EP0118536A1 - Pain relieving therapeutic composition - Google Patents
Pain relieving therapeutic compositionInfo
- Publication number
- EP0118536A1 EP0118536A1 EP19830902974 EP83902974A EP0118536A1 EP 0118536 A1 EP0118536 A1 EP 0118536A1 EP 19830902974 EP19830902974 EP 19830902974 EP 83902974 A EP83902974 A EP 83902974A EP 0118536 A1 EP0118536 A1 EP 0118536A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- analgesic
- para
- animal
- composition
- protective compound
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
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
- A61K31/60—Salicylic acid; Derivatives thereof
-
- 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
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
-
- 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
-
- 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
Definitions
- analgesics which are derivatives of para-aminophenol, i.e. the analgesics which consist of a benzene ring containing, in para relation, an amino group or derivative thereof and a hydroxyl group or derivative thereof.
- analgesics which consist of a benzene ring containing, in para relation, an amino group or derivative thereof and a hydroxyl group or derivative thereof.
- acetophenetidin more commonly known as phenacetin
- acetaminophen (sold under the trade name "Tylenol” and sometimes referred to as paracetamol), although in widespread use, is also believed to cause tissue damage in some individuals, particularly when used in conjunction with alcohol.
- tissue damage associated with para-aminophenol derived analgesics has been linked to the presence in the damaged tissues of plasma soluble substances known as soluble lipofuscins, which form highly toxic free radicals ij_ vivo.
- soluble lipofuscins which form highly toxic free radicals ij_ vivo.
- These lipofuscins are related to a class of compounds which had previously been described in the literature as "plasma lipo scins.” Plasma lipofuscins have been shown to be produced in blood plasma in the presence of catecholamines and catechol.
- vitamin C per se might have acted as an antioxidant and influenced the attack of hepatic macromolecules by the active metabolite of paracetamol. Such a mechanism is supported by the finding that in the animal experiment vitamin C administration reduced the mortality due to paracetamol.” Houston et al. (1976) J. Pharm. Sci. 65,
- the present invention features a therapeutic, pain-relieving composition for administration to an animal, e.g.
- a human being in need of relief from pain, the composition containing a pain-relieving amount of a para-aminophenol derived analgesic and a protective compound selected from the group consisting of D-isoascorbic acid, dialauryl thiodipropionate, D-penicillamine, thiosalicylic acid, 2-thiouracil, and disulfiram, the protective compound being present in an amount sufficient to inhibit lipofuscin formation caused by the analgesic in the animal.
- a protective compound selected from the group consisting of D-isoascorbic acid, dialauryl thiodipropionate, D-penicillamine, thiosalicylic acid, 2-thiouracil, and disulfiram
- analgesic and antioxidant are provided together in an orally-administered preparation such as a pill or tablet; the antioxidant is D-isoascorbic acid; and the analgesic has the formula
- R is H or COCH-
- R_ is H or lower alkyl (an alkyl group having one to five carbon atoms) , the analgesic most preferably being phenacetin or acetaminophen.
- each protective compound in an equimolar concentration compared to para-aminophenol, causes over 50% inhibition of lipofuscin formation from para-aminophenol in human blood plasma ij vitro compared to control plasma samples containing para-aminophenol but no added protective compound; and (2) the protective compound is not rapidly destroyed by blood components, as evidenced by maintainance of lipofuscin at a level less than 50% that of the controls for a period of at least four hours.
- the protective compound in addition to being administered admixed with the analgesic in one composition, can be administered in a separate preparation. In either case the protective compound can be admixed with a non-toxic, pharmaceutically acceptable carrier substance.
- the protective compound When the protective compound is administered separately, it must be administered close enough in time to the administration of the analgesic to inhibit lipofuscin formation. Normally, administration of the protective compound will be approximately simultaneous (within one hour, more preferaoly within fifteen minutes) with analgesic administration. In the case of time release preparations, however, the protective compound might be administered a considerably longer time (e.g. four hours) after analgesic administration.
- analgesic and protective compound can be administere ⁇ using any appropriate, medically acceptable method, e.g. intramuscular or intravenous administration.
- the mole ratio of protective compound: analgesic is at least 1:1, most preferably even higher.
- a 300 mg tablet of acetaminopnen is preferably co oineo with or administered at the same time with at least 400 mg D-isoascorDic acid, most preferably 500 mg or more.
- the protective compound: analgesic ratio could, however, under some circumstances, be as high as 10:1. In addition, some benefit could be obtained with a ratio as low as 0.1:1.
- the useful mole ratio range thus is generally about 0.1:1 to 10:1.
- the invention permits the much safer administration of any of the para-aminophenol derived analgesics, including phenacetin, which has been all but banned in recent years.
