Methods for the treatment and prevention of nonviral tick-borne diseases and their symptoms.

Abstract

Methods and compositions for treating or preventing nonviral tick-borne diseases and their symptoms by administering long-acting 8-aminoquinolines such as tafenoquine are disclosed. A kit comprising means for testing for nonviral tick-borne diseases and / or their symptoms, and long-acting 8-aminoquinolines such as tafenoquine, is also disclosed.

Description

[Background technology]

[0001] 8-aminoquinolines have the ability to suppress or kill intracellular and extracellular pathogens through the induction of oxidative stress, thereby preventing or treating diseases caused by such pathogens. However, this is subject to the following conditions: (i) the pathogen is inherently susceptible to tafenoquine or hydrogen peroxide-like mechanisms of action in mammalian hosts; (ii) 8-aminoquinolines have suitable substituents to confer a long half-life, thus avoiding frequent administration schedules; (iii) they can be safely administered at a high enough level to achieve the desired antimicrobial or antiparasitic effect over a sufficiently long period; and / or (iv) the selected dosage for administration is suitable for treating both immune and immunocompetent patients without dose adjustment. As outlined below, standard treatment and management options for human diseases caused by the transmission of certain microorganisms by mites are insufficient, and this can be improved by using long-half-life 8-aminoquinolines alone or in combination with other agents.

[0002] Ticks found throughout the United States include the American dog tick, blacklegged tick, brown dog tick, groundhog tick, gulf coast tick, lone star tick, Rocky Mountain wood tick, soft tick, and western blacklegged tick. Some ticks carry pathogens such as species of the genera Anaplasma, Babesia, Borrelia, Ehrlichia, Rickettsia, and Francisella, which can cause human diseases including, among others, African tick bite fever, anaplasmosis (formerly known as human granulocytic ehrlichiosis or "HGE"), babesiosis, ehrlichiosis, Lyme disease, Mediterranean spotted fever (also known as button fever), Rickettsia parkeri rickettsiosis, Rocky Mountain spotted fever, Southern tick-associated rash illness, tickborne relapsing fever, tularemia, and 364D rickettsiosis (a relatively new disease identified in the state of California, USA). All of these infectious organisms have an obligate intracellular life cycle in mammalian hosts (except for species of the genus Borrelia), and all are Gram-negative spirochetes (except for species of the genus Babesia). From 2004 to 2019, the total number of reported cases of tick-borne diseases in the United States increased from 20,000 to 60,000. The number of unreported cases is estimated to be 9 to 30 times higher, in the range of 180,000 to 1,800,000. The severity of diseases caused by ticks varies.

[0003] Babesiosis Babesiosis, caused by various species of the genus Babesia, has an incubation period of 1 to 9 weeks or more. Signs and symptoms of babesiosis include fever, chills, sweating, malaise, fatigue, myalgia, arthralgia, headache, gastrointestinal symptoms (e.g., loss of appetite and nausea, and less commonly, abdominal pain and vomiting), and dark urine. Less common signs and symptoms include cough, sore throat, mood swings, depression, photophobia, conjunctival hyperemia, mild splenomegaly, mild hepatomegaly, and jaundice. Common laboratory findings of babesiosis include decreased hematocrit due to hemolytic anemia, thrombocytopenia, elevated serum creatinine and blood urea nitrogen levels, and mildly elevated liver transaminase levels.

[0004] Conventional treatment for babesiosis involves a combination of two drugs, typically atovaquone plus azithromycin or clindamycin plus quinine, administered for at least 7–10 days. While these regimens generally cure most immunocompetent patients, they do not prevent the high rate of complications (>30%) in hospitalized patients, with approximately 10% of immunocompetent hospitalized patients and 25% of immunocompromised hospitalized patients requiring additional courses of chemotherapy. Mortality is 1–2% in the general hospitalized patient population, but can be considerably higher in immunocompromised individuals. In contrast, malaria, a disease caused by a parasitic protozoan that can similarly invade red blood cells and cause anemia and severe organ failure, has an effective 3-day oral and intravenous treatment with a mortality rate of 0.35% in the United States (Mace et al. 2021: Non-Patent Literature 1).

[0005] Lyme disease and Borreliosis Lyme disease and borreliosis are associated with infection by species of the genus Borrelia, the most important of which in the United States is Lyme disease borrelia (B. burgdorferi). The incubation period is 3 to 30 days, and signs and symptoms vary depending on the stage of the disease. In the localized stage, signs and symptoms include migratory erythema migrans ("EM") - red rashes that spread in rings or uniformly, flu-like symptoms (such as fatigue, headache, fever, myalgia, and arthralgia), and lymphadenopathy. In the disseminated stage, signs and symptoms include multiple secondary annular rashes, flu-like symptoms, lymphadenopathy, rheumatic symptoms, cardiac symptoms, neurological symptoms, conjunctivitis, keratitis, uveitis, mild hepatitis, and splenomegaly. Common laboratory findings include elevated erythrocyte sedimentation rate, mild elevation of hepatic transaminases, and microscopic hematuria or proteinuria. In Lyme disease meningitis, cerebrospinal fluid typically shows lymphocytic pleocytosis, a slight increase in protein, and normal glucose levels. Post-exposure prophylaxis for Lyme disease is a single dose of 200 mg doxycycline within 72 hours of a tick bite (Lantos et al. 2021: Non-Patent Literature 2). Migratory erythema is treated with oral antibiotic therapy for 10–14 days with doxycycline, cefuroxime axetil, and amoxicillin, and as a second-line treatment with azithromycin for 5–10 days (Lantos et al. 2021: Non-Patent Literature 2). The treatment of established infections and their complications is complex and may involve the administration of oral or intravenous antibiotics (including those mentioned above and penicillin G) and corticosteroids, depending on the situation (Lantos et al. 2021: Non-patent Literature 2).

[0006] Lyme disease is not associated with a high mortality rate; a review of mortality records in the United States from 1993 to 2003 found only one case consistent with the clinical presentation of Lyme disease (Kugeler et al. 2010: Non-Patent Literature 3). However, while standard antibiotic treatment successfully resolves clinical symptoms in over 80% of cases, the remaining patients may experience persistent Lyme disease as a syndrome with various symptoms known as post-treatment Lyme disease syndrome (PTLDS, Cabello et al. 2022: Non-Patent Literature 4). The exact cause of PTLDS is unknown (Cabello et al. 2022: Non-Patent Literature 4), but antimicrobial tolerance is one proposed mechanism. A period of transient intracellular localization of Borrelia organisms, which allows for evasion of immune defense, has also been proposed (Ma et al. 1991: Non-Patent Literature 5, Montgomery et al. 1993: Non-Patent Literature 6).

[0007] Another borreliosis is Borrelia miyamotoi disease, which has an incubation period of several days to several weeks. Signs and symptoms of Borrelia miyamotoi disease include fever, chills, fatigue, severe headache, arthralgia / myalgia, dizziness, confusion, vertigo, rash, shortness of breath, nausea, abdominal pain, diarrhea, and loss of appetite. Common laboratory findings of Borrelia miyamotoi disease include leukopenia, thrombocytopenia, and elevated liver transaminase levels. There is no generally accepted treatment for Borrelia miyamotoi disease, and antibiotics used to treat Lyme disease have been reported to be effective (at the same dosage).

[0008] tularemia Tularemia, caused by Fancisella tularemia, is a highly infectious disease with a mortality rate of up to 30%. The incubation period is 3 to 5 days, but can be up to 21 days. Signs and symptoms include fever, chills, headache, malaise, fatigue, loss of appetite, myalgia, chest discomfort, cough, sore throat, vomiting, diarrhea, and abdominal pain. Common laboratory findings include normal or elevated white blood cell count and sedimentation rate, thrombocytopenia, hyponatremia, elevated hepatic transaminases, and elevated creatine phosphokinase. Myoglobinuria and sterile pyuria may or may not be present. Conventional treatment for tularemia involves streptomycin, gentamicin, ciprofloxacin, and doxycycline.

[0009] Other tick-borne rickettsial diseases (Tick-Borne Rickettsial Disease: "TBRD") TBRD is caused by various obligate intracellular Rickettsia species, the most important of which in the United States are Rickettsia rickettsii, Ehrlichia chaffeensis, and Anaplasma phagocytophilum (Chapman et al. 2006: Non-Patent Literature 7). A brief description of some of the more important TBRDs is outlined below. What is generally true of all TBRDs is that their management can require hospitalization in up to 50% of cases, that there is a high rate of hospital-acquired complications, and that the standard treatment is the administration of tetracycline antibiotics, which are most effective in the early stages of infection when TBRD is difficult to differentiate from other infectious diseases (Chapman et al. 2006). While tetracyclines are considered standard treatment, mortality rates in treated populations can be high, ranging from 5% for Rocky Mountain spotted fever to 1-3% for anaplasmosis and ehrlichosis. Considering that diseases like malaria, with a low fatality rate of 0.35% (Mace et al. 2021: Non-Patent Literature 8), can be treated with a three-day oral or IV course of medication, it is clear that standard treatment for TBRD is inadequate and patients are generally not receiving adequate care.

[0010] In cases of anaplasmosis, the incubation period is generally 5 to 14 days, and signs and symptoms of anaplasmosis include fever, chills, shivering, severe headache, malaise, myalgia, gastrointestinal symptoms (such as nausea, vomiting, diarrhea, and loss of appetite), and rash. Typical laboratory findings of anaplasmosis observed during the first week of clinical illness include mild anemia, thrombocytopenia, leukopenia (characterized by relative and absolute lymphopenia and a left shift), and mild to moderate elevation of hepatic transaminases. The observation of morula in the cytoplasm of granulocytes during blood smear examination strongly suggests a diagnosis.

[0011] In cases of ehrlichiosis, the incubation period is 5 to 14 days, and signs and symptoms of ehrlichiosis include fever, chills, headache, fatigue, muscle pain, gastrointestinal symptoms (such as nausea, vomiting, diarrhea, and loss of appetite), altered mental state, and rash. Common laboratory findings of ehrlichiosis include thrombocytopenia, leukopenia (absolute), anemia (generally occurring at a more advanced stage of the disease than thrombocytopenia or leukopenia), and mild to moderate elevation of liver transaminases.

[0012] In cases of rickettsial disease caused by Rickettsia parcheri, the incubation period is 2 to 10 days, and signs and symptoms include fever, headache, rash (sparse maculopapular or papulavesicular rash on the trunk and limbs), and muscle pain. Common laboratory findings include mild elevation of liver transaminases, mild leukopenia, and mild thrombocytopenia.

[0013] In Rocky Mountain spotted fever, the incubation period is 3 to 12 days. Signs and symptoms include, in the first 1 to 4 days, high fever, severe headache, malaise, myalgia, edema around the eyes and on the back of the hands, and gastrointestinal symptoms (including nausea, vomiting, and loss of appetite). From the 5th day onward, however, changes in mental state, coma, cerebral edema, respiratory distress (pulmonary edema, ARDS), necrosis, and multiple organ damage (CNS, renal failure). The rash typically appears 2 to 5 days after the onset of symptoms. Common laboratory findings include thrombocytopenia, elevated hepatic transaminases, and hyponatremia.

[0014] In tick-borne relapsing fever, the incubation period is approximately 7 days, followed by recurrent fever episodes lasting about 3 days, interspersed with periods of about 7 days without fever. Signs and symptoms include headache, myalgia, chills, nausea, vomiting, arthralgia, and facial nerve paralysis. Common laboratory findings include normal to elevated white blood cell count with a left shift, a mild increase in serum bilirubin, mild to moderate thrombocytopenia, elevated erythrocyte sedimentation rate, and slight prolongation of prothrombin time and partial thromboplastin time. Conventional treatment for tick-borne relapsing fever involves tetracycline, erythromycin, and ceftriaxone.

