US20050220862A1 - Compositions with reduced hepatotoxicity - Google Patents
Compositions with reduced hepatotoxicity Download PDFInfo
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- US20050220862A1 US20050220862A1 US10/813,760 US81376004A US2005220862A1 US 20050220862 A1 US20050220862 A1 US 20050220862A1 US 81376004 A US81376004 A US 81376004A US 2005220862 A1 US2005220862 A1 US 2005220862A1
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- 239000000203 mixture Substances 0.000 title claims abstract description 71
- 231100000304 hepatotoxicity Toxicity 0.000 title claims abstract description 14
- 206010019851 Hepatotoxicity Diseases 0.000 title claims abstract description 11
- 230000007686 hepatotoxicity Effects 0.000 title claims abstract description 10
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 52
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 31
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 30
- 230000003082 hepatotoxic effect Effects 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 229960005489 paracetamol Drugs 0.000 claims abstract description 26
- 231100000334 hepatotoxic Toxicity 0.000 claims abstract description 25
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims abstract description 25
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims abstract description 24
- 229930182817 methionine Natural products 0.000 claims abstract description 24
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 17
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims abstract description 16
- 229960000485 methotrexate Drugs 0.000 claims abstract description 16
- 239000011570 nicotinamide Substances 0.000 claims abstract description 16
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 16
- 229960003966 nicotinamide Drugs 0.000 claims abstract description 16
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960000304 folic acid Drugs 0.000 claims abstract description 15
- 235000019152 folic acid Nutrition 0.000 claims abstract description 15
- 239000011724 folic acid Substances 0.000 claims abstract description 15
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 14
- 229960003512 nicotinic acid Drugs 0.000 claims abstract description 14
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 14
- 229940028937 divalproex sodium Drugs 0.000 claims abstract description 13
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960000604 valproic acid Drugs 0.000 claims abstract description 12
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims abstract description 10
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960005370 atorvastatin Drugs 0.000 claims abstract description 10
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims abstract description 9
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims abstract description 9
- 229960002855 simvastatin Drugs 0.000 claims abstract description 9
- -1 flucanozole Chemical compound 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 9
- 239000003826 tablet Substances 0.000 claims description 8
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 230000037406 food intake Effects 0.000 claims description 5
- 239000007894 caplet Substances 0.000 claims description 4
- 238000007918 intramuscular administration Methods 0.000 claims description 3
- 238000007913 intrathecal administration Methods 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 239000008174 sterile solution Substances 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 2
- 230000000116 mitigating effect Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 229960004452 methionine Drugs 0.000 description 19
- 235000006109 methionine Nutrition 0.000 description 19
- 239000003814 drug Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 9
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 9
- 229960004884 fluconazole Drugs 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- 206010067125 Liver injury Diseases 0.000 description 4
- 231100000234 hepatic damage Toxicity 0.000 description 4
- 230000002440 hepatic effect Effects 0.000 description 4
- 230000008818 liver damage Effects 0.000 description 4
- 230000007056 liver toxicity Effects 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 239000002221 antipyretic Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 206010027603 Migraine headaches Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000003529 anticholesteremic agent Substances 0.000 description 2
- 229940127226 anticholesterol agent Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 206010019692 hepatic necrosis Diseases 0.000 description 2
- 230000007866 hepatic necrosis Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000011708 vitamin B3 Substances 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 208000001294 Nociceptive Pain Diseases 0.000 description 1
- 206010050346 Oropharyngeal candidiasis Diseases 0.000 description 1
- 206010033296 Overdoses Diseases 0.000 description 1
- 201000007981 Reye syndrome Diseases 0.000 description 1
- 206010042464 Suicide attempt Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical class CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
Classifications
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- 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]
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/08—Antiepileptics; Anticonvulsants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/10—Antimycotics
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
Definitions
- compositions of pharmaceutical compounds having hepatotoxicity in which compositions the hepatotoxicity is mitigated. More particularly, this invention relates to compositions of hepatotoxic compounds such as acetaminophen, methotrexate, statin drugs, niacin, divalproex sodium, valproic acid or fluconazole, each of which is known to have hepatotoxic properties, in which compositions the hepatotoxicity of the compound is mitigated.