- the currently most preferred protective compound is D-isoascorbic acid, which causes 100% inhibition of lipofuscin formation ijn vitro and in addition is FDA-approved and is currently readily available.
- the FDA-approved compounds D-penicillamine, thiosalicylic acid, and 2-thiouracil are effective in inhioiting lipofuscin formation but have the disadvantage, at present, of being available only by prescription, because of possible toxic side effects.
- the FDA-approved compounds dilauryl thiodipropionate and disulfiram also inhibit lipofuscin formation. However, because they exhibit low solubility in plasma, they are less preferred for this purpose. What is claimed is:
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Composition thérapeutique antalgique à administrer à un animal dont la souffrance a besoin d'être soulagée, comprenant une certaine quantité antalgique d'un analgésique dérivé de para-aminophénol et un composé protecteur en quantité suffisante pour empêcher la formation de lipofuscine provoquée par l'analgésique dans l'animal, le composé protecteur étant l'acide D-isoascorbique, le thiodipropionate de dialauryle, la D-pénicillamine, l'acide thiosalicylique, le 2-thiouracile ou le disulfirame.Analgesic therapeutic composition for administration to an animal whose suffering needs to be relieved, comprising a certain analgesic amount of an analgesic derived from para-aminophenol and a protective compound in an amount sufficient to prevent the formation of lipofuscin caused by the analgesic in animals, the protective compound being D-isoascorbic acid, dialauryl thiodipropionate, D-penicillamine, thiosalicylic acid, 2-thiouracil or disulfiram.
Description
PAIN RELIEVING THERAPEUTIC COMPOSITION
Background of the Invention This invention relates to the inhibition of toxic side-effects of analgesics. Certain types of analgesic abuse are characterized by sometimes fatal kidney, liver, or brain damage. Such symptoms develop in some people who ingest, alone or in combination with aspirin or other pain relievers, analgesics which are derivatives of para-aminophenol, i.e. the analgesics which consist of a benzene ring containing, in para relation, an amino group or derivative thereof and a hydroxyl group or derivative thereof. One such para-aminophenol derivative, acetophenetidin (more commonly known as phenacetin) is so dangerous that its use has been very sharply curtailed in recent years. Another para-aminophenol derivative, acetaminophen (sold under the trade name "Tylenol" and sometimes referred to as paracetamol), although in widespread use, is also believed to cause tissue damage in some individuals, particularly when used in conjunction with alcohol. The tissue damage associated with para-aminophenol derived analgesics has been linked to the presence in the damaged tissues of plasma soluble substances known as soluble lipofuscins, which form highly toxic free radicals ij_ vivo. These lipofuscins are related to a class of compounds which had previously been described in the literature as "plasma lipo scins." Plasma lipofuscins have been shown to be produced in blood plasma in the presence of catecholamines and catechol.
Raghuram et al. (1978) Toxicity Letters 2_, 175-178 reported that "(i)t is common practice to prescribe vitamin C in megadoses along with analgesics and antipyretics such as paracetamol during infections." The editor reported, in the paper, tnat "(a)scorbic acid at a level of 500 mg/tablet is
incorporated in one of the paracetamol preparations marketed locally." The authors performed toxicity studies to determine whether vitamin C prevented acute (short term) liver damage in mice and humans, and concluded that vitamin C did provide protection. The authors speculated that vitamin C "may have preserved the hepatic glutathione levels thereby helping in detoxication of the reactive metabolite of paracetamol. Alternatively, vitamin C per se might have acted as an antioxidant and influenced the attack of hepatic macromolecules by the active metabolite of paracetamol. Such a mechanism is supported by the finding that in the animal experiment vitamin C administration reduced the mortality due to paracetamol." Houston et al. (1976) J. Pharm. Sci. 65,
1218-1221 reported tests in which three g of ascorbic acid were given to human volunteers 1.5 hrs. after the administration of 1 g of acetaminophen, and the composition of the subjects1 urine was monitored. The results of the study led the authors to conclude that "[t]he specific interaction between acetaminophen and ascorbic acid . . . is probably of little chemical significance under the usual conditions, i.e., when acetaminophen is taken in single recommended doses as an analgesic or antipyretic."
Walker et al. (1974) Chem. Sci. & Molecular Med. l_r 449-459 reported studies demonstrating that very large doses of acetaminophen caused liver necrosis in vitamin E-deficient rats, and that vitamin E administration minimized the damage. The authors concluded that "[t]he precise mechanism of paracetanol hepatotoxicity is not known," but speculated that "[t]he protective action of -tocopherol might suggest that the mechanism of paracetamol toxicity may perhaps be
mediated by lipid peroxidation. However, it is also possible that a more specific biochemical function involving microsomal drug-metabolizing systems may be involved. . . . It is noteworthy that glutathione, another potential antioxidant present in tissues, has been shown to reduce paracetamol hepatotoxicity in mice, perhaps by protecting nucleophilic protein groups from a toxic metabolite.