[0015] There is an urgent need for new methods to treat and prevent nonviral tick-borne diseases such as babesiosis and their symptoms. [Prior art documents] [Non-patent literature]

[0016] [Non-Patent Document 1] Mace et al.2021.Malaria Surveillance-United States,2017.MMWR;70:1-32 [Non-Patent Document 2] Lantos et al.2021.Clinical practice guidelines by the Infectious Diseases Society of America(IDSA),American Academy of Neurology(AAN),and American College of Rheumatology(ACR):2020 Guidelines for the Prevention,Diagnosis and Treatment of Lyme Disease.CID;72:1-8 [Non-Patent Document 3] Kugeler et al.2010.A ​​review of death certificates listing Lyme disease as a cause of death in the United States.CID;52:364-367 [Non-Patent Document 4] Cabello et al.2022.Borreliella burgdorferi Antimicrobial-Tolerant Persistence in Lyme Disease and Posttreatment Lyme Disease Syndromes mBIO:https: / / doi.org / 10.1128 / mbio.03440-21 [Non-Patent Document 5] Ma et al.1991.Intracellular localization of Borrelia burgdorferi within human Endothelial cells.Infection and Immunity;59:671-678 [Non-Patent Document 6] Montgomery et al.1993.The fate of Borrelia burgdorferi,the agent for lyme disease,in mouse macrophages.J Immunol;150:909-915 [Non-Patent Document 7] Chapman et al.2006.Diagnosis and management of tickborne rickettsial diseases:Rocky mountain spotted fever,ehrlichoses,and anaplasmosis-United States [Non-Patent Document 8] Mace et al.2021.Malaria Surveillance-United States,2017.MMWR;70:1-32 [Overview of the project] [Means for solving the problem]

[0017] The present invention relates to a method for treating or preventing a nonviral tick-borne disease or its symptoms in a human subject, comprising administering an effective amount of a long-half-life 8-aminoquinoline to a subject in need thereof. In some embodiments, the tick-borne organism is a species of the genera Babesia, Rickettsia, Francisella, Anaplasma, Ehrlichia, or Borrelia, and the disease caused may be, but is not limited to, one or more of the following: African tick-bite fever, anaplasmosis, babesiosis, borreliosis, ehrlichiosis, Lyme disease, Mediterranean spotted fever, relapsing tick-fever, rickettsial disease by Rickettsia parcheri, rickettsial disease, Rocky Mountain spotted fever, Southern tick-associated rash disease, tick-borne relapsing fever, tularemia, and 364D rickettsial disease. In some embodiments, long-half-life 8-aminoquinolines can treat or prevent tick-borne diseases with a minimum single dose of 50 mg or the minimum initial dose in a regimen. In some embodiments, the long-half-life 8-aminoquinolines are tafenoquine or pharmaceutically acceptable salts thereof.In some embodiments, administration follows one of the following regimens: (a) an initial dose of 50 mg followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg followed by one additional dose of 300 mg within one week of the initial dose; (f) an administration of 400 mg; (g) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the first loading dose; and (h) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg one week after the completion of the loading dose, followed by 200 mg once a week for up to 52 weeks. In some embodiments, the subjects requiring it are symptomatic outpatients, symptomatic outpatients with risk factors for disease progression, symptomatic outpatients with weakened immune function, symptomatic inpatients, symptomatic inpatients with risk factors for disease progression, symptomatic inpatients with weakened immune function, asymptomatic subjects, asymptomatic subjects without risk factors, asymptomatic subjects with risk factors, asymptomatic subjects at risk of tick bites, asymptomatic subjects without risk factors at risk of tick bites, asymptomatic subjects with risk factors at risk of tick bites, subjects without risk factors who have been bitten by ticks and are at risk of contracting the tick-borne disease, and subjects with risk factors who have been bitten by ticks and are at risk of contracting the tick-borne disease.

[0018] In some embodiments, the present invention relates to a method for treating or preventing a nonviral tick-borne disease or its symptoms in a human subject, comprising (a) administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising a compound of formula (I): [ka] [wherein R is any halogen-containing substituent with a molecular weight ≤ 205]. In some embodiments, the tick-borne organism is a species of the genera Babesia, Rickettsia, Francisella, Anaplasma, Ehrlichia, or Borrelia, and the resulting disease may be, but is not limited to, one or more of the following: African tick-bite fever, anaplasmosis, babesiosis, borreliosis, ehrlichiosis, Lyme disease, Mediterranean spotted fever, tick-induced relapsing fever, rickettsial disease by Rickettsia parcheri, rickettsial disease, Rocky Mountain spotted fever, Southern tick-associated rash disease, tick-borne relapsing fever, tularemia, and 364D rickettsial disease. In some embodiments, long-half-life 8-aminoquinolines can treat or prevent tick-borne diseases with a minimum single dose of 50 mg or a minimum initial dose in a regimen. In some embodiments, the long-half-life 8-aminoquinolines are tafenoquine or pharmaceutically acceptable salts thereof. In some embodiments, administration follows one of the following regimens: (a) an initial dose of 50 mg followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg followed by one additional dose of 300 mg within one week of the initial dose; (f) an administration of 400 mg; (g) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the first loading dose; and (h) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg one week after the completion of the loading dose, followed by 200 mg once a week for up to 52 weeks.In some embodiments, the subject in need thereof is a symptomatic outpatient subject, a symptomatic outpatient subject having a risk factor for disease progression, a symptomatic outpatient subject with a reduced immune function, a symptomatic inpatient subject, a symptomatic inpatient subject having a risk factor for disease progression, a symptomatic inpatient subject with a reduced immune function, an asymptomatic subject, an asymptomatic subject without a risk factor, an asymptomatic subject with a risk factor, an asymptomatic subject at risk of mite bite, an asymptomatic subject without a risk factor at risk of mite bite, an asymptomatic subject with a risk factor at risk of mite bite, a subject who has been bitten by a mite and is at risk of suffering from the mite-borne disease, a subject without a risk factor, and a subject who has been bitten by a mite and is at risk of suffering from the mite-borne disease, a subject with a risk factor.

[0019] In some embodiments, methods are provided for treating or preventing nonviral tick-borne diseases or their symptoms in human subjects, comprising administering tafenoquin to subjects in need. In some embodiments, the tick-borne organism is a species of the genera Babesia, Rickettsia, Francisella, Anaplasma, Ehrlichia, or Borrelia, and the disease caused may be, but is not limited to, one or more of the following: African tick-bite fever, anaplasmosis, babesiosis, borreliosis, ehrlichiosis, Lyme disease, Mediterranean spotted fever, tick-induced relapsing fever, rickettsial disease by Rickettsia parcheri, rickettsial disease, Rocky Mountain spotted fever, Southern tick-associated rash disease, tick-borne relapsing fever, tularemia, and 364D rickettsial disease. In some embodiments, long-half-life 8-aminoquinolines can treat or prevent tick-borne diseases with a minimum single dose of 50 mg or the minimum initial dose in a regimen. In some embodiments, the long-half-life 8-aminoquinolines are tafenoquine or pharmaceutically acceptable salts thereof.In some embodiments, administration follows one of the following regimens: (a) an initial dose of 50 mg followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg followed by one additional dose of 300 mg within one week of the initial dose; (f) an administration of 400 mg; (g) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the first loading dose; and (h) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg one week after the completion of the loading dose, followed by 200 mg once a week for up to 52 weeks. In some embodiments, the subjects requiring it are symptomatic outpatients, symptomatic outpatients with risk factors for disease progression, symptomatic outpatients with weakened immune function, symptomatic inpatients, symptomatic inpatients with risk factors for disease progression, symptomatic inpatients with weakened immune function, asymptomatic subjects, asymptomatic subjects without risk factors, asymptomatic subjects with risk factors, asymptomatic subjects at risk of tick bites, asymptomatic subjects without risk factors at risk of tick bites, asymptomatic subjects with risk factors at risk of tick bites, subjects without risk factors who have been bitten by ticks and are at risk of contracting the tick-borne disease, and subjects with risk factors who have been bitten by ticks and are at risk of contracting the tick-borne disease.

[0020] In some embodiments, the method of the invention further comprises administering a second and / or third agent, such as doxycycline, azithromycin-atovaquone, clindamycin-quinine, artesunate, artemether-lumefantrine, or any other agent recommended by the IDSA or CDC for the treatment or prevention of non-viral tick-borne diseases.

[0021] For the method of the invention, in some embodiments, the risk factors for disease progression are selected from the group consisting of age > 55 years, fatigue, nausea, diarrhea, symptom duration > 7 days, abnormal test values, such as decreased / increased white blood cell count, increased bilirubin and increased creatinine, or any existing condition or treatment that results in a state of reduced immune function, and combinations thereof.

[0022] For the method of the invention, in some embodiments, the state of reduced immune function is due to a state selected from the group consisting of asplenia, hyposplenism, pretreatment with immunosuppressive drugs, existing autoimmune diseases, or other states known to suppress the immune system, and combinations thereof.

[0023] In some embodiments, the pathogenic organism is a species of Babesia or the disease is babesiosis.

[0024] In some embodiments, the pathogenic organism is a species of Borrelia or the disease is borreliosis or Lyme disease.

[0025] In some embodiments, the pathogenic organism is a species of Rickettsia or the disease is ricketsiosis.

[0026] In some embodiments, the pathogenic organism is a species of Anaplasma or Ehrlichia and the disease is anaplasmosis or ehrlichiosis.

[0027] In some embodiments, the pathogenic organism is a species of Francisella and the disease is tularemia.

[0028] In some embodiments, administration is via the sublingual route and / or the buccal route and / or the intravenous route.

[0029] In some embodiments, administration is carried out according to the administration regimen in Table 1 and / or according to one of the examples.

[0030] In some embodiments, the amount of long-lived 8-aminoquinolines administered to the subject over a 12-month period is 11,000 mg or less.

[0031] In some embodiments, the amount of the compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) [wherein R is any halogen-containing substituent with a molecular weight ≤ 205] administered to the subject within a period of 12 months is 11,000 mg or less.

[0032] In some embodiments, a kit is provided comprising (a) means for testing for nonviral tick-borne diseases and / or symptoms thereof and / or glucose-6-dehydrogenase (G6PD deficiency), (b) a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), and (c) instructions for use, wherein R in formula (I) is any halogen-containing substituent with a molecular weight ≤ 205.

[0033] In some embodiments, a kit is provided comprising (a) means for testing for nonviral tick-borne diseases and / or symptoms thereof and / or glucose-6-dehydrogenase (G6PD deficiency), (b) long-half-life 8-aminoquinolines, and (c) instructions for use.

[0034] In some embodiments, a kit is provided comprising (a) means for testing for nonviral tick-borne diseases and / or symptoms thereof and / or glucose-6-dehydrogenase (G6PD deficiency), (b) tafenoquine, and (c) instructions for use.

[0035] In some embodiments, a method is provided for pretreatment of a nonviral tick-borne disease and / or its symptoms in a human subject, comprising administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising a compound of formula (I): [ka] [In the formula, R is any halogen-containing substituent with a molecular weight ≤ 205]. In some embodiments, the compound of formula (I) is tafenoquine or a salt thereof.

[0036] Summary of Embodiments The present invention relates to a method for treating and / or preventing tick-borne diseases or their symptoms in human subjects. The method comprises administering an effective amount of long-acting 8-aminoquinolines to subjects in need of treatment or prevention of tick-borne diseases. In another embodiment, the present invention relates to the use of long-acting 8-aminoquinolines for treating or preventing tick-borne diseases or their symptoms in human subjects, comprising administering an effective amount of long-acting 8-aminoquinolines to human subjects.

[0037] species of the genus Babesia In some embodiments of the present invention, the tick-borne disease is caused by a parasite of the genus Babesia. In these embodiments, the tick-borne disease may be babesiosis. In some embodiments, the present invention relates to treating a human subject for a tick-borne disease caused by a parasite of the genus Babesia, where the subject is diagnosed with infection by the parasite of the genus Babesia before administration of long-half-life 8-aminoquinolines to the subject. In some embodiments, for example, in embodiments where the subject is infected with a parasite of the genus Babesia, the subject may be co-infected with a spirochete of the genus Borrelia or a parasite of the genus Borrelia.

