Methods for use of 5'-adenosine diphosphate ribose (ADPR)

Abstract

To provide pharmaceutical compositions for treating, managing or preventing adenovirus-related diseases or conditions.SOLUTION: The present invention is directed to methods for the use of 5'-adenosine diphosphate ribose (ADPR), and compositions thereof, for treating, managing or preventing adenovirus-related diseases or conditions, eye disorders, cancer, or diseases or conditions caused by infection, inflammation, or physical, chemical, thermal, or radiation injuries.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 296,665, filed February 18, 2016, and U.S. Provisional Patent Application No. 62 / 296,665, filed December 1, 2016. This application claims the benefit of U.S. Provisional Patent Application No. 62 / 428,721, filed on 2006-02-13, each of which is hereby incorporated by reference in its entirety. The entirety of which is incorporated herein by reference.

[0002] 1 Field of the Invention The present invention relates to a method for treating adenovirus-associated diseases or conditions, such as eye disease, cancer, or infection, inflammation, or a disease caused by physical, chemical, thermal, or radiation injury. 5'-Adenosine diphosphate ribose for treating, managing, or preventing a disease or condition The present invention is directed to methods of use of (ADPR) and compositions thereof. [Background technology]

[0003] 2. Background of the Invention Human adenoviruses are infectious pathogens in both immunocompetent and immunocompromised individuals. Adenovirus infection in humans is well documented in immunocompromised individuals. It has been shown to be a cause of high morbidity and mortality. Despite their lethal nature, currently, no human adenoviruses There are no approved antiviral treatments for the infection (Lion, 2014, "Immune Responsiveness and Immune Deficiency" Adenovirus infection in sexually transmitted patients," Clin. Microbiol. Rev., 27(3):441-462;Martin Ez-Aguado et al., 2015, "Anti-adenovirus drug discovery: potential targets and evaluation methods," Drug Di (See Scov. Today, 20(10):1235-1242.) Cidofovir, ribavirin, and Broadly acting antiviral drugs such as cyclovir are currently available for the treatment of adenovirus infections. It is part of the next best treatment options. However, results are variable. It has been shown to have antiviral activity against all human adenovirus species. However, cidofovir has low bioavailability and a low correlation between pharmacological effect and prescribed dose. Ribavirin has been associated with poor clinical outcomes and dose-limiting nephrotoxicity. It has diverse activity against adenovirus types, with the greatest activity against subtype C However, in vivo evidence of the therapeutic efficacy of ribavirin is lacking. In light of the low plasma concentrations achieved with The use of ganciclovir has also been suggested to treat adenovirus infections. However, Its activity against this virus is relatively low.

[0004] 5′-Adenosine diphosphate ribose (ADPR) is a small molecule of natural origin that is commercially ADPR is also available in the US. Through its identification as a key contributor to the anti-cytotoxicity of the extract of B. galgaricus, It has been shown to have toxic properties. In vitro, ADPR as low as 5 mg / L Concentrations that showed measurable inhibition of tumor necrosis factor (TNF-α)-mediated cytotoxicity (Johns et al., 2007, “Cytoprotective Agents in Lactobacillus bulgaricus Extracts” nt in Lactobacillus bulgaricus Extracts)”, Current Microbiology, 54(2):131-135 (See ). The use of ADPR prevents, inhibits, or cures the harmful effects of solar radiation on the skin. ADPR is also suggested for treating In particular, certain chemotherapy, radiation therapy, or a combination thereof, may contribute to the development of mucositis. It has been shown to cause mucositis in susceptible individuals when administered before, during, or after commonly associated treatments. It has also been shown to provide effective mitigation (see WO 03 / 099297 A1).

[0005] The ADPR and compositions thereof provided herein are useful in treating adenovirus-associated diseases or is a condition, eye disease, cancer, or infection, inflammation, or physical, chemical, thermal, or radiation-induced Treat, manage, or prevent diseases or conditions caused by radiation injury It has been found that the above-mentioned methods can be effectively used for the purpose of Summary of the Invention

[0006] 3 Summary of the invention Provided herein are methods for treating a disease or condition such as those provided herein. Adenovirus-related diseases or conditions, eye diseases, cancer, or infections, inflammation, or diseases Illness or condition caused by physical, chemical, thermal, or radiation injury The present invention relates to a method for treating, managing, or preventing an adenovirus-associated disease. any disease or condition, eye disease, cancer, or infection, inflammation, or any other physical, chemical, thermal, or has or develops a disease or condition caused by radiation injury Patients at risk of developing rheumatoid arthritis were treated with 5′-adenosine diphosphate ribose (ADPR) or its pharmaceutical equivalents. Acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, prodromes, The method comprises administering to the patient a compound comprising administering to the patient a compound of formula (I) or a polymorph thereof, or a pharmaceutical composition thereof.

[0007] In specific embodiments, the compositions and methods provided herein are The ADPR compound for is in the form of its sodium salt. In another embodiment, the ADPR compound is in the form of its monosodium salt. It is in the form of the disodium salt.

[0008] In other specific embodiments, in the compositions and methods provided herein The ADPR compound for use is in the form of its lithium salt. In one embodiment, the ADPR The compound is in the form of its monolithium salt. In other embodiments, the ADPR compound is It is in the form of a dilithium salt.

[0009] In certain embodiments, the adenovirus-associated disease or condition is an infection of the eye, ear, mouth, A disease or condition that affects any part of the upper or lower respiratory tract. In the present invention, the adenovirus-associated diseases or conditions include, but are not limited to, ocular Diseases of conjunctivitis, keratitis, keratoconjunctivitis, corneal abrasion, ulcerative infectious keratitis, superficial keratitis, stromal keratitis, uveitis, acute glaucoma, blepharitis, otitis media, otitis externa, gingivitis, mucositis, pharyngitis , tonsillitis, rhinitis, sinusitis, laryngitis, croup, tracheitis, bronchitis, bronchiolitis, bronchitis Selected from pneumonia, pneumonia, asthma exacerbation, chronic obstructive pulmonary disease exacerbation, or emphysema exacerbation.

[0010] In certain embodiments, the cancer is lung cancer, lung adenocarcinoma, non-small cell lung cancer, pancreatic cancer, pancreatic adenocarcinoma, glioma, glioblastoma multiforme, or acute myeloid leukemia.

[0011] In certain embodiments, ADPR, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, The compounds, tautomers, stereoisomers, isotopic species, prodrugs, or polymorphs may be locally, The composition may be administered orally, parenterally, transmucosally, or by inhalation. In one embodiment, the ADPR described herein is administered by topical administration. In particular embodiments, local administration is administration to an internal cell or tissue surface. Local administration to certain cell or tissue surfaces may be achieved by aerosolization, nebulization, or oral administration to any surface of the respiratory tract. In another specific embodiment, the internal cells or Topical administration to tissue surfaces may be achieved by oral delivery, injection or enema (e.g., to any surface of the digestive tract). In another embodiment, the delivery system may be administered by administration of the drug to an internal cell or tissue surface. Administration is by parenteral injection or infusion into any internal organ. Administration can be to external tissue or organs, including, but not limited to, the skin, eyes, nails, hair, or ears. is to the tissue surface.

[0012] In certain embodiments, ADPR, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, Any derivatives, tautomers, stereoisomers, isotopic species, prodrugs, or polymorphs may be used without the prior written consent of other pharmaceutical companies. In certain embodiments, the other medication is administered in combination with an antiviral drug. In some embodiments, the other medicament is cidofovir, acitabine, In a specific embodiment, the other medicament is cidovir, clovir, or ganciclovir. In certain embodiments, the other medicament is lithium, zinc, cobalt, or In certain embodiments, the other medicament is lithium benzoate, lithium bromide. , lithium chloride, lithium sulfate, lithium tetraborate, lithium acetate, zinc chloride, zinc sulfate , zinc bromide, cobalt chloride, cobalt bromide, copper bromide (CuBr2), copper chloride (CuCl2), and sulfur In a specific embodiment, the other pharmaceutical agent is selected from the group consisting of lithium chloride. be.

[0013] Provided herein is a compound of the formula: [ka] or a solvate, hydrate, tautomer, stereoisomer, isotopic species, proline, It is a prodrug or a polymorph.

[0014] In one aspect, provided herein is a compound comprising: (i) ADPR·dilithium; or Any solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, or is a pharmaceutical composition comprising the polymorph, and (ii) one or more pharma- ceutically acceptable excipients; The amount of ADPR·dilithium in the pharmaceutical composition is about 0.001% w / w to about 0.5% w / w of the pharmaceutical composition. It is in the range of about 10% w / w.

[0015] In another aspect, provided herein is a method for treating cancer in a human patient. The method includes a method for treating, managing, or preventing a cancer, the method comprising administering to a patient having or developing cancer, the patient being treated with the method comprising administering to a patient a therapeutically effective amount of the cancer. An effective amount of ADPR dilithium, or a solvate, hydrate, or Administering tautomers, stereoisomers, isotopic species, prodrugs, or polymorphs In certain embodiments, the cancer is lung cancer, lung adenocarcinoma, non-small cell lung cancer, pancreatic cancer, pancreatic adenocarcinoma, glioma, glioblastoma multiforme, or acute myeloid leukemia. [Brief description of the drawings]

[0016] 4. Brief Description of the Drawings [Figure 1] FIG. 1 shows plaque formation from adenovirus serotype 3 in A549 cells and the effect of different concentrations of ADPR (monosodium salt), nicotinamide, cidofovir, and their combinations.

[0017] [Diagram 2] Figure 2 is a graph depicting the effect of ADPR (monosodium salt) on plaque formation in A549 cells using an adenovirus plaque inhibition assay. Specifically, Figure 2 depicts the plaque coverage (%) and the effect of ADPR (monosodium salt), nicotinamide, and cidofovir at various concentrations.

[0018] [Diagram 3] FIG. 3 depicts plaque formation from adenovirus serotype 3 in A549 cells and the effect of ADPR (monosodium salt), LiCl, and the combination of ADPR (monosodium salt) with LiCl at concentrations of 0.4 mM, 1.33 mM, and 4 mM.

[0019] [Figure 4] FIG. 4 is a graph depicting the percent coverage of plaques from adenovirus serotype 3 in A549 cells and the effect of ADPR (monosodium salt), LiCl, and the combination of ADPR (monosodium salt) with LiCl at a 4 mM concentration.

[0020] [Diagram 5]FIG. 5 shows representative images of the conjunctiva and cornea (slit lamp) from the left eye for Group 1 animal P7278 that did not receive any treatment (OS is the left eye and OD is the right eye). Only the OS was evaluated as the OD had a weak response to adenovirus. Image A - Day 1 (OS): Hyperemia score of "2". Image B - Day 3 (OS): Deep cornea could be present with increasing corneal opacity. Image C - Day 7 (OS): Increased corneal opacity, including areas of corneal abrasion. Image D - Day 10 (OS): Decreased corneal abrasion while general corneal opacity is still present.

[0021] [Figure 6] FIG. 6 shows representative images of the conjunctiva and cornea (slit lamp) from both eyes (OD is the right eye and OS is the left eye) for Group 2 animal P7279 treated with vehicle control. Image A-Day 1 (OD): Discharge from the conjunctiva is present. Image B-Day 1 (OD): Increased opacity around the corneal abrasion. Image C-Day 3 (OD): Increased opacity of the corneal abrasion. Image D-Day 3 (OS): Increased opacity of the corneal abrasion. Image E-Day 7 (OD): Increased opacity of the corneal abrasion. Image F-Day 7 (OS): Slight increase in opacity of the corneal abrasion. Image G-Day 10 (OD): Decreased opacity of the corneal abrasion.

[0022] [Figure 7]FIG. 7 shows representative images of the conjunctiva and cornea (slit lamp) from both eyes (OS is the left eye and OD is the right eye) for Group 3 animal P7280 treated with test article (2% ADPR, monosodium salt). Image A-Day 1 (OD): Corneal abrasion opacity increased. Image B-Day 1 (OS): Corneal abrasion opacity increased slightly. Image C-Day 3 (OD): Corneal abrasion opacity decreased. Image D-Day 3 (OS): Corneal abrasion opacity decreased. Image E-Day 7 (OD): Corneal abrasion opacity and number of inflamed areas decreased. Image F-Day 7 (OS): Corneal abrasion opacity decreased. Image G-Day 10 (OD): Corneal abrasion opacity decreased. Image H-Day 10 (OS): Hyperemic core of the third eyelid at "2". Image I-Day 10 (OS): Appearing abrasion healed. Image J-10th day (OS): The opacity of the corneal abrasion decreased.

[0023] [Figure 8] FIG. 8 shows the HPLC trace of ADPR·dilithium synthesized as described in Example 4.

[0024] [Figure 9] FIG. 9 shows mass spectrometry analysis of ADPR·dilithium synthesized as described in Example 4.

[0025] [Figure 10] Figure 10 shows the composite modified McDonald-Shadduck score (sum of all subscores) in both rabbit eyes at baseline on day 1 (24 hours after the second corneal scratching procedure and adenovirus inoculation, and immediately prior to the start of treatment) and at subsequent treatments on days 2, 3, and 7. All three ADPR·dilithium-treated groups (0.5%, 1%, and 2% TID) showed significant improvements (p<0.01) on days 3 and 7 compared to baseline on day 1. Vehicle-treated groups showed no significant changes.

[0026] [Figure 11]FIG. 11 shows the conjunctival injection (Image A) and subscores for corneal lesion surface area (Image B) from the modified McDonald-Shadduck score in both rabbit eyes at baseline on day 1 (24 hours after the second corneal scratching procedure and inoculation with adenovirus, and immediately prior to the start of treatment) and at subsequent treatments on days 2, 3, and 7. For conjunctival injection (Image A), all three treated groups (0.5%, 1%, and 2% TID) showed significant improvement (p<0.01) on days 3 and 7 compared to baseline on day 1. The vehicle-treated group showed no significant change. For corneal lesion surface area (Image B), all three treated groups (0.5%, 1%, and 2% TID) showed significant improvement (p≦0.05) on days 3 and 7 compared to baseline on day 1. The vehicle-treated group showed no significant change.

[0027] [Figure 12] FIG. 12 shows the percentage of cell proliferation relative to vehicle control following treatment with increasing concentrations of ADPR·dilithium (Image A), LiCl (Image B), and SN38 (Image C) for ASPC1 cells.

[0028] [Figure 13] FIG. 13 shows the percentage of cell proliferation relative to vehicle control following treatment with increasing concentrations of ADPR·dilithium (Image A), LiCl (Image B), and SN38 (Image C) for H1437 cells.

[0029] [Figure 14] FIG. 14 shows the percentage of cell proliferation relative to vehicle control following treatment with increasing concentrations of ADPR·dilithium (Image A), LiCl (Image B), and SN38 (Image C) for U87-MG cells.

[0030] [Figure 15]FIG. 15 shows the percentage of cell proliferation relative to vehicle control following treatment with increasing concentrations of ADPR·dilithium (Image A), LiCl (Image B), and SN38 (Image C) for MV411 cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] 5 Detailed explanation 5.1 Definition As used herein, the term "ADPR" refers to ADPR in its pharma- ceutically acceptable form. Salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, or is understood to include polymorphs.

[0032] As used herein, the term "dose" refers to a dose or doses administered at one time. , ADPR, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof , isotopic species, prodrugs, or polymorphs. A dose is a single unit dose. or alternatively, may comprise more than a single unit dosage form (e.g. , a single dose may contain two tablets) or in a dosage form less than a single unit (e.g. A single dose may even contain 1 / 2 of a tablet.

[0033] As used herein, the term "daily dose" refers to the amount of ADP administered in a 24-hour period. R, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isomer thereof. The daily dose refers to the amount of each isotopic species, prodrug, or polymorph. may be administered at once (i.e., one daily dose administration), or alternatively, the daily dose administration may be DPR or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof; Administration of the isotopic species, prodrug, or polymorph is twice daily, three times daily, Or even divided into four doses per day.

[0034] As used herein, the terms "patient" and "subject" include, but are not limited to, However, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, Animals, such as mammals, including monkeys, chickens, turkeys, quail, or guinea pigs, etc. In one embodiment, the term "patient" or "subject" as used herein means a mammal. In one embodiment, as used herein, the term " "Patient" or "subject" means a human.

