WO2005046675A2 - Procedes permettant d'ameliorer l'activite de la glutathione peroxydase - Google Patents

Procedes permettant d'ameliorer l'activite de la glutathione peroxydase Download PDF

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WO2005046675A2
WO2005046675A2 PCT/US2004/036837 US2004036837W WO2005046675A2 WO 2005046675 A2 WO2005046675 A2 WO 2005046675A2 US 2004036837 W US2004036837 W US 2004036837W WO 2005046675 A2 WO2005046675 A2 WO 2005046675A2
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inflammatory marker
statin
human interleukin
composition comprises
inflammatory
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WO2005046675A3 (fr
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Jordan Holtzman
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Jordan Holtzman
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to methods for enhancing glutathione peroxidase activity.
  • the present invention also relates to methods of treating atherosclerosis or vascular injury and methods for reducing the risk of oxidative damage to vasculature.
  • Glutathione is a tripeptide derived from glycine, glutamate, and cysteine. Glutathione, in a reduced form, can react with and eliminate lipid hydroperoxides, preventing injury to the vascular wall. This reaction is catalyzed by glutathione peroxidase. Therefore, a need exists for methods and compositions that enhance glutathione peroxidase activity.
  • the present invention generally relates to a method of increasing glutathione peroxidase activity in a subject.
  • the method includes administering a statin, a fibrate, a thiazolidinedione, metformin, betaine, phenobarbital, folic acid, pyridoxine, vitamin B12, N-acetyl cysteine, or the methyl ester of glutathione, a pharmaceutical composition including such a compound, or a combination of these compounds to a subject.
  • the present invention includes a method of treating atherosclerosis or vascular injury.
  • the method includes administering a compound or a pharmaceutical composition of the compound that can increase activity of glutathione peroxidase activity or increase the concentration of serum reduced glutathione.
  • the present invention also includes methods to treat other diseases that relate to atherosclerosis. This includes diseases such as coronary heart disease, hypertension, heart failure, myocardial infarction, stroke and the like.
  • the present invention also includes methods for reducing the risk of oxidative damage to vasculature, a type of vascular injury.
  • the present invention relates to methods of increasing the activity of glutathione peroxidase or increasing the reduced glutathione concentrations in serum.
  • This method can include administering compounds including a statin, a fibrate, a thiazolidinedione, metformin, betaine, phenobarbital, folic acid, pyridoxine, vitamin B12, N-acetyl cysteine, or the methyl ester of glutathione.
  • the present invention also relates to methods of treating or alleviating a symptom of atherosclerosis, methods of treating diseases that relate to atherosclerosis, and pharmaceutical compositions capable of increasing the activity of glutathione peroxidase or increasing the reduced glutathione levels.
  • This method can include administering compositions containing statins, fibrates, thiazolidinediones, metformin, betaine, phenobarbital, folic acid, pyridoxine, vitamin B12, N-acetyl cysteine, or the methyl ester of glutathione.
  • the present invention also relates to methods for reducing the risk of oxidative damage to vasculature via administration of compounds.
  • This method can include administering a statin, a fibrate, a thiazolidinedione, metformin, betaine, phenobarbital, folic acid, pyridoxine, vitamin B12, N-acetyl cysteine, or the methyl ester of glutathione.
  • Patient Population Methods of the present invention may include administering of compounds such as one or more of a statin, a fibrate, a thiazolidinedione, metformin, betaine, phenobarbital, folic acid, pyridoxine, vitamin B12, N-acetyl cysteine, and the methyl ester of glutathione to defined patient populations.
  • a statin such as one or more of a statin, a fibrate, a thiazolidinedione, metformin, betaine, phenobarbital, folic acid, pyridoxine, vitamin B12, N-acetyl cysteine, and the methyl ester of glutathione
  • One patient population in which the methods of the present population are effective is patients with elevated levels of inflammatory markers.
  • the patient population is healthy individuals with elevated levels of inflammatory markers.
  • the patient population is individuals with levels inflammatory markers that are above average as compared with the population generally.
  • the patient population can also be individuals with
  • the patient population may also be individuals with decreased levels of glutathione peroxidase activity, decreased levels of glutathione peroxidase, and/or decreased levels of glutathione.
  • inflammatory markers identified in atherosclerosis include C-reactive protein (CRP), albumin, fibrinogen, leukocyte count, serum amyloid A, cytokines, soluble cytokine receptors and antagonists, cellular adhesion molecules, and matrix degradation enzymes.