[0038] In some embodiments, the present invention relates to treating human subjects for a tick-borne disease caused by a parasite of the genus Babesia, wherein the subjects have been diagnosed with at least one of babesiosis infection and babesiosis disease. In some embodiments, the diagnosis includes clinical tests to confirm babesiosis infection and / or babesiosis disease.

[0039] In some embodiments, the subjects treated according to the present invention are symptomatic outpatients or symptomatic inpatients. In some embodiments, the subjects are symptomatic inpatients.

[0040] In some embodiments, the present invention relates to preventing tick-borne diseases in human subjects who are at increased risk of exposure to tick-borne pathogens, including parasites of the genus Babesia, or who have had potential exposure to tick-borne pathogens, including parasites of the genus Babesia.

[0041] Species not belonging to the genus Babesia In some embodiments of the present invention, the tick-borne disease is caused by a parasite of a species of non-Babesia genus. In these embodiments, the disease may be caused by a parasite of a species of Borrelia, Rickettsia, Francisella, Anaplasma, or Ehrlichia genus. In some embodiments, the tick-borne disease may be selected from one or more of Lyme disease, borreliosis, African tick-bite fever, anaplasmosis, ehrlichiosis, Mediterranean spotted fever, tick-induced relapsing fever, rickettsial disease by Rickettsia parcheri, rickettsial disease, Rocky Mountain spotted fever, Southern tick-associated rash disease, tick-borne relapsing fever, tularemia, and 364D rickettsial disease. In another embodiment, the tick-borne disease is caused by a parasite of a species of Borrelia genus, and long-lived 8-aminoquinolines are administered to subjects to prevent or reduce the severity of borreliosis and / or Lyme disease.

[0042] In some embodiments, such as embodiments including a treatment method, or embodiments including the use of long-lived 8-aminoquinolines to treat a subject, the subject has been diagnosed with infection with a parasite of the genera Borrelia, Rickettsia, Francisella, Anaplasma, or Ehrlichia prior to the administration of the long-lived 8-aminoquinolines. In another embodiment, the present invention relates to preventing tick-borne diseases in human subjects who are at increased risk of exposure to tick-borne pathogens, including parasites of the genera Babesia, or who have had potential exposure to tick-borne pathogens, including parasites of the genera Babesia.

[0043] Prevention of tick-borne diseases before and after exposure In embodiments of the present invention relating to the prevention of tick-borne diseases (e.g., those caused by parasites that are species of the Babesia genus or non-Babesia genus), a human subject may be identified as needing prevention if the subject is identified as being at increased risk of exposure to tick-borne pathogens. For example, in some embodiments, subjects at increased risk of exposure include subjects traveling to and / or engaging in recreational or professional activities in areas or environments associated with an increased risk of tick bites. In some embodiments, the present invention relates to identifying human subjects that need prevention. In some embodiments, an increased risk of tick bites includes an increased risk of bites from the black-footed tick.

[0044] In embodiments of the present invention relating to the prevention of tick-borne diseases, a human subject may be identified as needing prevention if it is identified that the subject has had a potential exposure to a tick-borne pathogen. Here, for example, in some embodiments, the tick-borne disease is caused by a parasite of a species of non-Babesia, and in other embodiments, by a parasite of a species of Babesia. In some embodiments, the potential exposure may be a known or suspected tick bite by a tick that has been identified or is suspected to be a black-legged tick. In some embodiments, the potential exposure is a known or suspected tick bite. In other embodiments, the potential exposure is a known tick bite by a black-legged tick.

[0045] Composition, use, and administration In each embodiment of the present invention, the long-lived 8-aminoquinolines may be compounds capable of treating or preventing tick-borne diseases with a minimum single dose of 50 mg or the minimum initial dose in a regimen. In some embodiments, the long-lived 8-aminoquinolines are compounds of formula (I), pharmaceutically acceptable salts thereof: [ka] [wherein R is any halogen-containing substituent with a molecular weight ≤ 205]. In another embodiment, the long-lived 8-aminoquinolines may be a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable carrier. In another embodiment, the long-lived 8-aminoquinolines are tafenoquine or a pharmaceutically acceptable salt thereof. In another embodiment, the long-lived 8-aminoquinolines may be a pharmaceutical composition comprising tafenoquine and a pharmaceutically acceptable carrier.

[0046] In each embodiment of the present invention, long-half-life 8-aminoquinolines may be administered to a subject (e.g., a subject requiring treatment or prevention of a tick-borne disease) according to one of the following regimens: (a) An initial dose of 50 mg, followed by one additional dose of 50 mg within one week of the initial dose; (b) An initial dose of 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) An initial dose of 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) An initial dose of 200 mg, followed by at least one and up to three additional doses within 15 days of the initial dose; (e) An initial dose of 300 mg, followed by one additional dose of 300 mg within one week of the initial dose; (f) Administration of 400 mg; (g) A loading dose of 600 mg administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the initial loading dose; and (h) A 600 mg loading dose administered over 1 to 5 days by the following regimens: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a 200 mg maintenance dose one week after completion of the loading dose, followed by 200 mg once weekly for up to 52 weeks.

[0047] In another embodiment, subjects requiring treatment or prevention may be administered approximately 200 mg of long-acting 8-aminoquinolines per day for 4 days, in which case the daily dose may be a single dose or divided doses. In some embodiments, for example, in which subjects are being treated for non-babesia infections such as borreliosis and / or Lyme disease, subjects may be further administered approximately 200 mg / week of long-acting 8-aminoquinolines for up to 52 weeks, in which case the weekly dose may be a single dose or divided doses. In each embodiment, long-acting 8-aminoquinolines may be administered to subjects via the sublingual route, the buccal route, and / or the intravenous route, or a combination of these routes. In some embodiments, the amount of long-acting 8-aminoquinolines administered to subjects over a 12-month period is 11,000 mg or less.

[0048] In some embodiments, the subject is also administered additional pharmaceuticals on one or more days of the treatment or prevention protocol. For example, in some embodiments, the additional pharmaceuticals include one or more of azithromycin, atovaquone, and / or doxycycline administered to the subject. In other embodiments, the treatment or prevention method, and / or the use of long-half-life 8-aminoquinolines, may further include administering to a human subject a second or third pharmaceutical selected from one or more of doxycycline, azithromycin-atovaquone, clindamycin-quinine, artesunate, artemether-rumefantrine, and any other pharmaceuticals recommended by the IDSA or CDC for the treatment of nonviral tick-borne diseases.

[0049] It should be understood that references to dosages or administrations used herein should be interpreted in accordance with their common use, for example, to the amount of the active ingredient administered to a subject (e.g., a dose of long-half-life 8-aminoquinolines or a pharmaceutically acceptable salt thereof). It should also be understood that the specific embodiments listed herein are illustrative in nature and are not intended to limit the entire scope of the applicant's invention, as would be understood from the applicant's disclosure to those skilled in the art.

[0050] The above will become clear from the following more specific description of exemplary embodiments of the present invention, as shown in the attached drawings. [Brief explanation of the drawing]

[0051] [Figure 1A] Molecular structures of primaquine and tafenoquine. [Figure 1B] Summary of the biological data mentioned in the text: Tafenoquin has a longer in vivo half-life, resulting in a more potent effect and a broader spectrum of effects on multiple organisms. [Modes for carrying out the invention]

[0052] definition Any of the following definitions of substituents are also applicable to the terms used in conjunction with other substituents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by a person of ordinary skill in the art to which this invention pertains.

[0053] As used herein, the singular forms "a," "and," and "the" include references to the plural unless the context makes this clear. Furthermore, the term "comprises" is intended to include embodiments of a method, apparatus, composition, etc., which consist essentially of the listed steps, components, etc., and / or embodiments comprising the listed steps, components, etc. Similarly, the term "consists essentially of" is intended to include embodiments of a method, apparatus, composition, etc., which consist essentially of the listed steps, components, etc.

[0054] As used herein, the term “approximately” refers to a number whose difference from a given number is less than 15%. In another embodiment, the term “approximately” indicates that the difference between that number and a given number is less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%.

[0055] As used herein, “asymptomatic” refers to a human subject who does not have symptoms of a tick-borne disease, and who may or may not have been bitten by a tick, and who may or may not be at risk of being bitten by a tick. For example, an asymptomatic person may be a person who has been bitten by a tick but has not experienced symptoms of a tick-borne disease, or a healthy person who is planning a trip or recreation that would increase the risk of being bitten by a tick.

[0056] As used herein, "G6PD" means glucose-6-phosphate dehydrogenase, and "G6PD deficiency" refers to a subject lacking this enzyme. In humans, treatment of subjects with G6PD deficiency with 8-aminoquinolines can cause hemolysis, which can sometimes have clinical significance. Generally, the methods described herein are for subjects without G6PD deficiency.

[0057] As used herein, “normal G6PD” refers to a human subject whose glucose-6-phosphate dehydrogenase levels are normal. Normal G6PD levels can be determined by approved clinical tests using validated methods known to those skilled in the art.

[0058] Human subjects may be adults or children. As used herein, “child” refers to human subjects from 1 day old to 17 years of age. The term “adult” refers to human subjects 18 years of age or older.

[0059] As used herein, “loading phase,” “loading dose,” or “initial dose” refers to the initial dose of the material, which is at least one dose. For example, the loading phase may consist of once a day for up to three consecutive days, after which the frequency of administration may be reduced.

[0060] As used herein, “subsequent dose” refers to a dose administered after the initial dose, and is at least one dose. The subsequent dose may be the same amount as the initial dose or a different amount. The subsequent dose may be administered within the same time frame as the initial dose or a different time frame.

[0061] As used herein, "maintenance dose" refers to a dose administered after the initial dose and subsequent doses.

[0062] As used herein, “per day” means within a given 24-hour period.

[0063] As used herein, “per week” means within a given 7-day period.

[0064] "Three doses per day" or "three times per day" as used herein means administering a composition three times at 24-hour intervals.

[0065] "Quadruple daily administration" (QDS) or "four times per day" as used herein means administering a composition four times at 24-hour intervals.

[0066] In particular, embodiments of the present method and composition may use a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof. The disclosed compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered as part of a pharmaceutical composition together with an acceptable pharmaceutical carrier or diluent, according to any of the administration regimens described herein for the methods described herein. The formulation of the administered compound varies depending on the chosen route of administration (e.g., solution, emulsion, capsule). A suitable pharmaceutical carrier may contain an inactive component that does not interact with the compound. Standard pharmaceutical formulation techniques, such as those described in "Remington's Pharmaceutical Sciences" (Mack Publishing Company, Easton, Pennsylvania), may be used. Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing approximately 0.9% mg / ml benzyl alcohol), phosphate-buffered saline, Hanks' solution, and Ringer's lactate solution. Methods for encapsulating compositions (for example, in a coating of rigid gelatin or cyclodextran) are known in the art (Baker, et al. "Controlled Release of Biological Active Agents," John Wiley and Sons, 1986).

[0067] "Pharmacologically acceptable carrier" means a non-therapeutic component that, when administered appropriately, typically does not cause adverse reactions, possesses sufficient purity and quality for use in the formulation of the compositions of the present invention, and is used as a medium for the active pharmaceutical ingredient (e.g., a compound of formula (I), such as tafenoquine).

[0068] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammal being treated with it.

[0069] A pharmaceutical preparation includes a carrier, diluent, or excipient that is both "pharmaceutically acceptable" and "physiologically acceptable." In this context, the terms "pharmaceutically acceptable" and "physiologically acceptable" include solvents (aqueous or nonaqueous), solutions, emulsions, dispersions, coatings, isotonic agents, and absorption enhancers or retarders that are suitable for pharmaceutical administration. Such preparations may be contained in liquids, such as emulsions, suspensions, syrups, or elixirs, or in solids, such as tablets (coated or uncoated), capsules (hard or soft), powders, granules, crystals, or microbeads. The composition may also incorporate auxiliary compounds (e.g., preservatives, antibacterial agents, antiviral agents, and antifungal agents).