[0035] As used herein, an "effective amount" is an amount that provides a therapeutic benefit in the treatment of a disease. or sufficient to delay or significantly minimize symptoms associated with the disease; ADPR, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof; The term "isotopic species," "prodrug," or "polymorph" refers to the amount of an isotopic species, prodrug, or polymorph. The disease is an adenovirus-associated disease or condition. In certain embodiments, the disease is an eye disease. In this case, disease is caused by infection, inflammation, or physical, chemical, thermal, or radiation injury. In certain embodiments, the disease is a disease or condition caused by a plant and / or a disease or condition affecting the crop.

[0036] As used herein, the terms "prevent" and "prevent The terms "prevention" and "prevention" are art-recognized and include, but are not limited to, adenovirus. any disease or condition related to eye disease, cancer, or infection, inflammation, or any physical, chemical, thermal A condition, such as a disease or condition caused by radiation or by injury from radiation or when used in connection with any other medical condition such as those described herein: As is well understood in the art, and compared to subjects not given the composition and administering a compound to the subject that reduces the frequency or delays the onset of symptoms of the condition. Includes.

[0037] As used herein, the terms "treat" and "treating" refer to )" and "treatment" refers to the alleviation or amelioration of symptoms, clinical signs, or a combination of both in a manner that improves or stabilizes the subject's condition. The term "treatment" refers to the reversal, reduction, or prevention of the underlying pathology of a condition. "To treat" and "treat" also refer to the eradication or amelioration of a disease or symptoms associated with the disease. In certain embodiments, such terms refer to the administration of the present invention to a patient suffering from a disease. and minimizing the spread or worsening of the disease as a result of administration of the compounds disclosed in the document. In certain embodiments, such diseases are adenovirus-associated diseases or is a condition. In certain embodiments, the disease is cancer. In some embodiments, the disease is an ocular disease. In some embodiments, the disease is an infectious, inflammatory, or physical disease. A disease or condition caused by chemical, thermal, or radiological injury. do.

[0038] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition for treating adenovirus-associated diseases. any disease or condition, eye disease, cancer, or infection, inflammation, or any other physical, chemical, thermal, or to treat, manage, or prevent a disease or condition caused by radiation injury. "Composition" refers to a composition that is suitable for the intended use or treatment when used in a pharmaceutical product.

[0039] As used herein, the term "pharmaceutically acceptable salt" means a salt that is acceptable to the patient based on sound medical judgment. It is capable of being in contact with human tissue without excessive toxicity, irritation, allergic reaction, etc., within the limits of its safety criteria. Those salts that are suitable for use in combination with other cormorant.

[0040] As used herein, and unless otherwise indicated, the terms "about" or "approximately" are used to "The" refers to the allowable error for a particular value as determined by a person skilled in the art. means that the error depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to a given value or 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of the range It means within.

[0041] All references to singular terms or limitations of the invention are to the singular unless otherwise indicated or mentioned. Unless the contrary is clearly implied by the context in which it is used, The term includes any word or limitation, and vice versa.

[0042] As used herein, all combinations of method or process steps are encompassed unless otherwise indicated. Unless otherwise specified or the context in which the combination is made makes it clear that the opposite is true Unless otherwise implied, they may be performed in any order.

[0043] The compositions and methods of the present invention may be prepared without the addition of any additional or optional ingredients, components, or In compositions and methods of the general type described or otherwise herein. The invention may include the essential elements and limitations of the invention described herein, together with limitations useful in the present invention. may consist solely of, or consist essentially of, such elements and limitations. It may consist of only 5.2 5′-Adenosine diphosphate ribose (ADPR)

[0044] The uses and compositions provided herein include 5′-adenosine diphosphate ribose ( ADPR; ADP-ribose; Adenosine 5′-(trihydrogen diphosphate), P with D-ribose ' → 5-ester; adenosine 5'-(trihydrogen pyrophosphate), D-ribofuranose Adenosine 5'-diphosphate, D-ribose ester; Adenosine Syn 5'-pyrophosphate, 5'→5-ester with D-ribofuranose; Ribofuranose Adenosine 5'-diphosphoryl-D-ribose; Adenosine 5'-diphosphoryl Adenosine diphosphate ribose; Adenosine diphosphoribose; Adenosine Adenosine diphosphate-ribose (syn pyrophosphate-ribose; adenosine diphosphate-ribose).

[0045] ADPR is a small molecule of natural origin well known in the chemical literature. It is often represented by the general formula C 15 H 23 N5O 14 P2 and corresponds, for example, to the general structure of formula (I): The term "salt" includes various salts such as: [ka]

[0046] ADPR can be readily prepared by methods well known in the chemical arts. It can also be purified and used. These are commercially available as raw materials, for example from Sigma or Sigma-Aldrich It can be purchased from Sigma-Aldrich Co.

[0047] The ADPR compounds for use in the compositions and methods provided herein include those , optionally including known or pharma- ceutically acceptable salts, non-limiting examples of which include acetate, adipate, Phosphates, alginates, citrates, aspartates, benzoates, benzenesulfones Acid salts, bisulfates, butyrates, camphorates, camphorsulfonates, diglycerides Diluconate, glycerophosphate, hemisulfate, hemisulfate Butanoate, hexanoate, fumarate, hydrogen chloride, hydrogen bromide, hydrogen iodide, 2-hydrogen Isethionate, lactate, maleate, methanesulfonate Salt, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate , persulfate, 3-phenylpropionate, picrate, pivalate, propionate , succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p- toluenesulfonate, undecanoate, or a combination thereof.

[0048] The ADPR compounds are characterized in that the basic nitrogen-containing groups are methyl, ethyl, propyl, chloride, bromide and iodide. and lower alkyl halides such as butyl; dimethyl, diethyl, dibutyl and Dialkyl sulfates such as diamyl; decyl, lauryl, myristyl chlorides, bromides and iodides and stearyl; aryl such as benzyl bromide and phenethyl; They are quaternized with materials such as alkyl halides, alkyl aryl halides, and many others. The term may also include derivatives thereof.

[0049] Examples of acids that can be used to form pharma- ceutically acceptable acid addition salts of ADPR include hydrochloric acid, Inorganic acids such as hydrobromic, sulfuric and phosphoric acid, as well as oxalic, maleic, succinic and This includes organic acids such as citric acid.

[0050] During the final isolation and purification of ADPR, the acid moiety is replaced with a pharma- ceutically acceptable metal ion. a suitable base, such as, but not limited to, a hydroxide, carbonate, or bicarbonate; can be made basic by reacting it with ammonia or with organic primary, secondary or tertiary amines. Salts may be prepared in situ. Non-limiting examples of pharma- ceutically acceptable salts include lithium (dilithium) salts. (including sodium, potassium, calcium, magnesium, aluminum, zinc Alkali metals, alkaline earth metals, transition metals, or elements such as ruthenium, cobalt, and copper salts, etc. Salts based on post-transition metals in the periodic table, Ammonium, tetramethylammonium, tetraethylammonium, methylamine , dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine Contains salts based on non-toxic quaternary ammonia and amine captions, including amines, etc. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethene, These include diethanolamine, piperidine, piperazine, and the like.

[0051] In one embodiment, for use in the compositions and methods provided herein The ADPR compounds include, but are not limited to, lithium hydroxide or sodium hydroxide. In the presence of alkaline bases, nicotinamide adenine dinucleotide (NAD+) In such an embodiment, the AD thus synthesized is The PR is isolated in the form of its corresponding base metal ion mono- or di-salt.

[0052] In specific embodiments, the compositions and methods for use in the methods provided herein include In one embodiment, the ADPR compound is in the form of its sodium salt. In another embodiment, the ADPR compound is in the form of its monosodium salt. It is in the form of the sodium salt.

[0053] In other specific embodiments, the use in the compositions and methods provided herein The ADPR compound for use is in the form of its lithium salt. In another embodiment, the ADPR compound is in the form of its monolithium salt. It is in the form of a lithium salt.

[0054] Further provided herein are prodrugs of ADPR, or pharma- ceutically acceptable derivatives thereof. Such prodrugs are, for example, intravenous, cerebrospinal, or intravenous salts or stereoisomers. Longer half-lives and longer release of the drug following administration via infusion or injection into the bloodstream or other body fluid compartments. Provides wider tissue distribution.

[0055] In one embodiment, the prodrug is a nucleotide analogue of the acceptor protein, peptide or amino acid. In such a prodrug concept, poly -ADPR is used as a depot form of ADPR, so that ADPR is not present in blood, ascites, Hydration in the cerebrospinal fluid, vitreous humor, aqueous humor, subcutaneous fluid, interstitial fluid, and other non-intracellular spaces It is slowly released by hydrolase to treat ADPR-responsive diseases. The general structure of a prodrug (associated with an acceptor protein) is represented by formula (II): Can be: [ka]

[0056] In certain embodiments, the prodrug of ADPR is a carboxylic acid, an amino acid, a fatty acid, or any combination thereof. In the present invention, ADPR is a terminal ribosomal protein, as represented, for example, by the general structure of formula (III): In the preparation of prodrugs of ADPR, Examples of fatty acids that may be used include, but are not limited to, palmitic acid, linoleic acid, sucrose, and glycerol. These include stearic acid, oleic acid, and other acids. Examples of carboxylic acids that may be used include, but are not limited to, 3-oxopentanoic acid, 3-hydroxypentanoic acid, These include prodrugs of ADPR, hydroxypentanoic acid, acetoacetic acid, and β-hydroxybutyric acid. Examples of amino acids that may be used in the preparation of the peptides include, but are not limited to, glutamine, arginine, riboflavin ... These include glycine, aspartic acid, lysine, and arginine. [ka]

[0057] 5.3 Treatment and prevention methods Provided herein are methods for treating adenovirus-associated diseases or conditions, eye diseases, For cancer, infection, inflammation, or physical, chemical, thermal, or radiation injury A method for treating and / or preventing a disease or condition caused by a any disease or condition associated with a virus, eye disease, cancer, or infectious, inflammatory, or physical Have a disease or condition caused by chemical, thermal, or radiation injury or a pharmacologic agent thereof. Salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, or is a method comprising administering the polymorph, or a pharmaceutical composition thereof.

[0058] In certain embodiments, provided herein are adenovirus-associated any disease or condition caused by infection, inflammation, or any other physical, chemical, thermal, or to treat or prevent a disease or condition caused by radiation injury. The method of claim 1, further comprising administering to a patient a disease or condition associated with an adenovirus, such as an eye disease, cancer, or infection, inflammation, or caused by physical, chemical, thermal, or radiation injury. Provide a pharmacologic agent that is pharmacologic to a patient who has or is at risk of developing a disease or condition that is associated with the disease or condition. Amount of ADPR, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof. The method includes administering to the subject a compound, an isotopic species, a prodrug, or a polymorph.

[0059] In certain embodiments, provided herein are adenovirus-associated A method for treating or preventing a disease or condition associated with an adenovirus, comprising administering to said patient a Patients who have a disease or condition, or who develop a disease or condition associated with an adenovirus. A pharmacologic effective amount of ADPR, or a pharmacologic acceptable salt or solvent thereof, is administered to the at-risk patient. Solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, or polymorphs wherein the adenovirus-associated disease or condition is an infection of the eye, ear, mouth, or other organs. The method is characterized in that the patient is suffering from a disease or condition affecting any part of the upper or lower respiratory tract. In some embodiments, the adenovirus-associated disease or condition includes, but is not limited to, Ocular diseases, including but not limited to conjunctivitis, keratitis, keratoconjunctivitis, corneal abrasion, infectious corneal ulcers inflammation, superficial keratitis, interstitial keratitis, uveitis, acute glaucoma, blepharitis, otitis media, otitis externa, dentition Melanitis, mucositis, pharyngitis, tonsillitis, rhinitis, sinusitis, laryngitis, croup, tracheitis, bronchitis , bronchiolitis, bronchopneumonia, pneumonia, asthma exacerbation, chronic obstructive pulmonary disease exacerbation, or emphysema exacerbation In certain embodiments, the adenovirus-associated disease or condition is selected from the group consisting of: Conjunctivitis, keratitis, keratoconjunctivitis, pharyngitis, tonsillitis, laryngitis, rhinitis, sinusitis, bronchitis, In one embodiment, the disease is an adenovirus-associated disease or The condition is keratitis, conjunctivitis, or keratoconjunctivitis. In another embodiment, the disease or condition associated with bronchitis is bronchitis or bronchiolitis. The adenovirus-associated disease or condition is pharyngitis, tonsillitis, or laryngitis.

[0060] In certain embodiments, provided herein are adenovirus-associated any disease or condition caused by infection, inflammation, or any other physical, chemical, thermal, or to treat or prevent a disease or condition caused by radiation injury. The method of claim 1, further comprising administering to a patient a disease or condition associated with an adenovirus, such as an eye disease, cancer, or infection, inflammation, or caused by physical, chemical, thermal, or radiation injury. Provide a pharmacologic agent that is pharmacologic to a patient who has or is at risk of developing a disease or condition that is associated with the disease or condition. Amount of ADPR, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof. and administering to the subject a compound, isotope, prodrug, or polymorph thereof, wherein the ADPR The compound is administered by topical, oral, parenteral, transmucosal, or inhalation routes of administration. In one embodiment, the ADPR described herein is administered by topical administration. In one embodiment, local administration is to an internal cell or tissue surface. In a specific embodiment, local administration to an internal cell or tissue surface is to any surface of the respiratory tract. By aerosolization onto a surface, spraying, oral delivery, injection, or similar methods. In an embodiment, local administration to an internal cell or tissue surface includes administration via the gut to any surface of the digestive tract. By oral delivery, injection or enema (e.g., from the mouth to the anus). Local administration to internal cells or tissue surfaces can be by parenteral injection or infusion into any internal organ. In other embodiments, topical administration includes, but is not limited to, administration to the skin, eyes, nails, hair, or to external cell or tissue surfaces, including the ear.

[0061] In certain embodiments, provided herein is a method for treating an ocular disease or at least an eye disease. A method for treating and / or preventing a microbial infection in one or more tissues, comprising administering to the eye of a patient In one embodiment, the method comprises administering one or more doses of a pharmaceutical composition provided herein. In certain embodiments, the prevention is prevention of infection following corneal abrasion or ophthalmic surgery. In this case, ADPR is in the form of its dilithium salt.

[0062] In one embodiment, the ocular disease includes, but is not limited to, ocular diseases of the cornea, conjunctiva, iris, aqueous humor, etc. (anterior chamber), lens, pupil, ciliary body and ciliary muscle, suspensory ligament, sclera, Schlemm's canal, and zonules of Zinn Affects any area of ​​the front of the eye, including the

[0063] In one embodiment, the eye disease is a microbial infection of at least one tissue of the eye, conjunctivitis, Keratitis, keratoconjunctivitis, corneal abrasion, ulcerative infectious keratitis, superficial keratitis, interstitial keratitis, cerebral keratitis In a specific embodiment, the present invention is selected from the group consisting of ocular inflammation, acute glaucoma, and blepharitis. The eye disease is infectious keratoconjunctivitis.

[0064] In one embodiment, the microorganism is a bacterium, a virus, a fungus, or an amoeba. In an embodiment, the bacterium is a mycobacterium.

[0065] In certain embodiments, provided herein are methods for treating infection, physical injury, or A method for treating and / or preventing a disease or condition caused by inflammation. The method includes the step of: The stereoisomers, isotopic species, prodrugs, or polymorphs, or pharmaceutical compositions thereof, may be prepared as described above. This includes administering the drug to patients who have or are at risk of developing the disease or condition. In a specific embodiment, the disease or condition is a corneal and / or conjunctival infection, a physical injury, or a corneal or conjunctival injury. In a specific embodiment, ADPR is caused by the biliary It is in the form of an ammonium salt.

[0066] In certain embodiments, provided herein are methods for treating a variety of conditions, including physical, chemical, thermal, to treat and / or prevent diseases or conditions caused by radiation or injury from radiation The method comprises administering to the patient a therapeutically effective amount of ADPR or a pharma- ceutically acceptable salt, solvate or hydrate thereof. , tautomers, stereoisomers, isotopic species, prodrugs, or polymorphs, or pharmaceutical forms thereof The pharmaceutical composition is administered to a patient having or at risk of developing the disease or condition. In a specific embodiment, the ADPR is in the form of its dilithium salt. .

