates, such that at least 15% of the dose is administered in the first hour, and the remaining portion (85% of the dose) of the first 72 hours' dose is administered over the remaining 71 hours.In a particular implementation, at least 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the dose is administered in the first hour, with the remainder administered in the subsequent 71 hours.

[0273] In a particular embodiment, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 8.1%, approximately 8.2%, approximately 8.3%, approximately 8.4%, approximately 8.5%, approximately 8.6%, approximately 8.7%, approximately 8.8%, approximately 8.9%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, or approximately 25% of the dose is administered during the first hour, and the remaining portion of the dose used for the first 72 hours is administered during the subsequent 71 hours, for example, approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, or approximately 75%. Any of these values ​​can be used to define the range of the percentage of dose administered in the first hour and the percentage of dose administered in the subsequent 71 hours. For example, the percentage of dose administered in the first hour could be 5% to 25%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 25%, 15% to 20%, 20% to 25%, 8% to 25%, 8% to 15%, 6% to 9%, or 7% to 9%. The remaining dose is administered in the subsequent 71 hours. For example, the percentage of dose administered in the subsequent 71 hours can range from 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 95%, 85% to 90%, 90% to 95%, 91% to 94%, 91% to 93%, 75% to 92%, or 85% to 92%.

[0274] As used in this article, a “pharmacologically acceptable” component is a component that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions) in proportion to a reasonable benefit / risk ratio.

[0275] As used herein, “formulation” is understood to mean an active ingredient bound to any pharmaceutically acceptable carrier, such as CoQ10, a metabolite of CoQ10, a biosynthetic precursor of CoQ10, or a CoQ10-related compound. Formulations may include, but are not limited to, aqueous formulations, liposome formulations, suspensions, emulsions, microemulsions, nanoemulsions, nanosuspensions, and formulations for a specific route of administration, such as injection or infusion.

[0276] As used herein, the term "safe and therapeutically effective amount" refers to the amount of a component that, when used in the manner disclosed herein, is sufficient to produce the desired therapeutic response in proportion to a reasonable benefit / risk ratio without excessive adverse side effects such as toxicity, irritation, and allergic reactions. "Therapeutically effective amount" indicates the amount of a compound of the present disclosure that effectively produces the desired therapeutic response. Specific safe and effective or therapeutically effective amounts will vary depending on factors such as the specific disease to be treated, the patient's physical condition, the type of mammal or animal to be treated, the duration of treatment, the nature of any concomitant treatments, and the structure of the specific formulation and compound or its derivatives used. "Therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the patient to be treated.

[0277] The term "therapeutic effect" refers to a local or systemic effect in animals, particularly mammals, and more particularly humans, caused by a pharmaceutically active substance. The term therefore means any substance intended for the diagnosis, cure, relief, treatment, or prevention of disease in animals or humans, or for the desired enhancement of physical or mental development and condition. The phrase "therapeutic effective amount" refers to the amount of such a substance that produces some desired local or systemic effect with a reasonable benefit / risk ratio suitable for any treatment. In a particular embodiment, the therapeutically effective amount of a compound will depend on the therapeutic index, solubility, etc.

[0278] "Adverse events" or "AEs" are characterized by a grading system based on their severity. Some AEs (e.g., nausea, low blood cell count, pain, impaired clotting) are treatable, allowing for the continuation or resumption of a specific chemotherapy regimen. Some adverse events (e.g., loss of cardiac, hepatic, or renal function; nausea) may be untreatable, requiring discontinuation of the drug. The determination of the AE grade and appropriate intervention can be determined by someone skilled in the art. The Common Terminology Criteria for Adverse Events v4.0 (CTCAE) (publication date: May 28, 2009) provides a grading scale for adverse events, as follows: Grade 1 - Mild; asymptomatic or mildly symptomatic; clinical or diagnostic observation only; no specified intervention.

[0279] Level 2 - Moderate; specify minimal, local or non-invasive intervention; limit age-appropriate devices for activities of daily living (ADL).

[0280] Level 3 - Severe or medically evident but not immediately fatal; requires or extends hospitalization; incapacitated, with limited self-care abilities (ADL).

[0281] Level 4 - Fatal consequences; requires emergency intervention.

[0282] Level 5 - Death related to an adverse event.

[0283] Adverse events include “coagulopathy” or “reduced clotting.” Methods for measuring clotting time are well-known and typically based on the International Normalized Ratio (INR), a ratio of prothrombin time (in seconds) to that of a normal individual. Prothrombin time is the time it takes for plasma to clot after the addition of tissue factor. The INR is designed to normalize clotting time results between individuals and tissue factors used in experiments prepared by different manufacturers. Each manufacturer assigns an ISI (International Sensitivity Index) value to any tissue factor for each batch of tissue factor they manufacture. The ISI value indicates how a particular batch of tissue factor compares to an international benchmark tissue factor. ISI is typically between 1.0 and 2.0. The INR is the ratio of a patient’s prothrombin time to a normal (control) sample, generated by exponentiation of the ISI value against the analytical system used. Such methods are routine in the art. The INR is commonly used to monitor patients treated with anticoagulant therapy (e.g., warfarin) or with other agents (e.g., agents used to treat cancer, including coenzyme Q10). The normal range for INR in healthy individuals not using warfarin is 0.8–1.2, while for those treated with warfarin, the target INR is typically 2.0–3.0. Therefore, an elevated INR exceeding the values ​​observed in healthy individuals (e.g., up to 1.5, 2.0, 2.5, or 3.0) is not necessarily considered an adverse event requiring intervention. This consideration is understandable to those skilled in the art. If the INR is outside the target range, a high INR indicates a higher risk of bleeding, while a low INR indicates a higher risk of clotting. Other methods for assessing clotting time are known in the art.

[0284] As used herein, “co-administration” or “combination therapy” is understood to mean the administration of two or more active agents, or in any order, using a single formulation or a single drug formulation, such that two (or all) active agents exert their biological activity simultaneously for a period of time. Co-administration does not require the agents to be administered at the same time, at the same frequency, or via the same route of administration. As used herein, “co-administration” or “combination therapy” includes the administration of a CoQ10 compound with one or more other anticancer agents (e.g., chemotherapeutic agents), or the administration of two or more CoQ10 compounds. Examples of anticancer agents, including chemotherapeutic agents, are provided herein.

[0285] As used in this article, the term "survival" refers to the continued life of a subject who has received treatment for a disease or condition (e.g., cancer). Survival time can be defined from any point in time, such as the time from entry into a clinical trial, the time from completion or failure of an early treatment regimen, the time from diagnosis, etc.

[0286] As used herein, the term "subject" refers to both humans and non-human animals, including veterinary subjects. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, including non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a human and may be referred to as a patient.

[0287] The articles “a,” “an,” and “the” are used in this text to refer to one or more (i.e., at least one) grammatical subject of the article, unless otherwise explicitly indicated otherwise. For example, “an element” means one element or more.

[0288] The term “including” is used in this document to mean the phrase “including but not limited to” and can be used interchangeably with that phrase.

[0289] The term “or” is used in this document to mean the term “and / or” and may be used interchangeably with it unless otherwise specified in the text.

[0290] The term “such” is used in this article to mean the phrase “such as but not limited to” and can be used interchangeably with that phrase.

[0291] Unless explicitly stated or obvious from the context, as used herein, the term "about" is understood to mean within normal tolerances in the art, for example, within 2 standard deviations of the mean. "About" can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.01% of the stated value. Unless otherwise clearly apparent from the context, all numerical values ​​provided herein may be modified by the term "about".

[0292] The ranges provided in this document are understood to include all values ​​within the range. For example, the range 1 to 50 is understood to include any number, combination of numbers, or subrange of numbers that is a group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0293] The enumeration of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the listed groups. References to embodiments of a variable or aspect herein include those embodiments as any single embodiment or in combination with any other embodiment or part thereof.

[0294] Any composition or method provided herein may be combined with one or more of any other compositions and methods provided herein, including but not limited to, combinations of administration rates, administration times, dosages, treatment methods, monitoring methods, selection methods, and the use of agents other than Coenzyme Q10.

[0295] I. Coenzyme Q10 compounds It will be understood that the methods provided herein are intended to be implemented using compositions comprising one or more coenzyme Q10 compounds. Coenzyme Q10 compounds are intended to include a class of CoQ10 compounds. Coenzyme Q10 compounds effectively used in the methods described herein include coenzyme Q10, metabolites of coenzyme Q10, biosynthetic precursors of coenzyme Q10, analogs of coenzyme Q10, derivatives of coenzyme Q10, and coenzyme Q10-related compounds. Coenzyme Q10 analogs include analogs that do not have an isopentenyl repeat or have at least one isopentenyl repeat. Coenzyme Q10 has the following structure: Where x is 10. In this invention, the CoQ10 compound may include a derivative of coenzyme Q10, wherein x is 4-10 of any isopentenyl monomers, or 6-10 of any isopentenyl monomers, or 8-10 of any isopentenyl monomers, or 9-10 isopentenyl monomers. Coenzyme Q10 includes a fully oxidized form (also known as ubiquinone), a partially oxidized form (also known as semiquinone or ubiquitin-semiquinone), or a fully reduced form (also known as ubiquinol); or any mixture or combination thereof. In a particular embodiment, the CoQ10 compound for cancer treatment is ubiquinone. In a particular embodiment, the CoQ10 compound for cancer treatment is ubiquinol.

[0296] In a particular embodiment of the invention, the therapeutic agent is coenzyme Q10 (CoQ10). Coenzyme Q10, also referred to herein as CoQ10, is also known as ubiquinone or ubiquitin. Coenzyme Q10 is well known and is further described in international publications No. WO 2005 / 069916 (application number PCT / US2005 / 001581), WO 2008 / 116135 (application number PCT / US08 / 57786), WO2010 / 132507 (application number PCT / US2010 / 034453), WO 2011 / 112900 (application number PCT / US2011 / 028042) and WO2012 / 174559 (application number PCT / US2012 / 043001), the entire contents of which are hereby cited and incorporated herein by reference. Coenzyme Q10 is one of a series of polyisoprene 2,3-dimethoxy-5-methylbenzoquinone (ubiquinone) present in the mitochondrial electron transport system of eukaryotic cells. Human cells specifically produce coenzyme Q10, and it is found in the mitochondrial membranes of cells and all human cells, with the highest levels in organs with high energy demands, such as the liver and heart. The body's pool of coenzyme Q10 is approximately 2 grams, of which more than 50% is endogenous. Approximately 0.5 grams of coenzyme Q10 is needed daily from diet or biosynthesis. Coenzyme Q10 is produced in tonnes from the global supplement market and is available from Kaneka, which has factories in Pasadena, Texas, and Takasagoshi, Japan.

[0297] II. Composition This disclosure provides compositions containing the CoQ10 compound for the treatment and prevention of cancer. The compositions of this disclosure can be administered by the patient or in a pharmaceutical composition mixed with a suitable carrier or excipient. When treating a patient exhibiting a target disease (e.g., cancer), a therapeutically effective amount of CoQ10 is administered. A therapeutically effective amount is the amount of the compound that results in at least a stable disease or prolonged survival in the patient.

[0298] Suitable routes of administration for the compositions of the present invention may include non-enteric delivery, including intravenous infusion, preferably continuous infusion. In a preferred embodiment, the IV infusion comprises an active agent, such as coenzyme Q10, at a concentration of approximately 40 mg / mL (4% w / v). In the case of administration of the composition by IV infusion, it may be diluted in a pharmaceutically acceptable aqueous solution, such as phosphate-buffered saline or physiological saline. In some embodiments, one or more routes of administration may be combined, such as, for example, intravenous and intratumoral, or intravenous and oral, or intravenous and oral, or intravenous and local, percutaneous or mucosal. However, the methods provided herein include administration of coenzyme Q10 by continuous intravenous infusion.

[0299] For example, CoQ10 compounds can be formulated for parenteral delivery, such as intravenous injection. The composition can be administered as a single concentrated dose, multiple injections, or by continuous infusion (e.g., intravenous or peritoneal dialysis). For parenteral administration, the composition can be formulated in a sterile, pyrogen-free form.

[0300] For the implementation of this invention, the compounds disclosed herein are formulated into dosage forms suitable for systemic administration using pharmaceutically acceptable carriers within the scope of this disclosure. Using appropriately selected carriers and suitable methods of manufacture, the compositions of this disclosure, particularly those formulated as solutions, can be administered parenterally, such as by intravenous injection.

[0301] The toxicity and therapeutic efficacy of the compound can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals, for example, to determine the LD50 (the dose that is 50% lethal to the population) and ED50 (the dose that is 50% therapeutically effective to the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index and can be expressed as the ratio LD50 / ED50. Compounds exhibiting a large therapeutic index may be desirable. Data obtained from these cell culture experiments and animal studies can be used to establish dosage ranges for human use. The dosage of the compound can be within a range of circulating concentrations, including the ED50, with little or no toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration employed.

[0302] Pharmaceutical compositions applicable to this invention include compositions in which the active ingredient is contained in an effective amount for the intended purpose. The determination of the effective amount is within the competence of those skilled in the art, particularly based on the detailed disclosure provided herein. In addition to the active ingredient, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers, including excipients and adjuvants (which facilitate the formulation of the active compound into a pharmaceutically usable formulation). Formulations formulated for intravenous administration may be in the form of a solution of a colloidal dispersion.

[0303] Pharmaceutical compositions intended for parenteral administration comprise an aqueous solution of the active compound in its water-soluble form. Alternatively, suspensions of the active compound can be formulated into suitable oily injectable suspensions. Suitable lipophilic solvents or mediators include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or substances that improve the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0304] III. Formulation Active agents, such as CoQ10 compounds, can be delivered in any pharmaceutically acceptable carrier for the desired route of administration. As used herein, formulations comprising CoQ10 compounds can be formulated for administration by injection or infusion. In certain embodiments, the CoQ10 compound is not delivered orally.

[0305] Preferred therapeutic formulations used in the methods of the present invention comprise an active agent in particulate form (e.g., a CoQ10 compound), for example, for intravenous administration. Such intravenous formulations are provided, for example, in WO2011 / 112900 (Application No. PCT / US2011 / 028042), the entire contents of which are intentionally incorporated herein by reference, and exemplary intravenous formulations as described in WO2011 / 112900 (Application No. PCT / US2011 / 028042) are used in the examples listed below. Through high-pressure homogenization, the active agent (e.g., a CoQ10 compound) particles are reduced to produce particles small enough to pass through a 200-nm sterile filter. Particles small enough to pass through a 200-nm sterile filter can be injected intravenously. These particles are much smaller than blood cells and therefore will not clog capillaries. For example, red blood cells are 6-micrometer × 2-micrometer discs. The particles are dispersed in a stabilizer and surrounded or encapsulated by the stabilizer. While not wishing to be bound by any theory, it is believed that stabilizers attach to hydrophobic therapeutic agents, such that the dispersed particles of the hydrophobic therapeutic agent are surrounded by the stabilizer, thereby forming a suspension or emulsion. The dispersed particles in the suspension or emulsion comprise a stabilizer surface and a core consisting of a hydrophobic therapeutic agent compound (e.g., CoQ10) in solid particulate form (suspension) or immiscible liquid form (emulsion). The dispersed particles may be enclosed within the lipophilic regions of liposomes.

[0306] The dispersed colloidal system allows for high drug loading in the formulation without the use of solubilizers. Furthermore, high and relatively reproducible plasma levels are achieved without dependence on endogenous low-density lipoprotein carriers. More importantly, the formulation allows for sustained high drug levels in tumor cells due to the passive accumulation of colloidal particles of the hydrophobic therapeutic agent.

[0307] Preferred intravenous formulations typically consist of a continuous aqueous phase and a dispersed solid substance (suspension) or a dispersed immiscible liquid (emulsion). If the dispersed colloidal system (in which the particles are largely composed of the active agent (drug) itself) is sufficiently stable, it can often deliver more drug per unit volume than a continuously solubilizing system.

[0308] As a formulation medium, aqueous solutions may include Hank's solution, Ringer's solution, phosphate-buffered saline (PBS), physiological saline buffer, or other suitable salts or combinations to obtain the appropriate pH and molar osmotic concentration for parenteral delivery. Aqueous solutions can be used to dilute formulations intended for administration to the desired concentration. For example, an aqueous solution can dilute a formulation intended for intravenous administration from a concentration of approximately 4% w / v to a lower concentration to facilitate the administration of lower doses of coenzyme Q10. Aqueous solutions may contain substances that increase solution viscosity, such as sodium carboxymethyl cellulose, sorbitol, or dextran.

[0309] An active agent (e.g., a CoQ10 compound) is dispersed in an aqueous solution to form a colloidal dispersion in which nanoparticles of a hydrophobic therapeutic agent are covered, encapsulated, or surrounded by a dispersion stabilizer to form a nanodispersion of the active agent (e.g., a CoQ10 compound) particles. The nanodispersed active agent (e.g., a CoQ10 compound) particles have a core formed by the hydrophobic therapeutic agent surrounded by the stabilizer. Similarly, in a particular aspect, the stabilizer is a phospholipid having both hydrophilic and lipophilic portions. The phospholipid forms liposomes or other nanoparticles upon homogenization. In a particular aspect, these liposomes are bilayer monolamellar liposomes, while in other embodiments, the liposomes are bilayer multilamellar liposomes. The dispersed active agent (e.g., a CoQ10 compound) particles are dispersed within the lipophilic portion of the bilayer structure of the liposome formed from the phospholipid. In certain other aspects, the core of the liposome, such as the core of a nanodispersion of an active agent (e.g., a CoQ10 compound), is formed of a hydrophobic therapeutic agent, and the outer layer is formed of a phospholipid bilayer structure. In a particular embodiment, the colloidal dispersion is processed by a lyophilization process, thereby converting the nanoparticle dispersion into a dry powder.

[0310] In some embodiments, the formulation used for injection or infusion is a 4% sterile aqueous colloidal dispersion containing coenzyme Q10 in a nanosuspension prepared as described in WO2011 / 112900. In a particular embodiment, the formulation comprises an aqueous solution; a hydrophobic active agent, such as coenzyme Q10, a coenzyme Q10 precursor or metabolite, or a coenzyme Q10-related compound, dispersed to form a colloidal nanodispersion of particles; and at least one of a dispersion stabilizer and a conditioning agent; wherein the colloidal nanodispersion of the active agent is dispersed into nanodispersion particles having an average size of less than 200 nm.

[0311] In certain embodiments, the dispersant stabilizer includes, but is not limited to, PEGylated castor oil, Cremophor® EL, Cremophor® RH 40, PEGylated vitamin E, vitamin E TPGS, and diamyristicophosphatidylcholine (DMPC).

[0312] In a particular implementation, the opsonizing agent is poloxamer or poloxamine.

[0313] In certain embodiments, the colloidal nanodispersion is a suspension or emulsion. Optionally, the colloidal nanodispersion is in crystalline or ultracold melt form.

[0314] In certain embodiments, the formulation for injection or infusion includes lyophilization protectants, such as nutritional sugars, including but not limited to lactose, mannose, maltose, galactose, fructose, sorbitol, raffinose, neuraminic acid, glucosamine, galactosamine, N-methylglucosamine, mannitol, sorbitol, arginine, glycine, and sucrose; or any combination thereof.

[0315] In certain embodiments, the formulation for injection or infusion comprises an aqueous solution; a hydrophobic active agent dispersed to form a colloidal nanodispersion of particles; and at least one of a dispersion stabilizer and a conditioner-reducing agent. The colloidal nanodispersion of the active agent is dispersed into nanodispersion particles having a size of less than 200 nm. In some embodiments, the dispersion stabilizer is selected from natural or semi-synthetic phospholipids. Suitable stabilizers include, for example, polyethoxylated (or PEGylated) castor oil (Cremophor® EL), polyethoxylated hydrogenated castor oil (Cremophor® RH 40), tocopherol polyethylene glycol succinate (PEGylated vitamin E, vitamin E TPGS), sorbitan fatty acid esters (Spans®), bile acids and bile salts, or myristoylphosphatidylcholine (DMPC). In some embodiments, the stabilizer is DMPC.

[0316] In certain embodiments, the formulation is suitable for parenteral administration, including intravenous, intraperitoneal, orthotopic, intracranial, intramuscular, subcutaneous, intramedullary injection, as well as intrathecal, direct intraventricular, intranasal, or intraocular injection. In certain embodiments, the formulation contains coenzyme Q10, myristoyl phosphatidylcholine, and poloxamer 188 in a 4:3:1.5 ratio, designed as a nanosuspension of stable particles. In some embodiments, the formulation comprises a phosphate-buffered saline solution containing disodium hydrogen phosphate, potassium dihydrogen phosphate, potassium chloride, sodium chloride, and water for injection. In a particular embodiment, a 4% sterile aqueous colloidal dispersion containing coenzyme Q10 in a nanosuspension is diluted in an aqueous phosphate-buffered saline solution to provide, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, or any other suitable ratio including any two of these values.

[0317] In some embodiments, the formulation for administration in this invention may include about 0.001% to about 20% (w / w) of coenzyme Q10, about 0.01% to about 20% (w / w) of coenzyme Q10, about 0.1% to about 20% (w / w) of coenzyme Q10, more preferably about 0.01% to about 15% and even more preferably about 0.1% to about 10% (w / w) of coenzyme Q10. In a particular embodiment, the formulation for any route of administration in this invention may include about 1% to about 10% (w / w) of coenzyme Q10. In a particular embodiment, the formulation for any route of administration in this invention may include about 2% to about 8% (w / w) of coenzyme Q10. In a particular embodiment, the formulation for any route of administration in this invention may include about 2% to about 7% (w / w) of coenzyme Q10. In a particular embodiment, the formulation for any route of administration in this invention may include about 3% to about 6% (w / w) of coenzyme Q10. In certain embodiments, the formulation for any route of administration in this invention may include about 3% to about 5% (w / w) of coenzyme Q10. In certain embodiments, the formulation for any route of administration in this invention may include about 3.5% to about 4.5% (w / w) of coenzyme Q10. In certain embodiments, the formulation for any route of administration in this invention may include about 3.5% to about 5% (w / w) of coenzyme Q10. In one embodiment, the formulation includes about 4% (w / w) of coenzyme Q10. In one embodiment, the formulation includes about 8% (w / w) of coenzyme Q10. In various embodiments, the formulation comprises about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% (w / w) of coenzyme Q10, or any range including any two of the stated values. In a particular embodiment, the formulation may be prepared as a weight-volume percentage rather than a weight-weight percentage. Depending on the formulation, the concentration of coenzyme Q10 may be the same or substantially the same as the w / w and w / v percentages. Coenzyme Q10 may be obtained from Kaneka Q10 (Pasadena, Texas, USA) in powder form as Kaneka Q10 (USP UBIDECATENONE).The coenzyme Q10 used in the methods exemplified in this article has the following characteristics: solvent residues conforming to USP 467 requirements; water content less than 0.0%, less than 0.05%, or less than 0.2%; residue on ignition of 0.0%, less than 0.05%, or less than 0.2%; heavy metal content less than 0.002%, or less than 0.001%; ​​and purity of 98-100%, 99.9%, or 99.5%.

[0318] In a specific embodiment, the coenzyme Q10 concentration in the formulation is from 1 mg / mL to 150 mg / mL. In one embodiment, the coenzyme Q10 concentration in the formulation is from 5 mg / mL to 125 mg / mL. In one embodiment, the coenzyme Q10 concentration in the formulation is from 10 mg / mL to 100 mg / mL. In one embodiment, the coenzyme Q10 concentration in the formulation is from 20 mg / mL to 90 mg / mL. In one embodiment, the coenzyme Q10 concentration in the formulation is from 30 mg / mL to 80 mg / mL. In one embodiment, the coenzyme Q10 concentration in the formulation is from 30 mg / mL to 70 mg / mL. In one embodiment, the coenzyme Q10 concentration in the formulation is from 30 mg / mL to 60 mg / mL. In one embodiment, the coenzyme Q10 concentration in the formulation is from 30 mg / mL to 50 mg / mL. In one embodiment, the coenzyme Q10 concentration in the formulation is from 35 mg / mL to 45 mg / mL. It should be understood that other ranges having any of the previous values ​​as upper or lower limits are also intended to be part of the invention, for example, 10 mg / mL to 50 mg / mL, or 20 mg / mL to 60 mg / mL.