- hepatotoxic compounds such as acetaminophen, methotrexate, statin drugs, niacin, divalproex sodium, valproic acid or fluconazole, each of which is known to have hepatotoxic properties, in which compositions the hepatotoxicity of the compound is mitigated.
- Acetaminophen is the active metabolite of phenacetin, a drug whose use extends back to the 1880's. Although acetaminophen was first used as an analgesic and antipyretic in 1893, it did not achieve widespread use until after 1949. For many years, acetaminophen was used as a second-line choice to aspirin as an analgesic/antipyretic, but the elucidation of the relationship between aspirin use and Reye's Syndrome and the recognition of aspirin's propensity to produce gastrointestinal bleeding vaulted acetaminophen into its current day position as the analgesic/antipyretic of first choice in both children and adults.
- acetaminophen While acetaminophen is usually well tolerated, its use can be accompanied by a very serious adverse effect—potentially fatal hepatic necrosis. Hepatic necrosis with acetaminophen is largely confined to two groups of patients: 1. Patients who ingest acute overdoses or who chronically utilize high dosage regimens of acetaminophen. 2. Ingestion of acetaminophen by alcoholics or in combination with alcohol ingestion. It has been reported that more than 26,000 patients per year are hospitalized in the U.S. for acetaminophen induced hepatic necroses, and of these, more than 400 die each year.
- Methotrexate an inhibitor of cell metabolism, has been utilized for several decades as a therapeutic agent widely used in several different diseases including rheumatoid arthritis and psoriasis. While methotrexate administration is associated with various other side effects, severe and sometimes fatal liver toxicity is a significant limiting factor in its therapeutic usefulness. Atorvastatin, simvastatin and other cholesterol reducing agents of the “statin” family are the most widely used pharmaceuticals in the world. In spite of their widespread use, liver toxicity is a significant problem, and patients with a history of old or active hepatitis must avoid these drugs even if they could benefit from their cholesterol lowering actions.
- Niacin also known as nicotinic acid or vitamin B 3
- Fluconazole a potent antifungal agent
- divalproex sodium and valproic acid widely used antiepileptics are three other agents whose clinical use is limited by their hepatotoxicity.
- nicotinamide also known as niacinamide
- methionine an essential amino acid which is a DL racemic mixture of D & L methionine
- nicotinamide and methionine can be administered in combination with hepatotoxic pharmaceutical compounds such as acetaminophen, methotrexate, a “statin” cholesterol lowering agent, fluconazole, divalproex sodium or valproic acid, in substantially lower doses than disclosed in the prior art, and when administered as such, can provide a substantive protective effect against the hepatotoxicity of these agents without negatively affecting their beneficial therapeutic activity.
- hepatotoxic pharmaceutical compounds such as acetaminophen, methotrexate, a “statin” cholesterol lowering agent, fluconazole, divalproex sodium or valproic acid
- hepatotoxic pharmaceutical compounds such as acetaminophen, methotrexate, atorvastatin, simvastatin, niacin, fluconazole, divalproex sodium, valproic acid, and related drugs
- compositions of hepatotoxic therapeutic drugs such as acetaminophen, methotrexate, the “statins,” niacin, fluconazole, divalproex sodium, valproic acid, and related drugs, which compositions provide the therapeutic benefits of the active drug with markedly reduced potential for serious hepatotoxicity.
- compositions in which the hepatotoxic properties are mitigated.
- the compositions can include a standard dose of the hepatotoxic compound, together with relatively low dosages of nicotinamide and methionine. Low dosages of folic acid also can be added to the compositions to further mitigate the hepatotoxic properties.
- Specific embodiments of the invention can be in the form of formulations of acetaminophen together with mixtures of low dosages of nicotinamide and methionine, or together with low dosages of nicotinamide, methionine and folic acid; or formulations of methotrexate together with mixtures of low dosages of nicotinamide and methionine, or together with low dosages of nicotinamide, methionine and folic acid.
- These formulations are incorporated into pharmaceutically acceptable vehicles for use in humans and animals.
- formulations of atorvastatin, simvastatin, niacin, fluconazole, divalproex sodium or valproic acid each can be formulated into pharmaceutically acceptable vehicles for use in humans and animals together with mixtures of low dosages of nicotinamide and methionine, or together with low dosages of nicotinamide, methionine and folic acid.