[0070] The compounds of the present invention can be formulated into pharmaceutically acceptable salt forms. pharmaceutically acceptable salts of the compounds of the present invention can be prepared using conventional techniques. “pharmaceutically acceptable salts” include both acid-added salts and base-added salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts described herein are pharmaceutically acceptable acid-added salts or pharmaceutically acceptable base-added salts.

[0071] A "pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, or phosphorous acid, which retains the biological efficacy and properties of the free base and is not biologically or otherwise undesirable. Salts formed with organic acids such as aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanos, hydroxyalkanoics, alkanedioics, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid are also included. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Salts of amino acids, such as alginates, glucons, and galacturons, are also conceivable (see, for example, Berge SM et al. "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds can be prepared by contacting the basic form with a sufficient amount of the desired acid to produce a salt, according to methods and techniques familiar to those skilled in the art.

[0072] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological efficacy and properties of a free acid and is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. Pharmaceutically acceptable base addition salts can be formed from metals or amines such as alkali metals, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Examples of salts derived from organic bases include, but are not limited to, salts of primary amines, secondary and tertiary amines, substituted amines (e.g., naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (e.g., isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al. above.

[0073] The term “effective dose” means an amount of a drug that (i) treats or prevents a particular disease, condition, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as disclosed herein.

[0074] The term "immunely impaired" as used herein means a person having one or more of the following conditions: asplenia, hyposplenism, autoimmune disease, being treated with immunosuppressants (e.g., drugs selected from the following non-exclusive list: rituximab, cyclophosphamide, vincristine, prednisone, hydrocortisone, and doxyrubicin), or having any pre-existing medical condition that suppresses the immune system (e.g., conditions selected from the following non-exclusive list: organ transplant recipient, AIDS, B-cell lymphoma, multiple myeloma, and conditions associated with B-cell depletion, hereditary spherocytosis, Evan syndrome, brain tumor, cancer, gastric cancer, and x-linked agammaglobulinemia).

[0075] When used herein, the term "immunely functioning normally" means a person whose immune function is not impaired as described above.

[0076] As used herein, “semi-immune” refers to a resident of a malaria-endemic country who, due to numerous previous exposures to symptomatic malaria, has acquired partial immunity, which typically results in the absence of clinical signs and symptoms of malaria, even when the presence of malaria parasites in the blood is confirmed by microscopic examination. Antimalarial drugs exert their effects at different dosages for semi-immune and non-immune individuals.

[0077] As used herein, “non-immune” refers to an individual whose prior exposure to malaria was insufficient to immunize him against the signs and symptoms of malaria, as confirmed by microscopic examination of the presence of the malaria parasite. A non-immune individual may also be malaria naive if he has never been previously exposed to malaria.

[0078] As used herein, a human or non-human animal subject (preferably human) "needs" a treatment if it derives a biological, medical, or quality-of-life benefit from that treatment. In some embodiments, the subject has symptoms characteristic of babesiosis or other nonviral tick-borne disease and requires treatment. In other embodiments, the subject is suspected of or has been bitten by a tick and requires post-exposure prophylaxis to prevent the onset of a symptomatic disease. In some embodiments, the subject anticipates undertaking travel or recreational activities (e.g., hiking or camping) that may be associated with an increased risk of tick bites and therefore requires prophylaxis. In some embodiments, the subject is at increased risk of occupational exposure to tick bites than others in a group (e.g., a forest worker or wilderness guide).

[0079] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or biological process.

[0080] As used herein, the terms “subject,” “patient,” and “individual” are interchangeable and refer to a human being of any age or sex.

[0081] As used herein, the terms “to treat,” “to treat,” or “treatment” of any disease or disorder mean, in one embodiment, improving the disease or disorder (i.e., slowing, stopping, or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, “to treat,” “to treat,” or “treatment” means reducing or improving at least one physical parameter (including those that may not be recognizable to the subject). In yet another embodiment, “to treat,” “to treat,” or “treatment” means physically modulating the disease or disorder (e.g., stabilizing recognizable symptoms) or physiologically modulating it (e.g., stabilizing physical parameters), or both. In yet another embodiment, “to treat,” “to treat,” or “treatment” means prevention (preventing or delaying the onset, progression, or progression of the disease or disorder).

[0082] As used herein, for any disease or disorder, the terms “pre-treatment,” “pre-treatment,” or “pre-treatment” refer to embodiments describing “treatment,” “treatment,” or “treatment,” in which the initial dose precedes exposure (or potential exposure) to the disease or disorder. In particular embodiments, for any disease or disorder, “pre-treatment,” “pre-treatment,” or “pre-treatment” refers to reducing the severity of the disease or disorder or accelerating recovery from the disease or disorder, in which the initial dose precedes exposure (or potential exposure) to the disease or disorder.

[0083] As used herein, the term “administration” is intended to include, but is not limited to, the following methods of delivery: topical administration, oral administration, sublingual administration, buccal administration, parenteral administration, subcutaneous administration, transdermal administration, transchucal administration, intravascular (e.g., intravenous or intra-arterial) administration, intramuscular administration, subcutaneous administration, intranasal administration, and intraocular administration. Administration may be a topical administration at a specific anatomical site, such as the site of infection, or a systemic administration.

[0084] As used herein, “prevent” or “prevent” means to achieve, in part, substantially, or completely, one or more of the following results: to avoid disease, disorder or syndrome resulting from infection with a nonviral tick-borne pathogen; to avoid clinical symptoms or indicators associated with disease, disorder or syndrome resulting from infection with a nonviral tick-borne pathogen; to reduce the severity of disease, medical complications, disorder or syndrome resulting from infection with a nonviral tick-borne pathogen; or to avoid death.

[0085] As used herein, “symptomatic” means an subject who, at the time of clinical evaluation, exhibits evident symptoms of one or more nonviral tick-borne diseases.

[0086] As used herein, "tafenoquine" refers to the following structure: [ka] The term refers to the compound of formula (I) having (which has the alternative name N(4)-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline-8-yl]pentan-1,4-diamine), or a pharmaceutically acceptable salt thereof. Tafenoquine is also known as tafenoquine [INN:BAN], Etaquine, UNII-262P8GS9L9, C24H28F3N3O3, CHEBI:172505, AIDS006901, 106635-81-8 (maleate), AIDS-006901, CID115358, SB-252263, WR238605, WR-238605, WR238605, LS-172012, 1,4-pentanediamine, N4-(2,6-dimethoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)-8-quinolinyl-, 106635-80-7, N(4 )-(2,6-dimethoxy-4-methyl-5-((3-trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine, N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline-8-yl]diamine, (4-amino-1-methylbutyl){2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy](8-quinolyl)}amine, (R)-N3-(2,6-dimethoxy-4-methyl-5-(3-trifluoromethyl)phenoxy)quinoline-8-yl)pentane-1,4-diamine, (RS)-N 3 -(2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline-8-yl)pentan-1,4-diamine, also known as pharmaceutically acceptable salts thereof. These include, [ka] It contains [the substance]. The CAS number for the above structure, which is a succinate, is 106635-81-8.

[0087] Compounds of the present invention useful for carrying out the methods described herein may have one or more chiral centers and therefore may exist in several stereoisomers. All stereoisomers and mixtures thereof are within the scope of the present invention. Racemic compounds can be separated using preparative HPLC and columns with a chiral stationary phase, or divided to obtain individual enantiomers using methods known to those skilled in the art. In addition, chiral intermediate compounds may be divided and used to prepare the chiral compounds of the present invention.

[0088] The compounds described herein may exist in one or more tautomer forms. All tautomers and mixtures thereof are included within the scope of the present invention.

[0089] The compounds of the present invention can be administered as free bases or as pharmaceutically acceptable salts. For example, salts of compounds of the present invention containing amines or other basic groups can be obtained by reacting the compound with a suitable organic or inorganic acid to form a pharmaceutically acceptable anionic salt. Examples of anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, tartrate, bromide, calcium edetate, cansilate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estotate, esylate, fumarate, glyceptate, gluconate, glutamate, glycolylarsanilate, and hexylresorcinate. Examples include cinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucinate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, and triethiozide salts. In one embodiment, the compound of formula (I) is a hydrochloride salt.

[0090] As used herein, a dosage range indicated by two numbers means those dosages and all dosages within that range. For example, a dosage range of 10 mg to 11 mg means 10.0 mg, 10.05 mg, 10.10 mg, 10.15 mg, 10.20 mg, 10.25 mg, 10.30 mg, 10.35 mg, 10.40 mg, 10.45 mg, 10.50 mg, 10.55 mg, 10.60 mg, 10.65 mg, 10.70 mg, 10.75 mg, 10.80 mg, 10.85 mg, 10.90 mg, 10.95 mg, 11.00 mg, and any amount within that range, such as 10.34 mg, 10.78 mg, etc.

[0091] As used herein, “suspected nonviral tick-borne disease” means a subject with symptoms known to be consistent with a nonviral tick-borne disease. This does not need to be associated with evidence of a tick bite, because in many cases, the tick is not observed to be attached to the person, and / or the timing of the tick bite may be unknown. The type of suspected nonviral tick-borne disease depends on the most likely infectious organism. For example, findings of migratory erythema are likely to be Lyme disease caused by Borrelia burgdorferi, while symptoms with fever, malaise, loss of appetite, and anemia may suggest babesiosis if no other diagnosis is made.

[0092] Long-lived 8-aminoquinolines Substitutions at the 2, 4, and 5 positions of the 8-aminoquinoline ring are known to confer a longer half-life and a broader spectrum of action against pathogens such as Pneumocystis and Plasmodium. This appears to be true for some tick-borne diseases, as 4-methyl-substituted primaquine is more effective than primaquine against Babesia microti (Reubush et al. 1980). Furthermore, while one and three doses of tafenoquine were sufficient to clear and cure Babesia in immunocompromised mice and dogs (Liu et al. 2020), daily administration of primaquine in gerbils was only suppressive against Babesia microti, even though the gerbils were not reported to have immunocompromised status (Ruebush et al. 1980).

[0093] Substitutions at the 2, 4, and 5 positions of the quinoline ring are known to extend the half-life of 8-aminoquinolines, increasing their potency and expanding their spectrum of action compared to short-half-life 8-aminoquinolines such as primaquine. See Figures 1A and 1B. For example, primaquine has only weak activity against the blood stage of Plasmodium falciparum, while tafenoquine is highly effective (Baird et al. 2002. Am J Trop Med Hyg. 2002 Jun;66(6):659-60; McCarthy et al. 2019. Clin Infect Dis. 2019 Jul 18;69(3):480-486). Similarly, tafenoquine can cure Pneumocystis infection in mice when administered as a monotherapy, but primaquine must be used in combination with clindamycin to achieve the same result (Bartlett et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1991, Vol 35(2):277-282). Also, tafenoquine resolved babesiosis in mice with a single dose of 20 mg / kg (Mordue and Wormser 2019. 442 jid 2019:220, 1 August), whereas primaquine requires a much higher dose (100 mg / kg) (Yao et al. 2015. J Infect Dev Ctries. 2015 Sep 27;9(9):1004-10).

[0094] In thorough QTC studies, tafenoquin was not found to increase the upper limit of the 90% confidence interval for QTC intervals at doses up to 1200 mg over 3 days, thus meeting the generally accepted regulatory criteria for considering the drug to be free of cardiotoxic risks (Green et al. 2014. J Clin Pharmacol 54:995-1005). Importantly, tafenoquin did not increase the QTc prolongation known to be associated with chloroquine when administered co-administered with these two drugs (Green et al. 2014). Tafenoquin can be safely administered as a loading dose of 600 mg over 3 days, followed by weekly doses of 200 mg for up to 1 year, without increasing the overall incidence of adverse events experienced by patients compared to placebo. This is accompanied by mild to moderate gastrointestinal effects, and while corneal iteration is the only specific adverse event with an increased risk, these effects are reversible and not clinically significant [Moreno et al 2021].