[0319] In certain embodiments, the concentration of coenzyme Q10 in the formulation is about 10, 15, 20, 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 mg / mL. In one embodiment, the concentration of coenzyme Q10 in the formulation is about 50 mg / mL. In one embodiment, the concentration of coenzyme Q10 in the formulation is about 60 mg / mL. In one embodiment, the concentration of coenzyme Q10 in the formulation is about 30 mg / mL. In a preferred embodiment, the concentration of coenzyme Q10 in the formulation is about 40 mg / mL. It should be understood that other ranges having any of the preceding values ​​as upper or lower limits are also intended to be part of the invention, for example, 37 mg / mL to 47 mg / mL, or 31 mg / mL to 49 mg / mL. It should be understood that formulations containing coenzyme Q10 precursors, metabolites, and related compounds can be prepared similarly.

[0320] IV. Cancer Treatment This invention provides a method for treating cancer by continuous infusion of coenzyme Q10. In a particular embodiment, the cancer includes solid tumors. In a particular embodiment, the cancer includes leukemia. In a particular embodiment, the cancer is treated with coenzyme Q10 alone. In a particular embodiment, the cancer is treated with coenzyme Q10 and other agents. In a particular embodiment, the other agents are chemotherapy agents. In a particular embodiment, chemotherapy treatment is started concurrently with coenzyme Q10 treatment. In a particular embodiment, chemotherapy treatment is started after the start of coenzyme Q10 treatment. In a particular embodiment, treatment with other agents is started if the cancer progresses during coenzyme Q10 treatment. In a particular embodiment, treatment with other agents is started if there is no cancer progression during coenzyme Q10 treatment. In a particular embodiment, coenzyme Q10 treatment continues when the administration of other agents is started. In a particular embodiment, coenzyme Q10 treatment is stopped when the administration of other agents is started.

[0321] In certain embodiments, the formulations and methods of this disclosure can be used to treat solid tumors in subjects who have failed at least one prior chemotherapy regimen. Therefore, the present invention provides a method for treating cancer in a subject who has failed at least one prior chemotherapy regimen for cancer, the method comprising administering the formulation of the present invention to the subject in an amount sufficient to treat the cancer by continuous infusion, thereby treating the cancer. The formulations of the present invention can also be used to inhibit tumor cell growth in a subject who has failed at least one prior chemotherapy regimen. Therefore, the present invention further provides a method for inhibiting tumor cell growth in a subject who has failed at least one prior chemotherapy regimen, the method comprising administering the formulation of the present invention to the subject such that tumor cell growth is inhibited. In a preferred embodiment, inhibiting tumor growth comprises obtaining stable disease with at least a primary lesion according to RECIST 1.1 criteria. In a particular embodiment, the subject is a human subject.

[0322] Such formulations may include hydrophobic therapeutic agents in pharmaceutically acceptable carriers, such as coenzyme Q10, its metabolites, or coenzyme Q10-related compounds. In some embodiments, such formulations may include about 0.001% to about 20% (w / w) of coenzyme Q10, more preferably about 0.01% to about 15% and even more preferably about 0.1% to about 10% (w / w) of coenzyme Q10. In one embodiment, the formulation includes about 4% (w / w) of coenzyme Q10. In one embodiment, the formulation includes about 8% (w / w) of coenzyme Q10. In various embodiments, the formulation comprises about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% (w / w) of coenzyme Q10, or any range of these values. In certain embodiments, the formulation may be prepared as a weight-volume percentage rather than a weight-weight percentage. Depending on the formulation, the concentration of coenzyme Q10 may be the same or substantially the same on both w / w and w / v percentage basis. Also as described herein, the compositions of this disclosure may be in liquid form, which can be introduced into a subject by any method or route of administration within the skill of those skilled in the art. For example, the composition can be administered via routes including but not limited to intravenous, intratumoral, or combinations thereof.

[0323] In a particular embodiment of the invention, a method for treating or preventing cancer in humans is provided, which involves intravenously administering a formulation of coenzyme Q10, a coenzyme Q10 precursor, a metabolite, or a related compound to a human for treatment or prevention. This is achieved by continuous infusion (e.g., for at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 144 hours) of a coenzyme Q10 compound, such as coenzyme Q10, to a human. The 24-hour dose (e.g., average 24-hour dose) of the administered coenzyme Q10 compound (e.g., coenzyme Q10) ranges from about 0.5 mg / kg / dose to about 10,000 mg / kg / dose, from about 5 mg / kg / dose to about 5,000 mg / kg / dose, and from about 10 mg / kg / dose to about 3,000 mg / kg / dose. In one embodiment, the formulation is administered such that coenzyme Q10 is preferably administered at a 24-hour dose ranging from about 10 mg / kg / dose to about 1,400 mg / kg / dose. In one embodiment, the formulation is administered in a 24-hour dose, preferably in the range of about 10 mg / kg / dose to about 650 mg / kg / dose. In another embodiment, the formulation is administered in the range of about 10 mg / kg / dose to about 200 mg / kg / dose. In yet another embodiment, the formulation is administered in a 24-hour dose, preferably in the range of about 10 mg / kg / dose to about 100 mg / kg / dose. In yet another embodiment, the formulation is administered in a 24-hour dose, preferably in the range of about 10 mg / kg / dose to about 75 mg / kg / dose. In yet another embodiment, the formulation is administered in a 24-hour dose, preferably in the range of about 10 mg / kg / dose to about 65 mg / kg / dose. In one embodiment, the formulation is administered in a 24-hour dose such that coenzyme Q10 is preferably administered in the range of about 10 mg / kg / dose to about 15 mg / kg / dose, about 15 mg / kg / dose to about 20 mg / kg / dose, about 20 mg / kg / dose to about 25 mg / kg / dose, about 27 mg / kg / dose to about 35 mg / kg / dose, about 34 mg / kg / dose to about 42 mg / kg / dose, about 42 mg / kg / dose to about 52 mg / kg / dose, or about 53 mg / kg / dose to about 65 mg / kg / dose.In various implementation schemes, the formulation is administered preferably at concentrations of about 2 mg / kg / dose, 5 mg / kg / dose, 10 mg / kg / dose, 15 mg / kg / dose, 20 mg / kg / dose, 25 mg / kg / dose, 30 mg / kg / dose, 35 mg / kg / dose, 40 mg / kg / dose, 45 mg / kg / dose, 50 mg / kg / dose, 55 mg / kg / dose, 56 mg / kg / dose, 57 mg / kg / dose, 58 mg / kg / dose, 59 mg / kg / dose, 60 mg / kg / dose, 65 mg / kg / dose, 70 mg / kg / dose, 75 mg / kg / dose, 76 mg / kg / dose, 77 mg / kg / dose, 78 mg / kg / dose, 79 mg / kg / dose, and 80 mg / kg / dose. Coenzyme Q10 can be administered in 24-hour doses of 85 mg / kg / dose, 90 mg / kg / dose, 95 mg / kg / dose, 100 mg / kg / dose, 101 mg / kg / dose, 102 mg / kg / dose, 103 mg / kg / dose, 104 mg / kg / dose, 105 mg / kg / dose, 106 mg / kg / dose, 107 mg / kg / dose, 108 mg / kg / dose, 109 mg / kg / dose, 110 mg / kg / dose, 120 mg / kg / dose, 130 mg / kg / dose, 140 mg / kg / dose, 150 mg / kg / dose, 160 mg / kg / dose, 170 mg / kg / dose, 180 mg / kg / dose, 190 mg / kg / dose, or 200 mg / kg / dose.In different implementation schemes, the dosage of the formulation is administered over a 24-hour period, preferably at a concentration of at least 2 mg / kg / dose, 5 mg / kg / dose, 10 mg / kg / dose, 15 mg / kg / dose, 20 mg / kg / dose, 25 mg / kg / dose, 30 mg / kg / dose, 35 mg / kg / dose, 40 mg / kg / dose, 45 mg / kg / dose, 50 mg / kg / dose, 55 mg / kg / dose, 56 mg / kg / dose, 57 mg / kg / dose, 58 mg / kg / dose, 59 mg / kg / dose, 60 mg / kg / dose, 65 mg / kg / dose, 70 mg / kg / dose, 75 mg / kg / dose, 76 mg / kg / dose, 77 mg / kg / dose, 78 mg / kg / dose, 79 mg / kg / dose, or 80 mg / kg / dose. Coenzyme Q10 may be administered at doses of 85 mg / kg / dose, 90 mg / kg / dose, 95 mg / kg / dose, 100 mg / kg / dose, 101 mg / kg / dose, 102 mg / kg / dose, 103 mg / kg / dose, 104 mg / kg / dose, 105 mg / kg / dose, 106 mg / kg / dose, 107 mg / kg / dose, 108 mg / kg / dose, 109 mg / kg / dose, 110 mg / kg / dose, 120 mg / kg / dose, 130 mg / kg / dose, 140 mg / kg / dose, 150 mg / kg / dose, 160 mg / kg / dose, 170 mg / kg / dose, 180 mg / kg / dose, 190 mg / kg / dose, or 200 mg / kg / dose, wherein said doses do not cause any limiting toxicity. It should be understood that a range having any of these values ​​as an upper or lower limit for the 24-hour dose is also intended to be part of the invention, for example, about 50 mg / kg / dose to about 200 mg / kg / dose, or about 650 mg / kg / dose to about 140 mg / kg / dose, or about 55 mg / kg / dose to about 110 mg / kg / dose. In one embodiment, the administered 24-hour dose is at least about 1 mg / kg / dose, at least about 5 mg / kg / dose, at least about 10 mg / kg / dose, at least about 12.5 mg / kg / dose, at least about 15 mg / kg / dose, at least about 20 mg / kg / dose, at least about 25 mg / kg / dose, at least about 30 mg / kg / dose, at least about 35 mg / kg / dose, at least about 40 mg / kg / dose, at least about 45 mg / kg / dose, etc. At least about 50 mg / kg / dose, at least about 55 mg / kg / dose, at least about 60 mg / kg / dose, at least about 65 mg / kg / dose, at least about 75 mg / kg / dose, at least about 100 mg / kg / dose, at least about 125 mg / kg / dose, at least about 150 mg / kg / dose, at least about 175 mg / kg / dose, at least about 200 mg / kg / dose, at least about 300 mg / kg / dose, or at least about 400 mg / kg / dose.In a specific implementation scheme, the 24-hour dose administered does not exceed approximately 20 mg / kg / dose, approximately 25 mg / kg / dose, approximately 30 mg / kg / dose, approximately 35 mg / kg / dose, approximately 40 mg / kg / dose, approximately 45 mg / kg / dose, approximately 50 mg / kg / dose, approximately 55 mg / kg / dose, approximately 60 mg / kg / dose, approximately 75 mg / kg / dose, approximately 100 mg / kg / dose, approximately 125 mg / kg / dose, or approximately 150 mg / kg / dose. The dosages are approximately 175 mg / kg / dose, approximately 200 mg / kg / dose, approximately 300 mg / kg / dose, approximately 400 mg / kg / dose, approximately 500 mg / kg / dose, approximately 600 mg / kg / dose, approximately 700 mg / kg / dose, approximately 800 mg / kg / dose, approximately 900 mg / kg / dose, approximately 1000 mg / kg / dose, approximately 1100 mg / kg / dose, approximately 1200 mg / kg / dose, or approximately 1300 mg / kg / dose. It will be understood that any lower and upper limit value can be combined to form a range.

[0324] In a particular embodiment, the dose may be a 48-hour dose (i.e., about 2 days) administered by continuous infusion at any previously provided amount or range. In a particular embodiment, the total 48-hour dose administered by continuous infusion is twice the amount administered in the 24-hour dose. In a particular embodiment, the total 48-hour dose administered by continuous infusion is administered over 48 hours using the average 24-hour dose of any previously provided amount or range. In a particular embodiment, the total 48-hour dose administered by continuous infusion is equal to any previous 24-hour dose, but administered over 48 hours. In a particular embodiment, the total 48-hour dose is about 30 mg / kg to about 350 mg / kg, or about 30 mg / kg to about 300 mg / kg. In a particular embodiment, the total 48-hour continuous infusion dose is about 50 mg / kg to 250 mg / kg. In a specific implementation, the total 48-hour continuous infusion dose is approximately 38 mg / kg, approximately 50 mg / kg, approximately 66 mg / kg, approximately 88 mg / kg, approximately 110 mg / kg, approximately 137 mg / kg, approximately 171 mg / kg, or approximately 215 mg / kg.

[0325] In a particular embodiment, the dose may be a 96-hour dose (i.e., about 4 days) administered by continuous infusion at any provided amount or range. In a particular embodiment, the total 96-hour dose administered by continuous infusion is four times the amount administered in a 24-hour dose. In a particular embodiment, the 96-hour dose administered by continuous infusion is administered over 96 hours using the average 24-hour dose of any previously provided amount or range. In a particular embodiment, the total 96-hour dose administered by continuous infusion is equal to any previous 24-hour dose, but administered over 96 hours. In a particular embodiment, the total 96-hour dose is about 30 mg / kg to about 450 mg / kg, 30 mg / kg to about 400 mg / kg, about 30 mg / kg to about 350 mg / kg, or about 30 mg / kg to about 300 mg / kg. In a particular embodiment, the total 96-hour continuous infusion dose is about 50 mg / kg to 250 mg / kg. In certain embodiments, the total 96-hour dose is about 100 mg / kg to 430 mg / kg, about 100 mg / kg to 200 mg / kg, about 200 mg / kg to 350 mg / kg, or about 300 mg / kg to 450 mg / kg. In certain embodiments, the total 96-hour continuous infusion dose is about 38 mg / kg, about 50 mg / kg, about 66 mg / kg, about 88 mg / kg, about 110 mg / kg, about 137 mg / kg, about 171 mg / kg, about 215 mg / kg, about 100 mg / kg, about 132 mg / kg, about 176 mg / kg, about 220 mg / kg, about 274 mg / kg, about 342 mg / kg, or about 430 mg / kg.

[0326] In a particular embodiment, the dose may be a 72-hour dose (i.e., about 3 days) administered by continuous infusion at any provided amount or range. In a particular embodiment, the total 72-hour dose administered by continuous infusion is three times the amount administered in a 24-hour dose. In a particular embodiment, the 72-hour dose administered by continuous infusion is administered over 72 hours using the average 24-hour dose of any previously provided amount or range. In a particular embodiment, the total 72-hour dose administered by continuous infusion is equal to any previous 24-hour dose, but administered over 72 hours. In a particular embodiment, the total 72-hour dose is about 30 mg / kg to about 350 mg / kg, or about 30 mg / kg to about 300 mg / kg. In a particular embodiment, the total 72-hour continuous infusion dose is about 50 mg / kg to 250 mg / kg. In a specific implementation, the total 72-hour continuous infusion dose is approximately 38 mg / kg, approximately 50 mg / kg, approximately 66 mg / kg, approximately 88 mg / kg, approximately 110 mg / kg, approximately 137 mg / kg, approximately 171 mg / kg, or approximately 215 mg / kg.

[0327] In a particular embodiment, the dose may be a 144-hour dose (i.e., about 6 days) administered by continuous infusion at any previously provided amount or range. In a particular embodiment, the total 144-hour dose administered by continuous infusion is 6 times the amount administered in a 24-hour dose. In a particular embodiment, the 144-hour dose administered by continuous infusion is administered over 144 hours using the average 24-hour dose of any previously provided amount or range. In a particular embodiment, the total 144-hour dose administered by continuous infusion is equal to any previous 24-hour dose, but administered over 144 hours. In a particular embodiment, the total 144-hour dose is about 30 mg / kg to about 350 mg / kg, or about 30 mg / kg to about 300 mg / kg. In one embodiment, the total 144-hour dose is about 75 mg / kg to about 350 mg / kg. In a particular embodiment, the total 144-hour continuous infusion dose is about 50 mg / kg to 250 mg / kg. In certain embodiments, the total 144-hour continuous infusion dose is approximately 38 mg / kg, approximately 50 mg / kg, approximately 66 mg / kg, approximately 88 mg / kg, approximately 110 mg / kg, approximately 137 mg / kg, approximately 171 mg / kg, or approximately 215 mg / kg. In certain embodiments, the total 144-hour continuous infusion dose is approximately 76 mg / kg, approximately 100 mg / kg, approximately 132 mg / kg, approximately 176 mg / kg, approximately 220 mg / kg, approximately 274 mg / kg, or approximately 342 mg / kg. In one embodiment, the coenzyme Q10 preparation is administered once weekly. In one embodiment, the coenzyme Q10 preparation is administered twice weekly. In one embodiment, the coenzyme Q10 preparation is administered three times weekly. In one embodiment, the coenzyme Q10 preparation is administered four times weekly. In one embodiment, the coenzyme Q10 preparation is administered five times weekly. In one embodiment, the coenzyme Q10 preparation is administered once daily. In certain embodiments, the preparation is administered over more than 4 hours. In a specific embodiment, the formulation is administered over a period of 8 hours or longer. In a specific embodiment, the formulation is administered over a period of 12 hours or longer. In a specific embodiment, the formulation is administered over a period of 18 hours or longer. In a specific embodiment, the formulation is administered over a period of 24 hours or longer (i.e., by continuous infusion). In a specific embodiment, the formulation is administered over approximately 24 hours. In a specific embodiment, the formulation is administered over at least approximately 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 192 hours, 216 hours, 240 hours, 264 hours, 288 hours, 312 hours, 336 hours, 360 hours, 384 hours, 408 hours, 432 hours, 456 hours, or 480 hours.In a particular embodiment, the formulation is administered within approximately 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 192 hours, 216 hours, 240 hours, 264 hours, 288 hours, 312 hours, 336 hours, 360 hours, 384 hours, 408 hours, 432 hours, 456 hours, or 480 hours. Any of these values ​​can be used to define the range of hours for formulation administration. For example, the formulation can be administered within approximately 48 hours to approximately 480 hours, approximately 48 hours to approximately 144 hours, or approximately 48 hours to approximately 96 hours.

[0328] In a particular embodiment, the amount of CoQ10 administered is the same for each 24-hour period and is independent of the administration rate during each 24-hour period of continuous infusion. In a particular embodiment, the amount of CoQ10 administered differs for one or more 24-hour periods of continuous infusion. In a particular embodiment, the amount of CoQ10 administered during the first 24-hour period differs from the amount administered during the remaining 24-hour periods of continuous infusion. In a particular embodiment, the amount of CoQ10 administered is the same for all 24-hour periods, but the administration rate of CoQ10 during the first 24-hour period differs from that during the remaining 24-hour periods of continuous infusion.

[0329] In a particular embodiment, a loading dose of coenzyme Q10 is used to initiate a continuous infusion. In a preferred embodiment, the dose administered over 24, 48, or 72 hours is initially administered at a rate higher than that of the remaining portion of the 24, 48, or 72-hour infusion. In a particular embodiment, at least 5% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 6% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 7% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 8% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 9% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 10% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 8% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 15% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 17.5% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 20% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 22.5% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. In a particular embodiment, at least 25% of the dose for the first 24, 48, or 72 hours is administered at a higher rate during the first hour of administration. After administering a portion of the dose at a higher rate during the first hour of a 24, 48, or 72-hour period, the remainder of the dose is administered at a second, lower rate over the remaining 23, 47, or 73 hours. Typically, continuous infusion is continued to provide at least 96 hours (i.e., two 48-hour infusions with a short pause between them) or at least 144 hours (i.e., two 72-hour infusions with a short pause between them). This continuity may be at a third infusion rate between the two previously used infusion rates, such that the amount of Coenzyme Q10 administered every 48 hours (for a 96-hour infusion) or every 72 hours (for a 144-hour infusion) is the same. Methods for adjusting the infusion rate to provide a loading dose at the start of the infusion are entirely within the capabilities of those skilled in the art.

[0330] In a particular embodiment, the infusion rate for the loading dose during the first hour of continuous administration is from about 0.1 ml / min to about 1.5 ml / min. For example, the loading dose for the first hour of infusion can be about 0.1 ml / min, 0.15 ml / min, 0.2 ml / min, 0.25 ml / min, 0.3 ml / min, 0.35 ml / min, 0.4 ml / min, 0.45 ml / min, 0.50 ml / min, 0.55 ml / min, 0.6 ml / min, 0.65 ml / min, 0.7 ml / min, 0.75 ml / min, 0.8 ml / min, 0.85 ml / min, 0.9 ml / min, 0.95 ml / min, 1.0 ml / min, 1.1 ml / min, 1.2 ml / min, 1.3 ml / min, 1.4 ml / min, 1.5 ml / min or higher, or any range included by any two of the provided values.

[0331] In a specific implementation (e.g., for a 96-hr continuous infusion), the loading dose rate (first rate) for coenzyme Q10 administration is at least 1 mg / kg / hr, at least 2 mg / kg / hr, at least 3 mg / kg / hr, at least 4 mg / kg / hr, at least 5 mg / kg / hr, at least 6 mg / kg / hr, at least 7 mg / kg / hr, at least 8 mg / kg / hr, at least 9 mg / kg / hr, at least 10 mg / kg / hr, at least 11 mg / kg / hr, at least 12 mg / kg / hr, at least 13 mg / kg / hr, at least 14 mg / kg / hr, at least 15 mg / kg / hr, at least 16 mg / kg / hr, at least 17 mg / kg / hr, at least 18 mg / kg / hr, at least 19 mg / kg / hr, at least 20 mg / kg / hr, at least 25 mg / kg / hr, at least 30 mg / kg / hr, at least 35 mg / kg / hr, at least 40 mg / kg / hr, at least 45 mg / kg / hr, or at least 50 mg / kg / hr, where “kg” is the weight of the subject to be treated. In a particular embodiment, the loading dose rate for coenzyme Q10 administration is about 3.1 mg / kg / hr, about 4.2 mg / kg / hr, about 5.5 mg / kg / hr, about 7.4 mg / kg / hr, about 9.2 mg / kg / hr, about 11 mg / kg / hr, about 14 mg / kg / hr, or about 18 mg / kg / hr. In a specific implementation (e.g., for a 144-hour continuous infusion), the loading dose rate for coenzyme Q10 administration is about 3.1 mg / kg / hr, about 4.1 mg / kg / hr, about 5.4 mg / kg / hr, about 7.2 mg / kg / hr, about 9.0 mg / kg / hr, about 11.2 mg / kg / hr, about 14.0 mg / kg / hr, or about 17.6 mg / kg / hr. Any of these values ​​can be used to define a range of loading dose rates for coenzyme Q10 administration. For example, the loading dose rate (first rate) range can be about 1 mg / kg / hr to about 50 mg / kg / hr, about 1 mg / kg / hr to about 20 mg / kg / hr, about 3 mg / kg / hr to about 15 mg / kg / hr, about 5 mg / kg / hr to about 20 mg / kg / hr, or about 3.1 mg / kg / hr to about 18 mg / kg / hr.

[0332] In a preferred embodiment, the dose rate (first rate) for the loading dose does not exceed 26.0 mg / kg / hr. In a preferred embodiment, the dose rate does not exceed 19.6 mg / kg / hr. In a preferred embodiment, the dose rate does not exceed 14.5 mg / kg / hr.