  • Cytokines that serve as markers of inflammation can include human interleukins 1-17 and particularly, IL-1B, IL-4, IL-6, and TNF-c .
  • Soluble cytokine receptors and antagonists that can serve as markers of inflammation include soluble IL-6 receptor, soluble TNF receptor, and soluble IL-1 receptor antagonists.
  • Cellular adhesion molecules include integrins, ICAM-1, ICAM-3, BL-CAM, LFA- 2, VCAM-1, NCAM, and PECAM, and particularly soluble ICAM-1, soluble
  • Matrix degradation enzymes include matrix metalloproteinases 3 and 9. Any of these markers of inflammation can be used individually or in combination.
  • Compounds useful in the methods of the invention include agents to increase glutathione peroxidase activity, agents to reduce homocysteine inhibition of glutathione peroxidase, and agents to increase the serum reduced glutathione levels.
  • compounds of the invention include statins, fibrates, thiazolidinediones, metformin, betaine, phenobarbital, folic acid; pyridoxine, vitamin B12, N-acetyl cysteine, and the methyl ester of glutathione, and combinations thereof.
  • HMG-CoA reductase inhibitors HMG-CoA reductase inhibitors.
  • HMG-CoA reductase (3- hydroxy-3-methylglutarylrCoenzyme A) is the microsomal enzyme that catalyzes the rate limiting reaction in cholesterol biosynthesis. Therefore, statins inhibit or interfere with the synthesis of cholesterol. Accordingly to the present method, administering statins increases the activity of glutathione peroxidase.
  • statins such as lovastatin and mevinolin disclosed in U.S Pat. No. 4,231,938, pravastatin and pravastatin sodium disclosed in U.S. Pat. No.
  • Lovastatin an inactive lactone
  • Lovastatin is a white, nonhygroscopic crystalline powder isolated from a strain of AspergiUus terreus that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.
  • Lovastatin is hydrolyzed after oral ingestion to the corresponding (beta)-hydroxyacid.
  • This metabolite is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
  • tablets can contain 10 to 40 mg of lovastatin together with pharmaceutically acceptable excipients.
  • a starting dose of Mevacor is preferably given with a meal.
  • the dosage range for lovastatin can be from 2 mg to 80 mg daily.
  • Fluvastatin also known as fluvastatin sodium
  • fluvastatin sodium a synthetic HMG-CoA reductase inhibitor
  • capsules can contain 20 to 40 mg of fluvastatin together with pharmaceutically acceptable excipients.
  • fluvastatin is absorbed rapidly and completely with peak concentrations reached in less than 1 hour. Administration with food reduces the rate but not the extent of absorption.
  • the dosage range for fluvastatin can be from 2 mg to 50 mg daily.
  • Atorvastatin (or Atorvastatin calcium 2:1) is a white to off-white crystalline trihydrate powder that is insoluble in aqueous solutions of pH 4 and below, and is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly soluble in ethanol, and freely soluble in methanol.
  • tablets can contain 10 to 80 mg of atorvastatin as well as pharmaceutically acceptable excipients.
  • Atorvastatin can be administered as a single dose at any time of the day, with or without food.
  • the dosage range for Atorvastatin can be from 2 mg to 100 mg daily.
  • Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.
  • Simvastatin is derived synthetically from a fermentation product of AspergiUus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding (beta)-hydroxyacid form which is an inliibitor of 3- hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase.
  • HMG-CoA 3- hydroxy-3-methyl-glutaryl-coenzyme A
  • tablets can contain 5 mg to 80 mg of simvastatin as well as pharmaceutically acceptable excipients.
  • the dosage range for simvastatin can be from 2 mg to 100 mg daily.
  • Cerivastatin or Cerivastatin sodium
  • Cerivastatin sodium is a white to off-white hygroscopic amorphous powder that is soluble in water, methanol, and ethanol, and very slightly soluble in acetone.
  • Cerivastatin sodium is a synthetic, enantiomerically pure competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • Cerivastatin systemic exposure (area under the curve, AUC) and C max are not sensitive to a food effect, but once daily doses of 0.2 mg can be more efficacious than twice daily doses of 0.1 mg.
  • the dosage range for cerivastatin can be from 0.05 mg to 2 mg daily.