[0095] Patient group The patient populations requiring prevention or treatment of nonviral tick-borne diseases include, but are not limited to, the following: patient populations that are symptomatic outpatients; patient populations that are symptomatic inpatients; patient populations that are symptomatic outpatients or inpatients who have risk factors for disease progression other than immunosuppression (in the case of babesiosis, age > 55 years, fatigue, nausea, diarrhea, duration of symptoms > 7 days, abnormal laboratory values, e.g., decreased / increased white blood cell count, elevated bilirubin, elevated creatinine, and parasitemia > 10%, or any pre-existing conditions or treatments that result in a weakened immune state, and combinations thereof); and symptomatic outpatients or inpatients The patient population includes individuals with weakened immune systems (in the case of babesiosis, those with asplenia, hyposplenism, autoimmune diseases, those being treated with immunosuppressants, or any pre-existing medical conditions that suppress the immune system), asymptomatic individuals at risk of tick bites (with or without risk factors), and individuals that have been bitten by ticks and are at risk of developing babesiosis or other nonviral tick-borne diseases caused by species of the genera Babesia and / or Borrelia and / or Anaplasma and / or Rickettsia and / or Ehrlichia and / or Francisella (with or without risk factors).

[0096] Diagnostic criteria With respect to the treatment indications of the claimed invention, the diagnostic criteria include, but are not limited to, the following criteria: laboratory-confirmed tick-borne diseases (such as babesiosis) by tests such as blood smear and / or polymerase chain reaction ("PCR"); parasitic burden (such as parasitemia in blood smears); and suspected infection based on the diagnostic criteria.

[0097] Administration regimen The administration regimen of the present invention is effective in preventing and / or treating nonviral tick-borne diseases in a given subject. Oral administration and / or oral formulations are carried out in such a way that gastrointestinal ("GI") side effects in the subject are minimized, particularly when doses of ≥400 mg / day are given. Doses of tafenoquin exceeding 400 mg are often not well tolerated by adult subjects, regardless of the subject's G6PD status (e.g., this dose can cause gastrointestinal problems or gastrointestinal toxicity). In G6PD-normal adult subjects, doses of tafenoquin up to 400 mg are well tolerated, whereas in G6PD-deficient subjects, doses of 300 mg or more may be poorly tolerated. GI side effects can be minimized and / or prevented and / or mitigated by oral mucosal administration, sublingual administration, intravascular (e.g., intravenous or intra-arterial) administration, and / or by using delivery designs that minimize GI side effects (tablets, blister packs, etc.). Maintenance therapy may be continued for 6 months to 1 year as needed, provided that the total dose administered over a 12-month period does not exceed 11,000 mg.

[0098] In certain embodiments, the long-lived 8-aminoquinolines are tafenoquine or pharmaceutically acceptable salts thereof. The long-lived 8-aminoquinolines may be administered to human subjects as at least one initial (loading) dose. In certain embodiments, doses of 50 mg to 400 mg are administered.

[0099] In a further embodiment, a method for treating and / or preventing a nonviral tick-borne disease further includes administering a second agent, such as a drug, to a human subject. In another embodiment, the method includes administering an effective amount of the second agent to the subject. In a further embodiment, the administration of tafenoquine or the compound of formula (I) and the administration of the second agent are simultaneous. In yet another embodiment, the administration of tafenoquine or the compound of formula (I) and the administration of the second agent are not simultaneous. In a further embodiment, the second agent is not administered.

[0100] In another embodiment, the (one or more) second agent is selected from one or more of the following: artemether, artesunate, atovaquone, atovaquone-proguanil, azithromycin, clindamycin, doxycycline, lumefantrine, quinine, and tetracycline.

[0101] One embodiment of the present invention is a dosing regimen according to Table 1, with or without a second agent. In particular, both a method for treating nonviral tick-borne diseases and a method for preventing nonviral tick-borne diseases involve providing the subject with an effective amount of tafenoquin or a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing tafenoquin or a compound of formula (I): [ka] [In the formula, R is any halogen-containing substituent with a molecular weight ≤ 205.] This includes administering the drug, which is administered according to the administration regimen in Table 1.

[0102] [Table 1]

[0103] Exemplary Embodiments Embodiment 1 - A method for treating or preventing a nonviral tick-borne disease or its symptoms in a human subject, comprising administering an effective amount of a long-acting 8-aminoquinoline to a subject in need thereof.

[0104] Embodiment 2 - The method of Embodiment 1, in which a tick-borne organism is caused by a species of the genera Babesia, Rickettsia, Francisella, Anaplasma, Ehrlichia, or Borrelia, and the resulting disease may be, but is not limited to, one or more of the following: African tick-bite fever, anaplasmosis, babesiosis, borreliosis, ehrlichiosis, Lyme disease, Mediterranean spotted fever, tick-induced relapsing fever, rickettsial disease by Rickettsia parcheri, rickettsial disease, Rocky Mountain spotted fever, Southern tick-associated rash disease, tick-borne relapsing fever, tularemia, and 364D rickettsial disease.

[0105] Embodiment 3 - The method of Embodiment 1 or Embodiment 2, wherein a long-half-life 8-aminoquinoline can treat or prevent nonviral tick-borne diseases with a minimum single dose of 50 mg or the minimum initial dose in a regimen.

[0106] Embodiment 4 - A method from any one of Embodiments 1 to 3, wherein the long-half-life 8-aminoquinolines are tafenoquine or a pharmaceutically acceptable salt thereof.

[0107] Embodiment 5 - A method of any one of Embodiments 1 to 4, wherein the administration follows one of the following regimens: (a) an initial dose of 50 mg followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg followed by an additional dose of 300 mg within one week of the initial dose (f) A single dose of 400 mg; (g) A 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a 200 mg maintenance dose within 12 days of the initial loading dose; and (h) A 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a 200 mg maintenance dose one week after the completion of the loading dose, followed by 200 mg once a week for up to 52 weeks.

[0108] Embodiment 6 - Any one of Embodiments 1 to 5, wherein the subject requiring it is a symptomatic outpatient, a symptomatic outpatient with risk factors for disease progression, a symptomatic outpatient with weakened immune function, a symptomatic inpatient, a symptomatic inpatient with risk factors for disease progression, a symptomatic inpatient with weakened immune function, an asymptomatic subject, an asymptomatic subject without risk factors, an asymptomatic subject with risk factors, an asymptomatic subject at risk of tick bites, an asymptomatic subject without risk factors at risk of tick bites, an asymptomatic subject with risk factors at risk of tick bites, a subject who has been bitten by a tick and is at risk of contracting the tick-borne disease, without risk factors, and a subject who has been bitten by a tick and is at risk of contracting the nonviral tick-borne disease, with risk factors.

[0109] Embodiment 7 - A method for treating or preventing nonviral tick-borne diseases or their symptoms in human subjects, (a) A method comprising administering to the subject an effective amount of the compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I): [ka] [In the formula, R is any halogen-containing substituent with a molecular weight ≤ 205.]

[0110] Embodiment 8 - The method of Embodiment 7, in which a tick-borne organism is caused by a species of the genera Babesia, Rickettsia, Francisella, Anaplasma, Ehrlichia, or Borrelia, and the resulting disease may be one or more of the following, but is not limited to: African tick-bite fever, anaplasmosis, babesiosis, borreliosis, ehrlichiosis, Lyme disease, Mediterranean spotted fever, tick-induced relapsing fever, rickettsial disease by Rickettsia parcheri, rickettsial disease, Rocky Mountain spotted fever, Southern tick-associated rash disease, tick-borne relapsing fever, tularemia, and 364D rickettsial disease.

[0111] Embodiment 9 - The method of Embodiment 7 or Embodiment 8, wherein a long-half-life 8-aminoquinoline can treat or prevent nonviral tick-borne diseases with a minimum single dose of 50 mg or the minimum initial dose in a regimen.

[0112] Embodiment 10 - A method from any one of Embodiments 7 to 9, wherein the long-half-life 8-aminoquinolines are tafenoquine or a pharmaceutically acceptable salt thereof.

[0113] Embodiment 11 - Any one of Embodiments 7 to 10, wherein the administration follows one of the following regimens: (a) an initial dose of 50 mg followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg followed by 300 mg within one week of the initial dose (f) an additional dose; (g) a dose of 400 mg; (g) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the initial loading dose; and (h) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg one week after the completion of the loading dose, followed by 200 mg once a week for up to 52 weeks.

[0114] Embodiment 12 - A method according to any one of Embodiments 7 to 11, wherein the subject requiring the method is a symptomatic outpatient, a symptomatic outpatient with risk factors for disease progression, a symptomatic outpatient with weakened immune function, a symptomatic inpatient, a symptomatic inpatient with risk factors for disease progression, a symptomatic inpatient with weakened immune function, an asymptomatic subject, an asymptomatic subject without risk factors, an asymptomatic subject with risk factors, an asymptomatic subject at risk of tick bites, an asymptomatic subject without risk factors at risk of tick bites, an asymptomatic subject with risk factors at risk of tick bites, a subject who has been bitten by a tick and is at risk of contracting the nonviral tick-borne disease, a subject without risk factors, and a subject who has been bitten by a tick and is at risk of contracting the nonviral tick-borne disease, a subject with risk factors.

[0115] Embodiment 13 - A method for treating or preventing a nonviral tick-borne disease or its symptoms in a human subject, comprising administering tafenoquin to a subject in need thereof.

[0116] Embodiment 14 - The method according to Embodiment 13, in which a tick-borne organism is caused by a species of the genera Babesia, Rickettsia, Francisella, Anaplasma, Ehrlichia, or Borrelia, and the disease caused may be one or more of the following: African tick-bite fever, anaplasmosis, babesiosis, borreliosis, ehrlichiosis, Lyme disease, Mediterranean spotted fever, tick-induced relapsing fever, rickettsial disease by Rickettsia parcheri, rickettsial disease, Rocky Mountain spotted fever, Southern tick-associated rash disease, tick-borne relapsing fever, tularemia, and 364D rickettsial disease.

[0117] Embodiment 15 - A method according to Embodiment 13 or Embodiment 14, wherein a long-half-life 8-aminoquinoline can treat or prevent nonviral tick-borne diseases with a minimum single dose of 50 mg or the minimum initial dose in a regimen.

[0118] Embodiment 16 - A method according to any one of Embodiments 13 to 15, wherein the long-half-life 8-aminoquinolines are tafenoquine or a pharmaceutically acceptable salt thereof.

[0119] Embodiment 17 - A method according to any one of Embodiments 13 to 16, wherein the administration follows one of the following regimens: (a) an initial dose of 50 mg followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg followed by 300 mg within one week of the initial dose. (f) an additional dose of 400 mg; (g) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a 200 mg maintenance dose within 12 days of the initial loading dose; and (h) a 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a 200 mg maintenance dose one week after the completion of the loading dose, followed by 200 mg once a week for up to 52 weeks.

[0120] Embodiment 18 - A method according to any one of Embodiments 13 to 17, wherein the subject requiring the method is a symptomatic outpatient, a symptomatic outpatient with risk factors for disease progression, a symptomatic outpatient with weakened immune function, a symptomatic inpatient, a symptomatic inpatient with risk factors for disease progression, a symptomatic inpatient with weakened immune function, an asymptomatic subject, an asymptomatic subject without risk factors, an asymptomatic subject with risk factors, an asymptomatic subject at risk of tick bites, an asymptomatic subject without risk factors at risk of tick bites, an asymptomatic subject with risk factors at risk of tick bites, a subject who has been bitten by a tick and is at risk of contracting the nonviral tick-borne disease, a subject without risk factors, and a subject who has been bitten by a tick and is at risk of contracting the nonviral tick-borne disease, or a subject with risk factors.

[0121] Embodiment 19 - A method according to any one of Embodiments 1 to 18, further comprising administering a second and / or third agent, such as doxycycline, azithromycin-atovaquone, clindamycin-quinine, artesunate, artemether-rumefantrine, or any other agent recommended by the IDSA or CDC for the treatment or prevention of nonviral tick-borne diseases.