[0067] In another aspect of the invention, provided herein is a method for treating and / or preventing cancer. The present invention relates to a method for preventing ADPR or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, Tautomers, stereoisomers, isotopic species, prodrugs, or polymorphs, or pharmaceuticals thereof administering the composition to a patient having or at risk of developing cancer. In a specific embodiment, ADPR is in the form of its dilithium salt.

[0068] In certain embodiments, provided herein are methods for treating and / or preventing cancer. A method for preventing ADPR, comprising administering a medicamentously effective amount of ADPR or a pharma- ceutical acceptable salt thereof. , solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, or The method includes administering the polymorph to a patient having cancer or at risk of developing cancer. In a specific embodiment, ADPR is in the form of its dilithium salt.

[0069] As used herein, and unless otherwise indicated, the term "cancer" refers to any cancer that occurs in a mammal. A physiological state in the mouse that is typically characterized by unregulated cell proliferation. Examples of cancer include solid tumors and hematological cancers. In some cases, the cancer is a primary cancer, and in others, the cancer has metastasized.

[0070] As used herein, a "solid tumor" includes, but is not limited to, bladder cancer ( cancer (including but not limited to superficial bladder cancer), breast cancer (including but not limited to endometrial cancer), cancers of the central nervous system (including but not limited to pulmonary B, ER+, PR+ and Her2+ breast cancer); , glioblastoma multiforme (GBM), glioma, medulloblastoma, and astrocytoma), colorectal cancer, ductal cancer (including, but not limited to, gastric, esophageal, and rectal cancer), endocrine gland cancer (including but not limited to thyroid cancer, and adrenal cancer), eye cancer (including but not limited to cancers of the female reproductive organs (including but not limited to placenta, uterus, vulvar, ovarian, and cervical cancers), head and neck cancers (including but not limited to pharyngeal, esophageal, , and tongue cancer), liver cancer, lung cancer (including but not limited to non-small cell lung cancer (NSCLC), C), small cell lung cancer (SCLC), mucoepidermoid carcinoma, bronchial carcinoma, squamous cell carcinoma (SQCC), and unspecified cancer / NSCLC), skin cancer (including but not limited to melanoma, and SQCC) soft tissue cancers (including but not limited to sarcoma, Ewing's sarcoma, and rhabdomyosarcoma) cancers of the bone (including but not limited to sarcoma, Ewing's sarcoma, and osteosarcoma); ), squamous cell carcinoma (including, but not limited to, lung, esophageal, neck, and head and neck cancers), pancreatic cancer, renal cancer (including but not limited to Wilms tumor of the kidney and renal cell carcinoma) In one embodiment, the solid tumor is a triple-negative tumor. In some embodiments, the solid tumor is not a tumor of the breast, colon, or rectal cancer (TNBC). In one such embodiment, the solid tumor is superficial bladder cancer. In another embodiment, the solid tumor is lung squamous cell carcinoma. In this case, the solid tumor is luminal B-type breast cancer.

[0071] As used herein, "blood cancer" includes, but is not limited to, leukemia ( These include, but are not limited to, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, precursor B-cell leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia, bone marrow Includes monoblastic / T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML) lymphomas (including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma, NHL), Burkitt lymphoma (BL), B-cell lymphoma, lymphoblastic lymphoma, follicular lymphoma FL, diffuse large B-cell lymphoma (DLBCL), large cell immunoblastic lymphoma including idiopathic pulmonary fibrosis, pulmonary fibrosis, and multiple myeloma.

[0072] In specific embodiments, provided herein are methods for treating and / or preventing cancer. A method for preventing ADPR, comprising administering to the patient a medicament ... Salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, or or a polymorph thereof to a patient having cancer or at risk of developing cancer. wherein the cancer is lung cancer, lung adenocarcinoma, non-small cell lung cancer, pancreatic cancer, pancreatic adenocarcinoma, glioma, multilineage cancer, In a specific embodiment, ADPR is selected from the group consisting of glioblastoma, glioblastoma resectable, and acute myeloid leukemia. It is in the form of a lithium salt.

[0073] In certain embodiments, provided herein are highly cytotoxic stress A method for increasing the amount of free ADPR or ATP in ADPR- or ATP-deficient cells under a physiological condition The method of claim 1, further comprising administering to said cells a sufficient amount of ATP to restore said cells to normal physiological cellular ADPR or ATP levels. The method comprises contacting the antibody with an amount of ADPR.

[0074] In one embodiment, the administering step comprises administering ADPR and a metal salt, The total amount of ADPR and metal salt is in the range of about 0.001 mg to about 5 mg per dose. In one embodiment, each dose is between 10 μl and 200 μl. Each dose is between 20 μl and 80 μl.

[0075] In one embodiment, the administering step comprises administering the pharmaceutical composition in the form of a solution. In one embodiment, the solution is administered to the eye 1 to 8 times per day. In this case, the solution is administered to the eye 1 to 24 times per day.

[0076] In one embodiment, the method further comprises administering to the subject a dose of at least 1 month prior to the administering step. Storing the composition for at least 3 months, at least 6 months, or at least 1 year.

[0077] All compounds described herein may be used in the methods described herein. In particular, the present invention relates to a disease or condition associated with an adenovirus, an eye disease, a cancer, or an infection, inflammation, or the like. is a disease or injury caused by physical, chemical, thermal or radiation injury. is expected to be of use in the prevention or treatment of the condition.

[0078] 5.4 Combination Therapy In certain embodiments, ADPR or a pharma- ceutically acceptable salt, solvate, or hydrate thereof is any tautomer, stereoisomer, isotopic species, prodrug, or polymorph thereof; The pharmaceutical compositions may be administered in combination with other pharmaceutical agents. Such combination therapy may be This may be achieved by means of the simultaneous, sequential or separate administration of the individual therapeutic components. and, when administered as a component of such a combination therapy, the AD PR and other medications may be synergistic, resulting in a daily increase in the levels of either or both of their components. Doses may be reduced compared to the dose of either component normally given as a monotherapy. Instead, when administered as a component of such a combination therapy, the ADPR and other medications may be additive, so that the daily doses of each of those components are The dosage will be similar or the same as that of either component normally given as a monotherapy.

[0079] In certain embodiments, the other medicament is an antiviral compound or metal salt. In some embodiments, the other medicament is cidofovir, acyclovir, or ganciclovir. In a particular embodiment, the other medicament is cidofovir. In certain embodiments, the other pharmaceutical agent is a lithium, zinc, cobalt, or copper salt. In the other drugs, lithium benzoate, lithium bromide, lithium chloride, lithium sulfate , lithium tetraborate, lithium acetate, zinc chloride, zinc sulfate, zinc bromide, cobalt chloride, Copper chloride (CuBr2), copper chloride (CuCl2) and copper sulfate. In a specific embodiment, the other pharmaceutical agent is lithium chloride.

[0080] In one embodiment, when ADPR is used in combination with cidofovir, The concentration of ovil is in the range of about 0.01% to about 0.2%. The concentration of cidofovir is about 0.01% to about 0.15%, about 0.01% to about 0.1%, about 0.01% to about 0.05 ... .05%, about 0.05% to about 0.2%, about 0.05% to about 0.15%, about 0.05% to about 0.1%, about 0.1% In particular, the range is from about 0.2%, from about 0.1% to about 0.15%, or from about 0.15% to about 0.2%. In certain embodiments, the concentration of cidofovir is about 0.1% or less. The concentrations of cidofovir were approximately 0.2%, approximately 0.15%, approximately 0.1%, approximately 0.05%, approximately 0.04%, and approximately 0.03%. %, about 0.02%, or about 0.01%.

[0081] In one embodiment, when ADPR is used in combination with cidofovir, The concentration of phospholipid is in the range of about 0.01 mM to about 10 mM. The concentration of dofovir is about 0.01 mM to about 5 mM, about 0.01 mM to about 3 mM, about 0.01 mM to about 1 mM M, about 0.01mM to about 0.5mM, about 0.01mM to about 0.1mM, about 0.01mM to about 0.05mM, about 0.01 from about 0.03 mM, from about 0.01 mM to about 0.02 mM, from about 0.05 mM to about 10 mM, from about 0.05 mM to about 5 mM, about 0.05 mM to about 3 mM, about 0.05 mM to about 1 mM, about 0.05 mM to about 0.5 mM, about 0.05 mM to about 0.1mM, about 0.1mM to about 10mM, about 0.1mM to about 5mM, about 0.1mM to about 3mM, about 0.1m M to about 1mM, about 0.1mM to about 0.5mM, about 0.5mM to about 10mM, about 0.5mM to about 5mM, about 0. 5mM to about 3mM, about 0.5mM to about 1mM, about 1mM to about 10mM, about 1mM to about 5mM, about 1mM from about 3 mM to about 3 mM, from about 3 mM to about 10 mM, from about 3 mM to about 5 mM, from about 5 mM to about 10 mM, from about 5 mM to about In a specific embodiment, the cidophobe The concentrations of the leucine are about 0.01 mM, about 0.02 mM, about 0.03 mM, about 0.05 mM, about 0.1 mM, about 0.2 mM, about 0.5 mM, About 0.7 mM, about 1 mM, about 1.5 mM, about 2 mM, about 2.5 mM, about 3 mM, about 3.5 mM, about 4 mM, about 4.5 mM , about 5 mM, about 5.5 mM, about 6 mM, about 6.5 mM, about 7 mM, about 7.5 mM, or about 8 mM. can be.

[0082] In one embodiment, when ADPR is used in combination with cidofovir, The molar ratio of fobil to fobil is in the range of about 0.1:1 to about 10,000:1. wherein the molar ratio of ADPR:cidofovir is from about 0.1:1 to about 7,000:1, from about 0.1:1 to about 5,000:1, About 0.1:1 to about 3,000:1, about 0.1:1 to about 1,000:1, about 0.5:1 to about 10,000:1, about 0.5:1 to about Approximately 7,000:1, approximately 0.5:1 to approximately 5,000:1, approximately 0.5:1 to approximately 3,000:1, approximately 0.5:1 to approximately 1,000:1, approximately 1 :1 to about 10,000:1, about 1:1 to about 7,000:1, about 1:1 to about 5,000:1, about 1:1 to about 3,000:1, about 1:1 to about 1,000:1, about 5:1 to about 10,000:1, about 5:1 to about 7,000:1, about 5:1 to about 5,000:1, About 5:1 to about 3,000:1, about 5:1 to about 1,000:1, about 10:1 to about 10,000:1, about 10:1 to about 7,000: 1, about 10:1 to about 5,000:1, about 10:1 to about 3,000:1, or about 10:1 to about 1,000:1. do.

[0083] In one embodiment, the molar ratio of ADPR:cidofovir ranges from about 0.1:1 to about 1,000:1. In some embodiments, the molar ratio of ADPR:cidofovir is within about 0.1:1 to about 700:1, about 0.1:1 to about 500:1, about 0.1:1 to about 200:1, about 0.1:1 to about 100:1, about 0.1:1 to about about 50:1, about 0.1:1 to about 10:1, about 0.1:1 to about 5:1, about 0.1:1 to about 1:1, about 0.1:1 to about 0.5 :1, about 0.5:1 to about 1,000:1, about 0.5:1 to about 700:1, about 0.5:1 to about 500:1, about 0.5:1 to about 2 00:1, about 0.5:1 to about 100:1, about 0.5:1 to about 50:1, about 0.5:1 to about 10:1, about 0.5:1 to about 5:1 , about 0.5:1 to about 1:1, about 1:1 to about 1,000:1, about 1:1 to about 700:1, about 1:1 to about 500:1, about 1: 1 to about 200:1, about 1:1 to about 100:1, about 1:1 to about 50:1, about 1:1 to about 10:1, about 1:1 to about 5:1 , about 5:1 to about 1,000:1, about 5:1 to about 700:1, about 5:1 to about 500:1, about 5:1 to about 200:1, about 5: 1 to about 100:1, about 5:1 to about 50:1, about 5:1 to about 10:1, about 10:1 to about 1,000:1, about 10:1 to about about 700:1, about 10:1 to about 500:1, about 10:1 to about 200:1, about 10:1 to about 100:1, about 10:1 to about 50 :1, about 50:1 to about 1,000:1, about 50:1 to about 700:1, about 50:1 to about 500:1, about 50:1 to about 200:1 , about 50:1 to about 100:1, about 100:1 to about 1,000:1, about 100:1 to about 700:1, about 100:1 to about 500: 1, about 100:1 to about 200:1, about 200:1 to about 1,000:1, about 200:1 to about 700:1, about 200:1 to about 5 00:1, about 500:1 to about 1,000:1, about 500:1 to about 700:1, or about 700:1 to about 1,000:1 It is.

[0084] In some embodiments, the molar ratio of ADPR:cidofovir is from about 50:1 to about 10,000:1 In some embodiments, the molar ratio of ADPR:cidofovir is in the range of about 50:1 to about 7,000:1, about 50:1 to about 5,000:1, about 50:1 to about 1,000:1, about 50:1 to about 700:1, about 50 :1 to about 500:1, about 50:1 to about 200:1, about 50:1 to about 100:1, about 200:1 to about 10,000:1, about 20 0:1 to about 7,000:1, about 200:1 to about 5,000:1, about 200:1 to about 1,000:1, about 200:1 to about 700:1 , about 200:1 to about 500:1, about 500:1 to about 10,000:1, about 500:1 to about 7,000:1, about 500:1 to about about 5,000:1, about 500:1 to about 1,000:1, about 500:1 to about 700:1, about 1,000:1 to about 10,000:1, about 1,000:1 to about 7,000:1, about 1,000:1 to about 5,000:1, about 1,000:1 to about 3,000:1, about 2,000:1 from about 10,000:1, from about 2,000:1 to about 7,000:1, from about 2,000:1 to about 5,000:1, from about 2,000:1 to about 3 ,000:1, about 3,000:1 to about 10,000:1, about 3,000:1 to about 7,000:1, about 3,000:1 to about 5,000:1 , about 3,000:1 to about 4,000:1, about 5,000:1 to about 10,000:1, about 5,000:1 to about 7,000:1, about 5,0 In particular embodiments, the ratio is in the range of about 00:1 to about 6,000:1, about 7,000:1 to about 10,000:1. and the molar ratio of ADPR:cidofovir is about 0.1:1, about 0.5:1, about 1:1, about 5:1, about 10:1, about 50:1. , Approx. 100:1, Approx. 150:1, Approx. 160:1, Approx. 170:1, Approx. 180:1, Approx. 190:1, Approx. 200:1, Approx. 250:1, Approx. 300: 1, approx. 350:1, approx. 400:1, approx. 500:1, approx. 600:1, approx. 700:1, approx. 800:1, approx. 900:1, approx. 1,000:1, approx. 2,000:1, about 5,000:1, about 7,000:1, or about 10,000:1.

[0085] 5.5 Dosage and Dosage Regimens In certain embodiments, the adenovirus-associated diseases described herein or condition, eye disease, cancer, or infection, inflammation, or physical, chemical, thermal, or The disease or condition caused by radiation injury is at about 0.005 mg / kg to about 1000 mg / kg. / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg 1. Administer from about 5.0 mg / kg to about 5.0 mg / kg of ADPR, or a pharma- ceutically acceptable salt, solvate, hydrate, or equivalent thereof. Any variants, stereoisomers, isotopic species, prodrugs, or polymorphs are also included herein. The compounds may be treated by administration to a patient having a disease or condition as described above.