- Such formulations include those suitable for oral administration such as capsules, tablets, caplets, or liquid solutions or suspensions, as well as sterile solutions or suspensions suitable for intradermal, subcutaneous, intramuscular, intravenous or intrathecal injection.
- acetaminophen 80 mg-1000 mg per single dose form, e.g. single capsule, single tablet, etc.
- methotrexate 2.5 mg-250 mg per single dose form
- atorvastatin or simvastatin 5 mg-100 mg per single dose form
- niacin 250 mg-1000 mg per single dose form
- fluconazole 10 mg-250 mg per single dose form
- divalproex sodium 100 mg-750 mg per single dose form
- valproic acid 25 mg-500 mg per single dose form
- methionine may be present in the amount of about 5 mg to about 500 mg per single dose form, and preferably about 10 mg to 100 mg per single dose form
- nicotinamide may be present in the amount of about 10 mg to 500 mg per single dose form, and preferably about 25 mg to about 200 mg per single dose form.
- Suitable pharmaceutical vehicles for the combinations of hepatotoxic compounds such as acetaminophen, methotrexate, atorvastatin, simvastatin, niacin, fluconazole, divalproex sodium or valproic acid, with hepatotoxicity mitigators methionine, nicotinamide and folic acid, and methods of preparing such formulations as are within the scope of the invention, will be readily apparent to and understood by those skilled in the art.
- compositions of the instant invention will be more readily comprehended from the following examples:
- Two tablets comprised of 500 mg acetaminophen, 50 mg methionine, and 25 mg nicotinamide, are administered to patients with painful osteoarthritis four times daily for 12 weeks producing substantial relief of joint pain without evidence of any hepatotoxicity.
- Capsules are prepared each containing by weight 325 mg acetaminophen, 50 mg methionine, 50 mg nicotinamide, and 500 mcg folic acid.
- One to two of such capsules are administered to patients with osteoarthritis or fibromyalgia pain four to six times daily for 6 months for relief of joint or soft tissue pain without evidence of damage to the patients' livers.
- Two caplets each containing 500 mg acetaminophen, 200 mg methionine, and 100 mg nicotinamide are administered four times daily for twelve (12) weeks to patients with osteoarthritis for relief of osteoarthritis pain without evidence of liver damage.
- Tablets are prepared each containing 2.5 mg methotrexate, 100 mg methionine, 100 mg nicotinamide and 100 mcg folic acid. Two of such tablets are administered to patients with psoriasis of the skin twice daily for 6 months. Such patients demonstrate improvement in their psoriatic lesions without evidence of serious methotrexate-induced liver damage.
- Tablets containing 250 mg divalproex sodium, 250 mg methionine and 100 mg nicotinamide by weight are administered twice daily to patients with migraine headaches to prevent or diminish the severity of migraine headaches without evidence of serious liver damage.
- Capsules are prepared each containing by weight 10 mg atorvastatin, 500 mg methionine, 100 mg nicotinamide, and 1.0 mg folic acid and administered to patients once daily. Such patients have lower serum cholesterol and triglycerides without vidence of significant alteration in their liver functions.
- An oral suspension containing 10 mg/ml fluconazole, 25 mg/ml methionine and 20 mg/ml nicotinamide is administered to children for treatment of oropharyngeal candidiasis at a dosage of 2-12 mg/kg per day for 3 weeks with a substantially lessened risk of liver toxicity than with standard fluconazole suspensions.