[0333] In a particular embodiment, the infusion rate for the remaining 23 hours of the first 24-hour dose, the remaining 47 hours of the first 48-hour dose, or the remaining 71 hours of the first 72-hour dose is about 0.02 ml / min to about 0.4 ml / min. In a particular embodiment, the infusion rate is about 0.02 ml / min, 0.03 ml / min, 0.04 ml / min, 0.05 ml / min, 0.06 ml / min, 0.07 ml / min, 0.08 ml / min, 0.09 ml / min, 0.1 ml / min, 0.11 ml / min, 0.12 ml / min, 0.13 ml / min, 0.14 ml / min, 0.15 ml / min, 0.16 ml / min, 0.17 ml / min, 0.18 ml / min, 0.19 ml / min, 0.20 ml / min, 0.21 ml / min, 0.22 ml / min, 0.23 ml / min, 0.24 ml / min, 0.25 ml / min, 0.30 ml / min, 0.35 ml / min or higher, or any range including any two of the provided values.

[0334] In a specific embodiment, the dose rate (i.e., the second dose rate) for the remaining 23 hours of the first 24-hour infusion, the remaining 47 hours of the first 48-hour infusion, or the remaining 71 hours of the first 72-hour infusion is at least 0.1 mg / kg / hr, at least 0.2 mg / kg / hr, at least 0.3 mg / kg / hr, at least 0.4 mg / kg / hr, at least 0.5 mg / kg / hr, at least 0.6 mg / kg / hr, at least 0.7 mg / kg / hr, at least 0.8 mg / kg / hr, at least 0.9 mg / kg / hr, and so on. At least 1.0 mg / kg / hr, at least 1.5 mg / kg / hr, at least 2.0 mg / kg / hr, at least 2.5 mg / kg / hr, at least 3.0 mg / kg / hr, at least 3.5 mg / kg / hr, at least 4.0 mg / kg / hr, at least 4.5 mg / kg / hr, at least 5.0 mg / kg / hr, at least 6.0 mg / kg / hr, at least 7.0 mg / kg / hr, at least 8.0 mg / kg / hr, at least 9.0 mg / kg / hr, or at least 10.0 mg / kg / hr. In a particular embodiment, the second rate (e.g., for a 48-hour infusion of coenzyme Q10) is about 3.1 mg / kg / hr, about 4.2 mg / kg / hr, about 5.5 mg / kg / hr, about 7.4 mg / kg / hr, about 9.2 mg / kg / hr, about 11 mg / kg / hr, about 14 mg / kg / hr, or about 18 mg / kg / hr. In a particular embodiment, the second rate (e.g., for a 72-hour infusion of coenzyme Q10) is about 0.49 mg / kg / hr, about 0.65 mg / kg / hr, about 0.85 mg / kg / hr, about 1.14 mg / kg / hr, about 1.42 mg / kg / hr, about 1.77 mg / kg / hr, about 2.21 mg / kg / hr, or about 2.78 mg / kg / hr. Any of these values ​​may be used to define a range of second dose rates for coenzyme Q10 administration. For example, the second dose rate range may be about 0.1 mg / kg / hr to about 10 mg / kg / hr, about 3.1 mg / kg / hr to about 18 mg / kg / hr, about 0.49 mg / kg / hr to about 2.78 mg / kg / hr, about 0.5 mg / kg / hr to about 2.5 mg / kg / hr, about 0.1 mg / kg / hr to about 5 mg / kg / hr, about 0.1 mg / kg / hr to about 3 mg / kg / hr, or about 0.5 mg / kg / hr to about 2.2 mg / kg / hr.

[0335] In a particular embodiment, the second dose rate does not exceed 35.8 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 28.7 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 26 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 22.9 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 19.6 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 18.4 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 14.5 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 11 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 9.2 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 8.3 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 7.4 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 5.5 mg / kg / hr. In a particular embodiment, the second dose rate does not exceed 4.2 mg / kg / hr.

[0336] Coenzyme Q10 can also be administered at a third rate, i.e., the rate of a second infusion following a short pause (e.g., a second 24-hour infusion after a 48-hour infusion, a second 48-hour infusion after a 96-hour continuous infusion, or a second 72-hour infusion after a 144-hour continuous infusion). In a particular embodiment, the third infusion rate is from about 0.03 ml / min to about 0.4 ml / min. In a particular embodiment, the third infusion rate is about 0.03 ml / min, 0.04 ml / min, 0.05 ml / min, 0.06 ml / min, 0.07 ml / min, 0.08 ml / min, 0.09 ml / min, 0.1 ml / min, 0.11 ml / min, 0.12 ml / min, 0.13 ml / min, 0.14 ml / min, 0.15 ml / min, 0.16 ml / min, 0.17 ml / min, 0.18 ml / min, 0.19 ml / min, 0.20 ml / min, 0.21 ml / min, 0.22 ml / min, 0.23 ml / min, 0.24 ml / min, 0.25 ml / min, 0.30 ml / min, 0.35 ml / min or higher, or any range including any two of the provided values.

[0337] In a particular embodiment, the third dose rate is at least 0.1 mg / kg / hr, at least 0.2 mg / kg / hr, at least 0.3 mg / kg / hr, at least 0.4 mg / kg / hr, at least 0.5 mg / kg / hr, at least 0.6 mg / kg / hr, at least 0.7 mg / kg / hr, at least 0.8 mg / kg / hr, at least 0.9 mg / kg / hr, at least 1.0 mg / kg / hr, at least 1.5 mg / kg / hr, at least 2.0 mg / kg / hr, at least 2.5 mg / kg / hr, at least 3.0 mg / kg / hr, at least 3.5 mg / kg / hr, at least 4.0 mg / kg / hr, at least 4.5 mg / kg / hr, at least 5.0 mg / kg / hr, at least 6.0 mg / kg / hr, at least 7.0 mg / kg / hr, at least 8.0 mg / kg / hr, at least 9.0 mg / kg / hr, or at least 10.0 mg / kg / hr. In a particular embodiment, the third dose rate (e.g., for a second 48-hour dose following a 96-hour continuous infusion) is about 0.8 mg / kg / hr, about 1.05 mg / kg / hr, about 1.38 mg / kg / hr, about 1.83 mg / kg / hr, about 2.29 mg / kg / hr, about 2.85 mg / kg / hr, about 3.56 mg / kg / hr, or about 4.48 mg / kg / hr. In a particular embodiment, the third dose rate (e.g., for a second 72-hour dose following a 144-hour continuous infusion) is about 0.53, about 0.69 mg / kg / hr, about 0.92 mg / kg / hr, about 1.22 mg / kg / hr, about 1.53 mg / kg / hr, about 1.90 mg / kg / hr, about 2.38 mg / kg / hr, or about 2.99 mg / kg / hr. Any of these values ​​may be used to define a range for the third dose rate. For example, the third dose rate range can be about 0.1 mg / kg / hr to about 10 mg / kg / hr, about 0.8 mg / kg / hr to about 4.48 mg / kg / hr, or about 0.53 mg / kg / hr to about 2.99 mg / kg / hr.

[0338] In a specific embodiment, the third dose rate does not exceed 35.8 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 28.7 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 26 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 22.9 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 19.6 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 18.4 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 14.5 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 11 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 9.2 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 8.3 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 7.4 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 5.5 mg / kg / hr. In a specific embodiment, the third dose rate does not exceed 4.2 mg / kg / hr.

[0339] Coenzyme Q10 can be administered at different daily doses depending on the dosing regimen. For example, in a particular embodiment, if a loading dose is used, the daily dose of coenzyme Q10 for the first day infusion (i.e., the first 24-hour infusion) is higher than the daily dose for the second day infusion (i.e., the second 24-hour infusion). In a particular embodiment, the daily dose for the third day infusion (e.g., hours 49-72 of a 72-hour infusion) is lower than the daily dose for the first day infusion but higher than the daily dose for the second day infusion. In a specific implementation scheme, the concentrations are at least 1 mg / kg / day (24 hours), at least 5 mg / kg / day (24 hours), at least 10 mg / kg / day (24 hours), at least 15 mg / kg / day (24 hours), at least 20 mg / kg / day (24 hours), at least 25 mg / kg / day (24 hours), at least 30 mg / kg / day (24 hours), at least 35 mg / kg / day (24 hours), at least 40 mg / kg / day (24 hours), at least 45 mg / kg / day (24 hours), at least 50 mg / kg / day (24 hours), at least 55 mg / kg / day (24 hours), at least 60 mg / kg / day (24 hours), at least 65 mg / kg / day (24 hours), at least 70 mg / kg / day (24 hours), and at least 75 mg / kg / day (24 hours). Coenzyme Q10 should be administered at doses of at least 80 mg / kg / day (24 hours), at least 85 mg / kg / day (24 hours), at least 90 mg / kg / day (24 hours), at least 95 mg / kg / day (24 hours), at least 100 mg / kg / day (24 hours), at least 110 mg / kg / day (24 hours), at least 120 mg / kg / day (24 hours), at least 130 mg / kg / day (24 hours), at least 140 mg / kg / day (24 hours), at least 150 mg / kg / day (24 hours), at least 200 mg / kg / day (24 hours), at least 250 mg / kg / day (24 hours), at least 300 mg / kg / day (24 hours), at least 400 mg / kg / day (24 hours), or at least 500 mg / kg / day (24 hours).In a specific embodiment, at least one of the following dosages is used: approximately 11.8 mg / kg / day (24 hours), approximately 12.5 mg / kg / day (24 hours), approximately 14.4 mg / kg / day (24 hours), approximately 15.6 mg / kg / day (24 hours), approximately 16.5 mg / kg / day (24 hours), approximately 19 mg / kg / day (24 hours), approximately 20.4 mg / kg / day (24 hours), approximately 22 mg / kg / day (24 hours), approximately... 25 mg / kg / day (24 hours), approximately 27.5 mg / kg / day (24 hours), approximately 29.3 mg / kg / day (24 hours), approximately 33 mg / kg / day (24 hours), approximately 34.2 mg / kg / day (24 hours), approximately 36.7 mg / kg / day (24 hours), approximately 41.7 mg / kg / day (24 hours), approximately 42.8 mg / kg / day (24 hours), approximately 44 mg / kg / day (24 hours), approximately 4 5.7 mg / kg / day (24 hours), approximately 51.9 mg / kg / day (24 hours), approximately 53.8 mg / kg / day (24 hours), approximately 55 mg / kg / day (24 hours), approximately 57 mg / kg / day (24 hours), approximately 58.7 mg / kg / day (24 hours), approximately 64.8 mg / kg / day (24 hours), approximately 66.7 mg / kg / day (24 hours), approximately 68.5 mg / kg / day (24 hours). Coenzyme Q10 can be administered at doses of approximately 71.7 mg / kg / day (24 hours), approximately 73.4 mg / kg / day (24 hours), approximately 81.5 mg / kg / day (24 hours), approximately 85.5 mg / kg / day (24 hours), approximately 91.7 mg / kg / day (24 hours), approximately 107.5 mg / kg / day (24 hours), approximately 114.6 mg / kg / day (24 hours), and approximately 143.3 mg / kg / day (24 hours). Any of these values ​​can be used to define the range of daily doses of coenzyme Q10. For example, the range of daily doses of coenzyme Q10 can be from 1 mg / kg / day (24 hours) to 500 mg / kg / day (24 hours), from 10 mg / kg / day (24 hours) to 150 mg / kg / day (24 hours), or from 11.8 mg / kg / day (24 hours) to 143.2 mg / kg / day (24 hours).

[0340] In one embodiment, the daily dose (e.g., average daily dose) of coenzyme Q10 used in the continuous infusion regimens of the present invention (e.g., 48-hour, 72-hour, 96-hour, or 144-hour continuous infusion) ranges from 10-65 mg / kg / day (24 hours), 10-15 mg / kg / day (24 hours), 15-20 mg / kg / day (24 hours), 20-25 mg / kg / day (24 hours), 25-35 mg / kg / day (24 hours), 35-42 mg / kg / day (24 hours), 42-52 mg / kg / day (24 hours), or 52-65 mg / kg / day (24 hours).

[0341] In a particular embodiment, the formulation, preferably a coenzyme Q10 formulation, can be administered in one or more cycles. For example, coenzyme Q10 can be administered continuously for 2, 3, 4, 5, 6, 7, 8 or more weeks, and then not administered for a period of 1, 2, 3, 4 or more weeks, thereby providing an administration cycle. In a particular embodiment, the cycle is administered without any pauses between cycles. In a particular embodiment, at the end of one or more cycles, the patient is evaluated to determine efficacy, toxicity, and to assess whether treatment should be continued, modified, or discontinued. In a particular embodiment, one or more cycles of coenzyme Q10 are administered together with one or more cycles of at least one anticancer agent. In a particular embodiment, treatment with another anticancer agent is initiated after the first cycle of coenzyme Q10 treatment. In a particular embodiment, treatment with another anticancer agent is initiated after at least one cycle of coenzyme Q10 treatment. In a particular embodiment, treatment with another anticancer agent is initiated after cancer progression in the subject following coenzyme Q10 treatment. In a particular embodiment, treatment with another anticancer agent is initiated when the subject has no cancer progression after coenzyme Q10 treatment.

[0342] The number of administration cycles depends on factors such as the subject's response, the severity of the disease, other therapeutic interventions used on the subject, or any adverse reactions in the subject. In a particular implementation, the coenzyme Q10 preparation is administered as long as the subject demonstrates at least a stable response to treatment and there are no serious adverse events, such as dose-limiting toxicities, Grade IV toxicities, or persistent Grade III toxicities that cannot be mitigated by other interventions.

[0343] In a specific embodiment, coenzyme Q10 is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles. In a specific embodiment, coenzyme Q10 is administered for no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles. Any of these values ​​can be used to define a range of cycles. For example, the range of cycles can be 1-20, 2-10, or 4-8.

[0344] In another embodiment, the formulation, preferably a coenzyme Q10 formulation, is administered as a coenzyme Q10 IV formulation at doses of about 10 mg / kg / dose to about 10,000 mg / kg / dose, about 20 mg / kg / dose to about 5,000 mg / kg / dose, about 50 mg / kg / dose to about 3,000 mg / kg / dose, about 100 mg / kg / dose to about 2,000 mg / kg / dose, about 200 mg / kg / dose to about 1,000 mg / kg / dose, about 300 mg / kg / dose to about 500 mg / kg / dose, or about 55 mg / kg / dose to about 110 mg / kg / dose, wherein the coenzyme Q10 formulation contains about 1% to 10% coenzyme Q10 (w / v). In one embodiment, the coenzyme Q10 formulation contains about 4% coenzyme Q10 (w / v). In one embodiment, the coenzyme Q10 IV formulation contains about 8% coenzyme Q10 (w / v). In other embodiments, the coenzyme Q10 IV formulation comprises about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% coenzyme Q10 (w / v). It should be understood that ranges having any of these values ​​as upper or lower limits are also intended to be part of the invention.

[0345] In cancer treatment, the formulation may be in a pharmaceutically acceptable carrier and may be administered to the subject as a single treatment, in combination with at least one other anticancer agent (e.g., a chemotherapeutic agent) for a given indication, in combination with radiotherapy following a surgical intervention to eradicate the tumor, in combination with other optional and / or complementary acceptable cancer treatments, etc., at a therapeutically effective amount.

[0346] Generally, the coenzyme Q10 formulations and methods described herein can be used to treat any tumor. In a particular embodiment, the formulations and methods are used to treat a subject with a solid tumor. In a particular embodiment, the formulations and methods are used to treat a subject with a non-solid tumor, such as leukemia. In a particular embodiment, the subject has failed at least one chemotherapy regimen prior to treatment with coenzyme Q10.

[0347] To avoid being bound by specific mechanisms, in certain implementations, the potential effects of coenzyme Q10 on cancer cells depend in part on the various metabolic states and oxygen fluxes exhibited by the cancer cells. Coenzyme Q10 can be used to interrupt and / or interfere with the glycolysis-dependent shift and increased lactate utilization in cancer cells. Because this involves the cancer state, such interference with glycolysis and oxygen flux in the tumor microenvironment can affect apoptosis and angiogenesis in a way that reduces the viability or proliferative capacity of cancer cells. In some implementations, the interaction of coenzyme Q10 with glycolysis and oxygen flux factors can enhance the ability of coenzyme Q10 to exert its restorative apoptosis-inducing effect in cancer. Although this disclosure focuses on coenzyme Q10 and its metabolites, other coenzyme Q10-related compounds that can be used in place of or in combination with coenzyme Q10 include, but are not limited to, benzoquinones, isoprene derivatives, farnesols, farnesol acetate, farnesol pyrophosphate, 1-phenylalanine, d-phenylalanine, dl-phenylalanine, 1-tyrosine, d-tyrosine, dl-tyrosine, 4-hydroxyphenylpyruvate, 4-hydroxyphenyl emulsion, 4-hydroxycinnamate, dipeptides and tripeptides of tyrosine or phenylalanine, 3,4-dihydroxymandelate, 3-methoxy-4-hydroxyphenylethylene glycol, 3-methoxy-4-hydroxymandelate, vanillic acid, phenylacetic acid, pyridoxine, S-adenosylmethionine, panthenol, mevalonic acid, isoamyl pyrophosphate, phenyl Butyrate, 4-hydroxybenzoate, decaisoprene pyrophosphate, β-hydroxybutyrate, 3-hydroxy-3-methylglutarate, acetylcarnitine, acetoacetylcarnitine, acetylglycine, acetoacetylglycine, carnitine, acetic acid, pyruvate, 3-hydroxy-3-methylglutarylcarnitine, serine, alanine, cysteine, glycine, threonine, hydroxyproline, lysine, isoleucine and leucine, all isomers of carnitine and glycine, even-carbon C4 to C8 fatty acid salts (butyric acid, hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid), such as palmitoylcarnitine and palmitoylglycine, and 4-hydroxybenzoic acid polyisopreneyltransferase, any salts of these compounds, and any combination thereof, etc.

[0348] In one embodiment, administration of coenzyme Q10 as described herein, compared to a suitable control, resulted in at least stable disease, reduced tumor size, inhibited tumor growth, and / or prolonged survival in subjects carrying tumors. Therefore, the invention also relates to a method of treating tumors in humans or other animals (including subjects who have failed at least one previous chemotherapy regimen) by administering an effective, non-toxic amount of coenzyme Q10 to humans or other animals (e.g., via intravenous administration, preferably continuous intravenous administration to administer an effective dose). Those skilled in the art can use the guidance provided herein to determine, through routine experiments, what effective, non-toxic amount of coenzyme Q10 for continuous intravenous administration is appropriate for the treatment of malignant tumors, including malignant tumors in subjects who have failed at least one previous chemotherapy regimen. For example, the therapeutically active amount of coenzyme Q10 can be varied based on factors such as disease stage (e.g., stage I vs. stage IV), the subject's age, sex, medical complications (conditions or diseases of immunosuppression, coagulopathy), and weight, as well as the ability of coenzyme Q10 to elicit a desired response in the subject. Dosing regimens can be adjusted to provide an optimal therapeutic response. For example, several separate doses may be administered daily, the dose may be administered via continuous infusion, or the dose may be reduced proportionally as indicated by the urgency of the treatment situation.

[0349] In a particular embodiment of the invention, the method further includes a treatment regimen, which includes any one or a combination of surgery, radiotherapy, chemotherapy, such as hormone therapy, antibody therapy, therapy using growth factors, cytokines, and anti-angiogenic therapy.

[0350] It should be understood that similar treatments can be performed by administering coenzyme Q10 precursors, metabolites, and related compounds.

[0351] In a specific embodiment of the invention, the method further includes monitoring reduced coagulation in the subject. In a specific embodiment, reduced coagulation in the subject is monitored before coenzyme Q10 is administered. In a specific embodiment, reduced coagulation in the subject is monitored after coenzyme Q10 is administered. In a specific embodiment, reduced coagulation in the subject is monitored both before and after coenzyme Q10 is administered. In a specific embodiment, monitoring reduced coagulation includes evaluating PT / PTT, INR, and / or platelet count. In a specific embodiment, reduced coagulation includes an INR greater than 2, while normal coagulation includes an INR of 2 or lower. In a specific embodiment, reduced coagulation includes an INR greater than 3, while normal coagulation includes an INR of 3 or lower. In a specific embodiment, reduced coagulation includes a platelet threshold of less than 50,000 / μL. In a specific embodiment, normal coagulation includes a platelet threshold of at least 50,000 / μL.

[0352] In a particular embodiment, the method further includes administering an agent to improve coagulation in a subject identified as having reduced coagulation. In a particular embodiment, the coagulation-enhancing agent is administered before coenzyme Q10 is administered to the subject. In a particular embodiment, the coagulation-enhancing agent is administered after coenzyme Q10 is administered to the subject. In a particular embodiment, the coagulation-enhancing agent includes vitamin K. In a particular embodiment, vitamin K is administered orally, intravenously, intramuscularly, or subcutaneously. In a particular embodiment, the coagulation-enhancing agent includes cryoprecipitate or fresh frozen plasma.

[0353] In a particular embodiment, the method further includes discontinuing treatment with coenzyme Q10 in subjects identified as having reduced coagulation. In a particular embodiment, the method further includes confirming that the subject has normal coagulation and initiating treatment with coenzyme Q10. In a particular embodiment, coenzyme Q10 is administered to the subject if the INR, PT, and PTT are less than or equal to 1.5 times the upper limit of normal and the platelet count is greater than or equal to 50,000 / μL. In a particular embodiment, the method further includes confirming that the subject has normal coagulation and continuing treatment with coenzyme Q10. In a particular embodiment, coenzyme Q10 is administered at two, three, four, or five different rates. In a particular embodiment, coenzyme Q10 is administered at two or more different rates, three or more different rates, four or more different rates, or five or more different rates. In certain embodiments, coenzyme Q10 is administered for at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, at least 216 hours, at least 240 hours, at least 264 hours, at least 288 hours, at least 312 hours, at least 336 hours, at least 360 hours, at least 384 hours, at least 408 hours, at least 432 hours, at least 456 hours, or at least 480 hours. Cancers treated using the methods of the present invention include, for example, all types of cancers or growths or malignant tumors found in mammals, including, but not limited to, leukemia, lymphoma, melanoma, carcinoma, and sarcoma. In one embodiment, cancers treated using the methods of the present invention include melanoma, carcinoma, and sarcoma. In a preferred embodiment, the coenzyme Q10 composition is used to treat various types of solid tumors, such as breast cancer, bladder cancer, colorectal cancer, endometrial cancer, kidney (renal cell) cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, bone cancer, brain cancer, cervical cancer, liver cancer, gastric cancer, oral and oral cavity cancer, neuroblastoma, testicular cancer, uterine cancer, thyroid cancer, head and neck cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, and medulloblastoma, as well as vulvar cancer. In a particular embodiment, solid tumors include breast cancer, including triple-negative breast cancer. In a particular embodiment, skin cancer includes melanoma, squamous cell carcinoma, and cutaneous T-cell lymphoma (CTCL). In a particular embodiment, cancer includes leukemia. In a particular embodiment, leukemia includes acute leukemia. In a particular embodiment, leukemia includes chronic leukemia. In certain implementations, leukemia includes acute lymphoblastic (or lymphoblastic) leukemia (ALL), acute myeloid (or myeloid or non-lymphoblastic) leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).More types of leukemia include hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, and adult T-cell leukemia. However, treatment using coenzyme Q10 combinations is not limited to these types of cancer.

[0354] As used herein, the terms “cancer,” “vesicle,” and “tumor” are used interchangeably and, in both singular and plural forms, refer to cells that have undergone a malignant transformation that makes them pathological to the host organism. Primary cancer cells (i.e., cells derived from the vicinity of the site of malignant transformation) can be easily distinguished from non-cancer cells by well-established techniques, particularly histological examination. As used herein, the definition of cancer cells includes not only primary cancer cells but also any cells derived from cancer cell progenitors. This includes metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to cancer types that typically present as solid tumors, a “clinically detectable” tumor is based on the detectability of the tumor mass; for example, detectable by procedures such as CAT scans, MR imaging, X-rays, ultrasound, or palpation, and / or by the expression of one or more cancer-specific antigens in a sample obtainable from the patient. Leukemia is clinically detectable using one or more of the following tests: complete blood count, pallor, blood smear, and bone marrow smear. Advanced leukemia in certain subjects may present as a solid tumor.

