WO2009105234A2 - Procédés et compositions pour le traitement de troubles associés à des défauts du gène ou de la protéine du régulateur de la conductance transmembranaire d'une fibrose kystique - Google Patents

Procédés et compositions pour le traitement de troubles associés à des défauts du gène ou de la protéine du régulateur de la conductance transmembranaire d'une fibrose kystique Download PDF

Info

Publication number
WO2009105234A2
WO2009105234A2 PCT/US2009/001061 US2009001061W WO2009105234A2 WO 2009105234 A2 WO2009105234 A2 WO 2009105234A2 US 2009001061 W US2009001061 W US 2009001061W WO 2009105234 A2 WO2009105234 A2 WO 2009105234A2
Authority
WO
WIPO (PCT)
Prior art keywords
agents
composition
kit
agent selected
statin
Prior art date
Application number
PCT/US2009/001061
Other languages
English (en)
Other versions
WO2009105234A3 (fr
Inventor
Stephen Lin
Jane Staunton
Jinliang Sui
Original Assignee
Combinatorx, Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Combinatorx, Incorporated filed Critical Combinatorx, Incorporated
Publication of WO2009105234A2 publication Critical patent/WO2009105234A2/fr
Publication of WO2009105234A3 publication Critical patent/WO2009105234A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • Cystic fibrosis is a lethal, autosomal-recessive genetic disease, affecting approximately 30,000 individuals in the United States.
  • CF is characterized by defective chloride transport, resulting from a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
  • the CFTR gene encodes a linear chloride channel protein in the plasma membrane of certain epithelial cells, where it regulates the flow of chloride ions in response to phosphorylation by a cyclic AMP-dependent kinase.
  • Many mutations of the CFTR protein have been reported, the most common of which is a deletion of a phenylalanine residue ( ⁇ F508 CFTR). Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent CF.
  • CF CFTR fibrosis .
  • the principal clinical manifestation of CF is the resulting respiratory disease, characterized by airway obstruction due to the presence of thick mucus that is difficult to clear from airway passages. This airway mucus contributes to recurrent bacterial infections and impaired respiration, eventually resulting in death.
  • Treatment of CF involves the thinning of mucosal obstructions, treating bacterial infections, using anti-inflammatory compositions to treat lung inflammation, and opening airways with bronchodilators.
  • frequent hospitalization is often required as the disease progresses. Accordingly, improvements are needed for the treatment of CF and other disorders associated with defects of the CFTR gene or protein.
  • the present invention features compositions, methods, and kits for treating or ameliorating disorders associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein (e.g., cystic fibrosis).
  • CFTR cystic fibrosis transmembrane conductance regulator
  • the invention features a composition that includes an agent selected from Table 1. Desirably, the agent is present in an amount that, when administered to a patient, is sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. In another aspect, the invention features a composition that includes a first agent selected from Table 1 or 2 and a second, different agent selected from Table 1, 2, or 3. Desirably, the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. In another aspect, the invention features a composition that includes active ingredients and excipients, wherein the active ingredients are, for example, a first compound from Table 1 or 2 and a second compound from Table 1, 2, or 3.
  • the invention features a composition that includes a first agent selected from Table 1, a second agent selected from Table 2, and a third agent selected from Table 3.
  • the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein.
  • compositions of the invention may be formulated, for example, for oral administration, systemic administration, or for inhalation.
  • the invention also features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein by administering to a patient an agent selected from Table 1 in an amount sufficient to treat or ameliorate the disorder.
  • the invention features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein that includes administering to a patient a first agent selected from Table 1 and a second, different agent selected from Table 1, 2, or 3, wherein the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate the disorder.
  • the invention features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein that includes administering to a patient a first agent selected from Table 1, a second agent selected from Table 2, and a third agent selected from Table 3, wherein the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate the disorder.
  • the agents of the methods may be administered substantially simultaneously in amounts that together are sufficient to treat or ameliorate the disorder.
  • the agents may be administered within 1, 2, 4, 6, 12, or 24 hours of each other, within 7 days of each other, within 14 days of each other, or within 28 days of each other.
  • the agents may be administered by any appropriate route, e.g., by oral administration, systemic administration, or inhalation.
  • the invention also features a kit that includes at least one agent selected from Table 1 and instructions for administering the agent to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis).
  • a disorder associated with a defect in the CFTR gene or protein e.g., cystic fibrosis
  • the invention features a kit that includes a first agent selected from Table 1, a second, different agent selected from Table 1, 2, or 3, and instructions for administering the agents to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis).
  • a disorder associated with a defect in the CFTR gene or protein e.g., cystic fibrosis
  • the invention features a kit that includes a first agent selected from Table 1, a second agent selected from Table 2, a third agent selected from Table 3, and instructions for administering the agents to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis).
  • a disorder associated with a defect in the CFTR gene or protein e.g., cystic fibrosis.
  • Combinations of the compounds described herein may be used as therapeutic agents in the compositions, methods, and kits of the present invention.
  • Such combinations include, e.g., Corr-4a and HC toxin; Corr-4a and valproic acid; Corr-4a and suberoylanilide hydroxamic acid; atorvastatin calcium and HC toxin; prednisolone and suberoylanilide hydroxamic acid; quinestrol and suberoylanilide hydroxamic acid; chlormadinone acetate and Corr-4a; 2-APB and histone deacetylase inhibitor III; staurosporine and suberoylanilide hydroxamic acid; BAY 60-7550 and suberoylanilide hydroxamic acid; drotaverine hydrochloride and suberoylanilide hydroxamic acid; BAY 60-7550 and CF-C3; CF-C6 and gliquidone; Corr-4a and LY
  • an amount sufficient is meant the amount of a compound, alone or in combination with another compound or therapeutic regimen, required to treat or ameliorate a disorder, such as cystic fibrosis, in a clinically relevant manner.
  • a sufficient amount of an active compound used to practice the present invention for therapeutic treatment of, e.g., cystic fibrosis varies depending upon the manner of administration, age, and general health of the patient.
  • the prescribers will decide the appropriate amount and dosage regimen.
  • an effective amount may be an amount of compound in the combination of the invention that is safe and efficacious in the treatment of a patient having a disorder, such as cystic fibrosis, over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug Administration).
  • Candidate compounds may include, for example, peptides, polypeptides, synthetic organic molecules, naturally-occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components and derivatives thereof.
  • Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs thereof, as well as racemic mixtures. Compounds useful in the invention may also be isotopically labeled compounds.
  • Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl).
  • Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically- labeled reagent in place of a non-isotopically-labeled reagent.
  • disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein is meant any disorder resulting from a mutation of the CFTR gene or protein (e.g., a deletion of F508, a G542X mutation, a G551D mutation, a N1303K mutation, or a W1282X mutation).
  • exemplary disorders include cystic fibrosis, the congenital absence of the vas deferens, and some forms of pancreatitis.
  • a “high dosage” is meant at least 5% more (e.g., at least 10%, 20%, 30%, 40%, 50%, 100%, 150%, 200%, or 300%) than the highest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any disease or condition.
  • a high dosage of an agent that treats or prevents cystic fibrosis and that is formulated for intravenous administration may differ from a high dosage of the same agent formulated for oral administration.
  • a “low dosage” is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for the treatment of any disease or condition.
  • patient is meant any animal, e.g., a mammal (e.g., a human).
  • compositions, methods, and kits of the invention include, e.g., horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds.
  • a patient who is being treated for a disorder associated with a CFTR defect is one who has been diagnosed by a medical practitioner as having such a condition. Diagnosis may be performed by any suitable means, such as those described herein.
  • salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include, e.g., acetate, ascorbate, aspartate, benzoate, citrate, digluconate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, lactate, malate, maleate, malonate, mesylate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, valerate salts, and the like.