[0086] In certain embodiments, the adenovirus-associated diseases described herein or condition, eye disease, cancer, or infection, inflammation, or physical, chemical, thermal, or A disease or condition caused by radiation injury may range from about 0.005 mg to about 1000 mg; about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about ADPR in an amount of about 0.1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5.0 mg, or 0.1 mg to about 1 mg or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, The isotopic species, prodrugs, or polymorphs may be administered to treat any of the diseases or conditions described herein. The method is to treat a patient having or at risk of developing the condition by administering the In one embodiment, ADPR, or a pharma- ceutically acceptable salt, solvate, or water thereof is obtained. The concentration of solvates, tautomers, stereoisomers, isotopic species, prodrugs, or polymorphs is In another embodiment, the ADPR or its Pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species The concentration of the drug, prodrug, or polymorph is in the range of about 1 mg / mL to about 20 mg / mL. In certain such embodiments, the ADPR described herein is administered topically, orally. In one embodiment, the composition is administered by parenteral, transmucosal, or inhalation routes of administration. The ADPR described herein is administered by topical administration. In one embodiment, In particular embodiments, local administration is administration to an internal cell or tissue surface. Local administration to certain cell or tissue surfaces may be achieved by aerosolization, nebulization, or oral administration to any surface of the respiratory tract. In another specific embodiment, the internal cells or Topical administration to tissue surfaces may be achieved by oral delivery, injection or enema (e.g., to any surface of the digestive tract). In another specific embodiment, the internal cell or tissue surface Local administration to any internal organ is by parenteral injection or infusion. Thus, topical administration includes administration to external tissues, including, but not limited to, the skin, eyes, nails, hair, or ears. To a cell or tissue surface. In a specific embodiment, The ADPR is administered topically at a concentration ranging from about 0.05 mg / mL to about 30 mg / mL. In some embodiments, the ADPR described herein is administered at a concentration ranging from about 1 mg / mL to about 20 mg / mL. It is administered topically at a dose of 100 mg / kg.

[0087] In certain embodiments, the adenovirus-associated diseases described herein or condition, eye disease, cancer, or infection, inflammation, or physical, chemical, thermal, or A disease or condition caused by radiation injury may range from about 0.005 mg to about 1000 mg; about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about A daily dose of about 0.1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5.0 mg, 0.1 mg to about 1 mg or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isomer thereof. The compounds, isotopomers, prodrugs, or polymorphs may be used in combination with any of the compounds described herein for the treatment of diseases. or by administering to a patient having or at risk of developing a condition. In one embodiment, ADPR, or a pharma- ceutically acceptable salt or solvate thereof, of a compound, hydrate, tautomer, stereoisomer, isotopic species, prodrug, or polymorph The concentration is in the range of about 0.05 mg / mL to about 30 mg / mL. and its pharma- ceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopes, The concentration of the molecular species, prodrug, or polymorph is in the range of about 1 mg / mL to about 20 mg / mL. In certain such embodiments, the ADPR described herein is administered locally. In one embodiment, the composition is administered by oral, parenteral, transmucosal, or inhalation routes of administration. In one embodiment, the ADPR described herein is administered by topical administration. In certain embodiments, local administration is administration to an internal cell or tissue surface. In addition, local administration to internal cell or tissue surfaces may be achieved by aerosolization, spraying, or administration to any surface of the respiratory tract. , by oral delivery, injection or similar methods. Local administration to a cell or tissue surface can include oral delivery, injection or infusion to any surface of the digestive tract. In another specific embodiment, the internal cells or tissues are Local administration to a tissue surface can be by parenteral injection or infusion into any internal organ. In the present invention, topical administration includes, but is not limited to, administration to the skin, eyes, nails, hair, or ears. To an external cell or tissue surface. The ADPR is administered topically at a concentration ranging from about 0.05 mg / mL to about 30 mg / mL. In embodiments, the ADPR described herein is in the range of about 1 mg / mL to about 20 mg / mL. is administered locally at a concentration of

[0088] A disease or condition associated with an adenovirus as described herein, an eye disease, a cancer, or Caused by infection, inflammation, or physical, chemical, thermal, or radiation injury. ADPR, or a pharma- ceutically acceptable derivative thereof, for the treatment or prophylaxis of a disease or condition caused by Salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, The suitability of the polymorphs or polymorphs may be confirmed by using the assays described herein. For example, adenoviruses can be identified by viral culture and polymerase chain reaction. or bodily fluids (saliva, tears, or other fluids sampled by swabbing or similar methods) Rapid tests such as Adenoplus® from It can be diagnosed by.

[0089] 5.6 Pharmaceutical Compositions The pharmaceutical compositions may be used to prepare individual single unit dosage forms. The compositions and dosage forms include ADPR, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or derivative thereof. The pharmaceutical composition of the present invention includes isomers, stereoisomers, isotopic species, prodrugs, or polymorphs. The compositions and dosage forms may be formulated using any known method to form or produce the selected product form. or otherwise effective methods. For example, ADPR, or a pharma- ceutical acceptable salt thereof. Acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, The compound or polymorph may be formulated with a common excipient, diluent, or carrier, and Tablets, capsules, solutions, suspensions, emulsions, microemulsions, nanoemulsions, Drops, elixirs, sprays, powders, aerosols (e.g., dry powder aerosols, liquid aerosols) aerosols), dissolution media (e.g., fast dissolving tablets, films, or strips), suppositories, ointments or any other suitable dosage form. The product is in the form of a solution.

[0090] Non-limiting examples of suitable excipients, diluents, or carriers include starch, sugar, mannitol, and silicon. Fillers and extenders such as derivatives; carboxymethyl cellulose and others cellulose derivatives, alginates, gelatin, and binders such as polyvinylpyrrolidone. Combinations; humectants such as glycerin; disintegrants such as calcium carbonate and sodium bicarbonate decomposition retarders such as paraffin; absorption enhancers such as quaternary ammonium compounds; surfactants such as glycerol monostearate; kaolin and ventilated Adsorption carriers such as nites; carriers such as propylene glycol and ethyl alcohol; Also talc, calcium and magnesium stearate, and solid polyethylene glycol. Contains a lubricant such as cholesteryl.

[0091] The amounts and types of excipients, as well as the active ingredients (e.g., those disclosed herein) in the dosage form can be adjusted to suit the individual dosage forms. The amount and specific type of ADPR administered to a patient may include, but is not limited to, In certain embodiments, the AD PR or its pharma- ceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isomers, Administration of a pharmaceutical composition or dosage form that includes a polymorph, prodrug, or polymorph may be As used herein, the term "administration" can be by oral, parenteral, transmucosal, or inhalation routes. When referring to administration of a substance, the term "parenteral" refers to administration of a substance that is administered intravenously or intraarterially, such as intravitreal, intraocular, intracorneal, subcutaneous, intradermal, intravenous, or intraarterial. Such injections include intravascular injections, intramuscular, intraluminal and any other similar injection or infusion techniques. In certain embodiments, ADPR, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. , tautomers, stereoisomers, isotopic species, prodrugs, or polymorphs may be used, for example, in the formulation of tablets. In certain embodiments, the ADPR, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotope thereof. The species, prodrug, or polymorph may be administered locally. In the present invention, ADPR or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is The isomers, isotopic species, prodrugs, or polymorphs may be administered intranasally or by inhalation. It is possible.

[0092] The topical administration described herein involves administering a pharma- ceutical effective amount of ADPR, or a pharma- ceutical acceptable salt thereof. Acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, The drug or polymorph may be administered to, but is not limited to, the skin, eyes, ears, nose, sinuses, mouth, lips, throat, , larynx, epiglottis, trachea, bronchi, bronchioles, alveoli, esophagus, stomach, intestines, colon, rectum, anus, vagina , neck, and any other part of the skin, gastrointestinal, respiratory, and / or genitourinary tract. The present invention also includes application to any mucosal and / or epithelial surface of the body, including those In the present invention, the topical administration is carried out by administering a pharmacologic effective amount of ADPR or a pharmaceutical agent thereof. Pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, protons, The drug or polymorph may be administered to any wound due to injury, surgery, infection, inflammation, or cancer. This includes applying.

[0093] In addition, ADPR or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, isomer, or derivative thereof may be used. Conformal isomers, isotopic species, prodrugs, or polymorphs may be used with the active ingredient alone or in combination with the preferred or in certain parts of the intestinal tract, preferably for a long period of time or for a longer period of time to further enhance efficacy. Sustained or prolonged release dosage forms, including dosage forms that release over an extended or prolonged time The compounds described herein may also be formulated as sustained release dosage forms. The ADPR described delivers the active ingredient only or preferably in a specific part of the respiratory tract. Preferably, an extended or prolonged time is administered to further enhance efficacy. e) formulated into sustained or extended release dosage forms, including dosage forms that release over a period of time. Coatings, envelopes, and protective matrices for such dosage forms are well known in the pharmaceutical arts, e.g. The adhesive may be prepared from any of the known polymeric substances or waxes.

[0094] In one embodiment, provided herein is a pharmaceutical composition comprising ADPR. wherein the amount of ADPR in the pharmaceutical composition is from about 0.001% w / w to about 10% w / w of the pharmaceutical composition. In one embodiment, the amount of ADPR in the pharmaceutical composition is within the range of about 0.001% w / w to about 7% w / w, about 0.001% w / w to about 5% w / w, about 0.001% w / w to about 3% w / w, about 0.001% w / w to about 1% w / w, about 0.001% w / w to about 0.5% w / w, about 0.001% w / w to about 0.1% w / w, About 0.001% w / w to about 0.05% w / w, about 0.001% w / w to about 0.01% w / w, about 0.001% w / w to about 0.00 5% w / w, about 0.005% w / w to about 10% w / w, about 0.005% w / w to about 7% w / w, about 0.005% w / w to about 5 % w / w, about 0.005% w / w to about 3% w / w, about 0.005% w / w to about 1% w / w, about 0.005% w / w to about 0.5 % w / w, about 0.005% w / w to about 0.1% w / w, about 0.005% w / w to about 0.05% w / w, about 0.005% w / w to about 0.05% w / w About 0.01% w / w, about 0.01% w / w to about 10% w / w, about 0.01% w / w to about 7% w / w, about 0.01% w / w to About 5% w / w, about 0.01% w / w to about 3% w / w, about 0.01% w / w to about 1% w / w, about 0.01% w / w to about 0.5 % w / w, about 0.01% w / w to about 0.1% w / w, about 0.01% w / w to about 0.05% w / w, about 0.05% w / w to about 1 0% w / w, about 0.05% w / w to about 7% w / w, about 0.05% w / w to about 5% w / w, about 0.05% w / w to about 3% w / w w, about 0.05% w / w to about 1% w / w, about 0.05% w / w to about 0.5% w / w, about 0.05% w / w to about 0.1% w / w , about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 7% w / w, about 0.1% w / w to about 5% w / w, about 0. 1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.1% w / w to about 0.5% w / w, about 0.5% w / w from about 0.5% w / w to about 10% w / w, from about 0.5% w / w to about 7% w / w, from about 0.5% w / w to about 5% w / w, from about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 7% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 7% w / w % w / w, about 3% w / w to about 5% w / w, about 5% w / w to about 10% w / w, about 5% w / w to about 7% w / w, or about It is in the range of 7% w / w to about 10% w / w.

[0095] In one embodiment, the amount of ADPR in the pharmaceutical composition ranges from about 0.01% w / w to about 1% w / w of the pharmaceutical composition. In one embodiment, the amount of ADPR in the pharmaceutical composition is in the range of 0% w / w. In another embodiment, the pharmaceutical composition is The amount of ADPR ranges from about 0.5% w / w to about 2% w / w of the pharmaceutical composition.

[0096] In one embodiment, provided herein are methods for treating eye, respiratory tract, and / or digestive tract infections. The present invention relates to a method for treating and / or preventing a microbial infection or disease in at least one tissue of the eye, rectum, or esophagus. a pharmaceutical composition suitable for topical administration to the esophagus, intestine, and / or gastrointestinal tract, wherein the pharmaceutical composition The composition comprises ADPR, wherein the amount of ADPR is from about 0.01% w / w to about 10% w / w of the pharmaceutical composition. It is within range.

[0097] In one embodiment, provided herein are methods for treating eye, respiratory tract, and / or digestive tract infections. The present invention relates to a method for treating and / or preventing a microbial infection or disease in at least one tissue of the eye, rectum, or esophagus. a pharmaceutical composition suitable for topical administration to the esophagus, intestine, and / or gastrointestinal tract, wherein the pharmaceutical composition The composition includes: a) ADPR, wherein the amount of ADPR is from about 0.01% w / w to about 10% w / w of the pharmaceutical composition. and b) one or more metal salts, where the metals are lithium, zinc, copper, In one embodiment, the pharmaceutical composition comprises a compound selected from the group consisting of ballast, copper, and copper. The amount of metal salt in the composition ranges from about 0.0001% w / w to about 2% w / w of the pharmaceutical composition. In embodiments, the amount of metal salt in the pharmaceutical composition is from about 0.01% w / w to about 1% w / w of the pharmaceutical composition. is within the range.

[0098] In one embodiment, the microorganism is selected from the group consisting of bacteria, viruses, fungi, and amoebas. In one embodiment, the bacterium is a mycobacterium. In this context, the prevention is the prevention of infection following corneal abrasion or ophthalmic surgery.

[0099] In one embodiment, the pharmaceutical composition is suitable for administration to the eye. In the present invention, the pharmaceutical composition suitable for administration to the eye further contains a local anesthetic to relieve pain. In one embodiment, the local anesthetic is proparacaine, lidocaine, tetracaine, and and combinations thereof.

[0100] In one embodiment, the pharmaceutical composition enhances penetration of ADPR into tissues of the eye, respiratory tract, or gastrointestinal tract. In a specific embodiment, the penetration enhancer is a local anesthetic It is.

[0101] In one embodiment, the pharmaceutical composition further comprises an antimicrobial preservative. The antibacterial preservatives are sodium tetraborate, boric acid, benzalkonium chloride, and thimerosal. Alcohol, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol from the group consisting of EDTA, sorbic acid, Onamer M and combinations thereof In one embodiment, the amount of antimicrobial preservative in the pharmaceutical composition is selected from the group consisting of In a specific embodiment, the range is from about 0.001% w / w to about 1.0% w / w by weight. The pharmaceutical composition is in the form of a solution.

[0102] In one embodiment, the pharmaceutical composition further comprises a co-solvent / surfactant. In this case, the co-solvents / surfactants were Polysorbate 20, Polysorbate 60, Polysorbate 100, and Polysorbate 101. Rubet 80, Pluronic F68, Pluronic F84, Pluronic P103, Sik A compound selected from the group consisting of rhodextrin, tyloxapol, and combinations thereof. In an embodiment, the amount of co-solvent / surfactant in the pharmaceutical composition is about 0.01% w / v of the pharmaceutical composition. w to about 2% w / w.

[0103] In one embodiment, the pharmaceutical composition further comprises one or more viscosity enhancing agents. In the present invention, the thickening agent is polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, Hydroxypropyl methylcellulose, Hydroxyethyl cellulose, Carboxymethyl Cellulose, hydroxypropyl cellulose, polyethylene glycol, and combinations thereof In one embodiment, the amount of viscosity enhancing agent in the pharmaceutical composition is selected from the group consisting of: In a specific embodiment, the pharmaceutical composition is administered in an amount of about 0.01% w / w to about 2% w / w. The pharmaceutical composition is in the form of a solution.

[0104] In one embodiment, the pharmaceutical composition is a solution, suspension, emulsion, ointment, cream, gel. In one embodiment, the pharmaceutical composition is in the form of a water-soluble, aqueous, or controlled release / sustained release formulation. It is in the form of a solution.

[0105] 5.6.1 Topical Ophthalmic Formulations In certain embodiments, the pharmaceutical formulations are specifically adapted for topical application to the eye. In certain specific embodiments, disclosed herein are topical ophthalmic and a pharmaceutical formulation comprising the ADPR described herein as a therapeutic solution or suspension (eye drops). , which is a sterile isotonic (i.e., from about 3 to about 8, Generally available as a solution having a pH of about 4 to about 8, about 7 to about 8, or about 7.4. .

[0106] As used herein, the term "eye drop" refers to a drug administered in the form of drops to the outer surface of the eye. The posterior portion of the eye, including the choroid, retinal pigment epithelium, retina, macula, fovea, optic nerve, and vitreous humor, 1 shows a pharmaceutical liquid formulation having a local effect.

[0107] That is, in certain embodiments, the present invention includes an ADPR as described herein. The pharmaceutical formulations provided herein may be formulated using pure water and at physiological pH and equivalents. Examples of buffers for maintaining or adjusting pH include, but are not limited to: Examples of suitable buffers include acetate buffer, citrate buffer, phosphate buffer and borate buffer. Examples of stabilizers are sodium chloride, mannitol and glycerin.

[0108] The eye drop formulation is then optionally dispensed into a plurality of individual sterile disposable cartridges, each is aliquoted into suitable unit doses or into single cartridges for unit doses. Such a single disposable cartridge may, for example, be separated from the container at one end. The container has a side wall that can be squeezed radially about a longitudinal axis to dispense the container contents. Such a disposable container may be a conical or cylindrical dispenser of a specific volume. can be used to dispense eye drops at 0.3 to 0.4 mL per unit dose, and Ideally suited for release.