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Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/813,760 US20050220862A1 (en) | 2004-03-31 | 2004-03-31 | Compositions with reduced hepatotoxicity |
| EP05731289A EP1729769A4 (en) | 2004-03-31 | 2005-03-23 | COMPOSITIONS WITH REDUCED HEPATOTOXICITY |
| JP2007506267A JP2007530688A (ja) | 2004-03-31 | 2005-03-23 | 肝毒性が減少した組成物 |
| CA002561619A CA2561619A1 (en) | 2004-03-31 | 2005-03-23 | Compositions with reduced hepatotoxicity |
| KR1020067020315A KR20070003995A (ko) | 2004-03-31 | 2005-03-23 | 감소된 간독성을 갖는 조성물 |
| PCT/US2005/009795 WO2005097120A1 (en) | 2004-03-31 | 2005-03-23 | Compositions with reduced hepatotoxicity |
| US13/197,581 US9238017B2 (en) | 2004-03-31 | 2011-08-03 | Compositions with reduced hepatotoxicity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/813,760 US20050220862A1 (en) | 2004-03-31 | 2004-03-31 | Compositions with reduced hepatotoxicity |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US13/197,581 Division US9238017B2 (en) | 2004-03-31 | 2011-08-03 | Compositions with reduced hepatotoxicity |
Publications (1)
| Publication Number | Publication Date |
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| US20050220862A1 true US20050220862A1 (en) | 2005-10-06 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/813,760 Abandoned US20050220862A1 (en) | 2004-03-31 | 2004-03-31 | Compositions with reduced hepatotoxicity |
| US13/197,581 Expired - Lifetime US9238017B2 (en) | 2004-03-31 | 2011-08-03 | Compositions with reduced hepatotoxicity |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US13/197,581 Expired - Lifetime US9238017B2 (en) | 2004-03-31 | 2011-08-03 | Compositions with reduced hepatotoxicity |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US20050220862A1 (ko) |
| EP (1) | EP1729769A4 (ko) |
| JP (1) | JP2007530688A (ko) |
| KR (1) | KR20070003995A (ko) |
| CA (1) | CA2561619A1 (ko) |
| WO (1) | WO2005097120A1 (ko) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080015893A1 (en) * | 2006-07-17 | 2008-01-17 | Walgreen Co. | Identification of Inappropriate Medications In A Medication Therapy Regimen |
| US20080097784A1 (en) * | 2006-07-17 | 2008-04-24 | Walgreen Co. | Appropriateness Of A Medication Therapy Regimen |
| US20080126130A1 (en) * | 2006-07-17 | 2008-05-29 | Walgreen Co. | Compliance With A Medication Therapy Regimen |
| US20080126117A1 (en) * | 2006-07-17 | 2008-05-29 | Walgreen Co. | Optimization Of A Medication Therapy Regimen |
| WO2023144118A1 (en) * | 2022-01-25 | 2023-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of therapy comprising simultaneous administration of methotrexate and folic acid |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2222274B1 (en) * | 2007-11-29 | 2012-01-25 | AllTranz Inc. | Methods and compositons for enhancing the viability of microneedle pores |
| ITMI20080187A1 (it) * | 2008-02-07 | 2009-08-08 | Velleja Res Srl | Formulazioni di amminoacidi per la prevenzione del danno epatico da paracetamolo |
| WO2012090218A1 (en) * | 2010-12-30 | 2012-07-05 | Zota Health Care Ltd | Synergistic effects of the combination of the specific compounds with paracetamol and their effects on various diseases |
| CN106390130B (zh) * | 2016-09-18 | 2018-06-01 | 中国人民解放军第二军医大学 | 烟酰胺作为抗真菌药物增效剂的用途 |
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| US3983250A (en) * | 1974-10-02 | 1976-09-28 | The Dow Chemical Company | Halophenyl acetamidines as anxiolytic antidepressants |
| US4181719A (en) * | 1977-05-26 | 1980-01-01 | Sterling Drug Inc. | Analgesic N-acetyl-para-aminophenyl N'-acetylaminothioalkanoates |
| US4314989A (en) * | 1980-05-07 | 1982-02-09 | Rosen Gerald M | Methionine sulfoxide amflioration of acetaminophen toxicity |
| US4401657A (en) * | 1980-12-27 | 1983-08-30 | Snow Brand Milk Products Co., Ltd. | Nutrient composition suitable for enteral feeding |