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • sustained release or “controlled release” is meant that the therapeutically active component is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the component are maintained over an extended period of time ranging from, e.g., about 12 to about 24 hours, thus, providing, for example, a 12-hour or a 24-hour dosage form.
  • systemic administration is meant any non-dermal route of administration, and specifically excludes topical and transdermal routes of administration.
  • therapeutic agent is meant any agent that produces a healing, curative, stabilizing, or ameliorative effect.
  • treating or ameliorating is meant ameliorating a condition or symptoms of the condition (e.g., cystic fibrosis) before or after its onset.
  • amelioration or degree of treatment is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • Exemplary therapeutic agents used for the treatment of any patient that has been diagnosed with a disorder associated with defects of a CFTR gene or protein are listed in Tables 1, 2, and 3.
  • Mibefradil e.g., dihydrochloride hydrate salt
  • Neomycin e.g., trisulfate salt hydrate
  • Protopine e.g., hydrochloride salt
  • Thioridazine e.g., hydrochloride salt
  • Figure 1 is a representative graph showing the fluorescence of FRT cells ( ⁇ F508; eYFP) incubated with DMSO alone (FL DMS o) > with forskolin alone (FL FSK X or with forskolin and a candidate compound (FL FSK+GEN ) before and after contact with an iodide solution.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • cystic fibrosis for example, such administration may decrease mucus production, decrease sputum viscosity, decrease blood pressure of the lung, reduce inflammation of the sinuses, lung, and pancreas, decrease thickened secretions that block bile ducts, control CF-related diabetes, or maximize organ function.
  • compositions, methods, and kits of the present invention are useful for treating any patient that has been diagnosed with a disorder associated with defects of the CFTR gene or protein (e.g., cystic fibrosis).
  • a disorder associated with defects of the CFTR gene or protein e.g., cystic fibrosis.
  • patients of the invention may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors.
  • CFTR-defect disorders e.g., CF
  • CFTR-defect disorders may be diagnosed and monitored using, for example, sweat (or chloride) tests to measure the amount of chloride in the sweat, which involves stimulating sweat from the patient with a mild electric current. The sweat is collected onto a gauze pad and analyzed. Higher than normal concentrations of chloride may be suggestive of a CFTR-defect disorder.
  • Blood tests may also be performed to test for mutations in the CFTR gene. Chest x-rays, pulmonary function tests (e.g., diagnostic tests that help to measure the lungs' ability to exchange oxygen and carbon dioxide), sputum cultures, stool evaluations (e.g., to measure stool fat absorption), and pancreatic function tests may also be used to diagnosis CFTR-defect disorders. The use of any of the above tests or any other tests known in the art may be used to monitor the efficacy of the present treatment.
  • Chest x-rays pulmonary function tests (e.g., diagnostic tests that help to measure the lungs' ability to exchange oxygen and carbon dioxide), sputum cultures, stool evaluations (e.g., to measure stool fat absorption), and pancreatic function tests may also be used to diagnosis CFTR-defect disorders. The use of any of the above tests or any other tests known in the art may be used to monitor the efficacy of the present treatment.
  • Exemplary therapeutic agents used for the treatment of any patient that has been diagnosed with a disorder associated with defects of a CFTR gene or protein are listed in Tables 1, 2, and 3.
  • Preferred agents include, e.g., statins, steroids, flavonoids, dihydropyridines, HDAC inhibitors, sulfonylureas, PPAR agonists, estrogen/estradiol receptor modulators, PDE inhibitors and adenosine receptor modulators, kinase inhibitors, NSAIDs and leukotriene antagonists, proton pump inhibitors, channel modulators, and receptor modulators.
  • Statins may be used as therapeutic agents in the compositions, methods, and kits of the invention, alone or in combination with additional agents.
  • Statins of the invention include atorvastatin; cerivastatin; fluvastatin; lovastatin; rosuvastatin; acitemate; amlodipine/atorvastatin; BAY102987; BAY
  • SC371 1 1 SC45355; simvastatin; SQ33600; SR12813; SR45023A; U20685; and U88156.
  • statins and statin derivatives are described, for example, in U.S. Patent Nos. 2,956,066, 3,288,826, 4,397,786, 4,803,292, 6,689,590, 7,199,102, and 7,297,808, hereby incorporated by reference. Additional statins and analogs thereof useful in the methods and compositions of the present invention are described, for example, in U.S. Patent Nos.
  • Steroids may be used as therapeutic agents in the compositions, methods, and kits of the invention, alone or in combination with additional agents.
  • Steroids include, e.g., sex hormones and corticosteroids (e.g., glucocorticoids and mineralcorticoids).
  • steroids of the invention include corticosterone; fluocinonide; fluprednisolone; rimexolone; triamcinolone; 11 -alpha, 17-alpha,21-trihydroxypregn-4-ene-3,20-dione; 11- beta, 16-alpha, 17,21 -tetrahydroxypregn-4-ene-3,20-dione; 1 1 -beta, 16- alpha, 17,2 l-tetrahydroxypregn-l,4-diene-3,20-dione; 1 l-beta,17-alpha,21- trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione; 11-dehydrocorticosterone; 1 1-deoxycortisol; 11 -hydroxy- l,4-androstadiene-3, 17-dione; 1 1- ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17-trione; 15,17- dihydroxypro
  • Cortisol Cortisol; Cortisol acetate; Cortisol butyrate; Cortisol cypionate; Cortisol octanoate; Cortisol sodium phosphate; Cortisol sodium succinate; Cortisol valerate; cortisone; cortisone acetate; cortodoxone; daturaolone; deflazacort,
  • compositions, methods, and kits of the invention include, e.g., A-348441 ; adrenal cortex extract; alsactide; amebucort; amelometasone;
  • Lipocort Lipocort; locicortone; meclorisone; naflocort; NCX-1015; NCX- 1020; NCX-1022; nicocortonide; NIK-236; NS-126; Org-2766; Org-6632; P 16CM, propylmesterolone; RGH-1113; rofleponide; rofleponide palmitate; RPR-106541 ; RU-26559; Sch-19457; T25; TBI-PAB; ticabesone propionate; tifluadom; timobesone; TSC-5; and ZK-73634.
  • Standard recommended dosages for corticosteroids are provided, e.g., in the Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians' Desk Reference 2003 (57 th Ed. Medical Economics Staff et al., Medical Economics Co., 2002), hereby incorporated by reference.
  • the synthesis of steroids and steroid derivatives is described, for example, in DE 2361120 and in U.S. Patent Nos. 2,760,966, 2,760,975, 3,927,046, 4,102,925, 4,183,864, and 4,267,376, hereby incorporated by reference.
  • Flavonoids may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary flavonoids of the invention include, e.g., apigenin, genistein, isoliquiritigenin, quercetin, or 2-hydroxyflavanone.
  • Additional flavonoids include taxifolin, catechin, epicatechin, eriodictyol, naringenin, troxerutin, chrysin, tangeretin, luteolin, epigallocatechin and epigallocatechin gallate, fisetin, kaempferol, galangin, gallocatechin, and epicatechin gallate.
  • flavonoids and flavonoid derivatives are described, for example, in U.S. Patent Nos. 4,617,293, 5,756,538, 6,004,998, 6,028,088, 6,087,385, and 7,138,429, hereby incorporated by reference.
  • Dihydropyridines may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary dihydropyridines of the invention are felodipine, isradipine, nimodipine, or nisoldipine.
  • Additional dihydropyridines include, e.g., nicardipine, nifedipine nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, benidipine, azelnidipine, and lercanidipine.
  • dihydropyridines and dihydropyridine derivatives are described, for example, in DE 2904552, EP 63365, EP 106275, and in U.S. Patent Nos. 4,044,141, 4,179,570, 4,220,649, 4,448,964, 5,492,923, 5,661,157, 5,712,296, 6,239, 155, and 7,074,931, hereby incorporated by reference.
  • Histone Deacetylase Inhibitors and Analogs or Derivatives Thereof Histone deacetylase (HDAC) inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Histone deacetylase (HDAC) inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary HDAC inhibitors of the invention are suberoylanilide hydroxamic acid (SAHA) and derivatives thereof (e.g., SAHA)
  • peptidic compounds including certain tripeptides, cyclic tetrapeptides, cyclic disulfides, and ketone derivatives thereof (e.g., HC toxin, chlamydocin, apicidins, trapoxin A, trapoxin B, depudecin, WF-3161, WF27082 (U.S. Patent No.
  • HDAC inhibitors are described in Saito, et al. (Proc. Natl. Acad. ScL USA 96:4592-4597, 1999), Furamai et al. ⁇ Proc. Natl. Acad. Sci. USA 98:87-92, 2001), Komatsu et al. ⁇ Cancer Res. 61 :4459-4466, 2001), Su et al. ⁇ Cancer Res. 60:3137-3142, 2000), Suzuki et al. ⁇ J. Med. Chem. 42:3001- 3003, 1999), in U.S. Patent Application Publication Nos. 2008/0146623,
  • Sulfonylureas and peroxisome proliferator-activated receptor (PPAR) agonists may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • exemplary sulfonylureas and PPAR agonists are gliquidone; glitazones (e.g., balaglitazone, troglitazone, pioglitazone, ciglitazone, englitazone, rosiglitazone, darglitazone, englitazone, netoglitazone, KRP-297, JTT-501, NC-2100, NIP-223, MCC-555, L-764486, and CS-Ol 1); acetohexamide; chlorpropamide; tolbutamide; tolazamide; glipizide; gliclazide; glibenclamide; glyclopyramide; glimepiride; GI262570; [(S)-2-
  • Estrogen and estradiol receptor modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary estrogen and estradiol receptor modulators are quinestrol and its metabolites (e.g., ethinyl estradiol); megestrol; melengestrol; desmosterol; centchroman; estrogen; progestogen; estradiol; alfatradiol; estriol; droloxifene; raloxifene; lasofoxifene; TSE-424; tamoxifen; idoxifene; LY353381 ; LYl 17081 ; toremifene; fulvestrant; 4-[7-(2,2-dimethyl- 1 -oxopropoxy-4-methyl-2-[4-[2-( 1 -piperidiny l)ethoxy]phenyl]-2H- 1 - benzopyran-3-yl]-phenyl-2,2-