[0109] Ophthalmic drop solutions or suspensions are often packaged in plastic containers with eye droppers, for example. It may also be packaged in a unit dose form. Such formulations are designed to prevent microbial contamination after the container is opened. To prevent this, a preservative is optionally added. Suitable preservatives include, but are not limited to, tetraborane. Sodium acetate, boric acid, benzalkonium chloride, thimerosal, chlorobutanol, methyl Ralparaben, propylparaben, phenylethyl alcohol, disodium edetate, These include benzoyl peroxidase, polyquaternium-1, or other agents known to those skilled in the art, and All are contemplated for use in the present invention. Preservative-containing formulations may contain from about 0.001 to about 0.5% by weight of preservative. It may contain about 1.0% w / v preservative.

[0110] In certain embodiments, the viscosity of the vehicle is increased, thereby improving the cornering of the solution or suspension. In order to prolong the contact with the membrane and to enhance bioavailability, the polymer is added to the ophthalmic solution or suspension. In certain embodiments, such polymers include cellulose derivatives. (e.g., methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose) cellulose or carboxymethylcellulose), dextran 70, gelatin, polyols, Glycerin, Polyethylene Glycol 300, Polyethylene Glycol 400, Polysol Bate 80, propylene glycol, polyvinyl alcohol and povidone, or their derivatives is selected from a combination.

[0111] In certain embodiments, the ophthalmic solutions or suspensions disclosed herein comprise cyclode It may further include a stabilizer / solubilizer such as kistrin. In the above, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-Cyclodextrin, Hydroxypropyl-β-Cyclodextrin, Hydroxypropyl propyl-γ-cyclodextrin, dimethyl-β-cyclodextrin and dimethyl-γ - cyclodextrins.

[0112] In certain embodiments, the compositions described herein, such as pharmaceutical preparations comprising the ADPR described herein, are provided. The pharmaceutical formulations disclosed therein may be administered in sustained release ophthalmic solution or suspension formulations.

[0113] In certain embodiments, the compositions described herein, such as pharmaceutical preparations comprising the ADPR described herein, are provided. The pharmaceutical formulations disclosed herein may be formulated with nanoparticles, nanoparticles, or other suitable materials to maintain drug levels at the desired location. Based on micelles, liposomes, microemulsions, bioadhesive gels and fibrin sealants Eye medications such as, but not limited to, colloidal dosage forms, such as Other ocular drug delivery systems may be formulated for administration via a pharmaceutical delivery system. Drug-eluting contact lenses, ultrasound-mediated drug delivery, ocular iontophoresis, and drug co-delivery. The present invention includes a coating microneedle.

[0114] In certain embodiments, the frequency of administration may vary widely. Depending on the severity of the disease being treated, such administration may be once every 6 months, once every 5 months, once every 4 months, or once every 5 months. Once a month, once every 3 months, once every 2 months, once a month, once every 3 weeks, once every 2 weeks , once a week, once every 6 days, once every 5 days, once every 4 days, once every 3 days, once every 2 days, or Can occur once a day.

[0115] In certain embodiments, the frequency of administration will depend on the needs of each subject and the severity of the disease being treated. Depending on the severity of the condition, the administration can vary widely, from about three times a week to about three times a day, or The administration can be from about once a week to about 10 times a day, such as once or twice a day.

[0116] In one embodiment, provided herein is a method for treating at least one microbial infection or eye disease. Ophthalmic compositions suitable for topical administration to the eye, effective for treating and / or preventing diseases of either tissue wherein the ophthalmic composition comprises: a) ADPR, wherein the amount of ADPR is about 0.0% of the ophthalmic composition; In one embodiment, the medicament comprises: In the ophthalmic composition, the ophthalmic composition comprises: a) ADPR, wherein the amount of ADPR is from about 0.3% w / w to about 3% w / w), and b) cidofovir (wherein the amount of cidofovir is in the range of ophthalmic in the range of about 0.05% w / w to about 2% w / w of the composition.

[0117] 5.6.2 Formulations for nasal or inhaled administration In certain embodiments, the pharmaceutical compositions provided herein are administered intranasally or The pharmaceutical composition is administered by inhalation into the respiratory tract. (such as a nebulizer that uses electrohydrodynamics to create a fine mist), or inhalation. For delivery using a syringe, it may be used alone or with 1,1,1,2-tetrafluoroethane or In combination with a suitable propellant such as 1,1,1,2,3,3,3-heptafluoropropane The pharmaceutical compositions may be provided alone or in the form of a lactose or liquid. or in combination with an inert carrier such as a phospholipid, in the form of a dry powder for insufflation and in nasal drops. For intranasal use, the powder may be provided as a chitosan or cyclodextrin. The bioadhesive may include a bioadhesive comprising:

[0118] Solutions or suspensions for use in pressurized containers, pumps, sprays, nebulizers, or inhalers Ethyl ether may be used to disperse, solubilize, or extend the release of the active ingredients provided herein. nol, ethanol water, or suitable substitute; propellant as solvent; and / or sorbitan It is recommended to use surfactants such as trioleate, oleic acid, or oligolactic acid. It can be formulated into

[0119] The pharmaceutical compositions provided herein may be sized to have a diameter of about 50 μm or less, or about 10 μm or less. The particles may be micronized to a size suitable for delivery by inhalation. Ultrasonic jet milling, fluidized bed jet milling, and ultrafiltration for forming nanoparticles Using comminution methods known to those skilled in the art, such as supercritical fluid processing, high pressure homogenization, or spray drying. It can be prepared.

[0120] Capsules for use in an inhaler or insufflator, Bliss The cartridge contains a powder mix of the pharmaceutical composition provided herein; lactose or a suitable powder base such as starch; and l-leucine, mannitol, or stearic acid. May be formulated to contain performance modifiers such as magnesium. Lactose may be in the form of anhydrous or monohydrate. Other suitable excipients or carriers include, but are not limited to, Not specified, but may include dextran, glucose, maltose, sorbitol, xylitol, and furan. For inhaled / intranasal administration, the sugars referred to herein include saccharides, ... The pharmaceutical compositions provided herein may further comprise suitable phytoalanines, such as menthol and levomenthol. Laver, and / or sweeteners such as saccharin and sodium saccharin may be included.

[0121] 5.6.3 Oral Formulations Pharmaceutical compositions suitable for oral administration include, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms may be provided as individual dosage forms. Such dosage forms may contain predetermined amounts of active These compositions contain active ingredients and can be prepared by methods of pharmacy well known to those skilled in the art.

[0122] The oral dosage forms provided herein can be prepared by mixing the intimate mixture with conventional pharmaceutical compounding techniques. The formulation is prepared by combining the active ingredient in with at least one excipient. The pharmaceutical composition may take a wide variety of forms depending on the form of preparation desired for administration. Excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, , water, glycols, oils, alcohols, flavors, preservatives, and colorants. Excipients suitable for use in oral dosage forms (e.g., powders, tablets, capsules, and caplets) Examples of excipients include, but are not limited to, starch, sugar, microcrystalline cellulose, diluents, granulating agents, These include lubricants, binders, and disintegrants.

[0123] In one embodiment, the oral dosage form is a tablet or capsule, in which case the solid excipient is In another embodiment, tablets can be made by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms comprise an active ingredient in a carrier, such as a liquid carrier, a finely divided solid carrier, or the like. or both, and then, if necessary, the product is mixed to the desired form. It is prepared by shaping into a shape.

[0124] For example, tablets can be prepared by compression or molding. Compressed tablets can be prepared by pressing the tablets into a suitable container. In the machine, the active ingredient, optionally mixed with an excipient, is mixed in a free-flowing form, such as a powder or granules. It may be prepared by compression.

[0125] Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, Pharmaceutical compositions and dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in the present invention include, but are not limited to, corn starch, potato starch, and the like. Starch or other starches, gelatin, gum acacia, sodium alginate, alginic acid, etc. alginates, powdered tragacanth, natural and synthetic gums such as guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose, Calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone , methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, (e.g., No. 2 208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0126] Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL-PH-101, AVICEL -PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation's American Available from Rika Viscose Division, Avicel Sales, Marcus Hook, PA ), and mixtures thereof. Microcrystalline cellulose and carboxymethyl cellulose nanofibers, sold as EL RC-581. Suitable anhydrous or low moisture excipients or additives include A Other suitable forms of microcrystalline cellulose include VICEL-PH-103™ and Starch 1500 LM. Possibilities include, but are not limited to, PROSOLV 50, PROSOLV 90, PROSOLV HD90, PROSOLV 90 L Silica-containing microcrystalline cellulose, such as the material sold under the trade name M, and mixtures thereof. Includes.

[0127] Fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein Examples include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, Crystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid , sorbitol, starch, pregelatinized starch, and mixtures thereof. The agent or filler, in one embodiment, comprises from about 50 to about 99% by weight of the pharmaceutical composition or dosage form. It exists in %.

[0128] In certain embodiments, the filler may include, but is not limited to, ethylene oxide. and propylene oxide block copolymers. The polymer may be sold as POLOXAMER or PLURONIC, and may include, but is not limited to, , POLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and Mixtures of these are included.

[0129] In certain embodiments, the filler includes, but is not limited to, isomalt, lactose. , lactitol, mannitol, sorbitol, xylitol, erythritol, and the like. It may include mixtures of these.

[0130] Disintegrants are present in the composition to provide a tablet that disintegrates when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little disintegrant may Tablets containing the active ingredient may not disintegrate at a desired rate or under the desired conditions. A sufficient amount of disintegrant, but not too much and not too little, to adversely alter the release of the solid The amount of disintegrant used will depend on the type of formulation. The specific therapeutic agent may vary based on the therapeutic agent and is readily discernible to one of skill in the art. The composition comprises from about 0.5 to about 15% by weight of disintegrant, or from about 1 to about 5% by weight of disintegrant.

[0131] Disintegrants that can be used in the pharmaceutical compositions and dosage forms include, but are not limited to, cryogenic disintegrants. Ten, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium , povidone, crospovidone, polacrilin potassium, sodium starch glycolate, Potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins, other Includes cellulose, rubber, and mixtures thereof.

[0132] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, stearyl alcohol, glycerol, sorbitol, sorbitol diglycerides ... Calcium phosphate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol ethanol, mannitol, polyethylene glycol, other glycols, stearic acid, fumaric acid Sodium stearyl, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), ste Zinc phosphate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, Silica gel (AEROSIL 200, Baltimore, Maryland). (W.R. Grace Co., Plano, Texas); and aerosol of coagulated synthetic silica (W.R. Grace Co., Plano, Texas). Degussa Co.), CAB-O-SIL (Cabo, Boston, Massachusetts) (pyrogenic colloidal silicon dioxide products sold by t Co.), and mixtures thereof If used at all, a lubricant is a component of the pharmaceutical composition or dosage form in which it is incorporated. It may be used in an amount of less than about 1% by weight of the drug form.

[0133] Liquid dosage forms for oral administration may be prepared in the form of pharma- ceutically acceptable emulsions, microemulsions, or the like. Liquid dosage forms that contain the active ingredient in addition to the active ingredient include solutions, suspensions, syrups, and elixirs. The formulation may be, for example, water or other solvent, a solubilizing agent, and ethyl alcohol, isopropyl alcohol, or the like. Coal, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn Oil, Germ Oil, Olive Oil, Castor Oil, and Sesame Oil), Glycerol, Tetrahydrofuran emulsifiers such as diol, polyethylene glycol, and sorbitan fatty acid esters and mixtures thereof. obtain.

[0134] Besides inert diluents, the oral compositions can also include additives such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and additives. Adjuvants such as colorants, fragrances, and preservatives may also be included.

[0135] The suspension may contain, in addition to the active inhibitor, e.g., ethoxylated isostearyl alcohol, polyisoprene, Polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum Such as methacrylate, bentonite, agar and tragacanth, and mixtures thereof. The composition may contain such suspending agents.

[0136] 6. Working Example 6.1 Example 1. Plaque Inhibition Test of Two (2) Compounds Against Adenovirus Serotype 3 Experience

[0137] background Adenosine 5´-diphosphoribose sodium salt ("Compound A" or ADPR, 0 mg vial, Sigma A0752-500 mg, lot SLBJ4805V), and nicotinamide ("chemical Compound N", in one 100 gm vial, Sigma N0636-100 G, Lot SLB0315V) ("Compound N Compound A was obtained from Sigma at 120 mg / ml in water for irrigation. After that, DMEM (Dulbecco's modified Eagle's medium), 2% FBS (fetal bovine serum; Compound N was solubilized at 240 mg / ml in the nutrient medium, with the target concentrations of 6 mg / ml and 2 mg / ml. A 10 ml volume was made in water for irrigation. Additionally, a dilution of Compound N in DMEM, 2% FBS was made. On the same day, adenovirus plaque inhibition assays were prepared. The remaining Compound A was placed in the dark at 4°C.

[0138] Dilution

[0139] Solubilized compound A was diluted 1:20 or 1:60 in virus culture medium and incubated for 6 h at 4°C. The sample dilutions were made at 1 mg / ml and 2 mg / ml. The dilutions of compound N already contained compound A. The experimental design involving groups 1 through 5 is outlined in the text below. The results are shown and provided in Table 1. Groups 2, 3 and 4 were prepared by adding samples of various concentrations. The fourth group also consisted of a mixture of 100 mg of sidofuranoside, 100 mg of compound A, and 100 mg of compound N. It contains antiviral agents for ovirus and adenovirus.

[0140] Group 1: 0, 60, 600, and 6000 mcg / mL of Compound N

[0141] Group 2: 2000 mcg / mL Compound A with 0, 60, 600, and 6000 mcg / mL Compound N

[0142] Group 3: 6000 mcg / mL of Compound A (initial (as in research)

[0143] Group 4: 2000 mcg / mL of Compound A (initial As in the study, 20 micromolar cidofovir

[0144] Group 5: 0, 20, and 100 micromolar cidofovir

[0145] method

[0146] A549 cells were cultured at 7 x 10 in a 6-well plate. 4 Cells were plated at 100 x g / well. After 18 hours, the cells were cultured. The medium was removed and 1 ml of each sample mixture was added. Incubate at 37° C. for 1 hour. After incubation, approximately 50 to 75 plaque-forming units of influenza virus Ad per well were obtained. 3 was added.

[0147] The virus was allowed to adsorb to the cells for 2 hours, after which the medium was aspirated from the monolayer. and replaced with Ad3 medium containing the sample dilutions in Table 1 and agarose.

[0148] toxicity

[0149] Toxicity was assessed against the following criteria and was determined to be 0.01% at the end of the assay on the final day. The values ​​are listed in Table 1 as T values. It has been recorded. 0 - Non-toxic 1 - Cells are slightly sparser than cell control wells 2 - Cells are moderately sparse compared to cell control wells. Compared to the wells, the cells are moderately weakly stained and virus plaques are visible. 3 - Significantly sparser and missing cells compared to cell control wells The staining intensity of the cells was significantly weaker than that of the cell control wells, and there was no staining due to the absence of cells. , viral plaque is not visible

[0150] result

[0151] Treatment with Compound A at 2000 and 6000 μg / ml significantly reduced plaque size compared to controls. The plaque size was reduced. See Table 1 and Figure 1 for plaque counts. The addition of 6000 μg of riboflavin had the additional effect of reducing the number of visible plaques. Nicotinamide at a concentration of 600 μg / ml was toxic to A549 cell monolayers in all groups. At the same concentration of nicotinamide alone, adenovirus plaques appeared significantly larger. This was probably due to its effect on the cell monolayer. When nicotinamide at a concentration of 0 μg / ml was mixed with compound A, the number of visible plaques In group 4, the addition of 20 μM cidofovir was even more inhibitory. And it had a synergistic effect compared to group 3. These results were obtained by determining the plaque area percentage. This was confirmed by routine image analysis to confirm the presence of the markers (see Figure 2). This analysis was carried out using Photoshop. The contrast was adjusted equally across the plate for better identification. To avoid edge artifacts associated with plate A standard circular region of 78,456 pixels per pixel was selected. Then, the white pixels in the circular region were The “Color Range” function was used to determine the number of plaque surfaces. To calculate the area percentage, the area was divided by the total pixel area. The results were then displayed in Microsoft Excel. The analysis was performed on Cell 2016. The values ​​from the two plates were averaged. A synergistic inhibitory effect was observed between cidofovir (20 μM) and ADPR (2000 μg / ml). As a result, the combination may have a stronger effect than would be expected if the compounds were truly additive. had a nearly three-fold gain (0.25% observed vs. 0.69% expected).