| US4526788A (en) * | 1983-03-18 | 1985-07-02 | American Cyanamid Company | Polymeric[[(oxazolidinyl)alkyl]amino]anthraquinones |
| US4581348A (en) * | 1983-07-11 | 1986-04-08 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. | Synergistic pharmaceutical compositions |
| US4656159A (en) * | 1984-10-31 | 1987-04-07 | Georgetown University | Galactose-C-6 nitrogen mustard compounds and their uses |
| US4837239A (en) * | 1985-08-23 | 1989-06-06 | Syntex (U.S.A.) Inc. | Cardiotonic phosphodiesterase inhibitors complexed with water soluble vitamins |
| US5059592A (en) * | 1987-07-29 | 1991-10-22 | Fujisawa Pharmaceutical Co., Ltd. | Composition for prevention and (or) treatment of AIDS |
| US5284861A (en) * | 1990-07-14 | 1994-02-08 | Asta Medica Ag | Pharmaceutical composition comprising flupirtine and its use to combat Parkinson disorders |
| US5474757A (en) * | 1992-10-16 | 1995-12-12 | Rutgers University | Prevention of acetaminophen overdose toxicity with organosulfur compounds |
| US5478815A (en) * | 1993-12-02 | 1995-12-26 | Senji Pharmaceutical Co., Ltd. | Liver protectant tocophery-ascorbyl-phosphate |
| US5804567A (en) * | 1996-07-18 | 1998-09-08 | Cancer Institute (Hospital), Chinese Academy Of Medical Sciences | Method of increasing the effectiveness of anti-metabolites |
| US5994410A (en) * | 1995-10-26 | 1999-11-30 | National Science Council | Therapeutic use of water-soluble fullerene derivatives |
| US6048846A (en) * | 1998-02-26 | 2000-04-11 | Cochran; Timothy M. | Compositions used in human treatment |
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| US20090124606A1 (en) * | 2005-07-14 | 2009-05-14 | Istvan Gacsalyi | Composition for Treatment of Psychosis |
| US7557142B2 (en) * | 1996-10-03 | 2009-07-07 | Board Of Trustees Of Southern Illinois University | Therapeutic use of methionine to reduce the toxicity of platinum-containing anti-tumor compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3850429T2 (de) * | 1987-03-26 | 1994-11-24 | Univ London | Verhinderung von ADP-Ribosylierung von G-Proteinen. |
| US5597585A (en) * | 1995-12-26 | 1997-01-28 | Williams; Andrew H. | Vitamin/mineral composition |
-
2004
- 2004-03-31 US US10/813,760 patent/US20050220862A1/en not_active Abandoned
-
2005
- 2005-03-23 CA CA002561619A patent/CA2561619A1/en not_active Abandoned
- 2005-03-23 EP EP05731289A patent/EP1729769A4/en not_active Ceased
- 2005-03-23 WO PCT/US2005/009795 patent/WO2005097120A1/en not_active Application Discontinuation
- 2005-03-23 KR KR1020067020315A patent/KR20070003995A/ko not_active Application Discontinuation
- 2005-03-23 JP JP2007506267A patent/JP2007530688A/ja active Pending
-
2011
- 2011-08-03 US US13/197,581 patent/US9238017B2/en not_active Expired - Lifetime
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3983250A (en) * | 1974-10-02 | 1976-09-28 | The Dow Chemical Company | Halophenyl acetamidines as anxiolytic antidepressants |
| US4181719A (en) * | 1977-05-26 | 1980-01-01 | Sterling Drug Inc. | Analgesic N-acetyl-para-aminophenyl N'-acetylaminothioalkanoates |
| US4314989A (en) * | 1980-05-07 | 1982-02-09 | Rosen Gerald M | Methionine sulfoxide amflioration of acetaminophen toxicity |
| US4401657A (en) * | 1980-12-27 | 1983-08-30 | Snow Brand Milk Products Co., Ltd. | Nutrient composition suitable for enteral feeding |
| US4526788A (en) * | 1983-03-18 | 1985-07-02 | American Cyanamid Company | Polymeric[[(oxazolidinyl)alkyl]amino]anthraquinones |
| US4581348A (en) * | 1983-07-11 | 1986-04-08 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. | Synergistic pharmaceutical compositions |
| US4656159A (en) * | 1984-10-31 | 1987-04-07 | Georgetown University | Galactose-C-6 nitrogen mustard compounds and their uses |