[0355] For example, instances of non-solid tumors that cannot be detected by imaging or palpation, such as leukemia, can be detected by neutrophil count, platelet count, and by the detection of abnormal cells in the bone marrow, such as the presence of unexplained primitive cells (e.g., bone marrow regeneration after consolidation therapy), the presence of Auer rods, or the appearance of new developmental abnormalities.

[0356] The term "sarcoma" generally refers to a tumor composed of material such as embryonal connective tissue and typically consisting of tightly packed cells embedded in fibrous or homogeneous material. Examples of sarcomas that can be treated with the compositions of the present invention and optionally other anticancer agents (e.g., chemotherapeutic agents) include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, and Ewing's sarcoma. Sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, white sarcoma, malignant stromal tumor sarcoma, periosteal sarcoma, reticulocyte sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and capillary dilatational sarcoma.

[0357] The term "melanoma" is considered to refer to tumors arising from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compositions of the present invention and optionally other anticancer agents (e.g., chemotherapeutic agents) include, but are not limited to, acral lentigines melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harper-Parkinson's disease melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial diffuse melanoma.

[0358] The term "cancer" refers to a malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and cause metastasis. Cancers that can be treated with the compositions of the present invention and optionally other anticancer agents (e.g., chemotherapeutic agents) include, but are not limited to, acinar carcinoma, alveolar carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, neoplastic adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchiolar protocarcinoma, medullary carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus cancer, cribriform carcinoma, armored carcinoma, skin cancer, columnar cell carcinoma, ductal carcinoma, etc. Carcinoma, scleroderma, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial carcinoma, explant carcinoma, ulcerative carcinoma, fibrocarcinoma, colloid carcinoma, glial carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granular cell carcinoma, stromal carcinoma, hematopoietic carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, clear carcinoma, renal clear cell carcinoma (hypemephroid carcinoma), immature embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Crompke Herl carcinoma, Kurtchsky cell carcinoma, large cell carcinoma, lenticular carcinoma Carcinoma, lenticular carcinoma, lipoma-like carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma (carcinoma muciparum), mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous carcinoma (carcinoma mucosum), mucous carcinoma (mucous carcinoma), mucinoma-like carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthosis nigra, soft carcinoma, renal cell carcinoma, reservoir cell carcinoma, sarcomatoid carcinoma, Schneider carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spherical cell carcinoma, spindle cell carcinoma, soft carcinoma, squamous carcinoma, squamous cell carcinoma, cord carcinoma, angiomyolipoma (carcinomatelangiectaticum), angiomyolipoma (carcinoma) (telangiectodes), transitional cell carcinoma, nodular carcinoma (tuberosum), tuberous carcinoma, verrucous carcinoma, and villous carcinoma.

[0359] The term "leukemia" refers to a type of cancer of the blood or bone marrow characterized by an abnormal increase in immature white blood cells called "blasts." Leukemia is a broad term encompassing a range of diseases, including, in turn, parts of even broader categories of diseases affecting the blood, bone marrow, and lymphatic systems (also known as hematologic malignancies). Leukemia can be classified into four main types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). More types of leukemia include hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, and adult T-cell leukemia.

[0360] Acute leukemia is characterized by a rapid increase in the number of immature blood cells. The resulting aggregation of these cells prevents the bone marrow from producing healthy blood cells. Due to the rapid development and aggregation of malignant cells (which subsequently leak into the bloodstream and spread to other organs), acute leukemia requires immediate treatment. The acute form of leukemia is the most common form of childhood leukemia.

[0361] Chronic leukemia is characterized by an excessive accumulation of relatively mature but still abnormal white blood cells. It typically progresses over months or years, with cells produced at a much higher rate than normal, resulting in a large number of abnormal white blood cells. Acute leukemia requires immediate treatment; however, chronic forms are sometimes monitored for a period before treatment to ensure maximum therapeutic effectiveness.

[0362] Lymphoblastic or lymphocytic leukemia is caused by the excessive proliferation of bone marrow cells that produce lymphocytes (white blood cells) (usually B cells).

[0363] Myeloid or leukemia is caused by the excessive proliferation of bone marrow cells that produce red blood cells, some other types of white blood cells, and platelets.

[0364] Other cancers that can be treated with the compositions of the present invention include, for example, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, essential thrombocytosis, essential macroglobulinemia, small cell lung tumor, primary brain tumor, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid tumor, bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, and esophageal cancer. Urogenital tract cancers, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenocortical carcinoma, prostate cancer, pancreatic cancer, uterine sarcoma, myxoid liposarcoma, leiomyosarcoma, chondrosarcoma, osteosarcoma, colonic adenocarcinoma, cervical squamous cell carcinoma, tonsillar squamous cell carcinoma, papillary thyroid carcinoma, adenoid cystic carcinoma, synovial cell sarcoma, malignant fibrous histiocytoma, connective tissue proliferative sarcoma, hepatocellular carcinoma, spindle cell sarcoma, cholangiocarcinoma, and triple-negative breast cancer. In one embodiment, the method according to the invention can treat actinic keratosis or prevent it from developing into cancer.

[0365] V. Combined Treatment In certain embodiments, the formulations and methods of the present invention can be used in combination therapy with at least one other anticancer agent (e.g., a chemotherapeutic agent). In certain embodiments, treatment with the chemotherapeutic agent is initiated concurrently with treatment with coenzyme Q10. In certain embodiments, treatment with the chemotherapeutic agent is initiated after treatment with coenzyme Q10 is started. In certain embodiments, treatment with other agents is started if cancer progresses during treatment with coenzyme Q10. In certain embodiments, treatment with other agents is started if there is no cancer progression during treatment with coenzyme Q10. In certain embodiments, treatment with coenzyme Q10 continues when administration of other agents is started. In certain embodiments, treatment with coenzyme Q10 is discontinued when treatment with other agents is started.

[0366] The methods of treating cancer with continuous infusion of coenzyme Q10 as described herein include combination therapy with other anticancer agents or interventions (e.g., radiotherapy, surgery, bone marrow transplantation). In certain embodiments, "combination therapy" includes treatment with coenzyme Q10 to reduce tumor burden and / or improve clinical response. Administration of coenzyme Q10 with one or more palliative therapies to alleviate drug side effects (e.g., reducing nausea, pain, anxiety, or inflammation, normalizing coagulation) is not considered combination therapy for cancer.

[0367] In a preferred embodiment, treatment with continuously infused coenzyme Q10 is combined with standard treatment for the specific cancer to be treated. Standard treatment for a specific cancer type can be determined by those skilled in the art based on, for example, the type and severity of the cancer, the subject's age, weight, sex, and / or medical history, and the success or failure of previous treatments.

[0368] In a particular implementation, for the treatment of subjects with leukemia (especially ALL or AML), continuous infusion of coenzyme Q10 is combined with one or more of the following treatments.

[0369] 1. Fludarabine, preferably administered at a dose of 15 mg / m² every 12 hours, over a period of 15-30 minutes ± 15 minutes. 2 The intravenous dose was administered for 5 days (or 4 days in patients over 65 years of age or with an ECOG performance status of 3).

[0370] 2. Cytarabine, preferably administered at a dose of 0.5 mg / ml in 250 ml of physiological saline every 12 hours ± 2 hours, over a period of 2 hours ± 20 minutes. 2 Administer intravenously for 5 days (or for 4 days in patients over 65 years of age or with an ECOG performance status of 3).

[0371] In a specific embodiment, fludarabine and / or acytidine are administered on days 1-5 of an 18-day continuous coenzyme Q10 infusion. In a preferred embodiment, treatment with fludarabine and / or acytidine is initiated after the completion of the 18-day continuous coenzyme Q10 infusion alone. In a specific embodiment, 1, 2, 3, 4, or 5 cycles of combined treatment are administered to the subject. At the end of each cycle, the subject's response criteria are evaluated. Adverse events (e.g., coagulation, anemia, liver and kidney function, etc.) are also monitored throughout each cycle to ensure the treatment regimen is adequately tolerable.

[0372] In a particular implementation, treatment of a subject with a solid tumor via continuous infusion of coenzyme Q10 is combined with one or more of the following treatments.

[0373] 1. Gemcitabine, preferably at 600 mg / m² 2 The initial weekly dose is administered intravenously, and the dose is adjusted based on the subject's tolerance to the drug.

[0374] 2.5-Fluorouracil (5-FU), preferably bound to 100 mg / m². 2 Folic acid at 350 mg / m 2 The initial weekly dose is administered intravenously, and the dose is adjusted based on the subject's tolerance to the drug.

[0375] 3. Docetaxel, preferably at 20 mg / m² 2 The initial dose is administered intravenously once a week, and the dose is adjusted based on the subject's tolerance to the drug.

[0376] In a specific embodiment, gemcitabine, 5-FU, and folate and / or docetaxel are administered on days 1-5 of a 96-hour continuous coenzyme Q10 infusion. In a preferred embodiment, treatment with gemcitabine, 5-FU, folate, and / or docetaxel is initiated after an 18-day continuous coenzyme Q10 infusion alone. In a specific embodiment, 1, 2, 3, 4, or 5 cycles of combined treatment are administered to the subject. At the end of each cycle, the subject's response criteria are evaluated. Adverse events (e.g., coagulation, anemia, liver and kidney function, etc.) are also monitored throughout each cycle to ensure the treatment regimen is adequately tolerable.

[0377] In certain embodiments, if delivered alone, i.e., coenzyme Q10 is administered and / or functions as a therapeutic agent and not primarily as an agent to alleviate the side effects of other chemotherapy or other cancer treatments, coenzyme Q10 is administered in a therapeutically effective amount. Coenzyme Q10 and / or its pharmaceutical formulations may act in combination with other therapeutic agents, or more preferably synergistically. In one embodiment, coenzyme Q10 and / or its pharmaceutical formulations are administered concurrently with other anticancer agents (e.g., chemotherapeutic agents, antiangiogenic agents). In another embodiment, the compound and / or its pharmaceutical formulations are administered before or after administration of another anticancer agent, wherein both agents are present in the subject or simultaneously have therapeutic activity in the subject. In one embodiment, coenzyme Q10 and other anticancer agents act synergistically. In one embodiment, coenzyme Q10 and other anticancer agents act in combination.

[0378] In one embodiment, the treatment method of the present invention further includes administration of one or more other therapeutic agents, such as one or more anticancer agents, for example, anti-angiogenic agents, chemotherapeutic agents, such as small molecule anticancer agents, biological anticancer agents, including protein-based and nucleic acid-based therapeutic agents. For example, in one embodiment, other anticancer agents used in the treatment method of the present invention are chemotherapeutic agents.

[0379] Small molecule chemotherapeutic agents typically fall into various categories, including, for example: 1. Topoisomerase II inhibitors (cytotoxic antibiotics), such as anthracyclines / anthracyclines, such as doxorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone and loxoantrone; and podophyllotoxins, such as etoposide and teniposide; 2. Agents affecting microtubule formation (mitotic inhibitors), such as plant alkaloids (e.g., compounds belonging to the alkaloid family, biologically active and cytotoxic nitrogen-containing molecules derived from plants), such as taxanes such as paclitaxel and docetaxel; and vinca alkaloids such as vincristine, vinblastine, and vinorelbine; and podophyllotoxin derivatives; 3. Alkylating agents, such as nitrogen mustard, ethylenediamine compounds, alkyl sulfonates, and other compounds with alkylating properties, such as nitrosourea, azithromycin, cyclophosphamide, ifosfamide, and melphalan; 4. Antimetabolites (nucleoside inhibitors), such as folic acid derivatives, fluoropyrimidines, purine or pyrimidine analogs such as 5-fluorouracil, capecitabine, gemcitabine, methotrexate, and edarax; 5. Topoisomerase I inhibitors, such as topotecan, irinotecan, and 9-nitrocamptothecin, camptothecin derivatives, and retinoic acid; and 6. Platinum compounds / complexes, such as cisplatin, oxaliplatin, and carboplatin. Exemplary chemotherapeutic agents used in the methods of the present invention include, but are not limited to, amistin (amfoxitin), cisplatin, dazometazidine (DTIC), actinomycin, dichloromethyldiethylamine (nitrogen mustard), streptozotocin, cyclophosphamide, carmustine (BCNU), romustine (CCNU), doxorubicin (adriamycin), doxorubicin liposome (doxil), gemcitabine (gemzar), daunorubicin, daunorubicin liposome (daunoxome), mebenzylhydrazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vincristine, bleomycin, paclitaxel (paclitaxel), docetaxel (Tasocort), adelleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, and CPT-I. 1. 10-Hydroxy-7-ethylcamptothecin (SN38), dazometidine, SI capecitabine, furfural, 5'-deoxyfluorouridine, UFT, enuracil, deoxycytidine, 5-azacytosine, 5-azadeoxycytosine, allopurinol, 2-chloroadenosine, trimesatine, aminopterin, methylene-10-deazaaminopterin (MDAM), oxaplatin, picaloplatin, tetraplatin, saxaplatin, platinum-DACH, omaliplatin, CI-973, JM-216 and their analogues, epirubicin, etoposide phosphate, 9-aminocamptothecin, 10,11-Methylenedioxycamptothecin, karenitecin, 9-nitrocamptothecin, TAS 103, vinblastine, L-phenylalanine nitrogen mustard, ifosphamide mefosphamide, phosphatidylcholine, chlorocyclophosphamide carmustine Carmustine, semustine, epothilone (AE), raltitrexate (Tomudex), 6-mercaptopurine, 6-thioguanine, acridine, etoposide phosphate, (4S)-4-ethyl-4-hydroxy-11-(2-trimethylsilyl)ethyl)-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-3,14(4H,12H)-dione (karenitecin), acyclovir, valacyclovir, ganciclovir, amantadine, amantadine ethylamine, lamivudine, zidovudine, bevacizumab, trastuzumab, rituximab, 5-fluorouracil, capecitabine, pentostatin, trimesat, clopidogrel Ladribine, fluorouridine, fludarabine, hydroxyurea, ifosfamide, idarubicin, mesna, irinotecan, mitoxantrone, topotecan, leuprorelin, medroxyprogesterone acetate, melphalan, mercaptopurine, succinylpyridinium chloride, mitotane, pegapase, pentostatin, piperazine, succinylpyridinium chloride, streptozotocin, tamoxifen, teniposide, testrolide, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil, cisplatin, doxorubicin, paclitaxel, bleomycin, mTor, epidermal growth factor receptor (EGFR), and fibroblast growth factor (FGF), and combinations thereof that are readily understood by those skilled in the art based on appropriate standard treatment for a particular tumor or cancer.

[0380] In another embodiment, the other chemotherapeutic agents used in the combination therapy of the present invention are biological agents.

[0381] Biologics (also known as biological products) are products of biological systems, such as organisms, cells, or recombinant systems. Examples of such biologics include nucleic acid molecules (e.g., antisense nucleic acid molecules), interferons, interleukins, colony-stimulating factors, antibodies (e.g., monoclonal antibodies), anti-angiogenic agents, and cytokines. Exemplary biologics are discussed in more detail below and generally fall into various categories, including, for example: 1. hormones, hormone analogs, and hormone complexes, such as estrogens and estrogen analogs, progesterone, progesterone analogs and progesterone, androgens, corticosteroids, anti-estrogens, anti-androgens, anti-testosterone, adrenocorticosteroid inhibitors, and anti-luteinizing hormone; and 2. enzymes, proteins, peptides, polyclonal and / or monoclonal antibodies, such as interleukins, interferons, colony-stimulating factors, etc.

[0382] In one implementation, the biological agent is interferon. Interferons (IFNs) are a class of biological agents that are naturally produced in the body. Interferons are also produced in the laboratory and given to cancer patients in biotherapy. They have been shown to improve the way the immune system of cancer patients fights cancer cells.

[0383] Interferons can act directly on cancer cells to slow their growth, or they can cause cancer cells to transform into cells with more normal behavior. Some interferons can also stimulate natural killer (NK) cells, T cells, and macrophages, which are types of white blood cells in the bloodstream that help fight cancer cells.

[0384] In one implementation, the biological agent is interleukin. Interleukins (ILs) stimulate the growth and activity of many immune cells. They are proteins that are naturally produced in the body (cytokines and chemokines), but can also be produced in the laboratory. Some interleukins stimulate the growth and activity of immune cells, such as lymphocytes, which act to destroy cancer cells.

[0385] In another implementation, the biologic is colony-stimulating factor (CSF). CSF is a protein given to patients to encourage stem cells in the bone marrow to produce more blood cells. The body constantly needs new white blood cells, red blood cells, and platelets, especially in the presence of cancer. CSF is given along with chemotherapy to help strengthen the immune system. When cancer patients receive chemotherapy, the bone marrow's ability to produce new blood cells is suppressed, making patients more susceptible to infections. Parts of the immune system cannot function without blood cells, therefore CSF encourages bone marrow stem cells to produce white blood cells, platelets, and red blood cells.

[0386] With adequate cell production, other cancer treatments can continue, allowing patients to safely receive higher doses of chemotherapy.

[0387] In another implementation, the biological agent is an antibody. Antibodies, such as monoclonal antibodies, are agents produced in a laboratory that bind to cancer cells.

[0388] Monoclonal antibody agents do not damage healthy cells. Monoclonal antibodies exert their therapeutic effects through various mechanisms. They can have a direct effect on inducing apoptosis or programmed cell death. They can block growth factor receptors, thereby effectively inhibiting the proliferation of tumor cells. In cells expressing monoclonal antibodies, they can lead to the formation of anti-idiotype antibodies.

[0389] Examples of antibodies that can be used in combination therapies of the present invention include anti-CD20 antibodies, such as, but not limited to, cetuximab, tosimomab, rituximab, and teimomab. Anti-HER2 antibodies can also be used in combination with coenzyme Q10 for cancer treatment. In one embodiment, the anti-HER2 antibody is trastuzumab (Herceptin). Other examples of antibodies that can be used in combination with coenzyme Q10 to treat cancer include anti-CD52 antibodies (e.g., alemtuzumab), anti-CD22 antibodies (e.g., epazolidin), and anti-CD33 antibodies (e.g., gemtruzumab / oxzomidin). Anti-VEGF antibodies can also be used in combination with coenzyme Q10 for cancer treatment. In one embodiment, the anti-VEGF antibody is bevacizumab. In other embodiments, the biologic is an antibody that acts as an anti-EGFR antibody (e.g., cetuximab). Another example is the anti-glycoprotein 17-1A antibody ezetoxumab. Many other antitumor antibodies are known in the art and will be understood by those skilled in the art to be included in this invention.

[0390] In another implementation, the biological agent is a cytokine. Cytokine therapy uses proteins (cytokines) to help the subject's immune system recognize and destroy those cells that are cancerous. Cytokines are naturally produced in the body by the immune system, but can also be produced in a laboratory. This treatment is used for advanced melanoma in conjunction with adjuvant therapy (treatment given after or in addition to primary cancer treatment). Cytokine therapy reaches all parts of the body to kill cancer cells and stop tumor growth.

[0391] In another implementation, the biologic is a fusion protein. For example, recombinant human Apo2L / TRAIL (GENETECH) can be used in combination therapy. Apo2 / TRAIL is the first dual pro-apoptotic receptor agonist designed to activate both DR4 and DR5, which are involved in the regulation of apoptosis (programmed cell death).

[0392] In one embodiment, the biological agent is a therapeutic nucleic acid molecule. Nucleic acid therapeutic agents are well known in the art. Nucleic acid therapeutic agents comprise single-stranded and double-stranded nucleic acids (i.e., nucleic acid therapeutic agents having a complementary region of at least 15 nucleotides in length) that are complementary to a target sequence in the cell. Therapeutic nucleic acids can be substantially targeted at any target nucleic acid sequence in the cell. In a particular embodiment, the nucleic acid therapeutic agent targets a nucleic acid sequence encoding an angiogenesis stimulant (e.g., VEGF, FGF) or a tumor growth stimulant (e.g., EGFR).

[0393] Antisense nucleic acid therapeutics are single-stranded nucleic acid therapeutics, typically about 16 to 30 nucleotides long, and complementary to the target nucleic acid sequence in the target cells of a culture or organism.

[0394] In another aspect, the agent is a single-stranded antisense RNA molecule. The antisense RNA molecule is complementary to a sequence within the target mRNA. The antisense RNA can stoichiometrically inhibit translation by pairing with the bases of the mRNA and physically blocking the translation mechanism; see Dias, N. et al. (2002) Mol Cancer Ther 1:347-355. The antisense RNA molecule may have about 15-30 nucleotides complementary to the target mRNA. Patents have been provided relating to antisense nucleic acids, chemical modifications, and therapeutic uses, for example, U.S. Patent No. 5,898,031 relates to therapeutic compounds containing chemically modified RNA, and U.S. Patent No. 6,107,094 relates to methods of using these compounds as therapeutic agents. U.S. Patent No. 7,432,250 relates to a method of treating a patient by administering a single-stranded chemically modified RNA-like compound; and U.S. Patent No. 7,432,249 relates to pharmaceutical compositions containing a single-stranded chemically modified RNA-like compound. U.S. Patent No. 7,629,321 relates to a method for cleaving target mRNA using a single-stranded oligonucleotide having multiple RNA nucleosides and at least one chemical modification. The full contents of each patent listed in this paragraph are incorporated herein by reference.

[0395] Nucleic acid therapeutic agents used in the methods of this invention also include double-stranded nucleic acid therapeutic agents. The terms "RNAi agent," "double-stranded RNAi agent," and double-stranded RNA (dsRNA) molecules, also referred to herein as "dsRNA agent," "dsRNA," "siRNA," and "iRNA agent," are used interchangeably to refer to a complex of ribonucleic acid molecules having a double-stranded structure comprising two antiparallel and substantially complementary nucleic acid strands (as defined below). As used herein, RNAi agents may also include dsiRNA (see, for example, U.S. Patent Publication 20070104688, incorporated herein by reference). Typically, the majority of nucleotides in each strand are ribonucleotides, but as described herein, each or both strands may also include one or more non-ribonucleotides, such as deoxyribonucleotides and / or modified nucleotides. Furthermore, as used herein, "RNAi agent" may include chemically modified ribonucleotides; RNAi agents may include substantial modifications at multiple nucleotide sites. Such modifications may include all types of modifications disclosed herein or known in the art. For the purposes of this specification and claims, "RNAi agent" includes any such modifications as used in siRNA-type molecules. RNAi agents used in the methods of this invention include those having chemical modifications as disclosed, for example, in U.S. Provisional Application No. 61 / 561,710, filed November 8, 2011; International Application No. PCT / US2011 / 051597, filed September 15, 2010; and PCT Publication WO 2009 / 073809, the entire contents of which are incorporated herein by reference.

[0396] Other exemplary biological agents used in the methods of the present invention include, but are not limited to, gefitinib (Iressa), anastrozole, diethylstilbestrol, estradiol, primarin, raloxifene, progesterone, norethindrone, ethinylestradiol, dimesthisterone, megestrol acetate, medroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, methyltestosterone, testosterone, dexamethasone, prednisone, hydrocortisone, sodium methylprednisolone, tamoxifen, fulvestrant, toremifene, and aminophenazone. Triproxetine, droloxifene, anastrozole, bicalutamide, flutamide, nilumet, goserelin, flutamide, leuprorelin, triptorelin, aminoglutide, mitotane, goserelin, cetuximab, erlotinib, imatinib, tosimomab, alemtuzumab, trastuzumab, gemtuzumab, rituximab, tiimomab, bevacizumab, danilide, dazumab, interferon alpha, interferon beta, anti-4-lBB, anti-4-lBBL, anti-CD40, anti-CD40 154, anti-OX40, anti-OX40L, anti-CD28, anti-CD80, anti-CD86, anti-CD70, anti-CD27, anti-HVEM, anti-LIGHT, anti-GITR, anti-GITRL, anti-CTLA-4, soluble OX40L, soluble 4-IBBL, soluble CD154, soluble GITRL, soluble LIGHT, soluble CD70, soluble CD80, soluble CD86, soluble CTLA4-Ig, GVAX®, and combinations thereof (which are obvious to those skilled in the art based on appropriate standard treatments for specific tumors or cancers). The soluble form of the agent can be prepared as, for example, a fusion protein by operably linking, for example, an Ig-Fc region.