[0152] Table 1. Plaque counts, toxicity scores, and plate codes [Table 1]

[0153] Control drug

[0154] Cidofovir is known to reduce the size of adenovirus plaques. Cidofovir was used at the concentrations listed in Table 1. The size and number of larks was reduced.

[0155] raw material

[0156] Table 2. Raw materials [Table 2]

[0157] 6.2 Example 2. Plaque Inhibition of Adenovirus Serotype 3 by ADPR and Lithium Chloride background

[0158] Adenosine 5´-diphosphoribose sodium salt ("Sample A" or ADPR, Sigma A0752-500 mg, lot SLBJ4805V) in a 500 mg vial, and lithium chloride (" Sample L, one 100 gm vial, Amresco 0416-100 g, lot 3005C057) On the day of the assay, sample A was diluted in water for irrigation for 120 min. The virus was solubilized to a concentration of 200 mg / ml (200 mM) and then further added to the virus culture medium (DMEM, % fetal bovine serum (FBS) and antibiotics, antimycotics) at concentrations of 4 mM, 1.33 mM, and 0.44 mM. A 200 mM solution of sample L was made in water for irrigation. Next, dilutions of sample L are made in virus culture medium to reach the desired concentrations in Table 3. The remainder of the solubilized sample A was placed in the dark at 4°C.

[0159] Dilution

[0160] Solubilized samples A and L were diluted in virus medium at 1:50, 1:150 and 1:450. The mixture of samples A and L was diluted to 100 μl and used as sample dilutions. were made by dilution in culture medium.

[0161] method

[0162] A549 cells were cultured at 7 x 10 in a 6-well plate. 4 Cells were seeded at 1000 cells / well. After 18 hours, The medium was removed and 1 ml of each sample mixture was added. Incubate at 37° C. for 1 hour. After incubation, approximately 50 to 75 plaque-forming units of Ad3 were added per well. The medium was then aspirated from the monolayer and incubated for 2 h. The plate was replaced with virus culture medium containing the sample dilutions in Table 3 and agarose.

[0163] toxicity

[0164] Toxicity was assessed against the following criteria and was determined to be 0.01% at the end of the assay on the final day. The values ​​are reported in Table 3 as T values. It has been recorded. 0 - Non-toxic 1 - Cells are slightly sparser than cell control wells 2 - Cells are moderately sparse compared to cell control wells. Compared to the wells, the cells usually have a weak staining intensity and virus plaques are visible. 3 - Significantly sparser and missing cells compared to cell control wells The staining intensity of the cells was significantly weaker than that of the cell control wells, and there was no staining due to the absence of cells. , no viral plaque visible.

[0165] result

[0166] Treatment with sample A at 0.44, 1.33 and 4.0 mM reduced plaque size compared to the control. The adenovirus plaques were reduced by 1.33 mM concentration of sample L alone. The synergistic effect of the combination of Sample A and Sample L, each at 4 mM, was observed. -Plaques were determined to be smaller on average than in control treated cultures. None of the samples were toxic at the concentrations tested. Plaque counts were as follows: The results are depicted in Table 3, and a plate image is depicted in Figure 3. Figure 4 shows the results of 4 mM In the experiment, sample A (i.e., ADPR), sample L (i.e., LiCl), and sample A and sample L 4 depicts the percentage of plaque inhibition of adenovirus serotype 3 in combination with sample L. This analysis was performed with routine image analysis to determine the plaque area percentage (Figure 4 (See ). Image analysis was performed using Adobe Photoshop. In this study, contrast was applied across the plate to better identify plaque formation. To avoid edge artifacts associated with cell culture, Then, a standard circular area of ​​45,621 pixels per plate was selected at the center of each plate. Then, use the "Color Range" function to determine the number of white pixels in the circle region. is used and then divided by the total pixel area to calculate the plaque area percentage. The results were analyzed in Microsoft Excel 2016. The values ​​of the two plates were averaged. As shown in FIG. 4, sample A and sample L, each having a concentration of 4 mM, were combined. A synergistic effect was observed by combining the compounds. had a 31% improvement over the expected effect (6.31% observed vs. 9.11% expected). there was.

[0167] Table 3. Plaque counts, toxicity scores and plate codes [Table 3]

[0168] The assay used the same raw materials and controls as described in Example 1.

[0169] 6.3 Example 3. Development of a viral conjunctivitis model in New Zealand White rabbits Preliminary study of Aims / Objectives: The aim of this study was to determine whether viral conjunctival infection in New Zealand White rabbits The inflammation model was then induced.

[0170] protocol

[0171] Animal preparation: For the virus inoculation procedure, ketamine (up to 50 mg / kg) and xylazine ( Three animals were anesthetized with intramuscular injection of 10 mg / kg of naphthalene. After anesthesia, both eyes were disinfected with betadine. The wire lid speckles were then rinsed with basic salt solution (BSS). A catheter was inserted to retract the eyelids. One to two drops of proparacaine (0.5%) were placed in each eye. On day 0, corneal scrapings were performed. The epithelial layer of each cornea was scraped with a 25-gauge sterile needle for 3 min. After corneal abrasion, both corneas of each rabbit were abraded with 2 x 10 6 PFU of adenovirus, serotype 5 (Ad5), was inoculated locally. .1 x 10 8 0.02 mL of PFU Ad5 / mL solution was delivered locally using a sterile pipette. After inoculation, the animals were allowed to recover from anesthesia.

[0172] Test and Control Articles

[0173] Test article, 0.057% tetraborate, 1.20% boric acid, and 2.0% adenosine triphosphate (ADP) containing 0.02% PEG-300. A 2-diphosphoribose (sodium salt) formulation was prepared and its pH was adjusted to 7.08. A control, buffer containing 0.2% NaCl, 0.057% tetraborate, 1.20% boric acid, and 0.02% PEG-300. A buffer solution was prepared and its pH was brought to 6.97.

[0174] Administration of test and control articles

[0175] The study was carried out according to the following study protocol (Table 4). The drug was administered via topical administration (2 drops per administration, 25 μL per drop) three times daily (TID) throughout the study. It was.

[0176] Table 4. Study design [Table 4] TID: 3 times a day

[0177] Summary of results

[0178] Ophthalmic examination using the McDonald-Shadduck scoring system was performed on days 1 through 4, with normal (scores 100% and 110% for ophthalmic patients). However, the study showed that all of the secretions were not secreted by the 7-day test. By day 10, all animals except group 2 animal P7279 had more erythroblasts (score "2"). The discharge was less frequent. Conjunctival congestion was not as severe. For all three animals, the scores on day 1 were the highest (50% of the scores were a "2"). The majority of the conjunctival hyperemia scores on the 7th and 10th days were "2", but there was no evidence of hyperemia. The effect was limited to the third eyelid, which was responsible for the irritation and subsequent conjunctiva itself. It should be noted that the sensitivity of the stimuli to oxidative stress is even higher than that of the stimuli to oxidative stress.

[0179] 5-7 summarize the changes observed on the corneal surface at the site of viral inoculation. Corneal abrasions provide a starting point for the virus to attach to the corneal epithelium and cause corneal opacity and clouding. Over the course of the study, test article-treated animal number P7280 had The greatest improvements were seen in both membrane abrasion and corneal surface area, with reductions in corneal opacity. It was made clear that he possessed goodness.

[0180] conclusion

[0181] Test article dose A-2% reduced corneal opacity when compared to vehicle and untreated controls. This revealed that:

[0182] 6.4 Example 4. Synthesis of dilithium ADPR (Li2ADPR) Dilithium ADPR (Li2ADPR) is a nicotinamide hydrolysis product obtained under lithium hydroxide hydrolysis conditions. It is synthesized from the free acid of adenine dinucleotide (NAD+). The synthesis scheme is shown below. The summary is given:

[0183] Scheme 1. Synthesis of dilithium ADPR (Li2ADPR) [ka]

[0184] The materials used are shown in Table 5.

[0185] Table 5. Raw materials [Table 5]

[0186] Instrumentation parameters are presented in Table 6.

[0187] Table 6. Instrument operating parameters [Table 6]

[0188] The starting material, β-nicotinamide adenine dinucleotide (NAD+), is converted as a free acid into It is commercially available from Codexis and is hydrolyzed with lithium hydroxide to give The nicotinamide moiety is removed to give adenosine 5´-diphosphoribose (ADPR) lithium salt. Excess LiOH was used to maintain the pH of the reaction solution at 10 to 10.5. Hydrolysis was monitored by HPLC. Hydrolysis was complete after 8 days. The hydrolysis products were triturated in MeOH, water, and EtOH to remove excess LiOH and Ni. Cotinamide was removed and isolated.

[0189] Experiments and Results

[0190] NAD+ (10.00 g, 15.07 mmol) was dissolved in water (250 L). Solid LiOH was added to adjust the solution to pH 2. The amount of LiOH·H2O added was 0.809 g to adjust the pH to 11.21 from 78. A slight color change to pale yellow was noted and a slightly exothermic process was detected. A gradual pH drop was observed as the reaction proceeded. The solution was stirred at room temperature (RT) for 8 days and then During the reaction, LiOH·H2O was periodically added to maintain the pH of the reaction solution at 10 to 10.5. The total amount of LiOH·HO used to drive the reaction to completion was 1.624 g (2.57 eq.). The progress of the reaction was monitored by HPLC analysis. At the end of the reaction, a small amount of white precipitate was observed at the top of the solution. The solution had a wine-red color with the solids being removed by filtration. Approximately 35 g) was added. The mixture was stirred at RT for 20 h and filtered to give a pale yellow filtrate. The filtrate was concentrated by rotary evaporation. The residue was suspended in MeOH (100 mL) and heated at RT The mixture was stirred at rt for 1 h and filtered. An aliquot of the solid from the filtration was dissolved in water and The pH was 10. The filtrate was evaporated and the remaining solid was dried under high vacuum. An aliquot of was dissolved in water, and the pH was about 7. The solid was suspended in EtOH (50 mL). The suspension was stirred at RT for 2 days. The solid was collected by filtration and diluted with EtOH (10 mL). and further dried under high vacuum to give 3.246 g of a pale yellow solid.

[0191] This solid sample was subjected to elemental analysis, the results of which are shown in Table 7. The compound has the molecular formula C 15 H 21 Li2N5O 14 It has been confirmed that the dilithium salt is P2-1.1H2O. ADPR was further analyzed by HPLC (see FIG. 8) and mass spectrometry (see FIG. 9). This was confirmed by analysis.

[0192] Table 7. Elemental analysis results [Table 7]

[0193] 6.5 Example 5. Effect of ADPR·dilithium on adenovirus: in vitro studies background

[0194] ADPR·dilithium, 150 mg powder, was stored in a glass vial ( On the day of the assay, Sample A was diluted with 750 μL of PBS for irrigation. The compounds were solubilized in 100 mL of water at 200 mg / ml and then further diluted to the target concentration. The solubilized sample A was composed of adenovirus 3 and adenovirus 5 (A d3 and Ad5) were tested for their plaque-inhibiting properties.

[0195] Dilution

[0196] The solubilized sample A was incubated in a viral culture medium (DMEM, 2% fetal bovine serum (FBS) and antibiotics) The antibodies were diluted to 4 mg / mL, 2 mg / mL, 1 mg / mL, and 0.5 mg / mL in 0.1% ethanol (substance, antifungal agent).

[0197] method

[0198] A549 cells were cultured at 7x10 in a 6-well plate. 4 Cells were seeded at 1000 cells / well. After 18 hours, The medium was removed and 1 mL of each sample mixture was added per well. The plates were incubated at 37°C for 1 hour. After incubation, approximately 50-75 plaque forming units of Ad3 and separately A d5 was added. The virus was allowed to adsorb to the cells for 2 hours, and then the medium was removed from the monolayer. Aspirate and dilute sample A at 0, 0.5, 1.0, 2.0, and 4.0 mg / mL and agarose. The virus medium was replaced with the virus medium containing

[0199] result

[0200] The size and number of Ad3 and Ad5 plaques were reduced at 4 mg / mL and 2 mg / mL of sample A. In addition, at 4 and 2 mg / mL, the monolayers showed staining intensity lower than that of the control wells. The sparse monolayer represents a plaque. Compared to the control, very few plaques were visible. The size and number of plaques of Ad3 and Ad5 at the 0.5 mg / mL and 0.5 mg / mL dilutions were was reduced and the monolayer was slightly sparser compared to the cell control wells. The average plaque counts at the sample A concentrations were as follows: Ad3: 4 mg / mL - 29; 2 mg / mL - 10; 1 mg / mL - 44; 0.5 mg / mL - 54; 0 mg / mL - 55 Ad5: 4 mg / mL - 7; 2 mg / mL - 7; 1 mg / mL - 25; 0.5 mg / mL - 53; 0 mg / mL - 65

[0201] conclusion

[0202] ADPR·dilithium inhibited the proliferation of cell culture-grown adenovirus ( Cytopathic changes, as shown by the size and number of plaques produced by Ad3 and Ad5 In addition, the dose-responsive thinning of the monolayer was shown to effectively reduce the effect of This is consistent with the reduced replication observed in other cancer cell lines described in.

[0203] 6.6 Example 6. Efficacy in Keratoconjunctivitis - In Vivo Studies This study investigated the efficacy of ADPR·dilithium in a viral conjunctivitis model in rabbits. The study was designed to evaluate efficacy.

[0204] 6.6.1 Experimental design 6.6.1.1 Test system Species: European rabbit

[0205] Pedigree: New Zealand White Rabbit

[0206] Gender: Female

[0207] Age: Proportional to weight

[0208] Body weight: Approximately 2.5 to 3.0 kg at the start of the study.

[0209] Number: 8 (not used in testing)

[0210] Identification: Ear tags and cage labels

[0211] Minimum acclimatization: 5 days

[0212] 6.6.1.2 Husbandry Animals were housed under Animal Biosafety Level 2 (ABSL-2) conditions after inoculation with Ad5. The animals were kept in a cage with a ventilated area to reduce the possibility of eye trauma from other animals in the same cage. They were housed in isolation prior to and during the study.

[0213] 6.6.1.3 Test / Control Articles 1. Inoculation - Adenovirus serotype 5 (Ad5)

[0214] (a) Description of physicochemical characteristics and composition: The virus was cultured in DMEM containing 8% fetal bovine serum at 37°C for 1 h at 4°C. The cells were grown in 49 cells. Cells and supernatants were harvested, sonicated, and centrifuged at low speed. The infectious titer by TCID50 was 5.0 x 109 plaque forming units (PFU) / m L.

[0215] (b) Storage conditions: frozen at -60 to -80°C

[0216] 2. Test substance - ADPR·dilithium

[0217] (a) Molecular weight: approximately 571.18

[0218] (b) Storage conditions: refrigerated at 2 to 8°C.

[0219] 3. Control vehicle

[0220] (a) Composition: 0.31% sodium chloride, 0.1% sodium tetraborate in deionized (DI) water; 1% boric acid, 0.35% polyethylene glycol 300 (PEG-300)

[0221] (b) Storage conditions: refrigerated at 2°C to 8°C.

[0222] 4. Preparation of Test / Control Articles

[0223] (a) Ad5 was provided in a single dose on both days of inoculation. Just before, the virus was thawed and brought to room temperature. 0.05 mL (50 μL) of 5.0 x 10 9 PFU Ad5 / m The L solution was diluted with 1.5 mL of Dulbecco's modified Eagle's medium (DMEM) to obtain a 1.61 x 10 8 After the first inoculation on day -1, the remaining viral lysate was The solution was stored refrigerated at 2-8°C until the second inoculation on day 0. The virus solution should not be refrozen. It was not done.

[0224] (b) Vehicle: 55.8 mg sodium chloride, 18 mg sodium tetraborate, 180 mg boric acid, and 63 mg PEG-300 were weighed into a vial. 14 mL of deionized water was added, and The vial contents are swirled and vortexed, if necessary, until a clear solution is formed. The pH of the solution was tested using pH paper and If necessary, adjust the pH to 7.0 to 7.2 using sodium hydroxide (NaOH) or additional boric acid. The volume was then brought to 18 mL with additional deionized water and diluted with 0.31% sodium chloride, 0.1 % sodium tetraborate, 1% boric acid, 0.35% PEG-300 solution. The vial contents were The solution was sterile filtered through a 0.2 or 0.22 μm filter.