  • Pravastatin or pravastatin sodium
  • octanol/water a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It is soluble in methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether.
  • tablets When formulated as Pravachol® for oral administration, tablets can contain 10 to 40 mg of pravastatin.
  • the dosage range for pravastatin can be from 2 mg to 50 mg daily.
  • Itavastatin is an inhibitor of HMG-CoA reductase and can be dosed in tablets containing from about 1 mg to about 20 mg, preferably from about 2 mg to about 10 mg.
  • the dosage range for itavastatin can be from 0.2 mg to 100 mg
  • Rosuvastatin is an inhibitor of HMG-CoA reductase and can be dosed in tablets containing from about 4 or 5 mg to about 10 or 20 mg, with reported doses of up to about 80 mg per day when formulated as Crestor.
  • the dosage range for rosuvastatin can be from 2 mg to 100 mg.
  • the class of fibrates includes bezafibrate, cipro fibrate, clo fibrate, fenofibrate, and gemfibrozil. According to the present method, administering fibrates increases the activity of glutathione peroxidase.
  • Fenofibrate, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethylester is representative of the fibrates.
  • Fenofibrate is disclosed in U.S. Pat. No. 4,058,552.
  • Fenofibrate is sold commercially as TriCor® and is commonly given at dosages between 67-200 mg q.d. However, the dosage range for fenofibrate can be from 10 mg to 400 mg daily.
  • Gemfibrozil is another member of the fibrate class of lipid-regulating agents. Gemfibrozil is described in U.S. Pat. No. 3,674,836. Gemfibrozil is sold commercially as Lopid® and is commonly given 1200 mg bid. However, the dosage range for gemfibrozil can be from 200 mg to 4000 mg daily.
  • Thiazolidiones 1 are hypoglycemic agents which act through a second class of PPAR receptors known as the PPAR- class.
  • the class of thiazolidinediones include pioglitazone, rosiglitazone, and troglitazone. According to the present invention, administering thiazolidinediones increases the activity of glutathione peroxidase.
  • Pioglitazone, sold as Actos® is 5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl-2,4-thiazlidinedione and is typically dosed between 15-45 mg q.d.
  • Pioglitazone may be dosed from 5 to 100 mg daily. Rosiglitazone, sold as Avandia®, is typically dosed between 4-8 mg q.d., or 2-4 mg bid. However, Rosiglitazone may be dosed from 1 mg to 20 mg daily. Troglitazone, sold as Rezulin®, is 5-[[4-[(3,4-dihydro-6-hydroxy-2, 5, 1, 8- teramethyl-2H- 1 -benzopryran-2-yl)methoxy]phenyl]methyl] -2,4-thiazlidinedione. Troglitazone may be dosed from 1 mg to 20 mg daily.
  • Metformin Metformin sold as Glucophage®, is N,N-dimethylimidodicarbonimidic diamide. Metformin is also a hypoglycemic agent and is believed to increase the activity of glutathione peroxidase. Metformin is typically dosed between 500-3000 mg daily. However, metformin may be dosed from 50 mg to 6000 mg daily.
  • Homocysteine inhibits the activity of glutathione peroxidase. Accordingly, one approach to increasing the activity of glutathione peroxidase is to administer agents that are involved in converting homocysteine to methionine through methylation, thereby decreasing serum concentrations of homocysteine.
  • the betaine-homocysteine methyl transferase pathway involves the transfer of methyl groups from betaine (trimethylglycine) to homocysteine to give methionine. It has been shown that the administration of betaine can reduce the serum homocysteine levels in normal volunteers by as much as 90% (Brouwer et al. 2000).
  • Betaine is also known as Trimethylglycine. Betaine is typically dosed between 300 and 6000mg / day. However, Betaine may be dosed from 50 mg to 10,000 mg daily. In rats the level of the betaine-methyl transferase is enhanced by the administration of phenobarbital (Garcia- Allan et al. 2000). Therefore, administration of Phenobarbital enhances betaine-methyl transferase and therefore reduce serum homocysteine levels resulting in reduced inhibition of glutathione peroxidase. Phenobarbital is typically dosed between 30 mg and 120 mg daily. However, the dosage of Phenobarbital can range from 10 mg to 400 mg.
  • folic acid can be dosed from 100 ⁇ g to 8000 ⁇ g daily.
  • Pyridoxine can be dosed from 10 mg to 1000 mg daily.