  • Phosphodiesterase (PDE) inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Type I PDE inhibitors include (3- ⁇ ,16- ⁇ )-eburnamenine-14-carboxylic acid ethyl ester (Vinpocetine); l,8-methoxymethyl-3-isobutyl-l-methylxantine (MIMX); l-carboxy-23A4Mb ⁇ 6,6a,6bJ ⁇ 8a,8b,9,10, 10a,14, 16, 17,17a,17b,18, 19,19a, 19b, 20,21,21a,21b,22,23,23a-dotriacontahydro-14- hydroxy-8a, 1 Oa-bis(hydroxymethyl)- 14-(3-methoxy-3-oxopropyl)- 1 ,4,4a, 6,6a,17b,19b,21b-octamethyl beta-D-glucopyranos
  • Type II PDE inhibitors include erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA); 2,3,6,7-tetrahydro-9,10-dimethoxy-3-methyl-2-((2,4,6- trimethylphenyl)imino)-4H-pyrimido(6, 1 -a)isoquinolin-4-one (trequinsin); ND7001 ; and BAY 60-7550.
  • EHNA erythro-9-(2-hydroxy-3-nonyl)adenine
  • trequinsin 2,3,6,7-tetrahydro-9,10-dimethoxy-3-methyl-2-((2,4,6- trimethylphenyl)imino)-4H-pyrimido(6, 1 -a)isoquinolin-4-one
  • ND7001 ND7001
  • BAY 60-7550 BAY 60-7550.
  • Other Type II PDE inhibitors are described in U.S. Patent Application Publication No. 2003/0176316.
  • Type III PDE inhibitors include 3-isobutyl-l-methylxanthine (IBMX); 6-dihydro-2-methyl-6-oxo-3,4'-bipyridine)-5-carbonitrile (milrinone); zardaverine; and N-cyclohexyl-4-(( 1 ,2-dihydro-2-oxo-6-quinolinyl)oxy)-N- methyl-butanamide (cilostamide).
  • IBMX 3-isobutyl-l-methylxanthine
  • zardaverine zardaverine
  • Type III PDE inhibitors are described in EP 0653426, EP 0294647, EP 0357788, EP 0220044, EP 0326307, EP 0207500, EP 0406958, EP 0150937, EP 0075463, EP 0272914, and EP 01 12987, in U.S. Patent Nos. 4,963,561, 5,141,931, 6,897,229, and 6,156,753, in U.S. Patent Application Publication Nos. 2003/0158133, 2004/0097593, 2006/0030611, and 2006/0025463, in PCT Publication Nos.
  • Type IV PDE inhibitors include 4-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidone (rolipram); roflumilast; 4-(3-butoxy-4- methoxybenzyl)-2-imidazolidinone (Ro20-1724); and etazolate.
  • Other Type IV PDE inhibitors are described in U.S. Patent Nos.
  • Type V PDE inhibitors include sildenafil; vardenafil; and tadalafil.
  • Other Type V PDE inhibitors are described in U.S. Patent Nos. 6,992, 192, 6,984,641, 6,960,587, 6,943, 166, 6,878,711, and 6,869,950, and in U.S. Patent Application Publication Nos. 2003/0144296, 2003/0171384, 2004/0029891, 2004/0038996, 2004/0186046, 2004/0259792, 2004/0087561, 2005/0054660, 2005/0042177, 2005/0245544, and 2006/0009481.
  • Type VI PDE inhibitors include those described in U.S. Patent Application Publication Nos. 2004/0259792, 2004/0248957, 2004/0242673, and 2004/0259880.
  • Type VII PDE inhibitor includes BRL-50481.
  • Other Type VII PDE inhibitors include those described in U.S. Patent Nos.
  • Tofisopam is an exemplary Type X PDE inhibitor. Tofisopam analogs are described in HU 155572, GB 1202579, and in U.S. Patent No. 3,736,315. Kinase Inhibitors and Analogs and Derivatives Thereof
  • Kinase inhibitors e.g., tyrosine, GSK3, p38, CAMKK, Akt, Cdk,
  • EGFR, JNK, MAP, MEK, MLCK, PB, or VEGFR kinase inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • exemplary kinase inhibitors are bevacizumab; BIBW 2992; cetuximab; trastuzumab; sunitinib; erlotinib; neratinib; nilotinib; lapatinib; panitumumab; vandetinib; E7080; ranibizumab; pegaptanib; sorafenib; imatinib; motesanib; leflunomide; ZDl 839; erlotinib; canertinib; squalamine; SU 4312; SU 5416; ZD4190; vatalanib; PKI-166; GW2016; EKB-509; trastuzumab; EKB-569;
  • Exemplary kinase inhibitors are those described in DE 2347682 and EP
  • Non-steroidal anti-inflammatory drugs which include, e.g., COX-2 inhibitors and sulphonanilides, may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • NSAIDs are detoprofen; diclofenac; diflunisal; etodolac; etoricoxib; fenoprofen; flunixin meglumine; flurbiprofen; ibuprofen; indomethacin; ketoprofen; lumiracoxib; meclofenameate; mefenamic acid; meloxicam; nabumeone; naproxen sodium; oxaprozin; parecoxib; piroxicam; sulindac; tolmetin; valdecoxib; celecoxib; rofecoxib; aspirin; choline salicylate; salsalte; acemetacin; alminoprofen; am
  • Leukotriene antagonists may also be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Leukotriene antagonists include zileuton; 5-lipoxygenase;
  • MK-886 FLAP; montelukast; acitazanolast; iralukast; montelukast; zafirlukast; pranlukast; and velukast.
  • Proton pump inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary proton pump inhibitors are omeprazole; lansoprazole; esomeprazole; pantoprazole; and rabeprazole.
  • Channel modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary channel modulators are A-53930A; AE-0047;
  • R-(+), and racemic anipamil; 2-APB; AP-1067; aranidipine; atosiban; azelnidipine; barnidipine; BAY K8644; Bay-t-7207; Bay-y-5959; Bay-z-4406;
  • BBR-2160 belfosdil; BIII-890-CL; bisaramil; BMS-181 102; BMS-188107;
  • BMY-4301 1 BMY-4301 1 ; BRL-32872; buflomedil; capsaicin derivatives (e.g., TRPV); CD- 349; CD-832; CERM- 12816; CGP-28932; cilnidipine; dentiazem; clevidipine;
  • SIB- 1281 siratiazem; SKFA-45675; SKF-96365; SKT-M-26; SL-34.0829; SL-
  • Receptor modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • exemplary receptor modulators are otilonium bromide, drotaverine, dextromethorphan, and hydrobromide (opioid receptor modulators); promethazine (histamine receptor modulator); securinine and diazepam (GABA receptor modulators); and nebivolol and phenoxylbenzamine (adrenergic receptor modulators). Additional receptor modulators are described in BE 621917 and in U.S.
  • Fludarabine analogs are described in U.S. Patent No. 4,210,745 and U.S. Patent No. 4,357,324. Fludrocortisone analogs are described in U.S. Patent No. 2,957,013, GB 792224, and U.S. Patent No. 2,852,51 1. Flunisolide analogs are described in GB 933867, U.S. Patent No. 3,124,571, and U.S. Patent No. 3,126,375. Fluocinolone acetonide analogs are described in U.S. Patent No. 3,014,938 and U.S. Patent No. 3, 126,375. Fluocinonide analogs are described in GB 916996, U.S. Patent No.
  • Triflupromazine analogs are described in GB 813861.
  • Albendazole analogs are described in U.S. Patent No. 3,915,986.
  • Amitriptyline analogs are described in BE 584061, GB 858187, GB 858188, and U.S. Patent No. 3,205,264.
  • Amoxicillin analogs are described in GB 978178, U.S. Patent No. 3,192,198, DE 1942693, and GB 1241844.
  • Bepridil analogs are described in DE 2310918, U.S. Patent No. 3,962,238, and DE 2802864.
  • Bicalutamide analogs are described in EP 100172 and U.S. Patent No. 4,636,505.
  • Butoconazole analogs are described in U.S. Patent No. 4,078,071. Chlorquinaldol analogs are described in U.S. Patent No. 2,41 1 ,670. Chlorothymol analogs are described in DE 905738. Chlorprothixene analogs are described in GB 829763 and U.S. Patent No. 3,046,283. Clemastine fumarate analogs are described in GB
  • Clomipramine analogs are described in CH 371799 and U.S. Patent No. 3,467,650.
  • Cloperastine analogs are described in GB 670622 and GB 1179945.
  • Clopidogrel analogs are described in EP 99802, U.S. Patent No. 4,529,596, EP 281459, and U.S. Patent No. 4,847,265.
  • Clorofene analogs are described in U.S. Patent No. 1,967,825 and DE 703955.
  • Dienestrol analogs are described in U.S. Patent No. 2,464,203 and U.S. Patent No. 2,465,505.
  • Donepezil analogs are described in EP 296560 and U.S. Patent No. 4,895,841.
  • Doxepin analogs are described in U.S. Patent No. 3,438,981, NL 6407758, BE 641498, and U.S. Patent No. 3,420,851.
  • Ethinyl estradiol analogs are described in DE 702063, GB 516444, U.S. Patent No. 2,243,887, U.S. Patent No. 2,251,939, U.S. Patent No. 2,265,976, and U.S. Patent No. 2,267,257.
  • Ezetimibe analogs are described in WO 95/08532 and U.S. Patent No. 5,767,115.
  • Fenofibrate analogs are described in DE 2250327, DE 2003430, and U.S. Patent No. 4,058,552. Fenticlor analogs are described in DE 568944. Hydroxyzine analogs are described in U.S. Patent No. 2,899,436. Ibudilast analogs are described in DE 2315801 and U.S. Patent No. 3,850,941. Irsogladine analogs are described in DE 2506814 and U.S. Patent No. 3,966,728. Isradipine analogs are described in DE 2949491, U.S. Patent No. 4,466,972, and DE 3320616. Lansoprazole analogs are described in EP 174726 and U.S. Patent No. 4,628,098.
  • Nisoldipine analogs are described in DE 2549568 and U.S. Patent No. 4,154,839. Octyl methoxycinnamate analogs are described in U.S. Patent No. 4,713,473. Permethrin analogs are described in DE 2437882, DE 2544150, and U.S. Patent No. 4,1 13,968. Phenothiazine analogs are described in DE 25150, U.S. Patent No. 2,415,363, U.S. Patent No. 2,887,482, and U.S. Patent No. 3,000,887. Triclabendazole analogs are described in BE 865870 and U.S. Patent No. 4,197,307.
  • Zafirlukast analogs are described in U.S. Patent No. 4,859,692 and EP 199543.
  • Amiloride analogs are described in U.S. Patent No. 3,313,813 and BE 639386.
  • Amiodarone analogs are described in U.S. Patent No. 3,248,401 and FR 1339389.
  • Diltiazem analogs are described in U.S. Patent No. 4,552,695, DE 1805714, DE 3415035, and U.S. Patent No. 3,562,257.
  • Gabapentin analogs are described in U.S. Patent No. 4,024,175 and DE 2460891.
  • Ivermectin analogs are described in U.S. Patent No.
  • Penfluridol analogs are described in U.S. Patent No. 3,575,990 and DE 2040231. Phloretin analogs are described in U.S. Patent No. 2,789,995. Mibefradil analogs are described in U.S. Patent No. 4,808,605 and EP 268148. Letrazole analogs are described in U.S. Patent No. 4,978,672 and EP 236940. Medrysone analogs are described in U.S. Patent Nos. 2,864,837 and 2,968,655. Naltrexone analogs are described in U.S. Patent No. 3,332,950. Phenazopyridine analogs are described in U.S. Patent Nos.
  • Diazepam analogs are described in U.S. Patent Nos. 3,371,085, 3,109,843, 3,136,815, and 3,102,116.
  • Pramipexole analogs are described in U.S. Patent No. 4,886,821 and EP 186087. Rosiglitazone analogs are described in U.S. Patent No. 5,002,953 and EP 306228.