| US4837239A (en) * | 1985-08-23 | 1989-06-06 | Syntex (U.S.A.) Inc. | Cardiotonic phosphodiesterase inhibitors complexed with water soluble vitamins |
| US5059592A (en) * | 1987-07-29 | 1991-10-22 | Fujisawa Pharmaceutical Co., Ltd. | Composition for prevention and (or) treatment of AIDS |
| US5284861A (en) * | 1990-07-14 | 1994-02-08 | Asta Medica Ag | Pharmaceutical composition comprising flupirtine and its use to combat Parkinson disorders |
| US5474757A (en) * | 1992-10-16 | 1995-12-12 | Rutgers University | Prevention of acetaminophen overdose toxicity with organosulfur compounds |
| US6465511B1 (en) * | 1993-05-06 | 2002-10-15 | Molichem Medicines, Inc. | Treatment of septic shock |
| US5478815A (en) * | 1993-12-02 | 1995-12-26 | Senji Pharmaceutical Co., Ltd. | Liver protectant tocophery-ascorbyl-phosphate |
| US5994410A (en) * | 1995-10-26 | 1999-11-30 | National Science Council | Therapeutic use of water-soluble fullerene derivatives |
| US6673831B1 (en) * | 1996-04-17 | 2004-01-06 | Merck & Co., Inc. | Combination therapy for reducing the risks associated with cardiovascular disease |
| US5804567A (en) * | 1996-07-18 | 1998-09-08 | Cancer Institute (Hospital), Chinese Academy Of Medical Sciences | Method of increasing the effectiveness of anti-metabolites |
| US7557142B2 (en) * | 1996-10-03 | 2009-07-07 | Board Of Trustees Of Southern Illinois University | Therapeutic use of methionine to reduce the toxicity of platinum-containing anti-tumor compounds |
| US6881401B1 (en) * | 1996-10-25 | 2005-04-19 | Human Genome Sciences, Inc. | Methods of treatment of immune system related disorders using Neutrokine-alpha |
| US6048846A (en) * | 1998-02-26 | 2000-04-11 | Cochran; Timothy M. | Compositions used in human treatment |
| US6468967B1 (en) * | 1998-09-25 | 2002-10-22 | Cubist Pharmaceuticals, Incorporated | Methods for administration of antibiotics |
| US7371388B1 (en) * | 2000-05-04 | 2008-05-13 | Human Genome Sciences, Inc. | Treatment of Sjogren's syndrome by administration of TR18 polypeptides |
| US6733797B1 (en) * | 2000-11-15 | 2004-05-11 | William K. Summers | Neuroceutical for improving memory and cognitive abilities |
| US20090124606A1 (en) * | 2005-07-14 | 2009-05-14 | Istvan Gacsalyi | Composition for Treatment of Psychosis |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080015893A1 (en) * | 2006-07-17 | 2008-01-17 | Walgreen Co. | Identification of Inappropriate Medications In A Medication Therapy Regimen |
| US20080097784A1 (en) * | 2006-07-17 | 2008-04-24 | Walgreen Co. | Appropriateness Of A Medication Therapy Regimen |
| US20080126130A1 (en) * | 2006-07-17 | 2008-05-29 | Walgreen Co. | Compliance With A Medication Therapy Regimen |
| US20080126117A1 (en) * | 2006-07-17 | 2008-05-29 | Walgreen Co. | Optimization Of A Medication Therapy Regimen |
| US8478605B2 (en) | 2006-07-17 | 2013-07-02 | Walgreen Co. | Appropriateness of a medication therapy regimen |
| US8700430B2 (en) | 2006-07-17 | 2014-04-15 | Walgreen Co. | Optimization of a medication therapy regimen |
| WO2023144118A1 (en) * | 2022-01-25 | 2023-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of therapy comprising simultaneous administration of methotrexate and folic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| US9238017B2 (en) | 2016-01-19 |
| KR20070003995A (ko) | 2007-01-05 |
| EP1729769A4 (en) | 2008-11-05 |
| EP1729769A1 (en) | 2006-12-13 |
| US20110288099A1 (en) | 2011-11-24 |
| WO2005097120A1 (en) | 2005-10-20 |
| CA2561619A1 (en) | 2005-10-20 |
| JP2007530688A (ja) | 2007-11-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: WINSTON LABORATORIES, INC., ILLINOIS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BERNSTEIN, JOEL E.;REEL/FRAME:015164/0716 Effective date: 20040331 |
|
| STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- AFTER EXAMINER'S ANSWER OR BOARD OF APPEALS DECISION |