  • Vitamin B 12 can be dosed from 2 ⁇ g to 2000 ⁇ g daily.
  • the level of reduced glutathione in the serum is below the Km for the peroxidase. Therefore, any measure that can increase the level of this cofactor will enhance the overall peroxidase activity.
  • the level of reduced glutathione is dependent upon the supply of sulfur amino acids, such as cysteine. Accordingly, one can increase the level of reduced glutathione by administering N-acetyl cysteine or the methyl ester of glutathione.
  • N-acetyl cysteine can be dosed from 100 mg to 2000 mg daily.
  • the methyl ester of glutathione can be dosed from 50 mg to 2000 mg daily.
  • compositions Increases in the activity of glutathione peroxidase may be obtained via administration of a pharmaceutical composition including a therapeutically effective dose of a statins, fibrates, thiazolidinediones, metformin, betaine, phenobarbital, folic acid, pyridoxine, vitamin B12, N-acetyl cysteine, or the methyl ester of glutathione as described above.
  • “Therapeutically effective dose” is intended to mean a dose of the compound that achieves the desired goal of increasing the activity of glutathione peroxidase or increasing serum reduced glutathione levels.
  • An increase in glutathione peroxidase activity can either be measured relative to the level in the patient before administration, or as progressing towards a desired level of glutathione peroxidase activity.
  • a desired level of glutathione peroxidase activity can be characterized as a level that is sufficient to either decrease, or inhibit lipid hydroperoxide levels. The level could also be characterized as one that is sufficient to reduce or inhibit the display of symptoms commonly associated with atherosclerosis.
  • the invention is directed to methods of using a composition that can be employed to increase glutathione peroxidase activity, such as statins, fibrates, thiazolidinediones, metformin, betaine, phenobarbital, folic acid, pyridoxine, vitamin B 12, N-acetyl cysteine, or the methyl ester of glutathione.
  • the composition can include, for example, any pharmaceutically acceptable additive, carrier, or adjuvant that is suitable for administering an agent to a mammal.
  • the pharmaceutical composition can be employed in diagnosis, prevention, or treatment of a disease, disorder, or injury that relates to glutathione peroxidase activity levels in a patient.
  • the composition includes an agent in combination with a pharmaceutical carrier, additive, and/or adjuvant that can promote the transfer of the compound within or throughout the patient.
  • the composition typically contains a pharmaceutically acceptable carrier mixed with the agent and other components in the pharmaceutical composition.
  • pharmaceutically acceptable carrier is intended a carrier that is conventionally used in the art to facilitate the storage, administration, and/or the healing effect of the agent.
  • a carrier may also reduce any undesirable side effects of the agent.
  • a suitable carrier should be stable, i.e., incapable of reacting with other ingredients in the formulation. It should not produce significant local or systemic adverse effect in recipients at the dosages and concentrations employed for treatment.
  • a pharmaceutically acceptable carrier of the present invention is one that is suitable for human administration and does not include compounds that are utilized in animal toxicological studies.
  • Suitable carriers for this invention include those conventionally used such as albumin, gelatin, collagen, polysaccharide, monosaccharides, polyvinylpyrrolidone, polylactic acid, polyglycohc acid, polymeric amino acids, fixed oils, ethyl oleate, liposomes, glucose, sucrose, lactose, mannose, dextrose, dextran, cellulose, mannitol, sorbitol, polyethylene glycol (PEG), and the like.
  • Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic) for solutions.
  • the carrier can be selected from various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
  • compositions can be subjected to conventional pharmaceutical expedients, such as sterilization, and can contain conventional pharmaceutical additives, such as preservatives, stabilizing agents, wetting, or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like.
  • conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting, or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like.
  • Other acceptable components in the composition include, but are not limited to, buffers that enhance isotonicity such as water, saline, phosphate, citrate, succinate, acetic acid, and other organic acids or their salts.
  • the pharmaceutically acceptable carrier also includes one or more stabilizers, reducing agents, anti-oxidants and/or anti-oxidant chelating agents.
  • Suitable buffers include, for example, acetate, adipate, benzoate, citrate, lactate, maleate, phosphate, tartarate, borate, tri(hydroxymethyl aminomethane), succinate, glycine, histidine, the salts of various amino acids, or the like, or combinations thereof. See Wang (1980) at page 455.
  • Suitable salts and isotonicifiers include, for example, sodium chloride, dextrose, mannitol, sucrose, trehalose, or the like.