In Rosen U.S. Pat. No. 4,314,989, current theories relating to the mechanism by which para-aminopnenol derivatives cause tissue damage are discussed. Rosen says:
Because such diverse compounds as cysteamine, methionine, cystein, di ethylmercaptol, selenium and vitamin E have afforded varying degrees of protection in man and experimental animals against the hepatotoxicity of acetaminophen and because these compounds under certain circumstances can act as antioxidants, it has been suggested that other antioxidants would also provide protection. J. Kellerher et al., J. Int. Med Res. (1976) 4, Supplement (4) 138-144.
* * *
Other researchers concluded that the protective effects manifested by these vitamins cannot be attributed to their antioxidant activity because whereas vitamin E and propyl gallate reduce hepatotoxicity, diphenyl-p-phenylene-diamine (DDPD) , an antioxidant in vitro and one which gives protection against CCl. hepatotoxicity, enhances acetaminophen hepatotoxicity. J.
Kelleher et al., J. Int. Med. Res. supra. These authors speculate that the modification of hepatotoxicity may result from an alteration of the activity of the specific components of the microso ol drug metabolizing enzyme system.
Suprisingly and notwithstanding the published literature reporting that some anti-oxidants may provide protection against the hepatotoxic effects of acetaminophen, I have found that the omnipotent antioxidants BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole) profoundly enhance its hepatotoxicity.
I have now discovered that the para-aminophenol derived analgesics themselves are not responsible for lipofuscin formation, but that lipofuscin formation is instead caused by breakdown products, principally para-aminophenol itself, of the analgesics. I have also discovered that the pathway by which lipofuscin is formed is an oxidation process. Lipofuscin formation must be inhibiteα to curtail the chronic deleterious effects of prolonged use of para-aminophenol derived analgesics in therapeutic or near- therapeutic doses. Prevention of the acute toxic effects caused by overdoses of para-aminophenol derivatives is another matter and is outside the scope of the present invention.
. wipo
I have also discovered that certain specific protective compounds, all of which are antioxidants, are effective in inhibiting lipofuscin formation caused by para-aminophenol derived analgesics. Accordingly, the present invention features a therapeutic, pain-relieving composition for administration to an animal, e.g. a human being, in need of relief from pain, the composition containing a pain-relieving amount of a para-aminophenol derived analgesic and a protective compound selected from the group consisting of D-isoascorbic acid, dialauryl thiodipropionate, D-penicillamine, thiosalicylic acid, 2-thiouracil, and disulfiram, the protective compound being present in an amount sufficient to inhibit lipofuscin formation caused by the analgesic in the animal.
In preferred embodiments the analgesic and antioxidant are provided together in an orally-administered preparation such as a pill or tablet; the antioxidant is D-isoascorbic acid; and the analgesic has the formula
wherein R, is H or COCH-, and R_ is H or lower alkyl (an alkyl group having one to five carbon atoms) , the analgesic most preferably being phenacetin or acetaminophen.
The protective compounds of the invention all meet the following two criteria: (1) each protective compound, in an equimolar concentration compared to para-aminophenol, causes over 50% inhibition of lipofuscin formation from para-aminophenol in human
blood plasma ij vitro compared to control plasma samples containing para-aminophenol but no added protective compound; and (2) the protective compound is not rapidly destroyed by blood components, as evidenced by maintainance of lipofuscin at a level less than 50% that of the controls for a period of at least four hours.
In addition to being administered admixed with the analgesic in one composition, the protective compound can be administered in a separate preparation. In either case the protective compound can be admixed with a non-toxic, pharmaceutically acceptable carrier substance.
When the protective compound is administered separately, it must be administered close enough in time to the administration of the analgesic to inhibit lipofuscin formation. Normally, administration of the protective compound will be approximately simultaneous (within one hour, more preferaoly within fifteen minutes) with analgesic administration. In the case of time release preparations, however, the protective compound might be administered a considerably longer time (e.g. four hours) after analgesic administration.
Although oral administration is preferred, the analgesic and protective compound, separately or in combination, can be administereα using any appropriate, medically acceptable method, e.g. intramuscular or intravenous administration.
Preferably the mole ratio of protective compound: analgesic is at least 1:1, most preferably even higher. Thus, for example, since the molecular weight ratio of para-aminophenol der eu analgesics to D-isascorbic acid is about 2:3, a 300 mg tablet of acetaminopnen is preferably co oineo with or administered at the same time with at least 400 mg D-isoascorDic acid, most preferably 500 mg or more.