[0397] It should be noted that more than one other anticancer agent, such as two, three, four, five or more, can be administered in combination with the coenzyme Q10 formulation provided herein. For example, in one embodiment, two other chemotherapeutic agents can be administered in combination with coenzyme Q10. Appropriate dosages and routes of administration of the chemotherapeutic agents provided herein are known in the art.

[0398] VI. Decreased bone marrow suppression Myelosuppression is a known side effect of many chemotherapy agents. Dysregulation induced by myelosuppression can produce side effects ranging from fatigue to dose-limiting toxicities. Although agents such as pegfilgrastim can be used to stimulate the production of blood cells in the bone marrow to reduce the risk of infection due to chemotherapy-induced neutropenia in subjects with solid tumors, such agents cannot be used in subjects with leukemia and have their own adverse side effects. The combination therapy described in this article, including continuous infusion of coenzyme Q10, can reduce the risk of or prevent myelosuppression-induced dysregulation in subjects treated with chemotherapy agents that induce myelosuppression.

[0399] As used herein, “myelosuppression-induced dysregulation” includes those dysregulations that occur as a result of chemotherapy-induced myelosuppression and the symptoms of said dysregulation. Examples of myelosuppression-induced dysregulation include myelosuppression-induced anemia (which includes symptoms such as, for example, weakness, fatigue, malaise, poor concentration, shortness of breath, palpitations, angina, pallor, tachycardia, and cardiomegaly), myelosuppression-induced neutropenia (which includes symptoms such as, for example, an increased risk of severe infection or sepsis, fever, oral ulcers, diarrhea, and sore throat), or myelosuppression-induced thrombocytopenia (which includes symptoms such as, for example, an increased risk of bleeding, purpura, nosebleeds, and gingival bleeding).

[0400] In one embodiment, myelosuppression-induced dysregulation is myelosuppression-induced neutropenia. In yet another embodiment, myelosuppression-induced dysregulation is myelosuppression-induced infection, myelosuppression-induced fever, myelosuppression-induced oral ulcers, myelosuppression-induced diarrhea, and myelosuppression-induced sore throat. The statement "myelosuppression-induced infection" includes infections (e.g., sepsis) that occur as a result of chemotherapy-induced myelosuppression and / or chemotherapy-induced neutropenia.

[0401] In some embodiments, co-administration of coenzyme Q10 via the continuous infusion method provided herein can prevent or improve neutrophil depletion in subjects treated with chemotherapeutic agents. As used herein, "preventing neutrophil depletion" includes stopping or inhibiting neutrophil loss in subjects that may occur as a result of chemotherapeutic treatment. In some embodiments, the method of the present invention prevents at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of neutrophil depletion.

[0402] Reference will now be made in detail to preferred embodiments of the invention. Although the invention will be described in conjunction with preferred embodiments, it should be understood that it is not intended to limit the invention to these preferred embodiments. Rather, it is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the invention as defined by the appended claims.

[0403] Every patent, publication, and reference cited in this document is incorporated herein by reference in its entirety. In addition, WO 2008 / 116135 (PCT application number PCT / US2008 / 116135), WO2010 / 132507 (PCT application number PCT / US2010 / 034453), WO 2011 / 112900 (PCT application number PCT / US2011 / 028042), and WO2012 / 174559 (PCT application number PCT / US2012 / 043001), and U.S. Patent Application Publication No.: US201110027247 are incorporated herein by reference in their entirety.

[0404] Example 1 - Non-intestinal coenzyme Q10 preparations significantly improved the survival of leukemia animal models, including the elimination of paralysis caused by brain metastases. Leukemia cells exhibit intermediate metabolic changes similar to those in other cancers, with ATP source shifting from mitochondrial oxidative phosphorylation to glycolysis-dominant (the Warburg effect) to meet the demands of oncogenic proliferation. This metabolic shift results in a simultaneous short-circuiting of programmed cell death pathways, leading to immortalization programs in cancer cells, including leukemia. High-level coenzyme Q10 delivery in lipid nanodispersion mixtures has been demonstrated to preferentially shift metabolic networks in various cancers from glycolysis to mitochondrial-centric oxidative phosphorylation and reenact apoptosis pathways in in vitro and in vivo models. Given the central role of Bcl-2 in the etiology of leukemia, this study focuses on investigating the effectiveness of coenzyme Q10 in animal models of erythroleukemia and myeloid leukemia.

[0405] In immunocompromised mice, human acute erythroleukemia (K562) and acute myeloid leukemia (KG1) cells (1×10⁻⁶) were injected intraperitoneally. 6 Implantation is confirmed through a complete blood cell count, the presence of anemia, and a clinical evaluation of the animal's behavior.

[0406] Mice (n=120 for each model) were randomly divided into four treatment groups (n=30 / group). Each treatment regimen was administered over a four-week cycle (three weeks of treatment, one week of interruption): 1. Untreated (control) 2. Coenzyme Q10 (4%, administered at 75 mg / kg, once daily, via continuous infusion) 3. Chemotherapy (cytarabine / AraC 25mg / kg, 5 times / week; and doxorubicin / daunomycin 5mg / kg; 1 time / week) 4. Coenzyme Q10 (4%, administered at 75 mg / kg once daily via continuous infusion) + chemotherapy (cytarabine / AraC 25 mg / kg, 5 times / week; and doxorubicin / daunomycin 5 mg / kg, 1 time / week) All medications were administered intravenously, following a regimen of 3 weeks of treatment followed by 1 week of rest. Leukemia was monitored by pallor and blood smears, and bone marrow smears were performed post-mortem for analysis using Wright's staining. Figure 4 The study provides survival results from a mouse study of acute myeloid leukemia. Figure 5 The results show survival outcomes from a study of mice with acute erythroleukemia. Day 1 was the first day of treatment with coenzyme Q10 and / or chemotherapy.

[0407] In both leukemia models, coenzyme Q10 combined with chemotherapy was associated with significantly improved survival compared to other groups including the corresponding chemotherapy-only groups (p<0.00001). In myeloid leukemia, coenzyme Q10 alone was associated with improved survival compared to chemotherapy, but no improvement was observed in the erythroleukemia model, where coenzyme Q10 alone showed relatively similar survival compared to chemotherapy alone.

[0408] These results demonstrate that coenzyme Q10, whether alone or in combination with standard chemotherapy agents, is effective in the treatment of leukemia, especially acute leukemia.

[0409] In a separate study, a rat (Fisher 344) model of CNS leukemia, specifically MIA C51, was developed, exhibiting paralysis and urinary retention as a consequence of brain metastases. Administration of coenzyme Q10 (50 mg / kg / day, IP) was associated with complete remission of quadriplegia, demonstrating the ability of coenzyme Q10 to penetrate the CNS. Furthermore, administration of coenzyme Q10 (50 mg / kg / day, IP) was associated with significantly improved survival in animals with lung and liver metastases. These data provide encouraging evidence for the potential translocational use of coenzyme Q10 in the treatment of leukemia. The results from this study are discussed in detail in WO2012 / 138765, which is incorporated herein by reference in its entirety.

[0410] Example 2 - Coenzyme Q10 treatment reduced the survival rate of various cancer cells in vitro. Various cancer cell lines were treated with 100 μM coenzyme Q10 to determine its effect on cancer cell viability. The cancer cell lines tested were HT-29 (colon), A549 (lung), Hep3B (liver), MDA-MB231 (breast), SkBr-3 (breast), MCF7 (breast), MiaPaCa-2 (pancreas), SKOV-3 (ovary), and PC-3 (prostate). Cell viability was measured between 24 and 72 hours. In all tested cancer cell lines, the decrease in cell viability in response to coenzyme Q10 was evident as early as 24 hours and gradually increased between 48 and 72 hours. For example, Figure 6 Cell viability was shown with and without coenzyme Q10 treatment at 48 hours of exposure (for cell lines HT-29, A549, Hep3B, MDA-MB231, SkBr-3, and BT549) or 72 hours of exposure (for cell lines MCF7, MiaPaca-2, SKOV-3, and PC-3). Figure 6 The text at the bottom of the graph indicates the gene mutations and mutation rates for each cell line. For example, HT-29 cells contain the APC mutation and have a mutation rate of 126.

[0411] A consistent reduction in cell viability was observed across the tested cancer cell lines, independent of mutation status. Within each cell line, the degree of coenzyme Q10's effect on cell viability correlated with the duration of exposure; some cell lines showed higher sensitivity at 48 hours, while others exhibited reduced cell viability at 72 hours. This data suggests that the duration of exposure (an indirect measure of drug-cell contact) is a crucial factor in the effect of coenzyme Q10 on the viability of different cancer cell lineages.

[0412] Example 3 - Continuous infusion of coenzyme Q10 improved survival in animal models of pancreatic cancer, prostate cancer, and lung cancer.

[0413] Several studies were conducted to determine the effects of different dosing regimens of coenzyme Q10 nanosuspension formulation on animal survival in various cancer animal models.

[0414] For example, Figure 7 This diagram illustrates a study investigating three different coenzyme Q10 dosing regimens in an animal model of pancreatic cancer. The effects of coenzyme Q10 alone or in combination with gemcitabine on overall survival in a preclinical mouse model of pancreatic cancer were evaluated.

[0415] An equal number of MIAPaCa-2 human pancreatic tumor cells were suspended in MATRIGEL® and injected into NOD scidγ (NSG) mice. The NSG mouse model lacks both innate and adaptive immune systems and provides a biological environment suitable for the growth of human tumors in vivo. MIAPaCa-2 is a well-established human pancreatic cancer cell line that can be used to establish pancreatic tumors in immunosuppressed animals. Before treatment initiation, MIAPaca-2 tumors were allowed to develop in mice for at least 3 weeks on average. Animals with palpable tumors were randomly assigned to the treatment group.

[0416] The three treatment regimens used in the study included coenzyme Q10 administered once, twice, or three times daily, either alone or in combination with a fixed dose of gemcitabine (150 mg / kg body weight) at 50 mg / kg body weight (Rule 1 & 2) or 50 mg / kg or 75 mg / kg body weight (Rule 3). For example, mice treated twice daily received two 50 mg / kg doses of coenzyme Q10 for a total of 100 mg / kg / day, while mice treated three times daily received three 50 mg / kg doses of coenzyme Q10 for a total of 150 mg / kg / day. Each group of animals received at least three cycles of chemotherapy and maintenance to determine outcomes. In each group tested, animals treated with coenzyme Q10 alone showed improved survival compared to untreated animals or animals treated with chemotherapy alone. See also Figure 8A -C. Combined treatment with coenzyme Q10 and gemcitabine resulted in higher survival rates than coenzyme Q10 or gemcitabine alone, suggesting an additive effect of coenzyme Q10 and gemcitabine treatment. Figure 8A -C also provides that increasing the dose of coenzyme Q10 from once / day to three times / day was associated with a significant improvement in animal survival. Therefore, the improvement and maintenance in animals given multiple concentrated doses of 50 mg / kg coenzyme Q10 may be due to the longer duration of relatively constant levels of coenzyme Q10 in the blood compared to that obtained with a single daily dose.

[0417] Next, a continuous infusion protocol was implemented to determine the effect of constant coenzyme Q10 administration on survival in an animal model of pancreatic cancer. Infusion pumps were surgically implanted into the animals to facilitate a continuous infusion of coenzyme Q10 at daily doses of 25 mg / kg, 50 mg / kg, or 100 mg / kg body weight. Treatment continued throughout the study period. Figure 9 This study demonstrates the effect of continuous infusion of escalating concentrations of coenzyme Q10 on survival duration in an animal model of pancreatic cancer. Animals treated with continuous infusion of 25 mg / kg body weight / day ( Figure 9 The results showed that animals administered three doses of 50 mg / kg body weight / day ( ) were better than those administered three times daily. Figure 8CThe survival rate was higher. Therefore, continuous infusion of coenzyme Q10 at a dose of 25 mg / kg body weight over 24 hours resulted in a higher survival rate than higher doses of coenzyme Q10 three times a day (i.e., 50 mg / kg body weight).

[0418] Furthermore, using a continuous infusion administration method substantially improved overall survival in pancreatic cancer models by increasing the dose of coenzyme Q10. For example, animals treated with a continuous infusion of a total dose of 100 mg / kg coenzyme Q10 had higher survival rates than those treated with continuous infusions of 50 mg / kg or 25 mg / kg. See also Figure 9 Therefore, the effect of coenzyme Q10 on animal survival is dose-dependent.

[0419] The improvements observed in animal groups receiving continuous infusion of coenzyme Q10 have been replicated in other cancer animal models. For example, Figure 10 This study demonstrates the effect of continuous coenzyme Q10 infusion on survival duration in an animal model of prostate cancer. LnCaP human prostate adenocarcinoma cells were injected into immunocompromised mice. Coenzyme Q10 was administered using two different dosing regimens. One group received a total dose of 75 mg / kg body weight per day (multiple-concentration regimen) at 25 mg / kg body weight every 8 hours. In the second group, an infusion pump was surgically implanted into the animals to facilitate continuous infusion of a total daily dose of 75 mg / kg body weight of coenzyme Q10. Treatment continued throughout the study period. The group receiving 75 mg / kg body weight of coenzyme Q10 every 8 hours (multiple-concentration regimen) showed higher survival than the untreated control. See also Figure 10 However, the animal group administered the same dose of coenzyme Q10 via continuous infusion showed even higher survival rates compared to the multiple concentrated infusion regimen.

[0420] Figure 10 Data from the study showed that, for a given dose, such as 75 mg / kg body weight / day, the coenzyme Q10 administration regimen was a significant factor affecting animal survival. Continuous infusion of coenzyme Q10 (74 mg / kg body weight over 24 hours) was superior to three concentrated injections of the same total dose administered over the same time period. This result suggests that a continuous infusion regimen could potentially be used to maintain constant levels of coenzyme Q10 in the blood.

[0421] The role of coenzyme Q10 administration schedules has also been investigated in rats with liver or lung chloroma. Liver or lung clones of malignant chloroma derived from the stable myeloid leukemia (chloroleukemia) cell line MIA C51 were transplanted into rats (see, e.g., Jimenez and Yunis (1987)). ScienceClones that homed to the liver or lung and formed tumors in the liver or lung were selected. Rats were randomized to receive no treatment, 40 mg / mL (4%) coenzyme Q10 three times daily via injection, or 40 mg / mL (4%) coenzyme Q10 via an implanted pump for a total dose of 50 mg / kg body weight / day for each regimen. In rats with hepatic chloroma, 40 mg / mL coenzyme Q10 significantly prolonged survival compared to control in both the continuous infusion pump group and the three-times-daily injection group. However, for the lungs ( Figure 12 ) and liver ( Figure 13 For chloroma, continuous infusion was far more effective than injection. For example, on day 189, in a liver chloroma model, 45 out of 50 rats in the continuous infusion group were alive, compared to 26 out of 50 rats in the injection group. All control animals died on day 30. See also Figure 13 .

[0422] The effects of coenzyme Q10 administration regimens were further investigated in rats transplanted with H522 human lung cancer cells. Rats were randomized to receive no treatment (control), continuous coenzyme Q10 infusion, chemotherapy, or a combination of coenzyme Q10 and chemotherapy. The coenzyme Q10 dose was 50 mg / kg / day over 24 hours at a concentration of 4%. Chemotherapy was repeated in three-week cycles as follows: Week 1: IV cyclophosphamide, 35 mg / kg, 1x / week and IV doxorubicin 2.5 mg / kg, 3x / week; Weeks 2-3: no treatment. Figure 14 As shown, continuous CoQ10 infusion alone was more effective than chemotherapy alone in improving animal survival. Furthermore, combined continuous CoQ10 infusion and chemotherapy were more effective than either treatment alone.

[0423] In summary, these data demonstrate that dosage and administration regimen are important parameters related to survival outcomes in preclinical cancer models. First, increased coenzyme Q10 dosage was associated with a significant improvement in survival duration in animal cancer models. Furthermore, these data provide evidence that continuous coenzyme Q10 infusion is associated with a significant improvement in survival in cancer models. Therefore, the ability to maintain relatively constant blood concentrations of coenzyme Q10 using a continuous infusion protocol is an important criterion for improving overall survival in cancer models.

[0424] Example 4 - Coenzyme Q10 nanosuspension for intravenous injection pharmacokinetic, pharmacodynamic and safety studies A first-in-human phase 1 study was conducted in 50 patients with advanced solid tumors using a 40 mg / ml coenzyme Q10 nanosuspension to evaluate the safety, maximum tolerated dose, pharmacokinetic (PK), and drug-promoting (PD) parameters of coenzyme Q10. Specifically, a 4% coenzyme Q10 nanosuspension formulation (as described in WO 2011 / 112900, the full contents of which are hereby incorporated herein by reference) was administered via 4-hour IV infusion three times weekly over a 28-day cycle. Nine dose levels ranging from 5.62 to 139 mg / kg were investigated. Plasma concentration distribution and PK parameters were determined from blood samples collected before administration and at intervals up to 48 hours post-administration.

[0425] Evaluation of PK parameters showed linear or near-linear dose-proportioning for the 4-hour infusion schedule. The curves were similar for all doses. Some evidence of nonlinearity was present at the lowest dose level. However, for doses of 22.5 mg / kg or higher, the dose-proportioning was linear.

[0426] T max and C max It is usually associated with the end of the infusion. t 1 / 2 The range is 2.18 to 18.0 hr, t 1 / 2 There was little or no correlation with dosage. All dosage groups were considered, and there was no significant cumulative effect with increasing dosing duration.

[0427] Most adverse events (AEs) during the study were Grade 1 or 2 according to the Common Terminology Criteria for Adverse Events (CTCAE). The most common non-laboratory AEs (all combined causes) were fatigue; nausea; dyspnea; abdominal pain; fever; tachycardia; vomiting; anorexia; and diarrhea. Among these, AEs related to coenzyme Q10 included fatigue (24%), headache (10%), nausea (8%), fever (8%), chills (6%), and arthritis (4%).

[0428] The most common laboratory adverse events (AAEs) (all combined causes) were: anemia (98%), hyperglycemia (88%), prolonged PTT (82%), elevated INR (76%); decreased serum albumin (70%), elevated AST (66%), elevated alkaline phosphatase (62%), decreased platelet count (58%), and hypocalcemia (42%). Among these laboratory AAEs, those judged to be coenzyme Q10-related included prolonged PTT (80%), decreased platelet count (14%), elevated AST (8%), and elevated alkaline phosphatase (2%). In addition, 38 patients experienced abnormal INR values, and in 34 of these patients (68%), elevated INR was considered to be coenzyme Q10-related. Elevated INR was clinically significant in 14 patients, reaching grade 3 or causing bleeding events. Upon administration of vitamin K, all INRs decreased to grade 1 or disappeared. Of the 14 patients with clinically significant elevated INR, seven had a history of bleeding events or elevated coagulopathy prior to the study.

[0429] Although no dose-limiting toxicity (DLT) was confirmed using a 4-hour infusion schedule, two patients experienced serious bleeding events associated with increased INR at a dose level of 104.3 mg / kg. One of these serious adverse events (SAEs) resulted in the patient's death due to hemothorax.

[0430] During the study, twenty patients died due to disease progression or complications. Four patients discontinued treatment due to reported treatment-unrelated adverse events: grade 2 infection at the tumor site (1), grade 3 thrombocytopenia (2), and grade 4 elevated AST (1). Three patients were receiving active treatment while maintaining the study: two patients at a dose level of 104.3 mg / kg, and one patient who received two doses at a dose level of 139 mg / kg.

[0431] Two SAEs were reported that were possibly related to coenzyme Q10: grade 3 prolonged APTT and grade 3 hematuria. No clinically significant changes were observed in vital signs or physical examination findings. The best response to coenzyme Q10 was in stable disease (23 out of 50 patients, 46%). One patient with sarcoma had a partial response, while 15 patients (30%) had progressive disease. These results demonstrate the clinical response of some patients to coenzyme Q10 administered intravenously three times weekly via a four-hour infusion in a phase 1 dose escalation trial (where the primary objective was not treatment). Adverse events and dose-limiting toxicities included bleeding events and elevated INR at higher dose levels.

[0432] Example 5 - Coenzyme Q10 Nanosuspension for Intravenous Injection in Patients with Solid Tumors - A Phase 1a / b non-randomized, dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of a sterile coenzyme Q10 (ubidecene, USP) nanosuspension injection administered intravenously to patients with solid tumors.

[0433] A Phase 1 clinical trial is underway to treat metastatic or refractory solid tumors using coenzyme Q10 monotherapy and coenzyme Q10 in combination with chemotherapy. Coenzyme Q10 is provided as a 4% coenzyme Q10 nanosuspension formulation as described in WO2011 / 112900, the full contents of which are hereby incorporated by reference. This study is an open-label, non-randomized safety study with cross-assignment. Estimated enrollment is up to 45 subjects for monotherapy and up to 120 subjects for combination therapy.

[0434] Compared to the studies described in previous examples (4-hour infusions), this study was designed with a longer dosing schedule (e.g., 24-hour infusions, 48-hour infusions, or continuous 96-hour infusions). This extended dosing arrangement is intended to reduce coenzyme Q10 C levels. max To maintain a steady-state level. Not wanting to be bound by the mechanism, we propose prolonged dosing schedules and / or reduced infusion rates to avoid potential association with high C. max Level-related potential toxicity, thereby increasing the therapeutic range of coenzyme Q10 administered over shorter dosing periods and / or at higher infusion rates.

[0435] To improve adherence to three weekly 4-hour infusions and potentially reduce drug-related coagulation adverse events (AEs), a 48-hour dosing schedule was used, consisting of a loading dose (within one hour) followed by the remainder of the infusion over a 47-hour period. In this outpatient dosing regimen, patients returned to the clinic near the end of each 48-hour treatment period to discontinue the infusion and undergo reassessment. If the patient continued to meet their coenzyme Q10 therapy requirements, the infusion pump was refilled with a second 48-hour dose for continued administration at a uniform rate at home. This dosing regimen is effectively considered a 96-hour continuous infusion, despite short pauses in the infusion.

[0436] According to this schedule, for patient convenience and compliance, the dosage is started on days 1, 3, 8, 10, 15, 17, 22 and 24 of every 28-day cycle, especially for outpatients, as they require the minimum amount of time during their outpatient visits.

[0437] Concentration using two 48-hour infusion schedules The proposed coenzyme Q10 infusion schedule utilizes available data from the study CTL0510 discussed in the above examples, administering doses of 58.7, 78.2, and 104.3 mg / kg as three weekly 4-hour infusions to generate two 48-hour infusion schedules administered on Mondays and Wednesdays for four weeks. The total weekly doses are 176, 235, and 313 mg / kg, respectively (equivalent to approximately 44 mg / kg, 58.75 mg / kg, and 78.35 mg / kg per 24-hour period). A schedule was developed for continuous Monday-Wednesday infusions using total weekly doses of 176 (3 x 58.7), 235 (3 x 78.2), and 313 (3 x 104.3) mg / kg: • Two 48-hour infusions (equivalent to a 96-hour weekly infusion) begin on Monday and Wednesday, with brief 30-minute interruptions to change the pump and connect a second bag of infusion. This dosing regimen is considered a 96-hour continuous infusion, despite the short pauses in the infusion.