  • Ciclesonide analogs are described in U.S. Patent No. 5,482,934 and DE 4129535.
  • Auranofin analogs are described in U.S. Patent No. 3,635,945 and DE 2051495.
  • Clofoctol analogs are described in U.S. Patent No. 3,830,852. Clotrimazole analogs are described in U.S.
  • Patent No. 4,663,325 and EP 159566 Naftifine analogs are described in U.S. Patent No. 4,282,251, BE 853976, and ES 504432. Naltrexone analogs are described in U.S. Patent No. 3,332,950. Pimozide analogs are described in FR M3695. Rabeprazole analogs are described in U.S. Patent No. 5,045,552 and EP 268956. Tioconazole analogs are described in U.S. Patent No. 4,062,966 and BE 841309. Amprenavir analogs are described in U.S. Patent No. 5,585,397 and WO 94/05639.
  • Celecoxin analogs are described in U.S. Patent No. 5,466,823 and WO 95/15316.
  • Budesonide analogs are described in U.S. Patent No. 3,929,768 and DE 2323215.
  • Diacerein analogs are described in U.S. Patent Nos. 4,244,968 and 4,346,103, as well as DE 271 1493 and JP Kokai 83 225015.
  • Rolipram analogs are described in U.S. Patent No. 4,193,926 and BE 826923.
  • Biothionol analogs are described in DE 583055 and U.S. Patent No. 2,849,494.
  • Epirubicin analogs are described in DE 2510866, BE 898506, GB 2133005, and U.S. Patent No.
  • Trifluoperazine analogs are described in GB 813861 and U.S. Patent No. 2,921,069.
  • Nortriptyline analogs are described in NL 6408512 and U.S. Patent Nos. 3,442,949 and 3,922,305.
  • Tamoxifen analogs are described in BE 637389, BE 678807, and in U.S. Patent Nos. 4,536,516, 6,096,874, 6,576,645, 6,875,775, and 5,807,899.
  • Nebivolol analogs are described in EP 145067 and U.S. Patent No. 4,654,362.
  • Pranlukast analogs are described in EP 173516 and U.S. Patent No. 4,780, 469.
  • Emetine analogs are described in U.S. Patent No. 3, 102,118.
  • Diphenoxylate hydrochloride analogs are described in U.S. Patent No. 2,898,340.
  • Gestodene analogs are described in BE 847090 and U.S. Patent No. 4,081,537.
  • Diazolidinyl urea analogs are described in WO 81/00566 and U.S. Patent No. 4,271,176.
  • Oxymethurea analogs are described in U.S. Patent Nos. 1,863,426 and 2,436,355.
  • Chloramphenicol analogs are described in GB 795131, GB 796901, and in U.S. Patent Nos.
  • Cephapirin analogs are described in ZA 67 07783 and in U.S. Patent Nos. 3,422,100, 3,503,967, and 3,578,661.
  • Dioxybenzone analogs are described in U.S. Patent No. 2,853,521.
  • Efavirenz analogs are described in EP 582455 and U.S. Patent No. 5,519,021.
  • Saperconazole analogs are described in EP 283992 and U.S. Patent No. 4,916,134.
  • Securine analogs are described in GB 1169471 and U.S. Patent No. 3,538,103. Benproperine phosphate analogs are described in GB 914008 and U.S. Patent No. 3,117,059.
  • Epoxomicin analogs are described in EP 411660 and U.S. Patent No. 5,071,957.
  • Fenipentol analogs are described in GB 915815 and U.S. Patent No. 3,084,100.
  • Phenoxybenzamine analogs are described in U.S. Patent No. 2,599,000.
  • Telithromycin analogs are described in EP 680967 and U.S. Patent No.
  • Domperidone analogs are described in DE 2632870 and U.S. Patent No. 4,066,772. Vigabatrin analogs are described in U.S. Patent No. 3,960,927. Argatroban analogs are described in U.S. Patent No. 4,258,192. Mofebutazone analogs are described in GB 839057. MS-275 analogs are described in Japanese Patent Publication Hei No. 10-152462 and U.S. Patent No. 7,056,883. Sangivamycin analogs are described in U.S. Patent No. 3,423,398. Forskolin analogs are described in DE 2557784 and in U.S. Patent Nos. 4,088,659 and 4,476,140.
  • Padimate analogs are described in GB 1162337, FR 1566396, and U.S. Patent No. 3,403,207.
  • N-methyl-paroxetine analogs are described in U.S. Patent No. 4,007, 196 and WO 2007/034270.
  • Chenodeoxycholic acid analogs are described in U.S. Patent No. 4,425,273.
  • Sodium phenylbutyrate analogs are described in U.S. Patent Nos. 4,457,942 and 5,605,930.
  • 2- Methoxyestradiol analogs are described in WO 01/014405 and U.S. Patent No. 7,371,741.
  • AL-438 analogs are described in U.S. Patent Application Publication Nos.
  • APWAGl analogs are described in U.S. Patent Application Publication No. 2006/0252045.
  • HU-210 analogs are described in U.S. Patent Nos. 5,284,867, 6,096,740, and 7,297,796.
  • Icilin analogs are described in U.S. Patent No. 3,821,221.
  • 6-Iodonordihydro-capsaicin analogs are described in U.S. Patent Nos. 4,313,958, 4,401,663, 4,424,206, 4,443,473, 4,498,848, and 4,599,342.
  • TN- 16 analogs are described in U.S. Patent No. 6,693,125.
  • Farnesyl transferase inhibitors and their analogs are described in U.S. Patent Nos.
  • JNK inhibitors and their analogs are described in U.S. Patent Nos. 6,642,227, 7,084,159, 7,199,124, 7,211,594, 7,402,595, and 7,417,058.
  • RG-14620 analogs are described in U.S. Patent Nos. 6,225,346, 6,524,832, and 6,552,066.
  • Clove oil analogs are described in U.S. Patent No. 4,217,371.
  • GTP-14564 analogs are described in PCT Publication No. WO 06/135639 and in U.S. Patent Application Publication Nos.
  • Cetylpyridinium chloride analogs are described in U.S. Patent No. 4,154,744. Amsacrine analogs are described in U.S. Patent Nos. 5,604,237 and 6,207,673. Ro 48-8071 analogs are described in U.S. Patent No. 6,964,974. U 18666A analogs are described in U.S. Patent No. 5,998,433. Suxamethonium iodide analogs are described in U.S. Patent No. 5,418,226. Carboxymethylcellulose analogs are described in U.S. Patent Nos. 3,959,080, 4,988,806, and 5,023,246. Doripenem analogs are described in PCT Publication No.
  • N-(n- nonyl) deoxynojirimycin analogs are described in EP 0012278 and in U.S. Patent Nos. 4,611,058 and 4,806,650.
  • Aurintricarboxylic acid analogs are described in U.S. Patent Nos. 4,007,270, 4,1 13,879, and 4,880,788.
  • L-741,626 analogs are described in U.S. Patent Nos. 4,454,150 and 5,302,599.
  • TO- 901317 analogs are described in U.S. Patent Nos. 6,316,503 6,924,311, and 7,365,085.
  • tr ⁇ ns-4-Iodo,4'-boranyl-chalcone analogs are described in U.S. Patent Application Publication No. 2005/0176988.
  • Zinc protoporphyrin analogs are described in U.S. Patent Nos. 4,831,024 and 5,081,115. All of these references are hereby incorporated by reference.
  • the patient may also receive additional therapeutic regimens.
  • therapeutic agents may be administered with the agent or agents described herein at concentrations known to be effective for such therapeutic agents.
  • Particularly useful agents include those that treat or ameliorate symptoms of a disorder associated with a defect in the CFTR gene or protein.
  • Such agents include, for example, those that thin mucosal obstructions, treat bacterial infections, reduce inflammation, and open airway passages.
  • Exemplary agents are known therapeutics, ion-channel modulators, antiinflammatory agents, antimicrobial agents, analgesics, anesthetics, or bronchodilators.
  • Suitable agents include, e.g., 4-[4-oxo-2-thioxo- 3-(3-trifluoromethyl-phenyl)-thiazolidin-5-ylidenemethyl]-benzoic acid; (naphthalen-2-ylamino)-acetic acid (3,5-dibromo-2,4,-dihydroxy-benzylidene)- hydrazide; diarylsulfonylurea; 4-methyl-2-(5-phenyl-lH-pyrazol-3-yl)-phenol; 2-[(2-lH-indol-3-yl-acetyl)-methyl-amino]-N-(4-isopropyl-phenyl)-2-phenyl- acetamide; 6-(ethyl-phenyl-sulfonyl)-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid 2-
  • Suitable ion-channel modulators include, e.g., amiloride; 2-APB; BAY K8644; calciseptine; cilnidipine; diltiazem; flunarizine; FPL-64176; gabapentin; kuratoxin; SDZ- 202; tetrandrine; fipronil; IAA-94; 5-nitro-(3-phenylpropylamino) benzoic acid; batrachotoxin; bupivacaine; kavain; monensin; palytoxin; PD-85639; QX- 314; riluzole; and veratridine.
  • Suitable anti-inflammatory agents include, e.g., non-steroidal anti-inflammatory drugs (e.g., ibuprofen or tacrolimus), cyclooxygenase-2-specific inhibitors (e.g., rofecoxib (Vioxx®) and celecoxib (Celebrex®)), topical glucocorticoid agents, and specific cytokines directed at T lymphocyte function.
  • additional suitable anti-inflammatory agents include flubiprofen, diclofenac, and ketarolac. Antiinflammatory concentrations known to be effective may be used.
  • ibuprofen may be present in the composition at concentrations sufficient to deliver between 25-800 mg per day to the patient.
  • exemplary anti- inflammatory agents are listed in, e.g., U.S. Patent Nos. 7,112,578 and 7,199,1 19, hereby incorporated by reference.
  • Antimicrobial agents include, e.g., antibacterial, anti-fungal, and antiviral agents.
  • antibacterial agents examples include penicillins (e.g., penicillin G, ampicillin, methicillin, oxacillin, and amoxicillin), cephalosporins (e.g., cefadroxil, ceforanid, cefotaxime, and ceftriaxone), tetracyclines (e.g., doxycycline, minocycline, and tetracycline), aminoglycosides (e.g., amikacin, gentamycin, kanamycin, neomycin, streptomycin, and tobramycin), macrolides (e.g., azithromycin, clarithromycin, and erythromycin), fluoroquinolones (e.g., ciprofloxacin, lomefloxacin, moxifloxacin, and norfloxacin), and other antibiotics including chloramphenicol, clindamycin, cycloserine, isoniazid, rif
  • Anti-viral agents are substances capable of destroying or suppressing the replication of viruses.
  • antiviral agents are 1- ⁇ -D-ribofuranosyl- 1 ,2,4-triazole-3 carboxamide (ribavirin), 9-2-hydroxy-ethoxy methylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, adenine arabinoside, protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir.
  • Exemplary anti-viral agents are described in, e.g., U.S. Patent Nos. 6,093,550 and 6,894,033.
  • Anti-fungal agents include both fungicidal and fungistatic agents, e.g., amphotericin B, butylparaben, clindamycin, econaxole, fluconazole, flucytosine, griseofulvin, nystatin, and ketoconazole.
  • fungicidal and fungistatic agents e.g., amphotericin B, butylparaben, clindamycin, econaxole, fluconazole, flucytosine, griseofulvin, nystatin, and ketoconazole.