[0122] Embodiment 20 - The method according to Embodiment 6, Embodiment 12, or Embodiment 18, wherein the risk factors for disease progression are selected from the group consisting of age > 55 years, fatigue, nausea, diarrhea, duration of symptoms > 7 days, abnormal laboratory values ​​such as decreased / increased white blood cell count, increased bilirubin and increased creatinine, or any pre-existing conditions or treatments resulting in a state of weakened immune function, and combinations thereof.

[0123] Embodiment 21 - The method according to Embodiment 6, Embodiment 12, or Embodiment 18, wherein the state of reduced immune function is due to a condition selected from the group consisting of asplenia, hyposplenic insufficiency, prior treatment with immunosuppressants, a pre-existing autoimmune disease, or other conditions known to suppress the immune system, and combinations thereof.

[0124] Embodiment 22 - The method according to Embodiment 6, Embodiment 12, or Embodiment 18, wherein the pathogen is a species of the genus Babesia, or the disease is babesiosis.

[0125] Embodiment 23 - The method according to Embodiment 6, Embodiment 12, or Embodiment 18, wherein the pathogen is a species of the genus Borrelia, or the disease is borreliosis or Lyme disease.

[0126] Embodiment 24 - The method according to Embodiment 6, Embodiment 12, or Embodiment 18, wherein the pathogen is a species of the genus Rickettsia, or the disease is a ricketsiosis.

[0127] Embodiment 25 - The method according to Embodiment 6, Embodiment 12, or Embodiment 18, wherein the pathogen is a species of the genus Anaplasma or Ehrlichia, and the disease is anaplasmosis or ehrlichiosis.

[0128] Embodiment 26 - The method according to Embodiment 6, Embodiment 12, or Embodiment 18, wherein the pathogen is a species of the genus Francisella and the disease is tularemia.

[0129] Embodiment 27 - A method according to any one of Embodiments 1 to 26, wherein the administration is via a sublingual route and / or a buccal route and / or an intravenous route.

[0130] Embodiment 28 - A method according to any one of Embodiments 1 to 27, wherein the above administration is carried out according to the administration regimen in Table 1 and / or according to any of the examples.

[0131] Embodiment 29 - A method according to any one of Embodiments 1 to 28, wherein the above subject is administered 11,000 mg or less over a period of 12 months.

[0132] Embodiment 30-(a) means for testing for nonviral tick-borne diseases and / or symptoms thereof and / or glucose-6-dehydrogenase (G6PD deficiency), and (b) a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising a compound of formula (I), [ka] (c) Instructions for use and a kit including [wherein R is any halogen-containing substituent with a molecular weight ≤ 205].

[0133] Embodiment 31-(a) a kit comprising means for testing for nonviral tick-borne diseases and / or symptoms thereof and / or glucose-6-dehydrogenase (G6PD deficiency), (b) long-half-life 8-aminoquinolines, and (c) instructions for use.

[0134] Embodiment 32-(a) a kit comprising means for testing for nonviral tick-borne diseases and / or symptoms thereof and / or glucose-6-dehydrogenase (G6PD deficiency), (b) tafenoquine, and (c) instructions for use.

[0135] Embodiment 33 - A method for pretreatment of a nonviral tick-borne disease and / or its symptoms in a human subject, comprising administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I): [ka] [In the formula, R is any halogen-containing substituent with a molecular weight ≤ 205.]

[0136] Embodiment 34 - The method according to Embodiment 33, wherein the compound of formula (I) is tafenoquine or a salt thereof. [Examples]

[0137] Example 1: Substituted 8-aminoquinolines exhibit higher activity and a broader activity spectrum than primaquine. Tafenoquine, due to its long half-life (14 days vs. approximately 6 hours), exhibits a more potent and broader activity spectrum against malaria parasites and other pathogens. This occurs as a result of substitutions at positions 2, 4, and 5, which increase steric bulk, lipophilicity, and occlude metabolic attack sites. Furthermore, Ruebush et al. (1980) showed that the addition of a methyl group at position 4 of primaquine (a substitution also present in tafenoquine) resulted in higher efficacy against Babesia microti in animals than primaquine. Tafenoquine and similarly substituted 8-aminoquinolines, exemplified in Figures 1A and 2, exhibit a more potent and broader activity spectrum against tick-borne pathogens, similar to that described in the examples for tafenoquine.

[0138] Example 2 - Tafenoquin eliminates all blood-stage parasites in active malaria infection. Fukuda et al. compared tafenoquine with standard treatment in patients with Plasmodium vivax malaria. Symptomatic Plasmodium vivax malaria patients received either tafenoquine monotherapy (400 mg / day for 3 days) or standard treatment (primaquine + chloroquine). In the tafenoquine arm, all patients were cleared of their respective serophase by day 8, and there were no relapses during the follow-up period in patients for whom data were available (these could be relapses from the hematopoietic or hepatic phase and are not distinguishable in Plasmodium vivax infection). This suggests that tafenoquine monotherapy (1200 mg over 3 days) is sufficient to eliminate all hematopoietic organisms during treatment of symptomatic infection.

[0139] Example 3 - When administered at a dose of 800 mg prior to the establishment of infection in non-immune individuals, tafenoquin completely suppresses the development of blood-stage parasites. McCarthy et al. evaluated the effect of a 600 mg loading dose followed by 200 mg doses on the clearance of hematopoietic parasites of Plasmodium falciparum in non-immune volunteers in a human challenge trial (this was later approved by the FDA for malaria prophylaxis with the addition of a 200 mg weekly maintenance dose). The parasitic loading was administered 3 days after the last dose of 200 mg of tafenoquin. Subsequently, all control subjects developed hematopoietic parasitemia, but none of the tafenoquin subjects did. These data indicate that the FDA-approved regimen for malaria prophylaxis, a total dose of 800 mg and / or the first four doses of 200 mg, prevents the development of symptomatic malaria when administered prior to the onset of symptoms in non-immune subjects.

[0140] Example 4 - A single low-dose dose of tafenoquine eliminates Plasmodium falciparum gametocytes in semi-immune (i.e., normally immune) individuals. Stone demonstrated that in patients with asymptomatic Plasmodium falciparum infection, a single dose of 1.66 mg / kg of tafenoquin, when used in combination with dihydroartemisinin / piperaquin to eliminate asexual hematopoietic parasites, made gametocytes non-infectious to mosquitoes within 7 days. With dihydroartemisinin-piperaquin alone, this took 14 days. Therefore, in individuals with semi-immune status to malaria (i.e., normal immune function), tafenoquin eliminated gametocytes at a dose of only 1.66 mg / kg (83 mg for a 50 kg adult or adolescent).

[0141] Example 5 - A single low-dose dose of tafenoquine eliminates Plasmodium falciparum gametocytes in semi-immune (immunely functioning) individuals. Stone et al. demonstrated that in patients with asymptomatic Plasmodium falciparum infection, a single dose of primaquine, when used in combination with dihydroartemisinin / piperaquine to eliminate asexual hematopoietic parasites, made gametocytes statistically non-infectious to mosquitoes at levels below baseline within two days of administration. With dihydroartemisinin-piperaquine alone, this took 14–21 days. Therefore, in semi-immune (immunely functioning) individuals against malaria, primaquine, the 8-aminoquinoline precursor of tafenoquine, eliminated gametocytes with a single, low dose.

[0142] Example 6 - The mechanism of action of primaquine against Plasmodium falciparum gametocytes is site-specific induction of oxidative stress mediated by excessive hydrogen peroxide production. Cammarda et al. showed that when gametocytes of Plasmodium falciparum were exposed to primaquine, they were killed by site-specific (intra-bone marrow) overproduction of hydrogen peroxide and subsequent oxidative damage. The excess hydrogen peroxide is produced as a result of a two-step biochemical relay: (i) the sequential oxidation of primaquine to its hydroxylated metabolites is mediated by the cytochrome reductase-cytochrome P-450 2D6 complex, and (ii) the hydroxylated metabolites are spontaneously oxidized to quinone immine metabolites, which are then reduced back to the hydroxylated species that produce hydrogen peroxide. This hydrogen peroxide locally kills the parasite at the site of such metabolic activity (bone marrow, liver, etc.).

[0143] Example 7 - The mechanism of action of tafenoquin against Babesia parasites is through the induction of oxidative stress. Liu et al. demonstrated that 2 hours of hydrogen peroxide (100 μM) killed Babesia parasites in vitro by inducing the formation of large vacuoles. The same authors demonstrated that tafenoquin, after a single 20 mg / kg dose to mice, induced the formation of large vacuoles in the hematopoietic phase of Babesia rhodhaini, which were visually and quantitatively (i.e., in terms of size) indistinguishable from those produced in vitro by hydrogen peroxide. Antioxidant enzymes were also upregulated in Babesia rhodhaini after a single tafenoquin treatment in mice. Therefore, tafenoquin kills Babesia parasites by inducing oxidative stress in a manner similar to the effects of hydrogen peroxide and primaquine on Plasmodium falciparum gametocytes. See Example 6. Furthermore, Wilkinson et al. (2003) found that the blood-stage form of Trypanosome brucei, which is similarly vulnerable to tafenoquine, is killed by 90 minutes of exposure to approximately 140 μM hydrogen peroxide. These observations suggest that if a μM concentration of hydrogen peroxide kills an organism after several hours of exposure, that organism may be susceptible to the effects of tafenoquine in vivo under appropriate conditions.

[0144] Example 8 - The susceptibility of an organism to tafenoquine is related to its inherent susceptibility to the drug, rather than whether or not the organism undergoes an obligate intracellular life cycle in mammalian cells. Tafenokin kills Trypanosoma brucei in its extracellular hematopoietic phase and Leishmania major in its intracellular amastigote phase at similar titers (<4 μM, Yardley et al. 2010, Carvahlo et al. 2015), and Dow's U.S. Patent Application Publication 2021-0267963 disclosed that tafenokin activity is much lower against free-living Gram-negative bacteria than against free-living Gram-positive bacteria. Therefore, an organism's susceptibility to tafenokin is not determined by whether or not the organism has an obligate intracellular life cycle in mammalian cells. Thus, both obligate intracellular bacteria (species of the genera Rickettsia, Anaplasma, Ehrlichia, and Babesia) and bacteria that are considered to exhibit an extracellular life cycle in most cases (species of the genera Borrelia) can be susceptible to tafenokin.

[0145] Example 9 - Borrelia species and other spirochetes are vulnerable to hydrogen peroxide. Species of the genus Borrelia are Gram-negative organisms and, therefore, based on previous research (Dow's U.S. Patent Application Publication No. 2021-0267963), could be expected to be resistant to tafenoquin. However, some (but not all) strains of Lyme disease Borrelia (Borrelia burgdoferi) are vulnerable to hydrogen peroxide, and under certain physiological conditions, this vulnerability can be enhanced. For example, Ramsey et al. 2017 showed that the growth of strain B31 5A18NP1 was inhibited by hydrogen peroxide at a concentration of only 62.5 μM for 4 hours; Sambri et al. 1991 showed that enhanced iron absorption makes Lyme disease Borrelia more vulnerable to hydrogen peroxide; and Showman et al. 2016 showed that strains with mutations in their oxidation response genes that increase sensitivity to hydrogen peroxide also exhibit lower infectivity to mammalian hosts.

[0146] Steiner et al. 1984 showed that the growth of Treponema palludum, the bacterium that causes syphilis, is significantly inhibited by 2 hours of hydrogen peroxide at concentrations of 50 μM or 100 μM under a 3% oxygen atmosphere.

[0147] Murgia et al. showed that various serotypes of the genus Leptospira are killed by exposure to exogenous hydrogen peroxide concentrations of less than 180 μM for just 30 minutes.