The protective compound: analgesic ratio could, however, under some circumstances, be as high as 10:1. In addition, some benefit could be obtained with a ratio as low as 0.1:1. The useful mole ratio range thus is generally about 0.1:1 to 10:1.
The invention permits the much safer administration of any of the para-aminophenol derived analgesics, including phenacetin, which has been all but banned in recent years. The currently most preferred protective compound is D-isoascorbic acid, which causes 100% inhibition of lipofuscin formation ijn vitro and in addition is FDA-approved and is currently readily available. The FDA-approved compounds D-penicillamine, thiosalicylic acid, and 2-thiouracil are effective in inhioiting lipofuscin formation but have the disadvantage, at present, of being available only by prescription, because of possible toxic side effects. The FDA-approved compounds dilauryl thiodipropionate and disulfiram also inhibit lipofuscin formation. However, because they exhibit low solubility in plasma, they are less preferred for this purpose. What is claimed is:
Claims
1. A pain-relieving therapeutic composition for administration to an animal in need of relief from pain, said composition comprising a pain relieving amount of a para-aminophenol derived analgesic, and a protective compound selected from the group consisting of D-isoascorbic acid, dialauryl thiodipropionate, D-penicillamine, thiosalicylic acid, 2-thiouracil, and disulfiram, said compound being present in an amount sufficient to inhibit lipofuscin formation caused by said analgesic in said animal.
2. The composition of claim 1 wherein said analgesic and said antioxidant are provided together in a tablet or pill for oral administration to said animal.
3. The composition of claim 1 wherein said protective compound is D-isoascorbic acid.
4. The composition of any of claims 1-3 wherein said para-aminophenol derived analgesic has the formula
wherein R1 is H or COCH-. and R„ is H or lower alkyl.
5. The composition of claim 4 wπ rem said para-aminophenol derived analgesic is phenacetin.
6. The composition of claim 5 wherein said para-aminophenol derived analgesic is acetaminophen.
■*ξ\)RE
OMPI y ^ WIPO
7. The composition of claim 1 wherein said animal is a human.
8. A method of inhibiting lipofuscin formation in an animal being treated for pain by the administration to said animal of a para-aminophenol derived analgesic, said method comprising administering to said animal a protective compound in an amount sufficient to inhibit said lipofuscin formation, said administering of said protective compound being carried out close enough in time to said administration of said analgesic to inhibit said lipofuscin formation, said protective compound being selected from the group consisting of D-isoascorbic acid, dialauryl thiodipropionate, D-penicillamine, thiosalicylic acid, 2-thiouracil, and disulfiram.
9. The method of claim 8 wherein said analgesic and said protective compound are provided together in a tablet or pill for oral administration to said animal.
10. The method of claim 8 wherein said protective compound is D-isoascorbic acid.
11. The method of any of claims 8-10 wherein said para-aminophenol derived analgesic has the formula
wherein R_ is H or COCH3 and R2 is H or lower alkyl.
12. The method of claim 11 wherein said para- aminophenol derived analgesic is phenacetin.
13. The method of claim 11 wherein said para- aminophenol derived analgesic is acetaminophen.
14. Tne method of claim 8 wherein said animal is a human.
2 -- ∑-
OMPI
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41518582A | 1982-09-07 | 1982-09-07 | |
| US415185 | 1982-09-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0118536A1 true EP0118536A1 (en) | 1984-09-19 |
Family
ID=23644708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19830902974 Withdrawn EP0118536A1 (en) | 1982-09-07 | 1983-09-07 | Pain relieving therapeutic composition |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0118536A1 (en) |
| WO (1) | WO1984000887A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10369108B2 (en) | 2013-03-15 | 2019-08-06 | Mylan Laboratories, Inc. | Hot melt granulation formulations of poorly water-soluble active agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4314989A (en) * | 1980-05-07 | 1982-02-09 | Rosen Gerald M | Methionine sulfoxide amflioration of acetaminophen toxicity |
-
1983
- 1983-09-07 WO PCT/US1983/001343 patent/WO1984000887A1/en unknown
- 1983-09-07 EP EP19830902974 patent/EP0118536A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8400887A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1984000887A1 (en) | 1984-03-15 |
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Legal Events
| Date | Code | Title | Description |
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| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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| AK | Designated contracting states |
Designated state(s): AT BE CH DE FR GB LI LU NL SE |
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| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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| 18D | Application deemed to be withdrawn |
Effective date: 19840808 |
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| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: ALTSCHULE, MARK, D. |