US3890444A - Drug composition - Google Patents
Drug composition Download PDFInfo
- Publication number
- US3890444A US3890444A US354558A US35455873A US3890444A US 3890444 A US3890444 A US 3890444A US 354558 A US354558 A US 354558A US 35455873 A US35455873 A US 35455873A US 3890444 A US3890444 A US 3890444A
- Authority
- US
- United States
- Prior art keywords
- propoxyphene
- dextro
- phenyl butazone
- butazone
- phenyl
- 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.)
- Expired - Lifetime
Links
- 229940079593 drug Drugs 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 22
- 239000000203 mixture Substances 0.000 title claims abstract description 16
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 claims abstract description 38
- 229960002895 phenylbutazone Drugs 0.000 claims abstract description 34
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 claims abstract description 26
- 229960004193 dextropropoxyphene Drugs 0.000 claims abstract description 26
- 230000000202 analgesic effect Effects 0.000 claims abstract description 12
- 230000003356 anti-rheumatic effect Effects 0.000 claims abstract description 11
- 239000003435 antirheumatic agent Substances 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 4
- 208000025747 Rheumatic disease Diseases 0.000 claims description 3
- 230000000694 effects Effects 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 208000011580 syndromic disease Diseases 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 3
- 230000036592 analgesia Effects 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 201000009859 Osteochondrosis Diseases 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 208000012287 Prolapse Diseases 0.000 description 1
- 206010037779 Radiculopathy Diseases 0.000 description 1
- 241000950638 Symphysodon discus Species 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 206010007821 cauda equina syndrome Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- HOQADATXFBOEGG-UHFFFAOYSA-N isofenphos Chemical compound CCOP(=S)(NC(C)C)OC1=CC=CC=C1C(=O)OC(C)C HOQADATXFBOEGG-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 206010061928 radiculitis Diseases 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—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
- A61K31/415—1,2-Diazoles
Definitions
- the present invention relates to a drug compound antirheumatic and analgesic indication.
- phenyl butazone (1,2-diphenyl- 3,5-dioxo-4-n-butyl-pyrazolidine) has analgesic and antirheumatic effects.
- phenyl butazone was considered to be the most effective antirheumatic drug, apart from the steroids.
- the administration of phenyl butazone in effective dosages is accompanied by serious side effects, caused by its inhibiting action on certain enzymatic reactions taking place in the body.
- the objective underlying the present invention was therefore the discovery of a drug based on phenyl butazone which retains the known antirheumatic effects of phenyl butazone, while having a strong analgesic indication at reduced dosage, so that the known side effects are eliminated, or at least reduced.
- mice In a series of writhing tests performed on mice it was found that especially favorable results are obtained with a drug compound in which dextro-propoxyphene and phenyl butazone are present in a molar ratio of l to 2. These results are reflected in a table given below in which some of the readings obtained in the tests are listed by way of example. The effectiveness of the different drug compounds is stated as a percentage in relation to the l to 2 molar ratio.
- the extraordinary analgesic effects achieved are particularly evident in the category of post-traumatic conditions.
- the treatment results obtained in other typical categories of the rheumatoid group indicates that the antirheumatic effects of phenyl butazone in the disclosed combination fully match previously observed effects of treatment with phenyl butazone in its known large dosage, even though its dosage in the disclosed combination is substantially reduced.
- Drug composition having an antirheumatic and analgesic indication containing as active ingredients dextropropoxyphene and phenyl butazone in moleratio between 1 to l and l to 8.
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Drug composition having antirheumatic and analgesic indications containing as active ingredients dextro-propoxyphene and phenyl butazone, and treatment comprising administering as active ingredients dextro-propoxyphene and phenyl butazone.
Description
United States Patent 1 1 1111 3,890,444
Wawretschek June 17, 1975 [54] DRUG COMPOSITION 3,749,797 7/1973 Miller 424/308 [75] Inventor: Helmuth Wawretschek, Friesoythe, FOREIGN PATENTS OR APPLICATIONS Germany 1,081,105 8/1967 United Kingdom [73] Assignee: Servomed Arzneimittel Gmbl'l, OTHER PUBLICATIONS Oldenburg, Germany Filed: p 1973 Amer can Drug Index (I972) p. 174. pp 58 Primary Examiner--Stanley J. Friedman Attorney, Agent, or Firm-Robert R. Priddy; Burton [30] Foreign Application Priority Data Amermck 1' Apr. 26, 1972 Germany 2220500 [57] ABSTRACT I [52] US. Cl 424/273; 424/311 Drug composition having antirheumatic and analgesic [51] Int. Cl A6lk 27/00 indications containing as active ingredients dextro [58] Fleld of Search 424/273 propoxyphene and phenyl butazone and treatment comprising administering as active ingredients dextro- [56] References cued propoxyphene and phenyl butazone.