  • the carrier is a liquid, it is preferred that the carrier is hypotonic or isotonic with oral, conjunctival or dermal fluids and have a pH within the range of 4.5-8.5.
  • Suitable reducing agents which maintain the reduction of reduced cysteines, include dithiothreitol (DTT also known as Cleland's reagent) or dithioerythritol at 0.01% to 0.1% wt/wt; acetylcysteine or cysteine at 0.1% to 0.5% (pH 2-3); and thioglycerol at 0.1% to 0.5% (pH 3.5 to 7.0) and glutathione. See Alcers (1988) at pages 225 to 226.
  • DTT dithiothreitol
  • dithioerythritol dithioerythritol
  • acetylcysteine or cysteine at 0.1% to 0.5%
  • thioglycerol at 0.1% to 0.5% (pH 3.5 to 7.0) and glutathione.
  • Suitable antioxidants include sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, and ascorbic acid. See Akers (1988) at pages 225.
  • Suitable chelating agents which chelate trace metals to prevent the trace metal catalyzed oxidation of reduced cysteines, include citrate, tartarate, ethylenediaminetetraacetic acid (EDTA) in its disodium, tetrasodium, and calcium disodium salts, and diethylenetriamine pentaacetic acid (DTP A).
  • the composition can include one or more preservatives s ⁇ ch as phenol, cresol, paraaminobenzoic acid, BDSA, sorbitrate, chlorhexidine, benzalkonium chloride, or the like.
  • Suitable stabilizers include carbohydrates such as threlose or glycerol.
  • the composition can include a stabilizer such as one or more of microcrystalline cellulose, magnesium stearate, mannitol, sucrose to stabilize, for example, the physical form of the composition; and one or more of glycine, arginine, hydrolyzed collagen, or protease inhibitors to stabilize, for example, the chemical structure of the composition.
  • Suitable suspending agents include carboxymethyl cellulose, hydroxypropyl methylcellulose, hyaluronic acid, alginate, chondroitin sulfate, dextran, maltodextrin, dextran sulfate, or the like.
  • the composition can include an emulsifier such as polysorbate 20, polysorbate 80, pluronic, triolein, soybean oil, lecithins, squalene and squalanes, sorbitan trioleate, or the like.
  • the composition can include an antimicrobial such as phenylethyl alcohol, phenol, cresol, benzalkonium chloride, phenoxyethanol, chlorhexidine, thimerosol, or the like.
  • Suitable thickeners include natural polysaccharides such as mannans, arabinans, alginate, hyaluronic acid, dextrose, or the like; and synthetic ones like the PEG hydrogels of low molecular weight and aforementioned suspending agents.
  • the composition can include an adjuvant such as cetyl trimethyl ammonium bromide, BDSA, cholate, deoxycholate, polysorbate 20 and 80, fusidic acid, or the like.
  • Suitable sugars include glycerol, threose, glucose, galactose and mannitol, sorbitol.
  • a suitable protein is human serum albumin.
  • compositions include one or more of a solubility enhancing additive, preferably a cyclodextrin; a hydrophilic additive, preferably a mono or oligosaccharide; an absorption promoting additives, preferably a cholate, a deoxycholate, a fusidic acid, or a chitosan; a cationic surfactant, preferably a cetyl trimethyl ammonium bromide; a viscosity enhancing additive, preferably to promote residence time of the composition at the site of administration, preferably a carboxymethyl cellulose, a maltodextrin, an alginic acid, a hyaluronic acid, or a chondroitin sulfate; or a sustained release matrix, preferably a polyanhydride, a polyorthoester, a hydrogel, a particulate slow release depo system, preferably a polylactide, co-glycolides (PLG), a dep
  • the composition can include a bilayer destabilizing additive, preferably a phosphatidyl ethanolamine; a fusogenic additive, preferably a cholesterol hemisuccinate.
  • a bilayer destabilizing additive preferably a phosphatidyl ethanolamine
  • a fusogenic additive preferably a cholesterol hemisuccinate.
  • Other preferred compositions for sublingual administration include employing a bioadhesive to retain the agent sublingually; a spray, paint, or swab applied to the tongue; retaining a slow dissolving pill or lozenge under the tongue; or the like.
  • Administration of agent through the skin can be accomplished by a variety of methods known to those of skill in the art for transdermal delivery, including a transdermal patch, an ointment, an iontophoretic patch or device, and the like.