  • Exemplary anti-fungal agents are described in, e.g., U.S. Patent Nos. 5,627,153 and 7,125,842, hereby incorporated by reference.
  • any of the commonly used topical analgesics and anesthetics can be used as therapeutic agents in the invention.
  • useful anesthetics are procaine, lidocaine, tetracaine, dibucaine, benzocaine, p-buthylaminobenzoic acid 2-(diethylamino) ethyl ester HCl, mepivacaine, piperocaine, and dyclonine.
  • Exemplary anesthetics are listed in, e.g., U.S. Patent Nos. 6,562,363 and 6,569,839, hereby incorporated by reference.
  • Analgesics include opioids such as, e.g., morphine, codeine, hydrocodone, and oxycodone. Any of these analgesics may also be co- formulated with other compounds having analgesic or anti-inflammatory properties, such as acetaminophen, aspirin, codeine, naproxen, and ibuprofen. Exemplary analgesics are listed in, e.g., U.S. Patent Nos. 6,869,974 and 7,202,259, hereby incorporated by reference. Bronchodilators
  • bronchodilator can be used as a therapeutic agent in the invention described herein.
  • useful bronchodilators include, e.g., pirbuterol, epinephrine, albuterol, salbutamol, salmeterol, or levalbuterol.
  • Exemplary bronchodilators are described in, e.g., U.S. Patent Nos. 4,489,078, 4,591,588, 4,734,413, 6,299,863, and 6,555,583, hereby incorporated by reference.
  • therapeutic agents may be delivered separately or may be admixed into a single formulation.
  • routes of administration may be employed. Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (e.g., intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic or oral administration).
  • systemic administration refers to all non- dermal routes of administration, and specifically excludes topical and transdermal routes of administration.
  • the agent of the invention and additional therapeutic agents are administered within at least 1, 2, 4, 6, 10, 12, 18, 24 hours, 3 days, 7 days, 14 days, or 28 days apart.
  • the dosage and frequency of administration of each component of the combination can be controlled independently.
  • one compound may be administered three times per day, while the second compound may be administered once per day.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side effects.
  • the compounds may also be formulated together such that one administration delivers both compounds.
  • any of the agents of the combination may be administered in a low dosage or in a high dosage, each of which is defined herein.
  • the therapeutic agents of the invention may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions of the present invention to a mammal.
  • Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds described, for example, in the Merck Index, Merck & Co., Rahway, New Jersey. Slow release formulation or a slow release apparatus may be also be used for continuous administration.
  • the additional therapeutic regimen may involve, e.g., gene therapy, lung transplantation, or a modification to the lifestyle of the patient being treated.
  • lifestyle changes may be helpful to control the disorder and include weight loss, physical exercise, diet control, reduction in alcohol intake, or reduction in smoking.
  • the drugs used in any of the combinations described herein may be covalently attached to one another to form a conjugate of formula XXX.
  • (A) is a compound listed in, e.g., Table 1, Table 2, or
  • Table 3 covalently tethered via a linker (L) to (B), a compound of, e.g., Table 1, Table 2, or Table 3.
  • Conjugates of the invention can be administered to a subject by any route and for the treatment of any disease described herein.
  • the conjugates of the invention can be prodrugs, releasing drug (A) and drug (B) upon, for example, cleavage of the conjugate by intracellular and extracellular enzymes (e.g., amidases, esterases, and phosphatases).
  • the conjugates of the invention can also be designed to largely remain intact in vivo, resisting cleavage by intracellular and extracellular enzymes. The degradation of the conjugate in vivo can be controlled by the design of linker (L) and the covalent bonds formed with drug (A) and drug (B) during the synthesis of the conjugate.
  • Conjugates can be prepared using techniques familiar to those skilled in the art.
  • the conjugates can be prepared using the methods disclosed in G. Hermanson, Bioconjugate Techniques, Academic Press, Inc., 1996.
  • the synthesis of conjugates may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of drug (A), the linker, and/or drug (B).
  • commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m- nitrophenyl.
  • amides such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert- butylsulfonyl amides.
  • protecting groups for carboxyls include esters, such as methyl, ethyl, 9-fluorenylmethyl, 2- (trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho- esters, and halo-esters.
  • Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P- nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy- trityls), and silyl ethers.
  • Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls.
  • sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides).
  • Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a Lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule.
  • the conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis (2 nd Ed.), John Wiley & Sons, 1991 and P.J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below.
  • the linker component of the invention is, at its simplest, a bond between drug (A) and drug (B), but typically provides a linear, cyclic, or branched molecular skeleton having pendant groups covalently linking drug (A) to drug (B).
  • linking of drug (A) to drug (B) is achieved by covalent means, involving bond formation with one or more functional groups located on drug (A) and drug (B).
  • functional groups which may be employed for this purpose include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups.
  • the covalent linking of drug (A) and drug (B) may be effected using a linker, which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B).
  • a linker which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B).
  • an amine group of drug (A) may react with a carboxyl group of the linker, or an activated derivative thereof, resulting in the formation of an
  • N-Maleimide derivatives are also considered selective towards sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions.
  • Reagents such as 2- iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through conversion of an amino group, may be considered as sulfhydryl reagents if linking occurs through the formation of disulphide bridges.
  • Examples of reactive moieties capable of reaction with amino groups include, for example, alkylating and acylating agents.
  • aryl halides such as reactive nitrohaloaromatic compounds
  • alkyl halides as described, for example, by McKenzie et al., J
  • Representative amino-reactive acylating agents include:
  • active esters such as nitrophenylesters or N-hydroxysuccinimidyl esters
  • acylazides e.g. wherein the azide group is generated from a preformed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal Biochem. 58:347 (1974); and
  • reactive moieties capable of reaction with carboxy 1 groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv Protein Chem. 3: 169 (1947).
  • Carboxyl modifying reagents such as carbodiimides, which react through O-acylurea formation followed by amide bond formation, may also be employed.
  • functional groups in drug (A) and/or drug (B) may, if desired, be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity.
  • methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as ⁇ -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2- bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols
  • So-called zero-length linkers involving direct covalent joining of a reactive chemical group of drug (A) with a reactive chemical group of drug (B) without introducing additional linking material may, if desired, be used in accordance with the invention.
  • the linker will include two or more reactive moieties, as described above, connected by a spacer element.
  • the presence of such a spacer permits bifunctional linkers to react with specific functional groups within drug (A) and drug (B), resulting in a covalent linkage between the two.
  • the reactive moieties in a linker may be the same (homobi functional linker) or different (heterobifunctional linker, or, where several dissimilar reactive moieties are present, heteromultifunctional linker), providing a diversity of potential reagents that may bring about covalent attachment between drug (A) and drug (B).
  • Spacer elements in the linker typically consist of linear or branched chains and may include a C ⁇ 10 alkyl, C 2 _i 0 alkenyl, C 2 -io alkynyl, C 2 - ⁇ heterocyclyl, C 6 - I2 aryl, C 7 _ 14 alkaryl, C 3 _io alkheterocyclyl, or C 1 _ 1 o heteroalkyl.
  • the linker is described by formula (XXXI):
  • G is a bond between drug (A) and the linker; G is a bond between the linker and drug (B); Z 1 , Z 2 , Z 3 , and Z 4 each, independently, is selected from O, S, and NR 31 ; R 3 ] is hydrogen, C]_ 4 alkyl, C 2 _ 4 alkenyl, C 2 ⁇ alkynyl, C 2 _ 6 heterocyclyl, C ⁇ -n aryl, C 7 _i 4 alkaryl, C 3 _io alkheterocyclyl, or Ci_ 7 heteroalkyl; Y 1 and Y 2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; o, p, s, t, u, and v are each, independently, 0 or 1 ; and R 30 is a Ci_ 10 alkyl, C 2 _io alkenyl, C 2 _ 10 alkyny
  • homobifunctional linkers useful in the preparation of conjugates of the invention include, without limitation, diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1 ,4-butanediol, 1 ,6- hexanediol, cyclohexanediol, and polycaprolactone diol.
  • any of the agents employed according to the present invention may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is, e.g., suitable for the oral, parenteral (e.g., intravenous or intramuscular), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels (e.g., hydrogels), pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.