[0438] • On each Monday of the cycle, a portion of the weekly dose is used as a loading dose.

[0439] • The duration of the loading dose is approximately 1 hour, and the infusion rate is not higher than the infusion rate used for 4-hour infusions of doses of 58.7, 78.2, and 104.3 mg / kg.

[0440] • For the examples of doses of 58.7, 78.2, and 104.3 mg / kg, the maximum 1-hour rates were 14.5, 19.6, and 26.0 mg / kg / hr, respectively.

[0441] In all cases, the concentration of coenzyme Q10 was negligible on Sundays. Table 1 below shows the weekly C of three 4-hour infusions on Mondays, Wednesdays, and Fridays (using average data from Mondays of study CTL0510) versus two 48-hour infusion schedules on Mondays and Wednesdays. max and AUC values. The total weekly dose was the same in all cases. As expected, the C-value for the 4-hour infusion... max The values ​​are higher because of the faster infusion rate. The AUC values ​​are also higher for 4-hour infusions, which is not expected. Theoretically, they should be the same because the doses are the same.

[0442] In summary, twice-weekly 48-hour infusions are a viable alternative to three-weekly 4-hour infusions, resulting in more sustained plasma concentrations throughout the week.

[0443] Table 1. Estimated Weekly C max and AUC value

[0444] Assessment of the maximum tolerated dose (MTD) The primary outcome measures included the determination of the maximum tolerated dose (MTD) of the intravenous coenzyme Q10 formulation during the duration of cycle 1 treatment for up to 4 weeks in group 1 and 6 weeks in group 2.

[0445] Dose-limiting toxicities were assessed during cycle 1 of the study (the first four weeks of group 1 and week 6 of group 2). Blood samples were collected for pharmacokinetic and pharmacodynamic purposes during each cycle of monotherapy and combination therapy. Urine samples were collected only during cycle 1 of monotherapy and combination therapy to determine renal clearance of coenzyme Q10. PET scans were performed within 2 weeks before treatment initiation, 2 weeks after coenzyme Q10 treatment, and at 8 weeks of treatment in group 1 or 10 weeks of treatment in group 2. Core biopsies (2-3) were performed on baseline and week 2 PET scans in patients who were selected to participate in these exploratory studies.

[0446] Secondary outcome measures included evaluating the plasma pharmacokinetics (PK) of coenzyme Q10 at each cycle (every 4 weeks) for up to 1 year. To evaluate the plasma pharmacokinetics (PK) of coenzyme Q10 monotherapy and coenzyme Q10 in combination with chemotherapy during 96-hour IV infusion in patients with solid tumors. Urine samples were collected only during cycle 1 of monotherapy and combination therapy to determine renal clearance of coenzyme Q10. PET scans were performed within 2 weeks before treatment initiation, 2 weeks after coenzyme Q10 treatment, and at 8 weeks of group 1 treatment or 10 weeks of group 2 treatment. Core biopsies (2-3) were performed at baseline and at week 2 PET scans for patients selected to participate in these exploratory studies.

[0447] The treatment group is as follows: Table 2. Treatment Group

[0448] Research Objective The primary objective of this study was to determine the maximum tolerated dose (MTD) and to evaluate the safety and tolerability of coenzyme Q10 monotherapy and coenzyme Q10 in combination with chemotherapy administered via 96-hour intravenous (IV) infusion in patients with solid tumors.

[0449] The secondary objective of this study was to evaluate the plasma pharmacokinetics (PK) of coenzyme Q10 monotherapy and coenzyme Q10 in combination with chemotherapy during 96-hour IV infusion in patients with solid tumors and to estimate the renal clearance of coenzyme Q10.

[0450] The exploratory purpose of the study is: • Evaluate the pharmacodynamic (PD) correlation of plasma coenzyme Q10 activity as a single treatment and in combination with chemotherapy.

[0451] • Evaluate the role of coenzyme Q10 in the conversion of tumors to aerobic respiration using PET imaging.

[0452] • Evaluate tumor vascular distribution in at least 6 subjects who received MTD coenzyme Q10 within 24 hours before and after administration (using DCE-MRI).

[0453] • Evaluate tumor response (preliminary antitumor activity) after repeated administration of coenzyme Q10.

[0454] • For each treatment group, progression-free survival (PFS) and time to progression (TTP) were assessed.

[0455] • Compare the bone marrow suppression recorded in the combination therapy group with historical data for each treatment.

[0456] • Evaluate the long-term safety and tolerability of coenzyme Q10 as a single treatment and after repeated administration in combination with chemotherapy.

[0457] Research eligibility criteria The participants in the study were male and female adults aged at least 18 years with a clinically diagnosed solid tumor.

[0458] Inclusion criteria : • Patients with histologically confirmed solid tumors that are metastatic or unresectable, for which there is no standard treatment or which is no longer effective. (Patients with primary brain cancer or lymphoma are permitted. Patients with brain metastases are permitted if they have undergone whole-brain irradiation and demonstrated stability for ≥6 weeks.) • Patients with an ECOG performance status ≤2 • The patient has a life expectancy of >3 months.

[0459] • Patients who are sexually active and their partners consent to the use of recognized methods of contraception during the study. • Female patients who may be pregnant must have a negative pregnancy test within one week before starting the study treatment.

[0460] The patient has sufficient organ and bone marrow function as follows: • ANC ≥ 1500mm 3 Platelet count ≥100,000 / mm 3 Hemoglobin ≥9g / dL • Serum creatinine ≤1.8 mg / dL or creatinine clearance >50 mL / min; • Bilirubin ≤1.5mg / dL; if the liver is not involved, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal, or if the liver is involved, ≤5 times the upper limit of normal.

[0461] • The patient has serum electrolytes (including calcium, magnesium, phosphorus, sodium, and potassium) within normal limits (supplementation is permitted to maintain normal electrolyte levels).

[0462] • The patient has adequate clotting ability: prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) within normal limits.

[0463] • The patient was able to understand and comply with the experimental protocol and signed the informed consent form.

[0464] Exclusion criteria : • Patients have uncontrolled comorbidities, including, but not limited to, uncontrolled infections, symptomatic congestive heart failure (Class III and IV NYHA), uncontrolled arrhythmias, or mental illness / social situations that limit compliance with research needs. • Patients with active heart disease, including myocardial infarction within the previous 3 months, symptomatic coronary artery disease, uncontrolled arrhythmia, unstable angina, or uncontrolled congestive heart failure (Class III and IV NYHA). • The patient has received chemotherapy or radiation therapy within 4 weeks prior to the first dose of the study drug, or nitrosourea or mitomycin C within 6 weeks prior.

[0465] • The patient had received ≥25% bone marrow irradiation within 4 weeks of the first dose of the investigational drug.

[0466] • The patient had received the study drug within 30 days of the first dose.

[0467] • The patient did not recover from an adverse event (AE) caused by the study drug or other drugs (which were administered no more than 4 weeks before the first dose of the study drug) to grade ≤1.

[0468] The patient is pregnant or breastfeeding.

[0469] • The patient is known to be positive for human immunodeficiency virus (HIV). The role of coenzyme Q10 in HIV medication is unknown. Note: HIV testing is not required for eligibility, but the patient is ineligible for this study if they have previously been tested and found to be positive.

[0470] • Patients who are unable or unwilling to comply with the research protocol or fully cooperate with the researchers or their assigners.

[0471] The patient is currently taking an HMG-CoA reductase inhibitor (Statin).

[0472] The patient is currently receiving digoxin, digitoxin, digitoxin C, or any type of digitalis alkaloid.

[0473] The patient is receiving colony-stimulating factor (CSF) that cannot be delayed during dose-limiting toxicity (DLT) monitoring.

[0474] • The patient has a history of uncontrolled or severe coagulopathy or clinically significant bleeding within the past 6 months, such as hemoptysis, epistaxis, hematochezia, hematuria, or gastrointestinal bleeding.

[0475] • The patient has a known bleeding tendency, such as von Willebrand's disease or other such conditions.

[0476] • Patients require therapeutic doses of any clotting agents, including low molecular weight heparin (LMWH). Concomitant use of warfarin is prohibited, even at prophylactic doses.

[0477] The assessment of measurable lesions for determining eligibility is based on the following criteria.

[0478] Table 3. Baseline Eligibility

[0479] Table 4. Guidelines for the assessment of measurable diseases

[0480] Experimental Design This was a phase 1a / b, multicenter, open-label, non-randomized, dose-escalation study to examine the dose-limiting toxicities (DLT) of coenzyme Q10 administered as monotherapy (treatment group 1) and in combination with chemotherapy (treatment group 2) in patients with solid tumors via a 96-hour continuous intravenous (IV) infusion. In the phase 1a portion of the trial, patients meeting the eligibility criteria received two consecutive 48-hour coenzyme Q10 infusions twice weekly on Mondays and Wednesdays (i.e., days 1, 3, 8, 10, 15, 17, 22, and 24), essentially receiving 96 hours of coenzyme Q10 treatment per week in each 28-day cycle. Patients were treated with at least 8 hours of outpatient monitoring or inpatient monitoring of the first infusion in the first 24 hours of cycle 1 at each dose level in groups 1 and 2. All other treatments were administered in outpatient settings. DLT was evaluated during cycle 1.

[0481] The study followed a standard 3+3 dose escalation design, with doses escalating in consecutive cohorts of 3 to 6 patients. Toxicity at each dose level was graded according to the Common Terminology for Adverse Events (CTCAE v4.02). Safety oversight was provided by a cohort review committee (CRC). The CRC reviewed and validated all dose-dependent events (DLTs) and monitored safety throughout the study (including cohort 2).

[0482] At the end of cycle 2 and every two cycles thereafter, the antitumor activity of coenzyme Q10 is assessed using standard techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) for patients with measurable disease. Response is evaluated using the Responsive Criteria for Solid Tumor Response (RECIST) v1.1. Patients who do not experience unacceptable toxicity or disease progression may receive an additional 28-day cycle of group 1 or 2 for up to one year. Group 1 patients with disease progression may choose to continue coenzyme Q10 therapy in combination with gemcitabine, 5-FU, or docetaxel, at the discretion of their treating physician. Once the dose level of coenzyme Q10 monotherapy has been evaluated and the CRC determines that escalation to the next dose level is safe, group 1 of group 2 for coenzyme Q10 in combination with chemotherapy will be opened for addition. Group 1 patients in group 2 are enrolled in one of three chemotherapy regimens: gemcitabine, 5-FU, or docetaxel. For patients in Group 2, Cycle 1 of the combination therapy consisted of two doses of CoQ10 twice a week, Monday and Wednesday, for 6 weeks, with chemotherapy administered on Fridays (days 19, 26, and 33). Cycles 2-12 were four-week durations, with two doses of CoQ10 twice a week, Monday and Wednesday, for 4 weeks, with chemotherapy administered on Fridays (days 5, 12, and 19). Dose-limiting toxicities were evaluated during Cycle 1. Response was evaluated after Cycle 2 (10 weeks), and responders were evaluated every two cycles (8 weeks) to Cycles 2-12. In the absence of intolerable toxicities and progression, patients could continue with CoQ10 in combination with chemotherapy for up to 12 cycles. Group 2 patients who progressed during one type of chemotherapy were not required to switch to one of the other chemotherapy agents combined with CoQ10. However, if the chemotherapy component of the combination therapy (i.e., 5-FU, gemcitabine, or docetaxel) was discontinued due to chemotherapy-related toxicities, patients could continue with CoQ10 as monotherapy.

[0483] Once the maximum tolerated dose (MTD) of coenzyme Q10 as monotherapy and in combination with chemotherapy was determined, an expanded cohort was enrolled (12-15 patients in total for monotherapy and 10 patients in total for each combination therapy).

[0484] PK / PD Evaluation Blood samples were collected for pharmacokinetic and pharmacodynamic analyses during each cycle of monotherapy and combination therapy. Urine samples were collected only during cycle 1 of monotherapy and combination therapy to determine renal clearance of coenzyme Q10. PET scans were performed within 2 weeks before the start of treatment, 2 weeks after coenzyme Q10 treatment, and at 8 weeks of group 1 treatment or 10 weeks of group 2 treatment. Core biopsies were performed at baseline and at week 2 PET scans for patients who were selected to participate in these exploratory studies (2-3).

[0485] Number of patients Up to 45 patients were enrolled in treatment group 1, the dose-escalation and expansion portion of the study involving single-drug coenzyme Q10, and up to 120 patients were enrolled in treatment group 2, the dose-escalation and expansion portion of coenzyme Q10 combined with chemotherapy. The exact number will be determined by the number of dose escalations up to the mean time to treatment (MTD). Therefore, up to 165 patients could be enrolled.

[0486] Investigational drug, dosage and administration method Starting with a dose of 66 mg / kg every 96 hours, administer the coenzyme Q10 nano-suspension (40 mg / mL) intravenously over 96 hours. Each patient receives two consecutive 48-hour infusions per week (Mon-Wed and Wednesday-Friday) in every 28-day cycle. The dose may be increased by 25% in subsequent cohorts until the mean time to dose (MTD) is reached.

[0487] Upon safe completion of the coenzyme Q10 dose level as a single treatment, patients in treatment group 2 will be enrolled and treated with an evaluated and confirmed safe dose of coenzyme Q10 in combination with one of three chemotherapy regimens: • Once a week, intravenous gemcitabine at 600 mg / m² 2 The starting dose; • Once a week, IV 5-fluorouracil (5-FU) at 350 mg / m² 2 The starting dose, and formyltetrahydrofolate (LV) 100 mg / m 2 ; • Once a week, IV docetaxel at 20 mg / m² 2 Starting dose Duration of treatment The minimum duration of treatment was 8 weeks (2 cycles) for Group 1 and 10 weeks for Group 2.

[0488] For patients who do not progress after 2 cycles (8 weeks) of single-dose coenzyme Q10 therapy, treatment can continue for up to 12 cycles or until any discontinuation criterion is met. Patients who progress after 2 cycles (8 weeks) without unacceptable toxicity may continue coenzyme Q10 in combination with gemcitabine, 5-FU, or docetaxel.

[0489] For patients treated with coenzyme Q10 plus chemotherapy, treatment can continue for up to 12 cycles, or until either discontinuation criterion is met, provided there is no progressive disease or unacceptable toxicity. Eligible subjects may continue coenzyme Q10 treatment for more than one year under a separate experimental protocol, subject to the judgment of the cohort review committee (CRC).

[0490] Dose-limiting toxicity Adverse events are classified according to CTCAE v4.02. A copy of this classification scale can be obtained at the URL ctep.cancer.gov.

[0491] Dose-limiting toxicity (DLT) is defined as a laboratory value of at least one clinically significant adverse event or abnormality that is likely related to coenzyme Q10 and occurs during cycle 1, meeting any of the following criteria: According to CRC, there are potentially clinically significant risks that further dose escalation would expose patients in higher dose groups to irreversible medical injury risks or treatment-related adverse events requiring medical intervention to avoid irreversible medical injury.

[0492] • Any grade ≥3 non-hematologic toxicity (excluding hair loss) that may be associated with the study drug, and grade 3 diarrhea, nausea, and vomiting that subside to grade 2 or lower within 48 hours of establishing supportive care.

[0493] Grade 3 thrombocytopenia, with clinically significant bleeding.

[0494] • Any hematologic toxicity of grade 4 or higher, including, but not limited to, death, grade 4 anemia of any kind, grade 4 thrombocytopenia, grade 4 neutropenia lasting >5 days or grade 4 neutropenia of any duration accompanied by fever, or proven infection, shall be considered DLT.

[0495] • Grade 2 elevated INR / PTT, with clinically significant bleeding.

[0496] • Grade 3 INR / PTT abnormality (with or without bleeding).

[0497] • Elevated levels of transaminases and bilirubin that meet Hy's Law criteria.

[0498] • Grade 3 or higher electrolyte abnormality.

[0499] • Any grade 3 hypokalemia or hypomagnesemia, if standard measures do not reduce these to grade 2 or better within 7 days or less.

[0500] • Any prolonged grade 4 (fatal) hypokalemia or hypomagnesemia.

[0501] • Grade 3 renal and hepatic dysfunction of any duration.

[0502] The following is a non-restrictive, standard laboratory assessment form.

[0503] Table 5. List of Laboratories

[0504] DLT Measurement The patient population used for DLT assays consisted of patients who met the minimum safety assessment requirements for the trial. To be considered eligible for DLT assessment during treatment cycle 1, patients must have DLT (regardless of the number of doses received) or have completed the first cycle and received at least 80% of the predetermined coenzyme Q10 dose in group 1 and coenzyme Q10+ chemotherapy in group 2.

[0505] Patients who discontinue treatment prematurely due to disease progression or withdrawal are required to undergo all treatment completion safety assessments. If a patient withdraws from treatment during Cycle 1 for any reason other than DLT and does not meet the minimum safety assessment requirements described above, that patient should be replaced.

[0506] Maximum tolerated dose MTD is the highest dose that ≤1 out of 6 patients experienced DLT during cycle 1 of coenzyme Q10 treatment (28 days for group 1 or 6 weeks for group 2). If 2 or more patients in the treatment group experienced DLT, the MTD has been exceeded.

[0507] MTD measurement amplification For coenzyme Q10 monotherapy, a total of 12 to 15 patients were evaluated at the MTD level, and for coenzyme Q10 in combination with one of each chemotherapy regimen, up to 10 patients were evaluated at the MTD level to confirm the safety and tolerability of coenzyme Q10 at this dose, PK and PD.

[0508] The start of the combination chemotherapy group Once the dose level of coenzyme Q10 monotherapy has been evaluated and the CRC has determined that escalation to the next dose level is safe, coenzyme Q10 in combination with chemotherapy will be opened for group 2 to increase the number of patients at a reduced dose level. Based on the dose levels provided in this document, group 2 patients were enrolled on one of three chemotherapy regimens: gemcitabine, 5-FU, or docetaxel. Cycle 1 for group 2 patients was a 6-week duration, with coenzyme Q10 administered twice weekly on Mondays and Wednesdays for 6 weeks, and chemotherapy administered on Fridays on days 19, 26, and 33. Cycles 2–12 were 4-week durations, with coenzyme Q10 administered twice weekly on Mondays and Wednesdays for 4 weeks, and chemotherapy administered on Fridays on days 5, 12, and 19. Dose-limiting toxicities were evaluated during cycle 1. Response was evaluated after cycle 2 (10 weeks), and responders were evaluated every 2 cycles (8 weeks) to continue to cycles 2–12. In the absence of intolerable toxicities and progression, patients continued coenzyme Q10 in combination with chemotherapy for a maximum of 12 cycles.

[0509] Dosage group Single-dose coenzyme Q10 (treatment group 1) The starting dose level for Coenzyme Q10 is 66 mg / kg administered via 48-hour IV infusion twice a week for 28-day cycles (Table 3). Two doses are administered over four consecutive days, i.e., the first dose is administered Monday through Wednesday and the second dose is administered Wednesday through Friday. The study drug is administered undiluted via a central venous access device, and the infusion rate is controlled by a programmable flow infusion pump, such as the CADD Prizm VIP (model 6101) flow pump.

[0510] For the first dose of the week (i.e., days 1, 8, 15, and 22 of the cycle), a loading dose is infused over 1 hour using a CADD pump, followed by the remaining dose volume infused over 47 hours using the same CADD pump, as shown in Table 6 below for the CoQ10 nanosuspension for the injection dose groups (Group 1; single therapy). At each dose level in Groups 1 and 2, patients are treated with at least 8 hours of outpatient monitoring or the first 24 hours of inpatient monitoring following the first infusion of the first cycle. Patients are monitored for dose-limiting toxicities (DLTs) or adverse events requiring prolonged hospitalization. If no response to CoQ10 is observed, the patient is discontinued.

[0511] For the second dose of the week (i.e., days 3, 10, 17 and 24 of the cycle), the total dose volume is administered over 48 hours without a loading dose, as shown in Table 6 below for CoQ10 nanosuspension for injection dose groups (Group 1; single treatment).

[0512] Administer the prescribed dose group to patients for the duration of treatment. Intra-patient dose escalation is not permitted. If the starting dose of 66 mg / kg exceeds the MTD of coenzyme Q10, for group-1, the dose should be reduced to 50 mg / kg. No more than two dose reductions are permitted during the study. The minimum dose is dose level-1.

[0513] Table 6. Coenzyme Q10 nanosuspension for injection dose groups (Group 1; monotherapy) Treatment group 2 combined with chemotherapy Once the dose levels for coenzyme Q10 monotherapy have been evaluated and the CRC has determined that escalation to the next dose level is safe, Group 2, coenzyme Q10 in combination with chemotherapy, will be opened to increase participants at a reduced dose level (see Table 7, Coenzyme Q10 nanosuspension for injection dose groups (Group 2; combination therapy)). The standard 3+3 design will be used for Group 2 of the study, and the DLT constraints will be the same as those used in Group 1. Coenzyme Q10 will be started at a dose level lower than that already studied and determined to be safe in the monotherapy portion of the trial. Group 2 patients will be enrolled to one of three chemotherapy regimens—gemcitabine, 5-FU, or docetaxel—according to the following dose levels and schedule (see Tables 7-10, Doses for Chemotherapy Combinations in Group 2).

[0514] • Once a week, intravenous gemcitabine at 600 mg / m² 2 The starting dose; • Once a week, IV 5-fluorouracil (5-FU) at 350 mg / m² 2 The starting dose, combined with leucovorin (LV) 100 mg / m² 2 ;or • Once a week, IV docetaxel at 20 mg / m² 2 The starting dose.

[0515] • Note: Coenzyme Q10 and chemotherapy agents can be simultaneously escalated in groups 3 and 4 only if no DLT was observed in the previous groups. If one or more DLTs were observed, the intermediate dose level should be increased in the case of escalating only one agent.

[0516] Once assigned, patients cannot be switched to an optional cohort. For each chemotherapy combination, group 2 was expanded to 10 patients at the MTD dose to ensure safety and for additional PK modeling (30 additional patients in total). Note: Group 2 patients who progress under one type of chemotherapy cannot be switched to one of the other chemotherapy agents in combination with coenzyme Q10. However, if a chemotherapy component of the combination therapy (i.e., 5-FU, gemcitabine, or docetaxel) is discontinued due to chemotherapy-related toxicities, the patient may continue to receive coenzyme Q10 as monotherapy.

[0517] For patients in group 2, the first cycle lasted 6 weeks. Coenzyme Q10 was administered twice weekly, Monday and Wednesday, for 6 weeks, with chemotherapy administered on Fridays, days 19, 26, and 33. Chemotherapy was administered via IV infusion over 30 minutes at the clinic. Dose-limiting toxicities were evaluated during the first cycle. Response was evaluated after the second cycle (10 weeks), and responders continuing to cycles 3–12 were evaluated every 2 cycles (8 weeks). Cycles 2–12 lasted 4 weeks, with Coenzyme Q10 administered twice weekly, Monday and Wednesday, for 4 weeks, with chemotherapy administered on Fridays, days 5, 12, and 19.

[0518] Table 7. Coenzyme Q10 nanosuspensions for injection dose groups (Group 2; combination therapy) Table 8. Group 2 combination of coenzyme Q10 and gemcitabine.

[0519] Table 9. Group 2 combination of coenzyme Q10 and 5-fluorouracil.

[0520] Folic acid can be administered before 5-FU or both drugs can be given simultaneously.

[0521] Table 10. Group 2 combinations of coenzyme Q10 and docetaxel.

[0522] Dosage escalation of Coenzyme Q10 monotherapy (Group 1) & combination therapy (Group 2) The study followed a standard 3+3 design, with each coenzyme Q10 dose escalating in consecutive dose cohorts of 3 patients. Each dose level was administered to up to 3 to 6 patients, and each cohort never contained more than 6 patients. If none of the 3 patients in a cohort experienced DLT during the first cycle, then 3 new patients could be enrolled at the next higher dose level after a CRC review of safety and PK data from the lower cohort.