  • transdermal administration examples include a bioadhesive to retain the agent on or in the skin; a spray, paint, cosmetic, or swab applied to the skin; or the like.
  • GRAS generally regarded as safe
  • the pharmaceutical composition including at least one suitable compound can be formulated in a unit dosage and in a form such as a solution, suspension, or emulsion.
  • the agent may be administered to the nasal cavity as a powder, a granule, a solution, a cream, a spray (e.g., an aerosol), a gel, an ointment, an infusion, an injection, a drop, or sustained release composition, such as a polymer disk.
  • a spray e.g., an aerosol
  • the compositions can take the form of tablets or lozenges formulated in a conventional manner.
  • the compositions can be applied to the infected part of the body of the patient as a topical ointment or cream.
  • the compounds can be presented in an ointment, for instance with a water-soluble ointment base, or in a cream, for instance with an oil in water cream base.
  • the compound can be administered in biodegradable or non-degradable ocular inserts.
  • the drug may be released by matrix erosion or passively through a pore as in ethylene-vinylacetate polymer inserts.
  • powder discs may be placed under the tongue and active delivery systems may for in situ by slow hydration as in the formulation of liposomes from dried lipid mixtures or pro- liposomes.
  • compositions for administration include a suspension of a particulate, such as an emulsion, a liposome, an insert that releases the agent slowly, and the like.
  • the powder or granular forms of the pharmaceutical composition may be combined with a solution and with a diluting, dispersing or surface active agent.
  • Additional preferred compositions for administration include a bioadhesive to retain the agent at the site of administration; a spray, paint, or swab applied to the mucosa or epithelium; a slow dissolving pill or lozenge, or the like.
  • the composition can also be in the form of lyophilized powder, which can be converted into solution, suspension, or emulsion before administration.
  • the pharmaceutical composition having agent is preferably sterilized by membrane filtration and is stored in unit-dose or multi-dose containers such'as sealed vials or ampoules.
  • the method for formulating a pharmaceutical composition is generally known in the art. A thorough discussion of formulation and selection of pharmaceutically acceptable carriers, stabilizers, and osomolytes can be found in Remington's Pharmaceutical Sciences (18th ed.; Mack Publishing Company, Eaton, Pennsylvania, 1990).
  • a suitable compound for the method of the present invention can also be formulated in a sustained-release form to prolong the presence of the pharmaceutically active agent in the treated mammal, generally for longer than one day.
  • the agent can be entrapped in semipermeable matrices of solid hydrophobic polymers.
  • the matrices can be shaped into films or microcapsules. Examples of such matrices include, but are not limited to, polyesters, copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al. (1983) Biopolymers 22: 547-556), polylactides (U.S. Patent No.
  • polylactate polyglycolate such as polylactide-co-glycolide (see, for example, U.S. Patent Nos. 4,767,628 and 5,654,008), hydrogels (see, for example, Langer et al. (1981) J. Biomed. Mater. Res. 15: 167-277; Langer (1982) Chem. Tech. 12: 98- 105), non-degradable ethylene- vinyl acetate (e.g.
  • Suitable microcapsules can also include hydroxymethylcellulose or gelatin- microcapsules and polymethyl methacrylate microcapsules prepared by coacervation techniques or by interfacial polymerization. See the copending application entitled "Method for Producing Sustained-release Formulations," U.S. Patent Application Serial No.
  • microemulsions or colloidal drug delivery- systems such as liposomes and albumin microspheres, may also be used. See Remington's Pharmaceutical Sciences (18th ed.; Mack Publishing Company Co., Eaton, Pennsylvania, 1990).
  • Other preferred sustained release compositions employ a bioadhesive to retain the agent at the site of administration.
  • Administering the Compound A suitable compound of the method of the present invention is typically administered in a dose sufficient to provide a therapeutically effective level. It is recognized that the total amount of the compound administered as a unit dose to a particular tissue will depend upon the type of pharmaceutical composition being administered, that is whether the composition is in the form of, for example, a solution, a suspension, an emulsion, or a sustained-release formulation. For example, where the pharmaceutical composition including a therapeutically effective amount of a suitable compound is a sustained-release formulation, the compound is administered at a higher concentration. It should be apparent to a person skilled in the art that variations may be acceptable with respect to the therapeutically effective dose and frequency of the administration of a suitable compound in this embodiment of the invention.