[0225] (c) ADPR·Dilithium - High Dose: 240 mg of ADPR·Dilithium was weighed into a vial. 12 mg sodium tetraborate, 120 mg boric acid, and 42 mg PEG-300 were added to separate vials. 7 mL of deionized water was added and stirred until a clear solution was formed. If necessary, the vial contents are rotated, vortexed, and / or sonicated. The solution was transferred to a vial containing ADPR·dilithium. The volume was adjusted to 9.5 with deionized water. The vial contents are swirled, if necessary, until 5 mL is reached and a clear solution is formed. The solution was then diluted with water, vortexed, and / or sonicated. The pH of the solution was measured using pH paper. is tested and, if necessary, diluted with sodium hydroxide (NaOH) or additional boric acid. The pH was adjusted to 7.0-7.2. The volume was then brought to 12 mL with additional deionized water and 2.0% ADPR was added. The contents of the vial were filtered through a 0.2 or 0.22 μm filter. Sterile filtered.

[0226] (d) ADPR·dilithium – medium dose: One part vehicle and one part high dose formulation were mixed. The result was a 0.0% ADPR·dilithium solution.

[0227] (e) ADPR·dilithium – low dose: Three parts vehicle and one part high dose formulation were mixed and diluted to 0.5 % ADPR·dilithium solution.

[0228] (f) The dosing solution will be divided into equal amounts for each individual dose (3 vials per day). and stored refrigerated at 2-8° C. Prior to dosing, the dosing solutions were allowed to come to room temperature. After dosing, aliquots were stored or discarded in the room in which the research animals were kept and They were never returned to the drug room or any other room in the animal house.

[0229] 6.6.1.4 Test / Control Administration Details 1. Pre-treatment testing

[0230] Prior to entering the study, each animal underwent an ophthalmic examination (slit lamp biopsy) performed by the principal investigator. The modified McDonald-Shadduck scoring system (6.6.1.5) was used. Ocular findings were scored according to the criteria set forth in the Admission Criteria for Study Entry. received a score of “0” for all variables.

[0231] 2. Anesthesia

[0232] For the virus inoculation procedure, animals were inoculated with ketamine (up to approximately 50 mg / kg) and xylazine. The rats were anesthetized by intramuscular injection of 10 mg / kg (approximately).

[0233] 3. Corneal Scratching and Virus Inoculation Procedure

[0234] All study animals were inoculated with virus into both eyes on days -1 and 0. The animals were anesthetized as described above. Both eyes were disinfected with betadine (on day 0, betadine was not used). The wire lids were then rinsed with basic salt solution (BSS). A curette was inserted to retract the eyelid. One to two drops of proparacaine (0.5%) were Both eyes were instilled with topical anesthetic. Additional topical anesthetic may be used during the procedure if necessary. The epithelial layer of each cornea was scratched with a 25-gauge sterile needle in a 3 × 3 mesh pattern to create a corneal After the corneal scratching procedure, a sterile pipette was used to remove the corneal tissue from each inoculum. For 0.015 mL (15 μL), 1.61 x 10 8 PFU Ad5 / mL solution is delivered topically to each eye. Each rabbit was inoculated into both corneas, yielding 2.42 x 10 6 PFU Ad5 / eye use After each Ad5 inoculation, animals were allowed to recover from anesthesia.

[0235] 4. Group assignment

[0236] On day 1, prior to dosing, all animals were assessed for infection severity, and animals were Based on the severity of their disease, animals were assigned to one of four experimental groups (see below). were assigned a numerical rank from 1 to 8 in decreasing order of infection severity (most severe, (Animals with high infection were assigned rank=1). The animals were then assigned the following scheme: Thus, they were assigned to the experimental group: Group Allocation Table [Table 8]

[0237] 5. Administration of Test / Control Articles

[0238] According to the following study protocol, the test / control products were administered on the first day (approximately 24 hours after the second virus inoculation). ) for 7 days, 2 drops of 25 μL were administered topically to both eyes (OU) three times a day (8 hours a day). to be completed within 24 hours; morning, midday, and afternoon doses, all approximately 3 to 4 hours apart): [Table 9] OU: both eyes; NA: not applicable; TID: 3 times daily *Dosing occurred within 8 hours per day; morning, midday, and afternoon dosing were all done with minimal There was a gap of at least three or four hours. ** Day 1 examination and photography was performed before dosing began; all other examinations and photography were performed This was administered approximately 30 minutes after the third dose of the day.

[0239] 6. In-life observations and measurements

[0240] (a) General health observations: Animals were observed in their cages once daily throughout the study. Each animal was observed for changes in general appearance and behavior. Any abnormal observations were Results were reported to the principal investigator. General health observations were performed daily beginning on day -1 and This was conducted and recorded continuously throughout the duration of the study (9 days in total).

[0241] (b) Body weight: Animals were weighed before inoculation and before euthanasia.

[0242] (c) Clinical eye examination: Clinical eye examination (slit lamp biomicroscopy only) The tests were conducted on days 1, 2, 3, and 7. On day 1, the test was conducted before the start of dosing. On all other days, testing began after the last dose of that day (i.e., the third dose). The test was performed for approximately 30 minutes. On the seventh day, the test was performed immediately prior to euthanasia of the animals. The ocular findings were scored using the modified McDonald-Shadduck scoring system. The results were scored according to the method described in Section 6.6.1.5 below.

[0243] (d) Slit lamp photographs: Slit lamp photographs were taken on days 1, 3, and 7. On day 1, photographs were taken before dosing began. On all other days, The photographs were taken approximately 30 minutes after the last dose of the day (i.e., the third dose). The images were taken immediately prior to euthanasia of the animals.

[0244] 6.6.1.5 Modified McDonald-Shadduck Scoring System The modified McDonald-Shadduck scoring system is shown below (T. McDonald and J.A. Shadduck, "Eye irritation" in Advances in Modern Toxicology. "dermatological ritation" in Dermatoxicology, edited by F. Marzulli and HI Maibach, 579 - 582, Hemisphere Publishing, Washington, DC, USA, 1977 (Wanted):

[0245] 1. Testing

[0246] 1.1. Use of the slit lamp to observe:

[0247] A. Conjunctival discharge

[0248] B. Conjunctival hyperemia

[0249] C. Conjunctival swelling

[0250] D.Cornea

[0251] E. Surface area of ​​corneal lesion

[0252] F. pannus

[0253] G. Pupillary reflex

[0254] H. Aqueous Humor Flare

[0255] I. Aqueous cells

[0256] J. Iris Lesions

[0257] K. Crystalline lens

[0258] L. Vitreous flare

[0259] M. Vitreous cells

[0260] 1.2. Use of indirect ophthalmoscopy for:

[0261] A. Vitreous humor

[0262] B. Vitreous hemorrhage

[0263] C. Retinal detachment

[0264] D. Retinal hemorrhage

[0265] E. Choroidal / retinal inflammation

[0266] 1.3. Dilate the pupils for observation by using one of three solutions. The animals are then prepared. Usually, ophthalmic preparations of atropine, tropicamide, or phenylephrine are used. Two drops of the drug are sufficient.

[0267] A. The choice of dilator is typically outlined in the study protocol.

[0268] 1.4. Wait until the animal's pupils appear to be dilated. , times up to 60 minutes may be used.

[0269] 2. Conjunctival discharge

[0270] 2.1. Discharge is defined as a greyish-white precipitate from the eye.

[0271] 2.2. Marking can be understood as follows:

[0272] A. 0 = normal, no discharge.

[0273] B. 1 = More than normal discharge and no discharge present on the inside of the eye but not on the eyelid or eyelid hair. Existence.

[0274] C. 2 = Discharge is copious, easily observed, and collected on the eyelids and eyelid hairs. .

[0275] D. 3 = The secretion is on the skin around the eye, substantially moistening the hairs and spreading over the entire eyelid. It flows throughout the country.

[0276] 3. Conjunctival congestion

[0277] 3.1. Redness in the eyes causes the blood vessels in the eyes to become enlarged.

[0278] 3.2. Marking can be understood as follows:

[0279] A. 0 = Normal. The eyelid blood vessels and the conjunctiva of the eye are easily observed, and the perilimbic Without limbal injection (except at 12:00 and 6:00 positions), bleached or may appear reddish pink.

[0280] B. 1 = Predominantly hot reddish color with some perilimbal hyperemia. The cornea is then located on the conjunctiva of the eyelid, but mainly at the 4:00 to 7:00 position and at the 11:00 to 1:00 position. At position 0 it remained at the lower and upper parts of the eye.

[0281] C. 2 = Bright red color of the conjunctiva of the eyelid with perilimbal hyperemia in the perilimbal area. Covers at least 75% of the surrounding area.

[0282] D.3 = In addition to the declared perilimbal injection and the presence of petechiae on the conjunctiva, A dark, beefy red color with conjunctival congestion of both the eyelids and the eyes. Petechiae are generally It is prominent along the glaucoma membrane and upper eyelid conjunctiva.

[0283] 4. Conjunctival swelling

[0284] 4.1. Definition: conjunctival swelling

[0285] 4.2. Marking can be understood as follows:

[0286] A. 0 = normal or no swelling of conjunctival tissue

[0287] B. 1 = More than normal swelling without eversion of eyelids (upper and lower eyelids are normal). (easily identified by noting that the swelling is located as in It typically begins in the inferior fornix near the inner canthus.

[0288] C. 2 = Swelling with disproportion of normal approximation of the lower and upper eyelids; mainly limited to the upper eyelid Thus, in the first stage, eyelid misapproximation is caused by partial eversion of the upper eyelid. At this stage, swelling generally occurs superiorly with some swelling in the inferior fornix. The condition is limited to the eyelids of the

[0289] D.3 = Definite swelling with essentially equal partial eversion of upper and lower eyelids. This can be done by looking at the animal head on and noting the position of the eyelids. , can be easily observed; if the edges of the eyes do not meet, eversion has occurred.

[0290] E. 4 = Eversion of the upper eyelid with less pronounced eversion of the lower eyelid It is difficult to observe the perilimbal area with the eyelids closed.

[0291] 5. Iris Lesions

[0292] 5.1. Check the iris for vascular congestion.

[0293] 5.2. Marking can be understood as follows:

[0294] A. 0 = No vascular congestion, normal iris.

[0295] B. 1 = Minimal congestion of secondary vessels but not tertiary vessels. Generally uniform, but However, it may be of greater intensity at the 12:00 to 1:00 position or at the 6:00 position. If limited to a certain area, the third vessel must be substantially engorged.

[0296] C. 2=minimal congestion of tertiary vessels and minimal to moderate congestion of secondary vessels.

[0297] D. 3 = Moderate congestion of the second and third vessels with slight swelling of the iris stroma ( The iris surface is slightly wrinkled, usually most pronounced near the 3:00 and 9:00 positions. is noticeable).

[0298] E. 4 = Marked hyperemia of the second and third blood vessels with marked swelling of the iris stroma. may be accompanied by large hemorrhage in the anterior chamber (hyphema).

[0299] 6. Cornea

[0300] 6.1. Check the cornea for any abnormalities.

[0301] 6.2. Marking may be understood as follows:

[0302] A. 0 = normal cornea

[0303] B. 1 = Some loss of transparency. Only the epithelium and / or anterior half of the corneal stroma are involved. Although some degree of cloudiness may be easily seen, the underlying structure is clearly visible. come.

[0304] C. 2= Full thickness corneal stromal lesion. With diffuse illumination, the underlying structures are just barely visible. (Flare, iris, pupillary response, and lens still visible).

[0305] D. 3 = Full thickness stromal lesion. With diffuse illumination, no underlying structures are visible.

[0306] 7. Surface area of ​​corneal lesion

[0307] 7.1. Check the eye for haze in the stromal area.

[0308] 7.2. Marking may be understood as follows:

[0309] A. 0 = Normal

[0310] B. 1 = Haze of 1-25% area of ​​the corneal stroma.

[0311] C. 2 = Haze of 26-50% area of ​​the corneal stroma.

[0312] D. 3 = Haze of 51-75% area of ​​the corneal stroma.

[0313] E. 4 = Haze of 76% to 100% area of ​​the corneal stroma.

[0314] 8. Pannus

[0315] 8.1. Check for corneal neovascularization.

[0316] 8.2. Marking may be understood as follows:

[0317] A. 0 = no pannus (corneal neovascularization)

[0318] B. 1 = Neovascularization is present, but the vessels do not extend throughout the entire corneal periphery.

[0319] C. 2 = Vessels invade the entire corneal surface circumferentially for more than 2 mm.

[0320] 9. Pupillary reflex

[0321] 9.1. Check for any occlusion or stoppage reflex in the pupil area.

[0322] 9.2. Marking may be understood as follows:

[0323] A. 0=normal pupillary reflex.

[0324] B. 1 = Slow or incomplete pupillary response.

[0325] C. 2=no pupillary reflex.

[0326] D. 3=absent pupillary reflex due to pharmacological obstruction.

[0327] 10. Aqueous Humor Flare

[0328] 10.1. Breakdown of the blood-aqueous barrier.

[0329] 10.2. The area is a slit beam with dimensions of 1 mm x 1 mm.

[0330] 10.3. Scoring can be understood as follows (based on Jabs DA et al., 2005):

[0331] A. 0 = None

[0332] B. 1= faint

[0333] C. 2= Fair (iris and lens details are clear)

[0334] D. 3 = Severe (iris and lens details are obscured)

[0335] E. 4 = Strong (fibrin or plastic water)

[0336] 11. Vitreous flare

[0337] 11.1. Clouding or haze of the vitreous humor.

[0338] 11.2. Marking can be understood as follows (based on Opremcak EM, 2012):

[0339] A. 0 = None (the nerve fiber layer [NFL] is clearly visible)

[0340] B. 1 = Faint (optic nerve and blood vessels clear, NFL hazy)

[0341] C. 2 = Moderate (optic nerve and blood vessels are hazy)

[0342] D. 3 = Severe (only the optic nerve is visible)

[0343] E. 4 = Strong (optic nerve not visible)

[0344] 12. Aqueous cells

[0345] 12.1. Observation of cells in aqueous humor.

[0346] 12.2. The area is a slit beam with dimensions of 1 mm x 1 mm.

[0347] 12.3. Scoring can be understood as follows (based on Jabs DA et al., 2005):

[0348] A. 0 = None

[0349] B. 0.5= Trace (1 to 5)

[0350] C. 1= 6 to 15

[0351] D. 2 = 16 to 25

[0352] E. 3= 26 to 50

[0353] F.4=>50

[0354] 13. Vitreous cells

[0355] 13.1. Observation of cells in the vitreous humor.

[0356] 13.2. Marking can be understood as follows (based on Opremcak EM, 2012):

[0357] A. 0= Trace (0 to 10)

[0358] B. 1= 11 to 20

[0359] C. 2= 21 to 30

[0360] D. 3 = 31 to 100

[0361] E. 4= >100

[0362] 14. Crystalline lens

[0363] 14.1. Examine the lens for any cataracts.

[0364] 14.2. Marking may be understood as follows:

[0365] A. 0 = The lens is clear.

[0366] B. 1= anterior (cortical / capsular).

[0367] C. 2=nuclear.

[0368] D. 3=posterior (cortical / visual).

[0369] E. 4=Equatorial.

[0370] 15. Vitreous humor

[0371] 15.1. Examine the vitreous humor for any abnormalities.

[0372] 15.2. Marking may be understood as follows:

[0373] A. 0=clear vitreous humor.

[0374] B. 1 = A little scattered opacity, fundus intact.

[0375] C. 2 = Moderately scattered opacity, fundus details somewhat obscured.

[0376] D. 3 = Much opacity, significant blurring of fundus details.

[0377] E. 4 = Dense opacity, no fundus visibility

[0378] 16. Vitreous Hemorrhage

[0379] 16.1. Observe the vitreous humor for any bleeding.