[0523] With CRC approval, or if one of the three patients experiences DLT, the cohort can be expanded from the normal three patients to six. If one of the three patients experiences DLT during cycle 1, the cohort can be expanded to up to six patients. If no other patient experiences DLT at this dose, the next cohort level opens for expansion and dose escalation. If two or more patients in the cohort experience DLT during cycle 1, no further patient expansion is allowed at the start of this dose.

[0524] Doses for subsequent groups are escalated only after the safety of previous dose levels has been established.

[0525] In cases where DLT was not present at the previous dose level, the dose was increased in 25% increments from the previous dose group.

[0526] Continuous infusion drug delivery method and device Chemotherapy agents are administered using conventional methods known in the art. The following exemplary apparatus and methods are provided for continuous infusion of coenzyme Q10. It should be understood that other apparatuses and methods can achieve the same results as those provided in the table below. The exemplary apparatuses provided are non-limiting.

[0527] Table 11. Materials used to prepare coenzyme Q10 for IV infusion

[0528] a Polyvinyl chloride (PVC) plastic bags contain bis-2-ethylhexyl phthalate (DEHP) and are latex-free.

[0529] b PVC is plasticized with TOTM (trioctyl trimellitate).

[0530] c IV Dosing Setup for Use Only with Gemstar Flow Infusion Pumps d PVC plastic pipe, DEHP-free, latex-free.

[0531] e Plastic housing made of modified acrylic resin with Supor® film Hematologic toxicity Baseline laboratory requirements are ANC ≥ 1500 mm 3 Platelet count ≥ 100,000 / mm 3 Hemoglobin ≥ 9 g / dL, and INR, PT, and PTT within normal limits. Hematological and chemical evaluations are preferably performed weekly (Mondays), and coagulation should be repeated 24–72 hours before each dose initiation. Coenzyme Q10 must be maintained for any grade 3 or 4 hematological toxicities that are at least drug-related. Any grade 3 or 4 hematological toxicities must return to grade 1 or resolve before administration of coenzyme Q10 in cycles 2–12, except for INR, PT, and PTT (which must be within normal limits). A reduced dose of coenzyme Q10 may be resumed.

[0532] To monitor and mitigate coenzyme Q10-related coagulopathy, PT, PTT, INR, and platelet count must be evaluated before each dose of coenzyme Q10 is administered. INR values ​​≥ grade 2 require immediate treatment with vitamin K, cryoprecipitate, or fresh frozen plasma as clinically indicated. Any adverse events (AEs) must be reduced to ≤ grade 1, and INR must be normalized, before coenzyme Q10 treatment can be resumed.

[0533] If a second adverse event occurs with an INR or PTT elevation of grade 3 or higher, permanently discontinue the use of Coenzyme Q10.

[0534] Permanently discontinue Coenzyme Q10 in patients who have experienced clinically significant bleeding along with an elevation of INR or PTT of grade ≥2.

[0535] Non-hematologic toxicity Before administering coenzyme Q10 in cycles 2-12, at least any drug-related grade 3 or 4 non-hematological toxicities must be reduced to grade 1 or resolved. A reduced dose of coenzyme Q10 may be resumed.

[0536] Patients with toxicities that can be managed with supportive care may not require a dose reduction. Patients requiring more than two coenzyme Q10 dose reductions should withdraw from the study.

[0537] At the end of the study, patient responses to treatment with coenzyme Q10 monotherapy or coenzyme Q10 in combination with chemotherapy were evaluated using RECIST criteria. The frequency, duration, and extent of response were compared to cohorts or historical controls to determine the benefit of the treatment regimen to the subjects. Clinically relevant outcomes were demonstrated to the subjects based on the RECIST criteria described herein. Adverse outcomes were also evaluated in comparison to subjects treated with intravenous coenzyme Q10 delivered via a four-hour infusion at a higher infusion rate than used in this clinical trial. The increased infusion time was found to reduce adverse events in subjects, thus expanding the therapeutic range of coenzyme Q10 and allowing subjects to receive higher doses and / or more doses of coenzyme Q10 without significant adverse events, such as those requiring subjects to discontinue treatment and / or withdraw from the study. Myelosuppression was also evaluated in subjects, particularly in the combination therapy group. The level of myelosuppression in subjects in this study was compared to historical controls to identify reductions in myelosuppression in co-dosing regimens using coenzyme Q10.

[0538] Example 6 - Safety and efficacy results of a phase 1a / b study of a coenzyme Q10 nanosuspension for intravenous injection in patients with solid tumors. The following are interim results from a phase 1a / b non-randomized dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the intravenously administered coenzyme Q10 nanosuspension injection in patients with solid tumors as described in Example 5.

[0539] To date, forty-two participants have been enrolled and treated, including 17 in the single-treatment group and 25 in the combination group. Single treatment group Dose level 1 (66 mg / kg): 9 subjects were enrolled, 1 was active, and 8 withdrew from the study. 1 dose-limiting toxicity (DLT), grade 3 GGT. Dose levels are clear.

[0540] Dose level 2 (88 mg / kg): 4 subjects were enrolled, 0 active (1 crossed with gemcitabine). 0 DLT. Dose level clear.

[0541] Dose level 3 (110 mg / kg): 4 subjects were enrolled, 10 were active. 0 DLT. 2 subjects were replaced, 1 slot opened. Evaluation is ongoing.

[0542] Three additional dose levels are pending evaluation.

[0543] Joint Group Twenty-five participants were enrolled, with 12 active, 1 crossover participant, and 13 withdrawing from the study. Giscitabine Group Dose level 1 (50 mg / kg) was closed. Mild to moderate thrombocytopenia (gemcitabine-related adverse events) was observed, but no DLT. Dose level was clear.

[0545] Dose level 2 (66 mg / kg) was open and enrolled 3 subjects.

[0546] Four additional dose levels are pending evaluation.

[0547] 5-Fluorouracil (5FU) group Dose level 1 (50 mg / kg) was fully increased. No 5FU-related issues were observed. Dose levels were clear.

[0548] Dose level 2 (66 mg / kg) was fully increased. Dose levels were clear.

[0549] Three additional dose levels are pending evaluation.

[0550] Docetaxel group Dosage level 1 (50 mg / kg) was increased completely. There were no docetaxel-related issues. Dosage levels were clear.

[0551] Dose level 2 (66 mg / kg) was increased completely. No problems or DLT. Dose levels were clear.

[0552] Dose level 3 (88 mg / kg) was fully increased. No problems or DLT were observed. Evaluation is ongoing.

[0553] Three additional dose levels are pending evaluation.

[0554] The drug has been observed to be safe at current levels. In particular, minimal coagulation abnormalities were observed with continuous infusion regimens, aggressive preloading, or treatment with vitamin K. No bleeding events have been reported. A transient increase in triglycerides was observed, but it was not clinically significant (as confirmed by internal lipidomics evaluation). Mild to moderate thrombocytopenia was observed following gemcitabine treatment, with no diabetic thrombocytopenic purpura (DLT) at the initial dose. Pharmacokinetic studies at the initial test dose showed a linear distribution.

[0555] Coenzyme Q10 has shown early activity at low doses in a variety of solid tumors, including gastric cancer, pancreatic cancer, colon cancer, head and neck cancer, non-small cell lung cancer (NSCLC), mesothelioma, and triple-negative (TN) breast cancer. Eight of the twelve patients (75%) evaluable for efficacy at dose level 2 showed a variety of responses, including: tumor shrinkage, reduced FDG, cessation of tumor progression, stable disease, reduction in tumor markers, and clinically reflected improvements in quality of life (QOL) (i.e., reduced pain, increased energy, reduced serous discharge, etc.). Two exemplary patients are described below.

[0556] Patient 1 A 53-year-old Asian man with gastric adenocarcinoma and liver and lymph node metastases received dose level 1 (66 mg / kg / week) of coenzyme Q10. He had previously received extensive treatment with epirubicin, capecitabine, oxaliplatin, docetaxel, cisplatin, and irinotecan. Radiographic PET response was assessed at the end of two cycles, with a 40% reduction in PET-SUV (see [link to relevant documentation]). Figure 11 The target lesion size showed minimal change and cervical lymph node metastasis disappeared. This PET response was associated with clinical improvement in early satiety symptoms. Multi-omics tissue analysis demonstrated a shift from anaerobic-driven markers to oxidative phosphorylation. Furthermore, a 15-fold increase in intratumoral coenzyme Q10 concentration was observed. The patient subsequently showed disease progression after another 4 weeks and was switched to a combination group with weekly increases in docetaxel, where a metabolic response was again observed by PET / CT. The patient progressed after 2 combination cycles and withdrew from the study after 6.5 months.

[0557] Patient 2 A 70-year-old patient with metastatic bladder cancer that had metastasized to the abdomen / peritoneum, lung, and bone was treated with gemcitabine / coenzyme Q10 at 66 mg / kg. The patient had previously received multiple treatments, including radical cystectomy with skin-turning prostatectomy, short-range radiotherapy, and chemotherapy (pemetrexed, methotrexate, docetaxel). The patient was doing well and feeling much better during the third treatment cycle.

[0558] Normalized uptake values ​​(SUVs) increased before treatment and at week 2. A week 10 PET scan showed omental lesion 1 to be less dense, with no perceptible fluorodeoxyglucose (FDG) uptake. The maximum SUV decreased from 1.7 to 0.8. For omental lesion 2, the maximum SUV decreased from 3.5 to 2.8, indicating normal intestinal uptake. For the right iliac bone lesion, the maximum SUV decreased from 2.3 to 1.9. A complete response was present in one of the non-target lesions in the abdomen. There was a sustained decrease in the degree of peritoneal disease, with no clearly identifiable FDG avid focus for currently identified peritoneal disease.

[0559] The initial results described above suggest that coenzyme Q10 appears to be safe and well-tolerated in both monotherapy and combination therapy. Low levels of initial clinical and radiographic responses were observed in a variety of relapsed / refractory, previously heavily treated solid tumor patients, both in monotherapy and combination therapy. Multi-omics tissue analysis demonstrated a shift from anaerobic-driven markers to oxidative phosphorylation (i.e., reversal of Warburg's action).

[0560] Example 7 - A Phase 1a / b non-randomized, dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of a sterile coenzyme Q10 nanosuspension for intravenous administration in patients with solid tumors - 144-hour (6-day) continuous infusion This was a phase 1 clinical trial evaluating a 144-hour (6-day) continuous infusion of coenzyme Q10 as a treatment for solid tumors. Coenzyme Q10 was administered as monotherapy (Group 1) or in combination with chemotherapy (Group 2). Coenzyme Q10 was provided as a 4% coenzyme Q10 nanosuspension formulation as described in WO2011 / 112900, the entire contents of which are hereby cited and incorporated herein by reference. The study was an open-label, non-randomized dose-escalation study. The estimated enrollment was 45 patients for monotherapy (Group 1) and up to 120 patients for combination therapy (Group 2).

[0561] Compared to the studies described in Examples 5 and 6 (96-hour infusion), a longer dosing schedule (144-hour infusion) was used in the study design. This extended dosing schedule was designed to further reduce CoQ10 C levels. max This aims to maintain coenzyme Q10 steady-state levels for a longer period. To avoid being bound by the mechanism, a prolonged dosing schedule and / or reduced infusion rate are proposed to avoid potential association with high C. max Level-related potential toxicity, thereby increasing the therapeutic range of coenzyme Q10 compared to administration over shorter dosing periods and / or at higher infusion rates.

[0562] Use a two-72-hour dosing schedule. For the first 72-hour dose, a loading dose is administered over 1 hour, followed by the remainder of the dose infused at a lower rate over 71 hours. Near the end of the first 72-hour treatment, the patient returns to the clinic for reassessment. If the patient continues to meet their coenzyme Q10 treatment needs, fill the infusion pump with the second 72-hour dose for home administration at a uniform rate.

[0563] The treatment group is as follows: Group 1 (Coenzyme Q10 monotherapy) Patients who meet the eligibility criteria receive two consecutive 72-hour coenzyme Q10 infusions, twice a week on Tuesdays and Fridays (i.e., days 1, 4, 8, 11, 15, 18, 22, and 25), essentially 144 hours of coenzyme Q10 treatment per week in each 28-day cycle.

[0564] Group 2 (Coenzyme Q10 combined with chemotherapy) Treatment group 2 was enrolled when the coenzyme Q10 dose level was safely achieved as a single therapy, and patients were treated with an evaluated and confirmed safe dose of coenzyme Q10 in combination with one of three chemotherapy regimens: • Once a week, intravenous gemcitabine at 600 mg / m² 2 The starting dose; • Once a week, IV 5-fluorouracil (5-FU) at 350 mg / m² 2 The starting dose, combined with leucovorin (LV) 100 mg / m² 2 ;or • Once a week, IV docetaxel at 20 mg / m² 2 The starting dose.

[0565] The first cycle of combination therapy (Group 2) was a 6-week duration for patients, with coenzyme Q10 administered twice weekly on Tuesdays and Fridays for 6 weeks, and chemotherapy administered on Mondays, days 21, 28, and 35. Cycles 2-12 were 4-week durations, with coenzyme Q10 administered twice weekly on Tuesdays and Fridays for 4 weeks, and chemotherapy administered on Mondays, days 7, 14, and 21.

[0566] Research Objectives The primary objective of this study was to determine the maximum tolerated dose (MTD) and to evaluate the safety and tolerability of coenzyme Q10 monotherapy and coenzyme Q10 in combination with chemotherapy administered via intravenous (IV) infusion over 144 hours in patients with solid tumors.

[0567] Secondary objectives were to evaluate the plasma pharmacokinetics (PK) of coenzyme Q10 as monotherapy and coenzyme Q10 in combination with chemotherapy during 144-hour IV infusion in patients with solid tumors, and to estimate renal clearance.

[0568] The exploratory goal is: • Evaluate the pharmacodynamic (PD) correlation of serum coenzyme Q10 activity as a single treatment and in combination with chemotherapy.

[0569] • Evaluate the role of coenzyme Q10 in the transformation of tumors into aerobic respiration using PET imaging.

[0570] • Evaluate tumor vascular distribution in at least 6 patients who received MTD coenzyme Q10 within 24 hours before and after administration (using DCE-MRI).

[0571] • Evaluate tumor response (preliminary antitumor activity) after repeated administration of coenzyme Q10.

[0572] • Evaluate progression-free survival (PFS) and time to progression (TTP) for each treatment group.

[0573] • The bone marrow suppression recorded in the combination therapy group was compared with historical data for each treatment group.

[0574] • To evaluate the long-term safety and tolerability of coenzyme Q10 as a single treatment and after repeated administration in combination with chemotherapy.

[0575] Study eligibility criteria Inclusion criteria : In order to be included in clinical trials, patients must meet the following criteria: 1. Patients with histologically confirmed metastatic or unresectable solid tumors for which standard methods are no longer available or effective. (Patients with primary brain cancer or lymphoma are permitted. Patients with brain metastases are permitted if they have undergone whole-brain irradiation and demonstrated stability for ≥6 weeks).

[0576] 2. The patient must be at least 18 years old.

[0577] 3. The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

[0578] 4. The patient has a life expectancy of >3 months.

[0579] 5. Sexually active patients and their partners consent to the use of recognized methods of contraception during the study.

[0580] 7. Female patients who may be pregnant must have a negative pregnancy test within one week before starting the study treatment.

[0581] 8. The patient has sufficient organ and bone marrow function as follows: ANC≥1500mm 3 Platelet count ≥100,000 / mm 3 Hemoglobin ≥9g / dL Serum creatinine ≤1.8 mg / dL or creatinine clearance >50 mL / min; Bilirubin ≤1.5 mg / dL; if the liver is not involved, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal, or if the liver is involved, ≤5 times the upper limit of normal.

[0582] 9. The patient has serum electrolytes (including calcium, magnesium, phosphorus, sodium, and potassium) within normal limits (supplementation is permitted to maintain normal electrolyte levels).

[0583] 11. The patient has adequate clotting ability: prothrombin time (PT) ≤ 1.5 times the upper limit of normal, international normalized and partial thromboplastin time (PTT). 12. The patient was able to understand and comply with the experimental protocol and signed the informed consent document.

[0584] Exclusion criteria : The patient should be excluded from study participation if any of the following criteria are met: 1. The patient has uncontrolled comorbidities, including, but not limited to, uncontrolled infections, symptomatic congestive heart failure (Class III and IV NYHA), uncontrolled arrhythmias, or mental illness / social situations that would limit compliance with the study requirements.

[0585] 2. The patient has active cardiac disease, including myocardial infarction within the previous 3 months, symptomatic coronary artery disease, uncontrolled arrhythmia, unstable angina, or uncontrolled congestive heart failure (Class III and IV NYHA).

[0586] 3. The patient had received chemotherapy or radiotherapy within 4 weeks prior to the first dose of the study drug.

[0587] 4. Within 4 weeks of receiving the first dose of the study drug, the patient had received radiation to ≥25% of the bone marrow.

[0588] 5. The patient had received the study drug within 30 days of the first dose.

[0589] 6. Patients who have not recovered to grade ≤1 from adverse events (AEs) caused by the investigational drug or other drugs (which were administered no more than 2 weeks before the first dose of the investigational drug), except for neurotoxicity caused by oxaliplatin or taxane, must recover to <2 before the start of the study.

[0590] 7. The patient is pregnant or breastfeeding.

[0591] 8. The patient is known to be positive for human immunodeficiency virus (HIV). The role of coenzyme Q10 in HIV medication is unknown. Note: HIV testing is not required for eligibility, but the patient is ineligible for this study if they have previously been tested and the result was positive.

[0592] 9. The patient is unable or unwilling to comply with the research protocol or fully cooperate with the investigator or appointee.

[0593] 10. The patient is currently receiving digoxin, digitoxin, digitoxin C, or any type of digitalis alkaloid.

[0594] 11. The patient is receiving colony-stimulating factor (CSF) that cannot be delayed during monitoring for dose-limiting toxicities (DLT).

[0595] 12. The patient has a history of uncontrolled or severe coagulopathy or clinically significant bleeding within the past 6 months, such as hemoptysis, epistaxis, hematochezia, hematuria, or gastrointestinal bleeding.

[0596] 13. The patient has a known bleeding tendency, such as von Willebrand's disease or other such conditions.

[0597] 14. Any anticoagulant requiring a therapeutic dose, including low molecular weight heparin (LMWH). Concomitant use of warfarin is prohibited, even at prophylactic doses.

[0598] The evaluation of measurable lesions for determining eligibility was based on the criteria described in Example 4, Tables 3 and 4.

[0599] Experimental Design A phase 1 clinical trial was conducted to investigate the use of coenzyme Q10 as monotherapy and coenzyme Q10 in combination with chemotherapy for the treatment of solid tumors. The study was a multicenter, open-label, non-randomized, dose-escalation study to examine the dose-limiting toxicities (DLT) of coenzyme Q10 as monotherapy (treatment group 1) and in combination with chemotherapy (treatment group 2) as a 144-hour continuous intravenous (IV) infusion in patients with solid tumors. In the phase 1a portion of the trial, patients meeting eligibility parameters received two consecutive 72-hour coenzyme Q10 infusions twice a week on Tuesdays and Fridays (i.e., days 1, 4, 8, 11, 15, 18, 22, and 25), essentially a 28-day cycle of coenzyme Q10 treatment for 144 hours per week. At each dose level in groups 1 and 2, patients were treated with at least 8 hours of outpatient monitoring or inpatient monitoring for the first 24 hours of the first infusion of the first cycle. All other treatments were administered in outpatient settings. Dose-limiting toxicities were evaluated during the first cycle.

[0600] The study followed a standard 3+3 dose-escalation design, with doses escalating in consecutive cohorts of 3 to 6 patients. Toxicity at each dose level was graded according to the Common Terminology for Adverse Events (CTCAE v4.02). Safety oversight was provided by a cohort review committee (CRC). The CRC reviewed and validated all dose-dependent events (DLTs) and continuously monitored safety throughout the study (including cohort 2).

[0601] At the end of the second cycle and every two cycles thereafter, the antitumor activity of coenzyme Q10 is assessed using standard techniques, such as computed tomography (CT) or magnetic resonance imaging (MRI) for patients with measurable disease. Response is evaluated using the Recognition of Solid Tumor Response Criteria (RECIST) v1.1. Patients who do not experience unacceptable toxicity or disease progression may receive an additional 28-day cycle of group 1 or 2 for up to one year. Group 1 patients with disease progression may choose to continue coenzyme Q10 therapy in combination with gemcitabine, 5-FU, or docetaxel at the discretion of their treating physician. Once the dose level of coenzyme Q10 monotherapy has been evaluated and the CRC determines that escalation to the next dose level is safe, group 1 of group 2 will be opened for coenzyme Q10 in combination with chemotherapy. Group 1 patients in group 2 are enrolled in one of three chemotherapy regimens, gemcitabine, 5-FU, or docetaxel. The first cycle of combination therapy (Group 2) was a 6-week duration for patients, with Coenzyme Q10 administered twice weekly on Tuesdays and Fridays for 6 weeks, and chemotherapy administered on Mondays, days 21, 28, and 35. Cycles 2-12 were 4-week durations, with Coenzyme Q10 administered twice weekly on Tuesdays and Fridays for 4 weeks, and chemotherapy administered on Mondays, days 7, 14, and 21. Dose-limiting toxicities were evaluated during the first cycle. Response was evaluated after the second cycle (10 weeks), and responders were evaluated every 2 cycles (8 weeks) to continue to cycles 2-12. Patients who progressed and switched to Group 2 again agreed and had to meet eligibility criteria before restarting Coenzyme Q10. Crossover patients in Group 2 did not have their DLT evaluated, and all cycles of combination therapy were 4-week durations (cycles 1-12). For all crossover patients in Group 2, Coenzyme Q10 was administered twice weekly on Tuesdays and Fridays, and chemotherapy was administered on Mondays, days 7, 14, and 21. In the absence of intolerance toxicity and progression, patients may continue coenzyme Q10 in combination with chemotherapy for up to 12 cycles. Group 2 patients who progress during one type of chemotherapy may not switch to one of the other chemotherapy agents in combination with coenzyme Q10. However, if the chemotherapy component of the combination therapy (i.e., 5-FU, gemcitabine, or docetaxel) is discontinued due to chemotherapy-related toxicity, patients may continue to receive coenzyme Q10 as monotherapy.

[0602] Once the maximum tolerated dose (MTD) of coenzyme Q10 as monotherapy and in combination with chemotherapy was determined, an expanded cohort was enrolled (12-15 patients in total for monotherapy and 10 patients in total for each combination therapy).

[0603] PK / PD Evaluation The study evaluated safety observations and measurements including investigational drug exposure, adverse events, laboratory data (hematology, coagulation, serology, urinalysis), vital signs, ECOG performance status, and concomitant medications.

[0604] Blood samples were collected for pharmacokinetic (PK) and pharmacodynamic (PD) analyses during coenzyme Q10 monotherapy and combination therapy. Plasma coenzyme Q10 concentrations and PK parameters were analyzed in samples from cycle 1; samples collected from cycles 2–12 were analyzed for evidence of coenzyme Q10 accumulation. Urine samples were collected for coenzyme Q10 renal clearance analysis during cycle 1 of monotherapy and combination therapy. PET scans were performed within 2 weeks prior to treatment initiation, 2 weeks after coenzyme Q10 treatment, and 8 weeks after group 1 treatment or 10 weeks after group 2 treatment. Core biopsies (5) were performed at baseline and at the end of week 2 for patients who decided to participate in these exploratory studies. Patients who progressed in group 1 and crossed over to group 2 had PET scans and, if they consented, underwent 5 core biopsies within 2 weeks of restarting coenzyme Q10 and at week 3. Core biopsies were contraindicated in patients with highly vascularized tumors, tumors located near major blood vessels, or tumors close to vital organs.