  • the amount of the suitable compound administered will be inversely correlated with the frequency of administration.
  • an increase in the concentration of the suitable compound in a single administered dose, or an increase in the mean residence time in the case of a sustained release form of the compound generally will be coupled with a decrease in the frequency of administration.
  • the actual dose of a suitable compound will depend on a variety of factors that may be specific to the subject undergoing dosing. These factors should be taken into consideration when / determining the therapeutically effective dose of the compound and frequency of its administration.
  • the effective dose can depend on the species, age, weight, or general health of the subject; the severity of the disease or disorder; the size and location of the portion of the brain in which an effective amount of compound must be achieved; the frequency and duration of dosing; the type of formulation administered; the characteristics, such as lipophilicity, of the compound and composition; the nature of the agent and its receptors, if any; and the like. Generally, a higher dosage is preferred if the disease or disorder is more severe. Some minor degree of experimentation may be required to determine the most effective dose and frequency of dose administration, this being well within the capability of one skilled in the art once apprised of the present disclosure.
  • the pharmaceutical composition including the therapeutically effective dose of the compound is administered intermittently.
  • intermittent administration is intended administration of a therapeutically effective dose of the composition, followed by a time period of discontinuance, which is then followed by another administration of a therapeutically effective dose, and so forth.
  • Administration of the therapeutically effective dose may be achieved in a continuous manner as, for example, with a sustained-release formulation, or it may be achieved according to a desired daily dosage regimen, as for example, with one, two, three or more administrations per day.
  • time period of discontinuance is intended a discontinuing of the continuous sustained-released or daily administration of the composition. The time period of discontinuance may be longer or shorter than the period of continuous sustained-release or daily administration.
  • the compound level in the relevant tissue is substantially below the maximum level obtained during the treatment.
  • the preferred length of the discontinuance period depends on the concentration of the effective dose and the form of the composition used.
  • the discontinuance period can be at least 2 days, preferably is at least 4 days, more preferably is at least 1 week and generally does not exceed a period of 4 weeks.
  • the discontinuance period must be extended to account for the greater residence time of the composition at the site of injury.
  • the frequency of administration of the effective dose of the sustained-release formulation can be decreased accordingly.
  • An intermittent schedule of administration of the composition can continue until the desired therapeutic effect, and ultimately treatment of the disease or disorder, is achieved.
  • intermittent administration of the therapeutically effective dose of the composition is cyclic.
  • cyclic is intended intermittent administration accompanied by breaks in the administration, with cycles ranging from about 1 month to about 2, 3, 4, 5, or 6 months, more preferably about 3 months to about 6 months.
  • the administration schedule might be intermittent administration of the effective dose of the composition, wherein a single short-term dose is given once per week for 4 weeks, followed by a break in intermittent administration for a period of 3 months, followed by intermittent administration by administration of a single short-term dose given once per week for 4 weeks, followed by a break in intermittent administration for a period of 3 months, and so forth.
  • a single short-term dose may be given once per week for 2 weeks, followed by a break in intermittent administration for a period of 1 month, followed by a single short-term dose given once per week for 2 weeks, followed by a break in intermittent administration for a period of 1 month, and so forth.
  • a cyclic intermittent schedule of administration of agent to subject may continue until the desired therapeutic effect, and ultimately treatment of the disorder or disease, is achieved.
  • Example 1 Activity of Glutathione Peroxidase Glutathione peroxidase was found to be inactive when tested with a kinetic assay using Tris buffer and glutathione concentrations equivalent to those found in the serum. However, when phosphate buffer was used, significant glutathione peroxidase activity was observed in the presence of glutathione concentrations equivalent to those found in the serum (Fig.l).
  • Example 2 Inhibition of Glutathione Peroxidase by Homocysteine The effect of reduced homocysteine on the purified, human, serum, reduced glutathione peroxidase, prepared by a modification of the method of Maddipati and Marnett (1987), was determined. It was found that in the presence of 9 ⁇ M reduced glutathione 5 ⁇ M reduced homocysteine completely inhibited the peroxidase (Fig.2) (Chen et al. 2000). Similar inhibition was observed in a chemiluminescence assay. Hom ocysteine ( ⁇ M)
  • Serum protein fractions were prepared by a standard centrifugation procedure which cleanly separates the albumin and low density lipoprotein (LDL) from the total high density lipoprotein (HDL) (Procedure #15 of Chung et al. 1986). When the glutathione peroxidase activity in these fractions was examined, it was found to be associated only with the HDL. rmmunoblotting of the lipid fractions also demonstrated that all of the glutathione peroxidase was in the HDL fraction.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • FIGURE 3 The Correlation Between the Serum, Reduced Glutathione, Peroxidase Activity and the Plasma A) HDL and B) LDL Concentrations.