  • the compounds of the invention may be delivered in the form of, e.g., a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges made, for example, from gelatin
  • an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • each agent may be formulated in a variety of ways that are known in the art. Desirably, the agents are formulated together for the simultaneous or near simultaneous administration of the agents.
  • Such co-formulated compositions can include the two agents formulated together in the same, e.g., pill, capsule, or liquid. It is to be understood that, when referring to the formulation of such combinations, the formulation technology employed is also useful for the formulation of the individual agents of the combination, as well as other combinations of the invention. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be suitably matched.
  • kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, or two topical creams.
  • the kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized intravenous delivery systems, or inhalers.
  • the unit dose kit can contain instructions for preparation and administration of the compositions.
  • the kit may be, e.g., manufactured as a single use unit dose for one patient, multiple uses for a particular patient (e.g., at a constant dose or in which the individual compounds may vary in potency as therapy progresses), or the kit may contain multiple doses suitable for administration to multiple patients (e.g., bulk packaging).
  • the kit components may be assembled in, e.g., cartons, blister packs, bottles, or tubes.
  • the dosage of any of the agents of the invention will depend on the nature of the agent, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day.
  • Administration of each drug, alone or in combination, can be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be required in many cases.
  • Appropriate dosages of compounds used in the methods described herein depend on several factors, including the administration method, the severity of the disorder, and the age, weight, and health of the patient to be treated. Additionally, pharmacogenomic information (e.g., the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic) about a particular patient may affect the dosage used.
  • pharmacogenomic information e.g., the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic
  • the compounds of the invention may be employed in mechanistic assays to determine whether other single agents or combinations of agents are effective in the treatment or amelioration of a disorder associated with a defect in CFTR gene or protein using assays generally known in the art, examples of which are described herein.
  • candidate compounds may be tested, alone or in combination and contacted with cells that express a mutated CFTR (e.g., CTFR- ⁇ F508) and a fluorescent marker (e.g., yellow fluorescent protein (YFP)) to determine the functionality (e.g., openness) and/or abundance of the CFTR channels. After a suitable time, iodide is applied to the cells.
  • a mutated CFTR e.g., CTFR- ⁇ F508
  • a fluorescent marker e.g., yellow fluorescent protein (YFP)
  • the CFTR therapeutic agents of the invention accelerate YFP quenching.
  • an increase in the rate of fluorescence decay in this particular assay would indicate that the candidate compound would be a suitable CFTR therapeutic agent for the treatment of a disorder associated with a defect in CFTR gene or protein.
  • Example 1 CFTR YFP Ranking Screen and Identification of Therapeutic Agents for the Treatment of a Disorder Associated with a Defect in the CFTR Gene or Protein
  • CFTR yellow fluorescent protein (YFP) ranking screen was to select single agents from a chemical library that increase recruitment of ⁇ F508 CFTR proteins to the plasma membrane of a cell or enhance existing CFTR channel activities. This screen was performed in Fischer rat thyroid (FRT) cell lines expressing both ⁇ F508 CFTR and YFP in a 384-well plate format. Four different assay protocols were used to identify these agents.
  • FRT Fischer rat thyroid
  • the cells were incubated with candidate compounds at 37°C for 24 hours. After washing, the cells were stimulated with forskolin and a compound known to open CFTR channels before being read on a plate reader.
  • the number of ⁇ F508 CFTR channels in the plasma membrane was increased by incubating the cells at 27°C for 24 hours. The cells were then washed and treated with forskolin and the candidate compounds.
  • the cells were incubated with candidate compounds at either 27°C or at 37°C for 24 hours, the plate-washing step was omitted, and the cells were stimulated with forskolin prior to reading on a plate reader.
  • YFP fluorescence intensity was read with a plate reader at high speed before and after iodide was injected into each well of the plate. Iodide enters the cell via open CFTR channels in the plasma membrane and quenches YFP fluorescence. The rate of fluorescence decay is directly related to the total CFTR activity in the cell membranes. By increasing the total number of ⁇ F508 CFTR channels in the plasma membrane or their open probability, CFTR- ⁇ F508 therapeutic agents accelerate YFP quenching.
  • ⁇ F508 CFTR and H148Q/I152L eYFP or H148Q/I152L eYFP only were cultured in T- 175 flasks (Corning, Catalog No. 431080) or CeIlF arm high-density flasks (Fisher, Catalog No. 13-700-407) with Coon's medium (Sigma, Catalog No. F6636) containing 10% FBS (Gibco, Catalog No. 26140), 1% Penicillin-Streptomycin (Cellgro, Catalog No. 30-002-CI), 2.68 g/L sodium bicarbonate, 2 mM L-glutamine (Gibco, Catalog No.
  • T- 175 flask of cells provided enough cells to seed two 384-well plates at 50,000 cells/well and 50 ⁇ l per well; one CellFarm flask seeded about ten times as much. Once the cells were confluent in the flasks, the cells were rinsed with
  • PBS (10 ml for a T- 175 flask; 50 ml for a CellFarm flask). Trypsin-EDTA was added to the cells (5 ml for a T- 175 flask; 50 ml for a CellFarm flask). The cells were incubated at 37°C for 10-15 minutes. Cell culture media was added to neutralize the trypsin and cells were vigorously pipetted to break apart cell clumps. For passaging, the cells were split at a ratio of 1 :3 or 1 :4 (30 ml media per T- 175 flask; 500 ml media per CellFarm flask). For seeding cells on assay plates, all cell suspensions were mixed together and the cell density was counted.
  • PBS-iodide solution was made with the following concentrations of salts: 0.7 mM CaCl 2 , 2.7 mM KCl, 1.5 mM KH 2 PO 4 , 1.1 mM MgCl 2 , 154 mM NaI, and 8.1 mM NaHPO 4 , with the pH adjusted to 7.4.
  • 50,000 cells in 50 ⁇ l media were plated in each well of a 384-well plate (Matrix).
  • the drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells.
  • the plates were then incubated for 24 hours at 37°C and 5% CO 2 .
  • the plates were washed twice with DPBS and stimulated with 20 ⁇ M forskolin and 3 ⁇ M CF-P3 in DPBS for 60 minutes at room temperature before making a fluorescence reading on a plate reader (Hamamatsu FDSS-6000).
  • the plates were incubated for 24 hours at 27°C and
  • the plates were washed twice with DPBS and treated with drugs, diluted 1 : 100 in culture media and then added at a ratio of 1 :10 to the wells, and 20 ⁇ M forskolin for 60 minutes at room temperature before reading on the plate reader.
  • the plates were incubated for 60 minutes at 27°C and
  • the drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells. The plates were then incubated for 24 hours at 27°C and 5% CO 2 . The following day, the plates were stimulated with 20 ⁇ M of forskolin added to the culture media and incubated for 60 minutes at room temperature before reading on the plate reader.
  • the plates were incubated for 60 minutes at 37°C and 5% CO 2 .
  • the drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells.
  • the plates were then incubated for 24 hours at 37°C and 5% CO 2 .
  • the following day, the plates were stimulated with 20 of ⁇ M forskolin for 60 minutes at room temperature before reading on the plate reader.
  • the cells were excited with UV light at 500 nm and the fluorescence emitted at 540 nm was read at 5 Hz. After a 6-second baseline read, PBS-iodide was added to the wells.
  • the user input included t 0 (injection time), t N (fluorescence level (FL) sample time), and tg (end of data fitting point).
  • the return values included QR (fluorescence quenching rate, inverse of decay time constant tau) and FL (fluorescence level given in percentage number at t t N ).
  • FLbackground mean of FL of background wells (FLB)
  • the fluorescence level (FL) was normalized (0 to 100) at the sampling point (tu). Each FL value was taken from the kinetic fitting results to reduce noise and spikes from raw data.
  • the quenching rate (QR) was determined by exponential fitting of the fluorescence decay from the point of iodide injection (to) to the end of fitting range (t E ). QR has a dimension of s "1 .
  • QRbackground mean of QR of background wells (QRB)
  • QR u m reated was the mean value of QR from an untreated well.
  • Table 4 shows enhancement of existing CFTR channel activities in cells contacted with the candidate compound compared to untreated cells (denoted as Max Fold).
  • Table 5 shows compounds that increased recruitment of ⁇ F508 CFTR proteins to the plasma membrane in cells when contacted with the candidate compound compared to untreated cells (denoted as Max Fold).
  • Table 6 shows the reference name and chemical name for each CF reference compound.
  • Tables 7-21 show combinations of compounds that enhanced CFTR channel activities in cells contacted with the candidate compounds compared to untreated cells (denoted as Max Combination Effect (MCE, based on Max Fold) and Synergy Score (SS)).
  • MCE Max Combination Effect
  • SS Synergy Score
  • the magnitude of the synergy score indicates the strength of the synergistic interaction.
  • HDAC Inhibitors x Ion Channel Modulators Table 13. HDAC Inhibitors x Kinase Inhibitors