[0148] These data suggest that spirochetes, despite being Gram-negative organisms, are susceptible to tafenoquin-like mechanisms of action under certain conditions. Concomitant administration of standard treatment regimens such as doxycycline is expected to enhance the vulnerability of tick-borne spirochetes to tafenoquin.

[0149] Example 10 - Tafenoquine is active against Babesia species in an animal model. Liu et al. showed that a single dose of 20 mg / kg of tafenoquin in Balb / c mice (with normal immune function) eliminated parasitemia and resulted in a 100% survival rate, whereas the infection was uniformly lethal in untreated animals. In immunocompromised SCID mice, a single dose of 20 mg / kg of tafenoquin eliminated the initial parasitemia, but it did not prevent recurrence. Therefore, while death was delayed, it did not prevent it as it did in Balb / c mice with normal immune function.

[0150] In dogs infected with Babesia gibsoni that underwent splenectomy, parasitemia resolved and death was prevented after a single dose of 100 mg alacoda tablets (9-11.5 mg / kg) on ​​days 12, 19, and 48. Symptoms of infection, such as loss of appetite and elevated respiration and pulse, were also alleviated in dogs treated with tafenoquin. An equivalent human administration regimen, adjusted for body surface area, would be approximately 4-6 mg / kg / day x 3, which for a 70 kg person would be 280-420 mg / day for 3 days.

[0151] Example 11 - Babesia was cured by a prophylactic tafenoquin regimen in a patient whose immune function was considered normal at that time. A patient hospitalized with a Babesia microti (B. microti) infection suspected to be due to immunosuppression induced by prior rituximab administration experienced two relapses after sequential azithromycin + atovaquone regimens, and a third relapse after a subsequent regimen of azithromycin + atovaquone + clindamycin. A fourth course of chemotherapy with high-dose malarone + atovaquone + clindamycin + azithromycin was discontinued due to adverse events. Subsequently, the patient was cured after 6 weeks of monotherapy with tafenoquin at a dose approved for malaria prophylaxis. This case demonstrates the potential usefulness of FDA-approved tafenoquin regimens for the treatment of babesiosis in humans.

[0152] Example 12 - The clinical effectiveness of antimalarial drugs in non-immune individuals cannot be predicted based on the effective dosage in semi-immune individuals. Given the complexity, cost, and risks of developing new medicines, it is important that drug regimens, if possible, be effective in both individuals with normal immune function and those with impaired immune function.

[0153] In the case of malaria, semi-immune individuals exhibit resistance to the symptoms of malaria and usually do not develop clinical malaria. However, even so, such semi-immune individuals can become infected with the parasite that causes malaria, and the parasite may be observed in blood samples by microscopic examination. On the other hand, non-immune malaria individuals have insufficient prior exposure to malaria to immunize them against the signs and symptoms of malaria, if the presence of the malaria parasite is confirmed by microscopic examination. Non-immune malaria individuals can also be malaria naive if they have never been exposed to malaria before.

[0154] In the case of malaria drugs, it is impossible to predict whether a drug will have useful prophylactic efficacy in non-immune or malaria-naive subjects based on data from clinical trials involving semi-immune individuals. The activity of azithromycin in non-immune / malaria-naive subjects was lower than in semi-immune individuals, and the level of efficacy was far below the therapeutic criteria necessary to justify further development of azithromycin (azithromycin has not been approved by the FDA for malaria prevention even 20 years after clinical research was conducted). The results of two trials of azithromycin are shown in the table below. Andersen et al., Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya 26(1)CUN INFECT Dis(1998)146-50 and Taylor et al., Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in rain Jaya, Indonesia 28(1)CUN INFECT Dis(1999)74-81. These data indicate that for some drugs, even at doses known to be safe and effective in other indications, useful prophylactic efficacy against Plasmodium falciparum (a mosquito-borne parasite that causes malaria) in malaria-naive subjects cannot be predicted.

[0155] [Table 2]

[0156] Example 13 - Tafenoquin is expected to be effective in treating babesiosis in outpatients and inpatients, regardless of their immune status. Patients with babesiosis are treated with either azithromycin-atovaquone or clindamycin-quinine for 7–10 days. In the majority of individuals with a functioning immune system, these regimens reduce parasitemia to a level that the patient's immune system can clear over 12 months (Krause 2008, Krause 2021). In immunocompromised patients, the immune system may not be able to clear residual parasitemia, which can lead to relapse, the need for multiple courses of antimicrobial therapy, and an increased risk of death and complications (Krause 2008).

[0157] In patients hospitalized with babesiosis, which can manifest in a wide range of immune states from normal to severely impaired, the mortality rate is low (1.6%), but the risk of complications such as red blood cell transfusion (20%), renal failure (20%), respiratory failure (6.8%), and heart failure (3.5%) is high (Bloch 2022).

[0158] In these populations, a dose of 800 mg of tafenoquin administered according to one of the dosing regimens listed in Table 1 is expected to yield the following clinical benefits.

[0159] - Outpatients: Tafenoquine monotherapy is expected to function similarly to standard treatment. That is, in most patients, the parasitic load will be largely eliminated by day 28, and an additional course of antimicrobial therapy will likely not be necessary.

[0160] - Hospitalized patients: Tafenoquine, combined with any standard treatment regimen, is expected to reduce the risk of complications (such as red blood cell transfusions, renal failure, respiratory failure, and heart failure) and shorten parasite clearance time compared to standard treatment.

[0161] - Patients with compromised immune function: In patients with compromised immune function, tafenoquin in combination with any standard treatment regimen [regardless of treatment status] is expected to reduce the risk of additional courses of antimicrobial therapy and hematological, pulmonary, and renal complications.

[0162] -When combined with artesunate or artemether-rumefantrine, a 3-day regimen of tafenoquin (200 mg / day for 3 days) is expected to provide the same benefits as an 800 mg regimen of tafenoquin without requiring the usual concurrent administration of standard treatment. Example 14 - Tafenoquine is expected to be effective as post-exposure prophylaxis for tick-borne diseases following tick bites.

[0163] Tick ​​bites are a delivery mechanism through which various protozoa and species of the genus Rickettsia are delivered, causing a range of diseases with considerable morbidity, particularly Lyme disease, babesiosis, ehrlichiosis, and anaplasmosis. Administering a single dose of doxycycline to asymptomatic individuals within 72 hours of a tick bite is an accepted treatment modality for preventing Lyme disease. There is no established post-exposure prophylaxis for babesiosis or other tick-borne diseases.

[0164] Due to its common mechanism of action involving hydrogen peroxide-like effects across various protozoan, fungal, and bacterial species, the vulnerability of Babesia species and spirochetes to hydrogen peroxide, tafenoquin's long half-life, and favorable safety profile, tafenoquin administered in single doses or cumulative doses of less than 800 mg, as outlined in Table 1, is expected to offer the following advantages when used as post-exposure prophylaxis after tick bites. - Monotherapy to reduce the risk of developing babesiosis. - Monotherapy to reduce the risk of contracting diseases caused by tick-borne microorganisms that do not cause Lyme disease or babesiosis. - Combination therapy with doxycycline to simultaneously prevent Lyme disease, babesiosis, and other tick-borne diseases.

[0165] Example 15 - FDA-approved malaria prophylactic drugs prevent babesiosis and other tick-borne diseases in individuals at high risk of exposure to infected ticks. The approved dose of tafenoquin for malaria prevention for up to 6 to 12 months (200 mg / day for 3 days, then 200 mg once weekly) is expected to reduce the risk of babesiosis and / or Lyme disease and / or rickettsial diseases and / or other tick-borne diseases when administered prophylactically to individuals at high risk of tick bites.

[0166] Example 16 - Tafenoquine is expected to be active in animal models, either alone or in combination with standard treatment regimens. Tafenoquin administered as monotherapy in three doses of 50 mg / kg or less, or in combination with a standard treatment regimen (such as doxycycline, azithromycin-atovaquone), is expected to increase survival rates and reduce microbial load, persistence, and antibiotic tolerance in appropriate animal models of tick-borne spirochetes (e.g., species of Borrelia, Rickettsia, Ehrlichia, and Anaplasma). In the specific case of Lyme disease, this may occur as a result of activity against both the normal extracellular morphology and / or the intracellular morphology in macrophages and endothelial (and possibly other) cells.

[0167] Example 17 - Human infections caused by tick-borne pathogens are expected to be susceptible to the same dose of tafenoquin as outlined in Example 13. Standard treatments for human tick-borne diseases, such as Lyme disease, Rocky Mountain spotted fever, and anaplasmosis, are incomplete because a cure is not achieved in a small number of patients, or because the spirochetes persist spontaneously or become resistant to antibiotics. Due to the common mechanism of action of tafenoquin across several pathogenic species, its long half-life, and safety profile, it is expected that combining standard treatment with tafenoquin in doses listed in Example 13 for the treatment of such diseases in patients with one or more of these infections will reduce in-hospital complications, and / or microbial clearance time, and / or sustained / antimicrobial tolerance and / or retreatment rates compared to standard treatment.

[0168] All patents, publications, and references cited herein are incorporated in their entirety by reference for any purpose.

[0169] Although the present invention has been specifically illustrated and described with reference to examples of its embodiments, it will be understood by those skilled in the art that various modifications can be made to the form and details without departing from the scope of the invention as encompassed in the appended claims.

[0170] References Bloch et al.2022.Epidemiology of Hospitalized Patients with Babesiosis,United States,2010-2016.Emerging Infectious Diseases;28:354-362. Cabello et al.2022.Borreliella burgdorferi Antimicrobial-Tolerant Persistence in Lyme Disease and Posttreatment Lyme Disease Syndromes mBIO:https: / / doi.org / 10.1128 / mbio.03440-21. Cammarda et al.2019.Antimalarial activity of primaquine operates via a two-step biochemical relay.Nature Communications;10:3226. Carvahlo et al.2015.The oral antimalarial drug tafenoquine shows activity against Trypanosoma brucei.Antimicrob Agents Chemo;59:6151-6160. Chapman et al.2006.Diagnosis and management of tickborne rickettsial diseases:Rocky mountain spotted fever,ehrlichoses,and anaplasmosis-United States.A practical guide for physicians and other health-care and public health professionals.MMWR;55(RR04):1-27. Fukuda et al.2017.A randomized,double-blind,active-control trial to evaluate the efficacy and safety of a three-day course of tafenoquine monotherapy for the treatment of Plasmodium vivax malaria.PLoS ONE 12(11):e0187376. Krause et al.2008.Persistent and Relapsing Babesiosis in Immunocompromised Patients.CID;46:370-6. Krause et al.2021.Clinical Practice Guidelines by the Infectious Diseases Society of America(IDSA):2020 Guideline on Diagnosis and Management of Babesiosis.CID;72:e49-e64. Kugeler et al.2010.A review of death certificates listing Lyme disease as a cause of death in the United States.CID;52:364-367. Lantos et al.2021.Clinical practice guidelines by the Infectious Diseases Society of America(IDSA),American Academy of Neurology(AAN),and American College of Rheumatology(ACR):2020 Guidelines for the Prevention,Diagnosis and Treatment of Lyme Disease.CID;72:1-8. Liu et al.2021.Tafenoquine is a promising drug candidate for the treatment of babesiosis.Antimicrobial Agents Chemo;65:e00204-21. Ma et al.1991.Intracellular localization of Borrelia burgdorferi within human Endothelial cells.Infection and Immunity;59:671-678. Mace et al.2021.Malaria Surveillance-United States,2017.MMWR;70:1-32. Marcos et al.2022.Use of tafenoquine to treat a patient with relapsing babesiosis with clinical and molecular evidence of resistance to azithromycin and atovaquone.IDCases;27:e01460. McCarthy et al.2019.Blood schizonticidal activity and safety of tafenoquine when administered as chemoprophylaxis to healthy,non-immune participants followed by blood stage Plasmodium falciparum challenge:A randomized,souble blind,placebo-controlled Phase Ib study.CID;69:480-486. Montgomery et al.1993.The fate of Borrelia burgdorferi,the agent for lyme disease,in mouse macrophages.J Immunol;150:909-915. Moreno et al 2021.Long-term safety of the tafenoquine antimalarial chemoprophylaxis regimen:A 12-month,randomized,double-blind,placebo-controlled trial.TMAID 45:102201 Murgia et al.2002.Leptospires are killed in vitro by both oxygen-dependent and independent reactions.Infection Immunity;70:7172-7175. Ramsey et al.A high throughput genetic screen identifies previously uncharacterized Borrelia burgdorferi genes important for resistance against reactive oxygen and nitrogen species.PLoS Pathog;13(2):e1006225. Rizk MA,El-Sayed SAE,Al-Araby M,Igarashi I(2022)Effect of methanolic extract from Capsicum annuum against the multiplication of several Babesia species and Theileria equi on in vitro cultures,and Babesia microti in mice,Veterinary World,15(1):76-82. Ruebush et al.1980.Chemotherapy of Babesia microti infections in Mongolian Jirds Antimicrob Agents Chemo;18:289-291. Sambri et al.1991.Susceptibility of iron-loaded Borrelia burgdorferi to killing by hydrogen peroxide and human polymorphonuclear leucocytes.FEMS Microbiol Lett,65:67-71. Showman et al.2016.Gene bb0318 is critical for the oxidative stress response and unfectivity of Borrelia burgdorferi.Infection and Immunity;84:3141-3151. Steiner et al.1984.Susceptibility of Treponema pallidum to the toxic products of oxygen reduction and the non-treponemal nature of its catalase.Br J Vener Dis;60:14-22. Stone et al.2022.Pyronaridine-artesunate or dihydroartemisinin-piperaquine combined with single low-dose primaquine to prevent Plasmodium falciparum malaria transmission in Oelessebougou,Mali:a four-arm,single-blind,phase 2 / 3,randomized trial.Lancet Microbe 2022;3:e41-e51. Stone et al.2022.Single low-dose tafenoquine combined with dihydroartemisinin-piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou,Male:a phase 2,single blind,randomized clinical trial.Lancet Microbe:https: / / doi.org / 10.1016 / S2666-5247(21)00356-6. Wlikinson et al.2003.RNA interference identifies two hydroperoxide metabolizing enzymes that are essential to the bloodstream form of the African trypanosome.J Biol Chem;278:31640-31646. Yardley et al.2010.Antileishmanial and antitrypanosomal activities of the 8-aminoquinoline tafenoquine.Antimicrob Agents Chemo 54:5356-5358.