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Abstract

La présente invention se rapporte à des procédés permettant d'améliorer l'activité de la glutathione péroxydase. L'invention concerne également des méthodes destinées à traiter l'athérosclérose ou les lésions vasculaires, ainsi que des méthodes destinées à réduire le risque de dommages oxydatifs infligés au système vasculaire.
PCT/US2004/036837 2003-11-07 2004-11-04 Procedes permettant d'ameliorer l'activite de la glutathione peroxydase WO2005046675A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006033287A1 (fr) * 2004-09-21 2006-03-30 Sankyo Company, Limited PRÉPARATION PHARMACEUTIQUE CONTENANT UN INHIBITEUR DE LA HMG-CoA RÉDUCTASE ET DE LA GLUTATHIONE
WO2009021113A1 (fr) * 2007-08-09 2009-02-12 Holtzman, Jordan, L. Procédés de stimulation de l'activité de la glutathion peroxydase
WO2010012616A1 (fr) * 2008-07-30 2010-02-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Glutathion sanguin comme biomarqueur pour le dépistage de patients asymptomatiques présentant un risque d'insuffisance cardiaque
GB2465796A (en) * 2008-12-01 2010-06-02 Bee Kang Tan Metformin for the therapeutic use of conditions with raised serum amyloid A levels

Citations (1)

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WO1998043630A1 (fr) * 1997-04-02 1998-10-08 Brigham And Women's Hospital, Inc. Moyen d'evaluation du profil a risque d'un individu pour les maladies atherosclereuses

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WO1998043630A1 (fr) * 1997-04-02 1998-10-08 Brigham And Women's Hospital, Inc. Moyen d'evaluation du profil a risque d'un individu pour les maladies atherosclereuses

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CHAN ET AL: "Effect of atrovastatin and fish oil on plasma high sensitivity c-reactive protein concentrations in individuals with visceral obesity" CLIN.CHEM, vol. 48, no. 6, 2002, - 2002 pages 877-883, XP002316706 *
CHEN ET AL: "physiologic concentrations of homocysteine inhibit the human plasma GSH peroxidase that reduces organic hydroperoxides" J.LAB.CLIN.MED, vol. 136, 2000, - 2000 pages 58-65, XP009043635 cited in the application *
FICHTLSCHERER ET AL: "DECREASE OF C-REACTIVE PROTEIN SERUM LEVELS DETERMINES THE EXTENT IMPROVEMENT IN ENDOTHELIAL DYSFUNCTION INDUCED BY SHORT TERM STATIN TREATMENT" CIRCULATION SUPPL. II, vol. 106, no. 19, 2002, - 2002 pages 704-704, XP009043640 *
HWANG S J ET AL: "CIRCULATING ADHESION MOLECULES VCAM-1, ICAM-1, AND E-SELECTIN IN CAROTID ATHEROSCLEROSIS AND INCIDENT CORONARY HEART DISEASE CASES. THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY" CIRCULATION, AMERICAN HEART ASSOCIATION, DALLAS, TX, US, vol. 96, 16 December 1997 (1997-12-16), pages 4219-4225, XP000943359 ISSN: 0009-7322 *
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006033287A1 (fr) * 2004-09-21 2006-03-30 Sankyo Company, Limited PRÉPARATION PHARMACEUTIQUE CONTENANT UN INHIBITEUR DE LA HMG-CoA RÉDUCTASE ET DE LA GLUTATHIONE
WO2009021113A1 (fr) * 2007-08-09 2009-02-12 Holtzman, Jordan, L. Procédés de stimulation de l'activité de la glutathion peroxydase
WO2010012616A1 (fr) * 2008-07-30 2010-02-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Glutathion sanguin comme biomarqueur pour le dépistage de patients asymptomatiques présentant un risque d'insuffisance cardiaque
GB2465796A (en) * 2008-12-01 2010-06-02 Bee Kang Tan Metformin for the therapeutic use of conditions with raised serum amyloid A levels

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