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur des compositions, des procédés et des coffrets pour traiter ou améliorer des troubles associés à un défaut dans le gène ou la protéine du régulateur de la conductance transmembranaire de la fibrose kystique (CFTR) (par exemple, fibrose kystique).
PCT/US2009/001061 2008-02-19 2009-02-19 Procédés et compositions pour le traitement de troubles associés à des défauts du gène ou de la protéine du régulateur de la conductance transmembranaire d'une fibrose kystique WO2009105234A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6625908P 2008-02-19 2008-02-19
US61/066,259 2008-02-19

Publications (2)

Publication Number Publication Date
WO2009105234A2 true WO2009105234A2 (fr) 2009-08-27
WO2009105234A3 WO2009105234A3 (fr) 2009-11-12

Family

ID=40986104

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/001061 WO2009105234A2 (fr) 2008-02-19 2009-02-19 Procédés et compositions pour le traitement de troubles associés à des défauts du gène ou de la protéine du régulateur de la conductance transmembranaire d'une fibrose kystique

Country Status (1)

Country Link
WO (1) WO2009105234A2 (fr)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITRM20110231A1 (it) * 2011-05-09 2012-11-10 Gb Pharma S R L Uso del tamoxifene nella terapia della fibrosi cistica.
EP2664326A1 (fr) * 2012-05-17 2013-11-20 I.E.R.F.C. European Institute for Cystic Fibrosis Research Thérapie combinée pour le traitement de la mucoviscidose
WO2014015672A1 (fr) * 2012-07-24 2014-01-30 兆科药业（广州）有限公司 Préparation d'un composé de lercanidipine et d'atorvastatine
WO2014026959A1 (fr) * 2012-08-13 2014-02-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de la fibrose cistique
WO2014086687A1 (fr) 2012-12-03 2014-06-12 Universita' Degli Studi Di Padova Correcteur de cftr pour le traitement de troubles génétiques affectant le muscle strié
WO2015116735A1 (fr) * 2014-01-28 2015-08-06 Mayo Foundation For Medical Education And Research Procédés et combinaisons pour tuer des cellules sénescentes et traiter des maladies et troubles associés à une sénescence
US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US9233103B2 (en) 2011-03-25 2016-01-12 Takeda Pharmaceuticals U.S.A., Inc. Methods for treating heartburn, gastric bleeding or hemorrhage in patients receiving clopidogrel therapy
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US20160220511A1 (en) * 2009-09-14 2016-08-04 Nestec S.A. Nutritional compositions for modulating inflammation including exogenous vitamin k2
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9701706B2 (en) 2015-08-06 2017-07-11 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
ITUA20162292A1 (it) * 2016-04-05 2017-10-05 Gb Pharma S R L Uso del tamoxifene per il trattamento della fibrosi cistica in pazienti di entrambi i sessi
US9849128B2 (en) 2014-01-28 2017-12-26 Unity Biotechnology, Inc. Unit dose of a cis-imidazoline for treating an osteoarthritic joint by removing senescent cells
US9884065B2 (en) 2011-12-13 2018-02-06 Buck Institute For Research On Aging Inhibiting activity of senescent cells using a glucocorticoid
US9901081B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse for determining the role of senescent cells in cancer
US9901080B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse having a transgene that converts a prodrug into a cytotoxic compound in senescent cells
US9968076B2 (en) 2011-06-21 2018-05-15 Mayo Foundation For Medical Education And Research Transgenic animals capable of being induced to delete senescent cells
WO2018141678A1 (fr) * 2017-01-31 2018-08-09 Medizinische Hochschule Hannover (Mhh) Composés naturels et fibrose
US10279018B2 (en) 2012-12-03 2019-05-07 Unity Biotechnology, Inc. Immunogenic compositions for inducing an immune response for elimination of senescent cells
US10328058B2 (en) 2014-01-28 2019-06-25 Mayo Foundation For Medical Education And Research Treating atherosclerosis by removing senescent foam cell macrophages from atherosclerotic plaques
US10378002B2 (en) 2012-04-17 2019-08-13 Unity Biotechnology, Inc. Replication conditional virus that specifically kills senescent cells
US10456344B2 (en) 2014-12-22 2019-10-29 Conopco, Inc. Hair composition
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
JP2020193188A (ja) * 2019-05-30 2020-12-03 国立大学法人福井大学 慢性副鼻腔炎の予防剤または治療剤、およびこれらを製造するためのスタチンの使用
WO2021130381A1 (fr) * 2019-12-26 2021-07-01 Centre D'etude Des Cellules Souches (Cecs) Combinaison d'un inhibiteur de hdac et de molécules vx, et son utilisation pour le traitement de la fibrose kystique
US11111264B2 (en) 2017-09-21 2021-09-07 Chimerix, Inc. Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof
CN115177615A (zh) * 2022-08-04 2022-10-14 湖南中医药大学 一种补骨脂素在促***药物中的应用
CN116196308A (zh) * 2023-03-13 2023-06-02 华中科技大学同济医学院附属同济医院 阿苯达唑在制备用于预防和/或治疗个体纤维化疾病的药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010006656A1 (en) * 1999-02-17 2001-07-05 University Of Washington Methods and compositions for inhibiting inflammation associated with pulmonary disease
US20030096762A1 (en) * 1997-10-16 2003-05-22 Children's Hospital Oakland Compositions and methods for cystic fibrosis therapy
US20050158747A1 (en) * 2003-05-30 2005-07-21 Whitsett Jeffrey A. CFTR modifier genes and expressed polypeptides useful in treating cystic fibrosis and methods and products for detecting and/or identifying same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030096762A1 (en) * 1997-10-16 2003-05-22 Children's Hospital Oakland Compositions and methods for cystic fibrosis therapy
US20010006656A1 (en) * 1999-02-17 2001-07-05 University Of Washington Methods and compositions for inhibiting inflammation associated with pulmonary disease
US20050158747A1 (en) * 2003-05-30 2005-07-21 Whitsett Jeffrey A. CFTR modifier genes and expressed polypeptides useful in treating cystic fibrosis and methods and products for detecting and/or identifying same

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BRICE MARCET ET AL.: 'General anesthetic octanol and related compounds activate wild-type and delF508 cystic fibrosis chloride channels.' BRITISH JOURNAL OF PHARMACOLOGY. vol. 141, no. 6, 2004, ISSN 0007-1188 pages 905 - 914 *
HENRY A. WOJTCZAK ET AL.: 'Beclomethasone diproprionate reduced airway inflammation without adrenal suppression in young children with cystic fibrosis: A pilot study.' PEDIATRIC PULMONOLOGY. vol. 32, no. 4, 2001, ISSN 8755-6863 pages 293 - 302 *
KREISELMEIER N.E. ET AL.: 'Statin-mediated correction of STAT1 signaling and inducible nitric oxide synthase expression in cystic fibrosis epithelial cells.' AMERICAN JOURNAL OF PHYSIOLOGY. LUNG CELLULAR AND MOLECULAR PHYSIOLOGY vol. 285, no. 6, 2003, ISSN 1040-0605 pages L1286 - L1295 *
PEDEMONTE N. ET AL.: 'Antihypertensive 1,4-dihydropyridines as Correctors of the Cystic Fibrosis transmembrance Conductance Regulator Channel Gating Defect caused by Cystic Fibrosis Mutations.' MOLECULAR PHARMACOLOGY vol. 68, no. 6, 2005, ISSN 0026-895X pages 1736 - 1746 *
SCHMIDT A. ET AL.: 'Prolonged treatment of cells with genistein modulates the expression and function of the cystic fibrosis transmembane conductance regulator.' BRITISH JOURNAL OF PHARMACOLOGY. vol. 153, no. 6, 28 January 2008, ISSN 0007-1188 pages 1311 - 1323 *