Claims

1. A method for treating a tick-borne disease or its symptoms in a human subject, comprising administering an effective amount of a long-acting 8-aminoquinoline to a subject in need thereof, wherein the tick-borne disease is caused by a parasite of the genus Babesia.

2. The method according to claim 1, wherein the tick-borne disease is babesiosis.

3. The method according to claim 1 or 2, wherein the subject has been diagnosed with infection with the parasite, which is a species of Babesia, prior to the administration.

4. The method according to claim 1, claim 2, or claim 3, wherein the subject is co-infected with a spirochete of the genus Borrelia.

5. The method according to any one of claims 1 to 4, wherein the long-half-life 8-aminoquinolines can treat the tick-borne disease with a minimum single dose of 50 mg or the minimum initial dose in a regimen.

6. The method according to any one of claims 1 to 4, wherein the long-lived 8-aminoquinolines are tafenoquine or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 6, wherein the effective amount of the long-half-life 8-aminoquinolines is selected from one of the following regimens: (a) an initial dose of 50 mg, followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by one additional dose of 300 mg within one week of the initial dose; (f) Administration of 400 mg; (g) A loading dose of 600 mg administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the initial dose of the loading dose; and (h) A 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg one week after completion of the loading dose, followed by 200 mg once weekly for up to 52 weeks.

8. The method according to any one of claims 1 to 6, wherein the effective amount of the long-half-life 8-aminoquinoline is approximately 200 mg per day over four days, and the daily dose may be administered as a single dose or in divided doses.

9. The method according to any one of claims 1 to 8, comprising administering the long-lived 8-aminoquinolines by one or more of the sublingual, buccal, and intravenous routes.

10. The method according to any one of claims 1 to 9, wherein the amount of the long-half-life 8-aminoquinoline administered to the subject within a period of 12 months is 11,000 mg or less.

11. The method according to any one of claims 1 to 10, wherein the subject is a symptomatic outpatient or a symptomatic inpatient.

12. The method according to claim 11, wherein the subject is a patient requiring symptomatic hospitalization.

13. The method according to any one of claims 1 to 12, wherein the subject is diagnosed with at least one of babesiosis infection and babesiosis disease, and the diagnosis includes a clinical examination to confirm at least one of babesiosis infection and babesiosis disease.

14. A method for treating a tick-borne disease or its symptoms in a human subject, comprising a pharmaceutical composition containing an effective amount of the compound of formula (I), a pharmaceutically acceptable salt thereof, or the compound of formula (I) in the subject: 【Chemistry 1】 [In the formula, R is any halogen-containing substituent with a molecular weight ≤ 205.] The method comprising administering a parasite, wherein the tick-borne disease is caused by a parasite of the genus Babesia.

15. The method according to claim 14, wherein the tick-borne disease is babesiosis.

16. The method according to claim 14 or claim 15, wherein the subject has been diagnosed with infection with the parasite, which is a species of Babesia, prior to the administration.

17. The method according to claim 14, claim 15, or claim 16, wherein the subject is co-infecting a parasite that is a species of the genus Borrelia.

18. The method according to any one of claims 14 to 17, wherein the pharmaceutical composition comprising the compound of formula (I) in an effective amount, the pharmaceutically acceptable salt thereof, or the compound of formula (I) is selected from one of the following regimens: (a) an initial dose of 50 mg, followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by one additional dose of 300 mg within one week of the initial dose; (f) Administration of 400 mg; (g) A loading dose of 600 mg administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the initial dose of the loading dose; and (h) A 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg one week after completion of the loading dose, followed by 200 mg once weekly for up to 52 weeks.

19. The method according to any one of claims 14 to 17, wherein the pharmaceutical composition comprising the compound of formula (I), a pharmaceutically acceptable salt thereof, or the compound of formula (I) is administered in an effective amount of approximately 200 mg per day over four days, and the daily dose may be administered as a single dose or in divided doses.

20. The method according to any one of claims 14 to 19, wherein the compound of formula (I), a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound of formula (I) is administered to the subject by one or more of the sublingual, buccal, and intravenous routes.

21. The method according to any one of claims 14 to 20, wherein the amount of the compound of formula (I), a pharmaceutically acceptable salt thereof, or the pharmaceutical composition containing the compound of formula (I) administered to the subject within a period of 12 months is 11,000 mg or less.

22. The method according to any one of claims 14 to 21, wherein the subject is a symptomatic outpatient or a symptomatic inpatient.

23. The method according to claim 22, wherein the subject is a patient requiring hospitalization due to symptoms.

24. The method according to any one of claims 14 to 23, wherein the subject is diagnosed with at least one of babesiosis infection and babesiosis disease, and the diagnosis includes a clinical examination to confirm at least one of babesiosis infection and babesiosis disease.

25. A method for treating a tick-borne disease or its symptoms in a human subject, comprising administering tafenoquin to a subject in need thereof, wherein the tick-borne disease is caused by a parasite of the genus Babesia.

26. The method according to claim 25, wherein the tick-borne disease is babesiosis.

27. The method according to claim 25 or claim 26, wherein the subject has been diagnosed with infection with the parasite, which is a species of Babesia, prior to the administration.

28. The method according to claim 25, claim 26, or claim 27, wherein the subject is co-infected with a parasite of the genus Borrelia.

29. The method according to any one of claims 25 to 28, wherein the tafenoquin is administered to the subject according to one of the following regimens: (a) an initial dose of 50 mg, followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by one additional dose of 300 mg within one week of the initial dose; (f) Administration of 400 mg; (g) A loading dose of 600 mg administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the initial dose of the loading dose; and (h) A 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg one week after completion of the loading dose, followed by 200 mg once weekly for up to 52 weeks.

30. The method according to any one of claims 25 to 28, comprising administering approximately 200 mg of tafenoquin per day to the subject over a period of four days, wherein the daily dose may be a single dose or divided doses.

31. The method according to any one of claims 25 to 30, wherein the administration of tafenoquin is selected from one or more of the sublingual, buccal, and intravenous routes.

32. The method according to any one of claims 25 to 31, wherein the amount of tafenoquin administered to the subject during a period of 12 months is 11,000 mg or less.

33. The method according to any one of claims 25 to 32, further comprising administering to the subject a second or third agent selected from one or more of doxycycline, azithromycin-atovaquone, clindamycin-quinine, artesunate, artemether-rumefantrine, and any other agents recommended by the IDSA or CDC for the treatment of nonviral tick-borne diseases.

34. The method according to any one of claims 25 to 33, wherein the subject is a symptomatic outpatient or a symptomatic inpatient.

35. The method according to claim 34, wherein the subject is a patient requiring hospitalization due to symptoms.

36. The method according to any one of claims 25 to 35, wherein the subject is diagnosed with at least one of babesiosis infection and babesiosis disease, and the diagnosis includes a clinical examination to confirm at least one of babesiosis infection and babesiosis disease.

37. The use of effective amounts of long-acting 8-aminoquinolines to treat tick-borne diseases or their symptoms caused by a parasite of the genus Babesia in humans.

38. The aforementioned long-half-life 8-aminoquinolines are compounds of formula (I): 【Chemistry 2】 The use according to claim 37, where R is any halogen-containing substituent having a molecular weight ≤ 205 or a pharmaceutically acceptable salt thereof.

39. The use according to claim 37, wherein the long-half-life 8-aminoquinolines are tafenoquine or a pharmaceutically acceptable salt thereof.

40. The use according to any one of claims 37 to 39, wherein the tick-borne disease is babesiosis.

41. The use according to any one of claims 37 to 40, wherein the subject has been diagnosed with infection with the parasite, which is a species of Babesia, prior to the administration.

42. The use according to any one of claims 37 to 41, wherein the subject is co-infecting a parasite that is a species of the genus Borrelia.

43. The use according to any one of claims 37 to 42, wherein the long-half-life 8-aminoquinolines is administered to the subject according to one of the following regimens: (a) an initial dose of 50 mg, followed by one additional dose of 50 mg within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by one additional dose of 300 mg within one week of the initial dose; (f) Administration of 400 mg; (g) A loading dose of 600 mg administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg within 12 days of the initial dose of the loading dose; and (h) A 600 mg loading dose administered over 1 to 5 days by the following methods: (i) 100 mg six times, or (ii) 150 mg four times, or (iii) 200 mg three times; followed by a maintenance dose of 200 mg one week after completion of the loading dose, followed by 200 mg once weekly for up to 52 weeks.

44. The use according to any one of claims 37 to 42, comprising administering approximately 200 mg of the long-half-life 8-aminoquinolines per day to the subject over a period of 4 days, wherein the daily dose may be administered as a single dose or in divided doses.

45. The use according to any one of claims 37 to 44, comprising administering the long-lived 8-aminoquinolines to the subject via one or more of the sublingual, buccal, and intravenous routes.

46. The use according to any one of claims 37 to 45, wherein the amount of the long-half-life 8-aminoquinoline administered to the subject within a period of 12 months is 11,000 mg or less.

47. The use according to any one of claims 37 to 46, further comprising administering to the subject one or more additional agents selected from doxycycline, azithromycin-atovaquone, clindamycin-quinine, artesunate, artemether-rumefantrine, and any other agents recommended by the IDSA or CDC for the treatment of nonviral tick-borne diseases.

48. The use according to any one of claims 37 to 47, wherein the subject is a symptomatic outpatient or a symptomatic inpatient.

49. The use according to any one of claims 37 to 48, wherein the subject has been diagnosed with at least one of babesiosis infection and babesiosis disease by a clinical examination that confirms at least one of babesiosis infection and babesiosis disease.

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