[0605] Biomarker levels of coenzyme Q10 activity in plasma and urine samples were evaluated, including but not limited to genomics (e.g., microarrays, SAGE, Northern blotting, gene expression), proteomics (e.g., LC / MS-based analysis, 2DE-MS, MALDITOF, antibody arrays, ELISA, immunohistochemistry, tissue microarrays, flow cytometry, Western blotting), metabolomics (e.g., overall analysis of metabolites in biological samples; identification of specific biomarkers of energy metabolism, e.g., pyruvate, lactate), and lipidomics (e.g., overall analysis of lipid classes; identification of specific lipids, e.g., palmitate, linoleic acid, arachidonic acid derivatives). These exploratory data were correlated with additional exploratory endpoints, including PFS and TTP. Finally, myelosuppression during combination therapy was compared with historical data for each chemotherapy regimen to evaluate whether coenzyme Q10 reduced or prevented chemotherapy-induced myelosuppression.

[0606] In the absence of progression and intolerance toxicity, response was evaluated using standard methods, such as CT, PET / CT, or MRI at screening / baseline and every two treatment cycles (8 weeks) for patients in treatment group 1 or those who progressed and crossed over to group 2. In the absence of progression and intolerance toxicity, patients in treatment group 2 were evaluated after the second cycle (10 weeks) and thereafter continued to be evaluated every two cycles (8 weeks). Evidence of antitumor activity was evaluated using the RECIST response criteria for solid tumors as described herein.

[0607] Tumor metabolic activity was evaluated (FDG-PET / CT) within 2 weeks of starting coenzyme Q10 treatment, and repeated at 2 weeks post-tr...

Claims

1. A method of treating a subject with cancer, comprising administering a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours.

2. A method of treating a subject's cancer, comprising administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein the coenzyme Q10 is administered at two or more different rates.

3. The method of claim 2, wherein coenzyme Q10 is administered sequentially at a first rate and a second rate, wherein the first rate is higher than the second rate.

4. The method of claim 3, further comprising administering coenzyme Q10 at a third rate after the second rate.

5. The method of claim 4, wherein the third rate is lower than the first rate but higher than the second rate.

6. The method of any one of claims 3-5, wherein coenzyme Q10 is administered at the first rate for about 0.5 hours to about 3 hours, or about 0.5 hours to about 2 hours.

7. The method of claim 6, wherein coenzyme Q10 is administered at the first rate for about 1 hour.

8. The method of any one of claims 3-7, wherein the total infusion time at the first rate plus the infusion time at the second rate is about 24 hours, about 48 hours, or about 72 hours.

9. The method of any one of claims 2-5, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 48 hours.

10. The method of any one of claims 1-5, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 72 hours.

11. The method of any one of claims 1-5, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 96 hours.

12. The method of any one of claims 1-5, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 144 hours.

13. The method of any one of claims 1-12, wherein the continuous intravenous infusion is administered once weekly.

14. The method of any one of claims 1-10, wherein the continuous infusion is administered twice weekly.

15. The method of any one of claims 1-5, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, at least 216 hours, at least 240 hours, at least 288 hours, at least 312 hours, at least 336 hours, at least 360 hours, at least 384 hours, at least 408 hours, at least 432 hours, at least 456 hours, or at least 480 hours.

16. The method of claim 15, wherein the continuous intravenous infusion is administered once every two weeks, once every three weeks, or once every four weeks.

17. The method of claim 3, wherein the first rate does not exceed 3.1 mg / kg / hr, 4.2 mg / kg / hour, 5.5 mg / kg / hour, 7.4 mg / kg / hour, 8.3 mg / kg / hour, 9.2 mg / kg / hour, 11.0 mg / kg / hour, 11.2 mg / kg / hour, 14 mg / kg / hour, 14.5 mg / kg / hour, 18.0 mg / kg / hour, 18.4 mg / kg / hour, 19.6 mg / kg / hour, 22.9 mg / kg / hour, 26.0 mg / kg / hour, 28.7 mg / kg / hour, or 35.8 mg / kg / hour.

18. A method for treating cancer in a subject, comprising: (a) Administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein coenzyme Q10 is administered at two or more different rates; (b) Monitor subjects for decreased coagulation; and (c) Discontinue Coenzyme Q10 treatment in subjects identified as having reduced coagulation.

19. A method for treating cancer in a subject, comprising: (a) Administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein coenzyme Q10 is administered at two or more different rates; (b) Monitor subjects for decreased coagulation; (c) Administering coagulation-enhancing agents to subjects identified as having a decoagulation-reducing effect; (d) Confirm that the subject has normal coagulation function; and (e) Continue treatment with Coenzyme Q10.

20. The method of claim 19, wherein the coagulation-enhancing agent comprises vitamin K.

21. A method for treating cancer in a subject, comprising: (a) Administering a composition containing coenzyme Q10 by continuous intravenous infusion, wherein coenzyme Q10 is administered at two or more different rates; (b) Monitor subjects for decreased coagulation; and (c) Continue treatment with coenzyme Q10 in subjects identified as having normal coagulation.

22. A method for treating cancer in a subject, comprising: (a) Administer a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) Monitor subjects for decreased coagulation; and (c) Discontinue Coenzyme Q10 treatment in subjects identified as having reduced coagulation.

23. A method for treating cancer in a subject, comprising: (a) Administer a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) Monitor subjects for decreased coagulation; and (c) Administering coagulation-enhancing agents to subjects identified as having a decoagulation-reducing effect; (d) Confirm that the subject has normal coagulation function; and (e) Continue treatment with Coenzyme Q10.

24. The method of claim 23, wherein the coagulation-enhancing agent comprises vitamin K.

25. A method for treating cancer in a subject, comprising: (a) Administer a composition containing coenzyme Q10 by continuous intravenous infusion for at least 48 hours; (b) Monitor subjects for decreased coagulation; and (c) Continue treatment with coenzyme Q10 in subjects identified as having normal coagulation.

26. The method of any one of claims 18-25, wherein reduced clotting comprises an INR higher than 2, while normal clotting comprises an INR of 2 or lower.

27. The method of any one of claims 18-25, wherein reduced clotting includes an INR higher than 3, while normal clotting includes an INR of 3 or lower.

28. The method of any one of claims 18-25, wherein the reduced coagulation comprises a platelet threshold of less than 50,000 / uL.

29. The method of any one of claims 18-25, wherein normal coagulation includes a platelet threshold of at least 50,000 / uL.

30. A method for preventing or limiting the severity of adverse events associated with the use of intravenous coenzyme Q10 to treat cancer, comprising administering a composition containing coenzyme Q10 to a subject with cancer by continuous intravenous infusion for at least 48 hours, wherein the severity of adverse events in the subject is reduced compared to intravenous administration of the same dose of coenzyme Q10 over a period of 6 hours or less.

31. The method of any one of claims 18-30, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 72 hours.

32. The method of any one of claims 18-30, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 96 hours.

33. The method of any one of claims 18-30, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 144 hours.

34. The method of any one of claims 18-31, wherein the continuous intravenous infusion dose is administered twice weekly.

35. The method of any one of claims 18-33, wherein the continuous intravenous infusion dose is administered once weekly.

36. The method of any one of claims 18-30, wherein coenzyme Q10 is administered by continuous intravenous infusion for at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, at least 216 hours, at least 240 hours, at least 264 hours, at least 288 hours, at least 312 hours, at least 336 hours, at least 360 hours, at least 384 hours, at least 408 hours, at least 432 hours, at least 456 hours, or at least 480 hours.

37. The method of claim 36, wherein the continuous intravenous infusion is administered once every two weeks, once every three weeks, or once every four weeks.

38. The method of claim 30, wherein the adverse event includes coagulopathy.

39. The method of claim 30, wherein the adverse event includes a bleeding event.

40. The method of claim 30, wherein the adverse event comprises at least 2 INRs or at least 3 INRs.

41. A method of treating cancer, comprising administering a composition comprising coenzyme Q10 by continuous intravenous infusion for about 96 hours, wherein the composition is administered sequentially at a first rate, a second rate, and a third rate, wherein: (a) The first rate is the highest rate applied during the first hour of the continuous intravenous infusion; (b) The second rate is the lowest rate administered during the second to 48 hours of the continuous intravenous infusion; and (c) The third rate is an intermediate rate between the first rate and the second rate, and is administered during the 49th to 96th hour of the continuous intravenous infusion.

42. The method of claim 41, wherein the amount of coenzyme Q10 administered during the first to 48 hours of the continuous intravenous infusion is equal to the amount of coenzyme Q10 administered during the 49th to 96th hours of the continuous intravenous infusion.

43. A method of treating cancer, comprising administering a composition comprising coenzyme Q10 by continuous intravenous infusion for about 144 hours, wherein the composition is administered sequentially at a first rate, a second rate, and a third rate, wherein: (a) The first rate is the highest rate applied during the first hour of the continuous intravenous infusion; (b) The second rate is the lowest rate administered during the second to 72 hours of the continuous intravenous infusion; and (c) The third rate is an intermediate rate between the first rate and the second rate, and is administered during the 73rd to 144th hour of the continuous intravenous infusion.

44. The method of claim 43, wherein the amount of coenzyme Q10 administered during the first to 72 hours of the continuous intravenous infusion is equal to the amount of coenzyme Q10 administered during the 73rd to 144th hours of the continuous intravenous infusion.

45. The method of any one of claims 41-44, wherein the first rate is selected from not more than 3.1 mg / kg / hour, not more than 4.2 mg / kg / hour, not more than 5.5 mg / kg / hour, not more than 7.4 mg / kg / hour, not more than 8.3 mg / kg / hour, not more than 9.2 mg / kg / hour, not more than 11.0 mg / kg / hour, not more than 11.2 mg / kg / hour, not more than 14.0 mg / kg / hour, not more than 14.5 mg / kg / hour, not more than 18.0 mg / kg / hour, not more than 18.4 mg / kg / hour, not more than 19.6 mg / kg / hour, not more than 22.9 mg / kg / hour, not more than 26.0 mg / kg / hour, not more than 28.7 mg / kg / hour, and not more than 35.8 mg / kg / hour.

46. ​​The method of claim 41 or 42, wherein the infusion dose is selected from about 50 mg / kg / 48 hours and the first rate is about 4.2 mg / kg / hour, about 66 mg / kg / 48 hours and the first rate is about 5.5 mg / kg / hour, about 88 mg / kg / 48 hours and the first rate is about 7.4 mg / kg / hour, about 110 mg / kg / 48 hours and the first rate is about 9.2 mg / kg / hour, about 137 mg / kg / hour, and the first rate is about 137 mg / kg / hour. Coenzyme Q10 is administered at a dose of approximately 11 mg / kg / hour and a first rate of approximately 171 mg / kg / 48 hours, at a dose of approximately 14 mg / kg / hour, at a dose of approximately 215 mg / kg / 48 hours and a first rate of approximately 18 mg / kg / hour, at a dose of approximately 40 mg / kg / 48 hours, and at a dose of approximately 3.4 mg / kg / hour to approximately 21 mg / kg / hour.

47. The method of claim 43 or 44, wherein the infusion dose is selected from about 38 mg / kg / 72 hours and the first infusion rate is about 3.1 mg / kg, about 50 mg / kg / 72 hours and the first infusion rate is about 4.1 mg / kg / hour, about 66 mg / kg / 72 hours and the first infusion rate is about 5.4 mg / kg / hour, about 88 mg / kg / 72 hours and the first infusion rate is about 7.2 mg / kg / hour, and about 110 mg / kg / 72 hours and the first infusion rate is about 9.0 mg / kg / hour. Coenzyme Q10 was administered at doses of approximately 137 mg / kg / hour, approximately 11.2 mg / kg / hour, approximately 171 mg / kg / hour, approximately 14.0 mg / kg / hour, approximately 215 mg / kg / hour, approximately 17.6 mg / kg / hour, approximately 38 mg / kg / hour, approximately 250 mg / kg / hour, approximately 3.1 mg / kg / hour, and approximately 21 mg / kg / hour.

48. The method of claim 41 or 42, wherein 3-5% of the total coenzyme Q10 administered during the first hour of the continuous intravenous infusion is applied during the 96-hour continuous intravenous infusion.

49. The method of claim 43 or 44, wherein 3-5% of the total coenzyme Q10 administered during the 144-hour continuous intravenous infusion is applied during the first hour of the continuous intravenous infusion.

50. A method of treating cancer, comprising administering a composition comprising coenzyme Q10 by continuous intravenous infusion for about 18 days, wherein the composition is administered sequentially at a first rate, a second rate, and a third rate, wherein: (a) The first rate is the highest rate applied during the first hour of the first day of the continuous infusion; (b) The second rate is the lowest rate applied during the second to 24 hours of the first day of the continuous infusion; and (c) The third rate includes an intermediate rate applied between the first rate and the second rate applied during the second to 17th days of the continuous infusion.

51. The method of claim 50, wherein the amount of coenzyme Q10 administered during each 24-hour period of the continuous intravenous infusion is equal.

52. The method of claim 50 or 51, wherein the first rate is selected from a rate not exceeding 4.2 mg / kg / hour, not exceeding 5.5 mg / kg / hour, not exceeding 7.4 mg / kg / hour, not exceeding 8.3 mg / kg / hour, not exceeding 9.2 mg / kg / hour, not exceeding 11.0 mg / kg / hour, not exceeding 14.5 mg / kg / hour, not exceeding 18.4 mg / kg / hour, not exceeding 19.6 mg / kg / hour, not exceeding 22.9 mg / kg / hour, not exceeding 26.0 mg / kg / hour, not exceeding 28.7 mg / kg / hour, and not exceeding 35.8 mg / kg / hour.

53. The method of claim 50 or 51, wherein the infusion dose is selected from about 33 mg / kg / 24 hours and the first infusion rate is about 8.3 mg / kg / hour, about 44 mg / kg / 24 hours and the first infusion rate is about 11 mg / kg / hour, about 58.7 mg / kg / 24 hours and the first infusion rate is about 14.7 mg / kg / hour, about 73.4 mg / kg / 24 hours and the first infusion rate is about 18.4 mg / kg / hour, about 91.7 mg / kg / 24 hours and the first infusion rate is about 18.4 mg / kg / hour, or about 91.7 mg / kg / 24 hours. Coenzyme Q10 is administered at a dose of approximately 22.9 mg / kg / hour over a 4-hour infusion, at a dose of approximately 114.6 mg / kg / 24-hour infusion, at a dose of approximately 28.7 mg / kg / hour over a 24-hour infusion, at a dose of approximately 143.3 mg / kg / 24-hour infusion, at a dose of approximately 35.8 mg / kg / hour over a 24-hour infusion, at a dose of approximately 30 mg / kg / 24-hour infusion, at a dose of approximately 170 mg / kg / 24-hour infusion, at a dose of approximately 7.5 mg / kg / hour over a 24-hour infusion, at a dose of approximately 42.5 mg / kg / hour over a 24-hour infusion.

54. The method of claim 50 or 51, wherein 20-30% of the total coenzyme Q10 administered during the first hour of the continuous infusion is administered during the first to 48 hours of the continuous infusion.

55. The method of any one of claims 1-54, wherein coenzyme Q10 is administered together with other pharmaceutical agents.

56. The method of claim 55, wherein the administration of said other agent begins on the same day that coenzyme Q10 is initiated.

57. The method of claim 55, wherein the administration of the other agent is initiated one week or more, two weeks or more, three weeks or more, four weeks or more, five weeks or more, six weeks or more, seven weeks or more, or eight weeks or more after the initiation of coenzyme Q10 administration.

58. The method of any one of claims 55-57, further comprising monitoring bone marrow suppression in the subject.

59. The method of claim 55, wherein the other agent is an anticancer agent.

60. The method of claim 55, wherein the other agent is a chemotherapeutic agent.

61. The method of claim 55, wherein the other agents are selected from gemcitabine, 5-fluorouracil, folate, docetaxel, fludarabine, cytarabine, cyclophosphamide, paclitaxel, docetaxel, busulfan, methotrexate, doxorubicin, doxorubicin, melphalan, cladribine, vincristine, vinblastine, chlorambucil, tamoxifen, paclitaxel, camptothecin, actinomycin-D, mitomycin C, cobustatin, cisplatin, etoposide, pentamethasone, podophyllotoxin, and 5-fluorouracil.

62. The method of claim 55, wherein the other agent is an anti-angiogenic agent.

63. The method of any one of claims 55-62, wherein the other agents are administered during cancer progression in the course of treatment using coenzyme Q10.

64. The method of any one of claims 55-62, wherein the other agents are administered during treatment using coenzyme Q10 when there is no cancer progression.

65. The method of any one of claims 55-64, wherein the adverse effects of the other drugs are limited or reduced in subjects who are administered coenzyme Q10 by continuous infusion together with the other drugs, compared with subjects who are not administered coenzyme Q10 together with the other drugs.

66. The method of claim 65, wherein the adverse event is myelosuppression.

67. The method of claim 65, wherein the adverse event is cardiac poisoning.

68. The method of any one of claims 1-67, wherein the cancer comprises a solid tumor.

69. The method of claim 68, wherein the solid tumor is selected from carcinoma, melanoma, sarcoma, and lymphoma.

70. The method of claim 68, wherein the solid tumor is selected from breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney (renal cell) cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, bone cancer, brain cancer, cervical cancer, liver cancer, stomach cancer, oral and oral cavity cancer, neuroblastoma, testicular cancer, uterine cancer, thyroid cancer, and vulvar cancer.

71. The method of claim 68, wherein the solid tumor comprises triple-negative breast cancer.

72. The method of claim 70, wherein the skin cancer includes melanoma, squamous cell carcinoma, and cutaneous T-cell lymphoma (CTCL).

73. The method of any one of claims 1-67, wherein the cancer includes leukemia.

74. The method of claim 73, wherein the leukemia is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia and adult T-cell leukemia.

75. The method of claim 73, wherein the leukemia is acute leukemia.

76. The method of any one of claims 1, 2, 18, 19, 21, 22, 23, 25, 30, 41, 43 and 50, wherein coenzyme Q10 is administered at a dose of about 10 mg / kg / day (24 hours) to about 150 mg / kg / day.

77. The method of any one of claims 1, 2, 18, 19, 21, 22, 23, 25, 30, 41, 43, and 50, wherein the dosage is selected from about 11.8 mg / kg / day (24 hours), about 12.5 mg / kg / day (24 hours), about 14.4 mg / kg / day (24 hours), about 15.6 mg / kg / day (24 hours), about 16.5 mg / kg / day (24 hours), about 19 mg / kg / day (24 hours), or about 20.4 mg / kg / day. / day (24 hours), approximately 22 mg / kg / day (24 hours), approximately 25 mg / kg / day (24 hours), approximately 27.5 mg / kg / day (24 hours), approximately 29.3 mg / kg / day (24 hours), approximately 33 mg / kg / day (24 hours), approximately 34.2 mg / kg / day (24 hours), approximately 36.7 mg / kg / day (24 hours), approximately 41.7 mg / kg / day (24 hours), approximately 42.8 mg / kg / day (24 hours), approximately 44 mg / kg / day (24 hours), approximately 45.7 mg / kg / day (24 hours), approximately 51.9 mg / kg / day (24 hours), approximately 53.8 mg / kg / day (24 hours), approximately 55 mg / kg / day (24 hours), approximately 57 mg / kg / day (24 hours), approximately 58.7 mg / kg / day (24 hours), approximately 64.8 mg / kg / day (24 hours), approximately 66.7 mg / kg / day (24 hours), approximately 68.5 mg / kg Coenzyme Q10 was administered at doses of approximately 71.7 mg / kg / day (24 hours), approximately 73.4 mg / kg / day (24 hours), approximately 81.5 mg / kg / day (24 hours), approximately 85.5 mg / kg / day (24 hours), approximately 91.7 mg / kg / day (24 hours), approximately 107.5 mg / kg / day (24 hours), approximately 114.6 mg / kg / day (24 hours), and approximately 143.3 mg / kg / day (24 hours).

78. The method of any one of claims 1, 2, 18, 19, 21, 22, 23, 25, 30, 41, 43 and 50, wherein coenzyme Q10 is administered at a dose selected from about 38 mg / kg / week, about 50 mg / kg / week, about 66 mg / kg / week, about 76 mg / kg / week, about 88 mg / kg / week, about 100 mg / kg / week, about 110 mg / kg / week, about 132 mg / kg / week, about 137 mg / kg / week, about 171 mg / kg / week, about 176 mg / kg / week, about 215 mg / kg / week, about 220 mg / kg / week, about 274 mg / kg / week, about 342 mg / kg / week and about 430 mg / kg / week.

79. The method of any one of claims 1, 2, 18, 19, 21, 22, 23, 25 and 30, wherein for the first hour of the infusion, a continuous intravenous infusion of coenzyme Q10 is administered at a higher rate.

80. The method of any one of claims 1, 2, 18, 19, 21, 22, 23, 25, 30, 41, 43 and 50, wherein at least 5%, 6%, 7%, 8%, 9% or 10% of the total dose of coenzyme Q10 administered during the first hour of the continuous intravenous infusion is applied.

81. The method of any one of claims 1, 2, 18, 19, 21, 22, 23, 25, 30, 41, 43 and 50, wherein at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27% or 28% of the total dose of coenzyme Q10 administered during the first hour of the continuous intravenous infusion is applied.

82. The method of any one of claims 1, 22, 23, 25 and 30, wherein the continuous intravenous infusion of coenzyme Q10 is performed at a constant rate.

83. The method of any one of claims 1-82, wherein the composition comprises 0.1% to 20% w / v coenzyme Q10.

84. The method of any one of claims 1-82, wherein the composition comprises 1% to 10% w / v coenzyme Q10.

85. The method of any one of claims 1-82, wherein the composition comprises 1% to 5% w / v coenzyme Q10.

86. The method of any one of claims 1-85, further comprising selecting a subject with cancer for treatment with coenzyme Q10, wherein the subject has adequate clotting ability.

87. The method of claim 86, wherein adequate coagulation comprises a platelet threshold of 50,000 / mcL, prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) within normal limits.

88. The method of any one of claims 1-87, further comprising selecting a subject with cancer for treatment with coenzyme Q10, wherein the subject exhibits at least one condition or characteristic selected from: (a) The subject was taking an HMG-CoA reductase inhibitor; (b) The subject was taking digoxin, digitoxin, digitoxin C or any type of digitalis alkaloid; (c) The subject has an uncontrolled or severe coagulopathy or a history of clinically significant bleeding within the past 6 months; (d) The subject suffers from at least one of hemoptysis, epistaxis, hematochezia, hematuria, or gastrointestinal bleeding; (e) The subject has a tendency to bleed; (f) The subject has been given an anticoagulant; (g) The subject has grade 3 thrombocytopenia with clinically significant bleeding; (h) The subject had ≥ grade 4 hematologic toxicity; (i) The subject had a grade 2 elevated INR / PTT, accompanied by clinically significant bleeding; and (j) The subject had grade 3 INR / PTT abnormalities.

89. The method of any one of claims 1-88, comprising improving the therapeutic index of intravenously administered coenzyme Q10 by increasing the infusion time of the coenzyme Q10 dose from no more than 6 hours to a continuous intravenous infusion of at least 48 hours.

90. A method for improving the therapeutic index of intravenously administered coenzyme Q10 by increasing the infusion time of the coenzyme Q10 dose from no more than 6 hours to continuous intravenous infusion for at least 48 hours.

91. The method of any one of claims 1-90, wherein coenzyme Q10 is administered for at least two cycles.

92. Intravenously administered coenzyme Q10 used in the method of any of the preceding claims.

93. Use of intravenously administered coenzyme Q10 in the method of any of the preceding claims.

94. A pharmaceutical composition comprising coenzyme Q10 for use in any of the preceding methods.

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