Cited By (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10603314B2 (en) 2005-02-03 2020-03-31 The General Hospital Corporation Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
US9630946B2 (en) 2007-10-17 2017-04-25 Wyeth Llc Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10035788B2 (en) 2007-10-17 2018-07-31 Wyeth Llc Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10111868B2 (en) 2008-06-17 2018-10-30 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US20160220511A1 (en) * 2009-09-14 2016-08-04 Nestec S.A. Nutritional compositions for modulating inflammation including exogenous vitamin k2
US9687456B2 (en) * 2009-09-14 2017-06-27 Nestec S.A. Nutritional compositions for modulating inflammation including exogenous vitamin K2
US9233103B2 (en) 2011-03-25 2016-01-12 Takeda Pharmaceuticals U.S.A., Inc. Methods for treating heartburn, gastric bleeding or hemorrhage in patients receiving clopidogrel therapy
US9889125B2 (en) 2011-03-25 2018-02-13 Takeda Pharmaceuticals U.S.A., Inc. Methods for treating heartburn, gastric bleeding or hemorrhage in patients receiving clopidogrel therapy
ITRM20110231A1 (it) * 2011-05-09 2012-11-10 Gb Pharma S R L Uso del tamoxifene nella terapia della fibrosi cistica.
US9968076B2 (en) 2011-06-21 2018-05-15 Mayo Foundation For Medical Education And Research Transgenic animals capable of being induced to delete senescent cells
US10251376B2 (en) 2011-06-21 2019-04-09 Mayo Foundation For Medical Education And Research Increasing healthy lifespan and delaying progression of age-related phenotypes by selectively removing senescent cells
US9884065B2 (en) 2011-12-13 2018-02-06 Buck Institute For Research On Aging Inhibiting activity of senescent cells using a glucocorticoid
US10378002B2 (en) 2012-04-17 2019-08-13 Unity Biotechnology, Inc. Replication conditional virus that specifically kills senescent cells
US9132123B2 (en) 2012-05-17 2015-09-15 I.E.R.F.C. European Institute For Cystic Fibrosis Research Combined therapy for cystic fibrosis
US9730922B2 (en) 2012-05-17 2017-08-15 I.E.R.F.C. Europ. Inst. for Cystic. Fibrosis Res. Combined therapy for cystic fibrosis
EP2664326A1 (fr) * 2012-05-17 2013-11-20 I.E.R.F.C. European Institute for Cystic Fibrosis Research Thérapie combinée pour le traitement de la mucoviscidose
WO2014015672A1 (fr) * 2012-07-24 2014-01-30 兆科药业（广州）有限公司 Préparation d'un composé de lercanidipine et d'atorvastatine
US9402821B2 (en) 2012-08-13 2016-08-02 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for treatment of cystic fibrosis
WO2014026959A1 (fr) * 2012-08-13 2014-02-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de la fibrose cistique
US10655144B2 (en) 2012-08-23 2020-05-19 Buck Institute For Research On Aging Nucleic acid construct with a p16 promoter that causes a prodrug converting enzyme to be expressed specifically in senescent cells
US9901080B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse having a transgene that converts a prodrug into a cytotoxic compound in senescent cells
US9901081B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse for determining the role of senescent cells in cancer
US10279018B2 (en) 2012-12-03 2019-05-07 Unity Biotechnology, Inc. Immunogenic compositions for inducing an immune response for elimination of senescent cells
WO2014086687A1 (fr) 2012-12-03 2014-06-12 Universita' Degli Studi Di Padova Correcteur de cftr pour le traitement de troubles génétiques affectant le muscle strié
US10478432B2 (en) 2014-01-28 2019-11-19 Unity Biotechnology, Inc. Compositions of matter for treatment of ophthalmic conditions by selectively removing senescent cells from the eye
US10010546B2 (en) 2014-01-28 2018-07-03 Unity Biotechnology, Inc. Treatment of ophthalmic conditions by selectively removing senescent cells from the eye
US11980616B2 (en) 2014-01-28 2024-05-14 Mayo Foundation For Medical Education And Research Treating liver disease by selectively eliminating senescent cells
US9993472B2 (en) 2014-01-28 2018-06-12 Unity Biotechnology, Inc. Treatment for osteoarthritis in a joint by administering a means for inhibiting MDM2
US10130628B2 (en) 2014-01-28 2018-11-20 Unity Biotechnology, Inc. Treatment of joint pain
US10213426B2 (en) 2014-01-28 2019-02-26 Unity Biotechnology, Inc. Method of optimizing conditions for selectively removing a plurality of senescent cells from a tissue or a mixed cell population
US9980962B2 (en) 2014-01-28 2018-05-29 Unity Biotechnology, Inc Use of sulfonamide inhibitors of Bcl-2 to treat senescence-associated lung conditions such as pulmonary fibrosis and chronic obstructive pulmonary disease
US10258618B2 (en) 2014-01-28 2019-04-16 Unity Biotechnology, Inc. Treating pulmonary conditions by selectively removing senescent cells from the lung using an intermittent dosing regimen
US11351167B2 (en) 2014-01-28 2022-06-07 Buck Institute For Research On Aging Treating cognitive decline and other neurodegenerative conditions by selectively removing senescent cells from neurological tissue
US9855266B2 (en) 2014-01-28 2018-01-02 Unity Biotechnology, Inc. Treatment for osteoarthritis by intra-articular administration of a cis-imidazoline
US10328073B2 (en) 2014-01-28 2019-06-25 Unity Biotechnology, Inc. Use of sulfonamide inhibitors of BCL-2 and BCL-xL to treat ophthalmic disease by selectively removing senescent cells
US10328058B2 (en) 2014-01-28 2019-06-25 Mayo Foundation For Medical Education And Research Treating atherosclerosis by removing senescent foam cell macrophages from atherosclerotic plaques
US9849128B2 (en) 2014-01-28 2017-12-26 Unity Biotechnology, Inc. Unit dose of a cis-imidazoline for treating an osteoarthritic joint by removing senescent cells
US11517572B2 (en) 2014-01-28 2022-12-06 Mayo Foundation For Medical Education And Research Killing senescent cells and treating senescence-associated conditions using a SRC inhibitor and a flavonoid
US10413542B2 (en) 2014-01-28 2019-09-17 Buck Institute For Research On Aging Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders using an inhibitor of Akt kinase
WO2015116735A1 (fr) * 2014-01-28 2015-08-06 Mayo Foundation For Medical Education And Research Procédés et combinaisons pour tuer des cellules sénescentes et traiter des maladies et troubles associés à une sénescence
US10478433B2 (en) 2014-01-28 2019-11-19 Unity Biotechnology, Inc. Unit dose of an aryl sulfonamide that is effective for treating eye disease and averting potential vision loss
US11963957B2 (en) 2014-01-28 2024-04-23 Mayo Foundation For Medical Education And Research Treating cardiovascular disease by selectively eliminating senescent cells
US10517866B2 (en) 2014-01-28 2019-12-31 Unity Biotechnology, Inc. Removing senescent cells from a mixed cell population or tissue using a phosphoinositide 3-kinase (PI3K) inhibitor
US10456344B2 (en) 2014-12-22 2019-10-29 Conopco, Inc. Hair composition
US10941175B2 (en) 2015-08-06 2021-03-09 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US9708359B2 (en) 2015-08-06 2017-07-18 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US9701706B2 (en) 2015-08-06 2017-07-11 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US10407457B2 (en) 2015-08-06 2019-09-10 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US11981700B2 (en) 2015-08-06 2024-05-14 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
ITUA20162292A1 (it) * 2016-04-05 2017-10-05 Gb Pharma S R L Uso del tamoxifene per il trattamento della fibrosi cistica in pazienti di entrambi i sessi
US11191738B2 (en) 2016-04-05 2021-12-07 Gb Pharma S.R.L. Use of tamoxifen for the treatment of cystic fibrosis in patients of both sexes
EA036682B1 (ru) * 2016-04-05 2020-12-08 Гб Фарма С.Р.Л. Применение тамоксифена для лечения кистозного фиброза у пациентов обоих полов
WO2017174529A1 (fr) * 2016-04-05 2017-10-12 Gb Pharma S.R.L. Utilisation de tamoxifène pour le traitement de la mucoviscidose chez des patients des deux sexes
JP2019510791A (ja) * 2016-04-05 2019-04-18 ジビ ファルマ エッセ．エッレ．エッレ 両性の患者における嚢胞性線維症の治療のためのタモキシフェンの使用
US11185539B2 (en) 2017-01-31 2021-11-30 Medizinische Hochschule Hannover (Mhh) Natural compounds and fibrosis
WO2018141678A1 (fr) * 2017-01-31 2018-08-09 Medizinische Hochschule Hannover (Mhh) Composés naturels et fibrose
US11111264B2 (en) 2017-09-21 2021-09-07 Chimerix, Inc. Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof
JP2020193188A (ja) * 2019-05-30 2020-12-03 国立大学法人福井大学 慢性副鼻腔炎の予防剤または治療剤、およびこれらを製造するためのスタチンの使用
WO2021130381A1 (fr) * 2019-12-26 2021-07-01 Centre D'etude Des Cellules Souches (Cecs) Combinaison d'un inhibiteur de hdac et de molécules vx, et son utilisation pour le traitement de la fibrose kystique
CN115177615A (zh) * 2022-08-04 2022-10-14 湖南中医药大学 一种补骨脂素在促***药物中的应用
CN116196308A (zh) * 2023-03-13 2023-06-02 华中科技大学同济医学院附属同济医院 阿苯达唑在制备用于预防和/或治疗个体纤维化疾病的药物中的应用

Also Published As

Publication number Publication date
WO2009105234A3 (fr) 2009-11-12

Similar Documents

Publication Publication Date Title
WO2009105234A2 (fr) Procédés et compositions pour le traitement de troubles associés à des défauts du gène ou de la protéine du régulateur de la conductance transmembranaire d'une fibrose kystique
US6232315B1 (en) Method for treating inflammatory diseases by administering a thrombin inhibitor
US20080161324A1 (en) Compositions and methods for treatment of viral diseases
US10383858B2 (en) PPAR compounds for use in the treatment of fibrotic diseases
US10632116B2 (en) Combinations of serotonin receptor agonists for treatment of movement disorders
CN104994854A (zh) 通过吸入罗氟司特n-氧化物治疗自身免疫、呼吸和/或炎性病症的方法
AU2018392985A1 (en) Compositions and methods of treatment for neurological disorders comprising motor neuron diseases
EP1872795A1 (fr) Agent thérapeutique pour le syndrome du côlon irritable
US20090192199A1 (en) Pharmacological modulation of positive ampa receptor modulator effects on neurotrophin expression
JP2020510045A (ja) ポネシモドを含有する医薬的組み合わせ
US20140221385A1 (en) Combinations of serotonin receptor agonists for treatment of movement disorders
US20060281722A1 (en) Compounds and uses thereof
CN110087653A (zh) 用于治疗肺高血压的组合疗法
US20080200489A1 (en) Combination of Organic Compounds
RU2322238C2 (ru) Лечение ревматоидного артрита
US20230158103A1 (en) Pld for use in combination in the treatment of coronavirus
US20220040162A1 (en) Compositions comprising a crac inhibitor and a corticosteroid and methods of use thereof
US20150164916A1 (en) Roflumilast compositions for the treatment of copd
EP3936132A1 (fr) Azelastine destiné au traitement antiviral
JP2024512816A (ja) 炎症を治療する方法
AU2015310545A1 (en) Method of treatment and compositions comprising a dual Pl3K delta-gamma kinase inhibitor and a corticosteroid
JP2003528050A (ja) 愛玩動物におけるピリミジン系のエンドセリンアンタゴニストの使用
NZ766879A (en) Method of treatment and compositions comprising a dual pi3k delta-gamma kinase inhibitor and a corticosteroid
JP2005539058A (ja) 選択的なホスホジエステラーゼ４−阻害物質による非アレルギー性鼻炎の治療
NZ729419B2 (en) Method of treatment and compositions comprising a dual pi3k delta-gamma kinase inhibitor and a corticosteroid

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09712036

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09712036

Country of ref document: EP

Kind code of ref document: A2