[0380] 16.2. Marking may be understood as follows:

[0381] A. 0 = None

[0382] B. 1= 1 to 25%

[0383] C. 2= 26 to 50%

[0384] D.3 = 51 to 75%

[0385] E. 4= 76 to 100%

[0386] 17. Retinal Detachment

[0387] 17.1. During retinal detachment, bleeding from small retinal blood vessels, which are usually filled with vitreous humor, occurs. This can cause the inside of the eye to become cloudy.

[0388] 17.2. Marking may be understood as follows:

[0389] A. 0 = None

[0390] B. 1 = Rhegmatogenous (network in the potential space between the neurosensory retina and the underlying retinal pigment epithelium) When fluid accumulates under the membrane, retinal detachment occurs.

[0391] C. 2 = Exudative (caused by inflammation, injury, or abnormality of blood vessels, resulting in holes, tears, or breaks without it, resulting in the accumulation of fluid under the retina).

[0392] D.3 = Traction (fibrous or fibrovascular caused by injury, inflammation, or angiogenesis) (This occurs when retinal tissue pulls the sensory retina away from the retinal pigment epithelium).

[0393] 18. Retinal Hemorrhage

[0394] 18.1. Abnormal bleeding of blood vessels in the retina.

[0395] 18.2. Marking may be understood as follows:

[0396] A. 0 = None

[0397] B. 1= 1 to 25%

[0398] C. 2= 26 to 50%

[0399] D.3 = 51 to 75%

[0400] E. 4= 76 to 100%

[0401] 19. Choroidal / Retinal Inflammation

[0402] 19.1. Inflammation of the retina and / or choroid.

[0403] 19.2 Marking may be understood as follows:

[0404] A. 0 = None

[0405] B. 1= Gentle

[0406] C. 2=Moderate

[0407] D. 3= Intense

[0408] 6.6.1.6 Results The combined injury and infection with corneal scratching and Ad5 inoculation resulted in consistent corneal and The composite score was calculated based on the baseline score on day 1. Compared with the baseline score, there was a significant improvement in all treatment groups on days 3 and 7 (p < 0.01). These results are presented graphically in Figure 10.

[0409] In addition, the subscores of conjunctival injection and surface area of ​​corneal lesions were primarily affected. found that, compared with baseline scores on day 1, on days 3 and 7, there were 100% improvement in all treatment groups. There was also a statistically significant improvement (p < 0.01 for conjunctival hyperemia and p < 0.01 for surface area of ​​corneal lesions). p ≦ 0.05). The results are presented graphically in Figures 11A and 11B.

[0410] 6.6.1.7 Conclusion The results showed that in eyes treated with ADPR·dilithium in solution, the adenovirus and physicochemical properties of the cells were significantly improved. The results showed rapid resolution of the combined effects of the pulmonary damage at all doses used (0.5%, 1.0%, and 2.0%) was effective with a greater than 80% reduction in the composite score by day 7, p < 0.01 The vehicle control group showed no meaningful improvement by day 7.

[0411] 6.7 Example 7. Effects on Cancer - Cell Viability Assay (In Vitro Study) Cell viability was assessed using the CellTiter-Glo® cell viability assay (Promega, Wisconsin). CellTiter-Glo® Luminescent Cell Viability Assay (Madison, TX) The experiment was based on the quantification of ATP present in the culture, which signals the presence of metabolically active cells. After treatment, CellTiter-Glo ( Molecular Derivatives® was added to the treatment wells and incubated at 37°C. Luminescence values ​​were measured using a vices Spectramax microplate reader.

[0412] Cells were grown to 70% confluency, trypsinized, counted, and then incubated for 384 h. Final concentration in wells of flat bottom plate: 1.0 x 10 3 ~1.5×10 3 Cells / well seeded (day 0 The cells were incubated in culture medium for 24 hours to allow for maximum adhesion. Drug treatment began on day 1 and continued for 72 hours. At the 72 hour time point, treatment-containing medium was removed. As described above, viable and non-viable cells were identified by the CellTiter-Glo® cell viability assay. The number of cells was counted. To measure proliferation inhibitory activity, experiments were performed in triplicate. Results from these studies showed that for each compound, IC 50 Inhibits cell proliferation to 50% of the control value ( was used to calculate the concentration of drug that causes toxicity.

[0413] Data Collection—For single agent and combination studies, data from each experiment are collected and It was expressed as % cell proliferation using the following formula:

[0414] (i) % cell proliferation = (f 試験 / f ビヒクル ) x 100

[0415] (ii) f 試験 is the luminescence of the tested sample, and f ビヒクル The drug is dissolved Dose-response graphs and IC 50 Values ​​were calculated using Prism 6 software (Graph Pad).

[0416] The following compounds (concentrations) were evaluated:

[0417] (i) Lithium chloride (30, 300, 1000, 3000 μM, and 6000 μM, 6000 μM only, MV41 1 cell was tested)

[0418] (ii) ADPR·dilithium (30, 300, 1000, and 3000 μM)

[0419] (iii) SN38 (0.03, 0.1, 0.3, 1.0, 3.0, 10, and 30 μM) as a positive control.

[0420] The following cell lines were evaluated:

[0421] (i) AsPC1 - human pancreatic adenocarcinoma

[0422] (ii) H1437 - Human lung adenocarcinoma, non-small cell lung cancer

[0423] (iii) U87-MG - human brain glioblastoma

[0424] (iv) MV411 - human myelomonocytic leukemia

[0425] The results are shown in the table below: 50 Shown as (μM, mean of duplicate values). [Table 10]

[0426] Conclusion: Lithium ions as lithium chloride in similar molar concentrations of ADPR·dilithium ADPR alone is not known to reduce cell replication, The inhibition of cell replication by PR·dilithium is noteworthy because it is a product of two components, lithium and and ADPR bind in a synergistic manner to stabilize these cancer cell lines and inhibit their replication. This indicates that the

[0427] 6.8 Example 8. ADPR alone (as the sodium salt) does not reduce replication and / or A549 cells Induces cytotoxicity of ADPR, sodium salt, (Sigma AO752), to measure its effect on replication ADPR was first tested in A549 (human alveolar adenocarcinoma) cell cultures (previously grown in monolayers). The five concentrations were evaluated using A549 cells (Figure 1) and incubated at 37°C for 48 hours. After incubation, each well was dosed with MTT (3-(4,5-dimethylthiazolium triphosphate). The dye (2-yl-2,5-diphenyltetrazolium bromide) was added and the The number of cells that were infected was measured by uptake of a blue dye.

[0428] The concentrations of ADPR (sodium salt) tested were 24, 12, 6, 3, 1.5, and 0 mg / mL. The mean MTT uptake measured by OD560 was 0.55±0.02, 0.69±0.01, and 0.72±0.0, respectively. 4, 0.61±0.09, 0.62±0.08, and 0.67±0.02.

[0429] ADPR (sodium salt) did not reduce MTT uptake up to 12 mg / mL and only moderately at 24 mg / mL. Therefore, ADPR alone (as the sodium salt) reduced the 12 did not reduce cell replication up to 21 mg / mL (equivalent to 21 mM) and showed a small reduction in cell replication at 24 mg / mL (equivalent to 42 mM). Therefore, this is not a consequence of the ADPR-II effect (as shown in Examples 6 and 7). The combination of lithium and ADPR as lithium shows significant synergy between lithium and ADPR. This further supports the idea that The present application provides the following invention. (Configuration 1) Treating, managing, or administering an adenovirus-associated disease or condition in a human patient. is a method for preventing, the method comprising administering to a patient an effective amount of 5'-adenosine diphosphate phosphatase. Acid ribose (ADPR), or a pharma- ceutically acceptable salt, solvate, hydrate, or tautomer thereof administering a species, stereoisomer, isotopic species, prodrug, or polymorph; wherein the patient has or develops a disease or condition associated with adenovirus. A method that carries the risk of causing disease. (Configuration 2) Adenovirus-associated diseases or conditions affecting any part of the eye, ear, mouth, upper respiratory tract, or lower respiratory tract. 2. The method of claim 1, wherein the disease or condition affects one or more parts of the body. (Configuration 3) Adenovirus-associated diseases or conditions include ocular diseases, conjunctivitis, keratitis, keratoconjunctivitis, , corneal abrasion, ulcerative infectious keratitis, superficial keratitis, interstitial keratitis, uveitis, acute glaucoma , blepharitis, otitis media, otitis externa, gingivitis, mucositis, pharyngitis, tonsillitis, rhinitis, sinusitis, laryngitis , croup, tracheitis, bronchitis, bronchiolitis, bronchopneumonia, pneumonia, asthma exacerbation, chronic obstructive pulmonary disease 2. The method of claim 1, wherein the symptom is an exacerbation of pulmonary disease or an exacerbation of emphysema. (Configuration 4) Adenovirus-related diseases or conditions include conjunctivitis, keratitis, keratoconjunctivitis, pharyngitis, tonsillar inflammation, 4. The method of claim 3, wherein the inflammation is rhinitis, laryngitis, rhinitis, sinusitis, bronchitis, bronchiolitis, or pneumonia. (Configuration 5) The adenovirus-associated disease or condition is keratitis, conjunctivitis, or keratoconjunctivitis. Method 4 of success. (Configuration 6) 5. The method according to claim 4, wherein the adenovirus-related disease or condition is bronchitis or bronchiolitis. method. (Configuration 7) The adenovirus-associated disease or condition is pharyngitis, tonsillitis, or laryngitis. 4 ways. (Configuration 8) The administration is by topical, oral, parenteral, transmucosal, or inhalation routes of administration. Method 1. (Configuration 9) 2. The method of embodiment 1, wherein the administration is by topical administration. (Configuration 10) 10. The method of claim 9, wherein the local administration is to a cell or tissue surface within a human patient. (Configuration 11) Local administration may be by aerosolization, nebulization, oral delivery, intratracheal instillation, intrabronchial, or airway administration. 10. Method of construction by surface injection. (Configuration 12) The method of claim 10, wherein local administration is by oral delivery, injection, or enema to the surface of the digestive tract. Law. (Configuration 13) 11. The method of claim 10, wherein local administration is by parenteral injection or infusion into an internal organ. (Configuration 14) 10. The method of claim 9, wherein the local administration is to an external cell or tissue surface. (Configuration 15) 15. The method of claim 14, wherein the external cell or tissue surface is a surface of the skin, eye, nail, hair, or ear. . (Configuration 16) 2. The method of claim 1, wherein administration is by intravenous, arterial, or intraductal injection. (Configuration 17) The pharmaceutical composition containing ADPR is a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, etc. tion, syrup, elixir, dry powder aerosol, liquid aerosol, tablet, or solution A method of composition 1, which is in the form of a medium. (Configuration 18) 20. The method of claim 17, wherein the dissolution medium is a fast dissolving tablet, film, or strip. (Configuration 19) 18. The method of claim 17, wherein the pharmaceutical composition comprising ADPR is in the form of a solution. (Configuration 20) 20. Any of claims 1 to 19, wherein the pharmaceutical composition comprising ADPR is administered in combination with another drug. Either one of the methods. (Configuration 21) 21. The method of claim 20, wherein the other pharmaceutical agent is an antiviral compound. (Configuration 22) The method according to claim 20, wherein the other medicament is cidofovir, acyclovir, or ganciclovir. Law. (Configuration 23) 23. The method of claim 22, wherein the other pharmaceutical agent is cidofovir. (Configuration 24) 21. The method of claim 20, wherein the other pharmaceutical agent is a metal salt. (Configuration 25) 25. The method of claim 24, wherein the other pharmaceutical agent is a lithium, zinc, cobalt, or copper salt. (Configuration 26) 26. The method of claim 25, wherein the lithium salt is lithium chloride. (Configuration 27) Treatment of microbial infections or diseases of at least one tissue of the eye, respiratory tract, and / or gastrointestinal tract; and / or preventively effective pharmaceutical compositions suitable for topical administration to the eye, respiratory tract, and / or gastrointestinal tract. wherein the pharmaceutical composition comprises ADPR, wherein the amount of ADPR is about 0.01% w / v of the pharmaceutical composition. The pharmaceutical composition is in the range of about 10% w / w to about 10% w / w. (Configuration 28) Treatment of microbial infections or diseases of at least one tissue of the eye, respiratory tract, and / or gastrointestinal tract; and / or preventively effective pharmaceutical compositions suitable for topical administration to the eye, respiratory tract, and / or gastrointestinal tract. wherein the pharmaceutical composition comprises: a) ADPR, wherein the amount of ADPR is about 0. 0.01% w / w to about 10% w / w; and b) one or more metal salts, wherein the metal is selected from the group consisting of lithium, zinc, cobalt, and copper. . (Configuration 29) 2. The method of embodiment 1, wherein ADPR is in the form of its sodium salt. (Configuration 30) 2. The method of embodiment 1, wherein ADPR is in the form of its lithium salt. (Configuration 31) 2. The method of embodiment 1, wherein ADPR is in the form of its dilithium salt. (Configuration 32) formula (chemical 1) A compound having the formula TIFF2025032189000016.tif66170, or a solvate, hydrate, tautomer, stereoisomer, or isotopic species thereof, Prodrugs, or polymorphs. (Configuration 33) (i) ADPR·dilithium, or a solvate, hydrate, tautomer, stereoisomer, or isomer thereof and (ii) one or more pharma- ceutically acceptable species, prodrugs, or polymorphs. A pharmaceutical composition comprising an excipient, wherein the amount of ADPR·dilithium in the pharmaceutical composition is in the range of about 0.001% w / w to about 10% w / w of the pharmaceutical composition. (Configuration 34) A method for treating, managing, or preventing cancer in a human patient, the method comprising: The present invention provides a method for administering to a patient an effective amount of ADPR dilithium, or a solvate, hydrate, tautomer, or isomer thereof. including administering a somatic isomer, isotopic species, prodrug, or polymorph; wherein the patient has or is at risk of developing cancer. (Configuration 35) The cancer is lung cancer, lung adenocarcinoma, non-small cell lung cancer, pancreatic cancer, pancreatic adenocarcinoma, glioma, glioblastoma multiforme, or is acute myeloid leukemia, composition 34 method. (Configuration 36) In human patients, eye disease or infection, inflammation, or physical, chemical, thermal, or to treat, manage, or prevent a disease or condition caused by radiation injury; A method for preventing, comprising administering to a patient an effective amount of ADPR·dilithium, or Any solvates, hydrates, tautomers, stereoisomers, isotopic species, prodrugs, or wherein the patient is suffering from an ocular disease, or an infection, inflammation, or disease Illness or condition caused by physical, chemical, thermal, or radiation injury having or at risk of developing the condition. (Configuration 37) Under high cytotoxic stress conditions, the amount of free ADPR or ATP in ADPR- or ATP-deficient cells A method for increasing the amount of ATP in a cell by restoring the cell to normal physiological cellular ADPR or ATP levels. The method comprises contacting said cell with a sufficient amount of ADPR to cause said cell to

Claims

1. 1. A pharmaceutical composition for treating, managing, or preventing cancer, comprising: ADPR dilithium or its solvates, hydrates, tautomers, stereoisomers, and isotopes The pharmaceutical composition comprises a species or polymorph.

2. The cancer is lung cancer, lung adenocarcinoma, non-small cell lung cancer, pancreatic cancer, pancreatic adenocarcinoma, glioma, glioblastoma multiforme.

2. The pharmaceutical composition according to claim 1, wherein the patient is a patient with acute myeloid leukemia or acute myeloid leukemia.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition comprises ADPR dilithium.

4. The pharmaceutical composition according to claim 3 , wherein the cancer is lung cancer.

5. The pharmaceutical composition according to claim 3, wherein the cancer is lung adenocarcinoma.

6. The pharmaceutical composition according to claim 3, wherein the cancer is non-small cell lung cancer.

7. The pharmaceutical composition according to claim 3 , wherein the cancer is pancreatic cancer.

8. The pharmaceutical composition according to claim 3 , wherein the cancer is pancreatic adenocarcinoma.

9. The pharmaceutical composition according to claim 3 , wherein the cancer is glioma.

10. The pharmaceutical composition according to claim 3, wherein the cancer is glioblastoma multiforme.

11. The pharmaceutical composition according to claim 3, wherein the cancer is acute myeloid leukemia.

12. The pharmaceutical composition of claim 1 , wherein the cancer is an eye cancer.

13. The pharmaceutical composition of claim 12, wherein the eye cancer is retinoblastoma.

14. 14. The pharmaceutical composition of claim 12 or 13, wherein the pharmaceutical composition comprises ADPR dilithium.

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