UNITED STATES PATENTS 6 Cl N D 3,482,021 12/1969 Gosling 424/273 'awmgs DRUG COMPOSITION t The present invention relates to a drug compound antirheumatic and analgesic indication.
It has been known, following the synthesis by H. Stenzel in 1946, that phenyl butazone (1,2-diphenyl- 3,5-dioxo-4-n-butyl-pyrazolidine) has analgesic and antirheumatic effects. Until the present time, phenyl butazone was considered to be the most effective antirheumatic drug, apart from the steroids. However, the administration of phenyl butazone in effective dosages is accompanied by serious side effects, caused by its inhibiting action on certain enzymatic reactions taking place in the body.
It is also known that these side effects can be avoided by using a combination of a reduced dosage of phenyl butazone with an analgesic.
From British Pat. No. 1,081,105 is known a drug which has anti-inflammatory and analgesic effects and which consists of a combination of butazone l-phenyl- 3,5-dioxo-4-n-butyl-butazolidine) and d-propoxyphene (1,2diphenyl-2-propionoxy-3-methyl-4- dimethylaminobutazone hydrochloride), the analgesic effect of the d-propoxyphene component being magnified through its combination with butazone. From this patent disclosure it is further known that this kind of magnification effect is not obtainable with combinations of phenyl butazone with propoxyphene, and that these combinations are therefore not suitable for medication. Yet, there has existed a long-standing basic need for such a combination, especially of phenyl butazone because of its very strong antirheumatic indication in comparison to butazone, with analgesic agents in which the magnifying characteristics would be present.
In the past, the magnifying effects of phenyl butazone have been obtained only in combination with such drugs as morphine, codeine, or methadone. However, these combinations have the drawback that they involve the risk of patient addiction, and for this reason they are not very desirable.
The objective underlying the present invention was therefore the discovery of a drug based on phenyl butazone which retains the known antirheumatic effects of phenyl butazone, while having a strong analgesic indication at reduced dosage, so that the known side effects are eliminated, or at least reduced.
In spite of the commonly held belief that combinations of phenyl butazone with propoxyphene are not suitable for medication purposes, the above objective has now been unexpectedly attained by the discovery of a drug compound consisting of phenyl butazone and dextro-propoxyphene.
The simultaneous administration of phenyl butazone and dextro-propoxyphene was found to produce an extraordinar'ily pronounced magnification of the analgesic-effects, in addition to a prolongation of the analgesia itself. It has thus become possible to make the therapeutic dosages of the active ingredients in the drug compound small enough to substantially eliminate the known side'effects. I
In the following the invention will be explained in more detail with reference to several embodiments.
In a series of writhing tests performed on mice it was found that especially favorable results are obtained with a drug compound in which dextro-propoxyphene and phenyl butazone are present in a molar ratio of l to 2. These results are reflected in a table given below in which some of the readings obtained in the tests are listed by way of example. The effectiveness of the different drug compounds is stated as a percentage in relation to the l to 2 molar ratio.
Table l Reciprocal values of ED values of various mixtures of dextro-propoxyphene-HCL with phenyl butazone, given as a percentage of the ED value of a mixture with a molar ratio of l to 2, which is equal to 100 percent (writhing test on mice):
Molar ratio: 45 min 90 min d-propoxyphene to phenyl butazone l to 16 57 l to 8 8l 7c 1 to 4 94 7c 97 l to 2 100 100 70 l to l 74 7b 98 7c tropropoxyphene with phenyl butazone when compared to dextropropoxyphene alone (A), produced an analgesia magnification of up to 4.2-fold, as shown by a comparison between the ED values of (A) and (B), taken 180 minutes after oral administration. The values which correspond to various other times elapsed are listed in Table 2 below:
Table 2 ED values obtained in writhing tests on mice, at times elapsed between 15 and 240 minutes after oral administration of compounds A, C, and B (values for B are computed from readings for C):
Compound 15 30 60 180 240 (A) dextro-propoxyphene 24 23 31 H (B) dextro-propoxyphene l3 1 1 I6 27 32 37 m mixture computed from (C) (C) mixture of dextro- 33 30 53 72 85 97 propoxyphene with phenyl butazone, molar ratio 1 to--2-- (D) phenyl butazone 350 360 390 650 650 900 ED, in mg per kg body weight duration in minutes 3 4 A magnification of effectiveness is evident and can Graph 1 also shows another interesting result with rebe computed from the ED values of Table 2. This spect to therapy: 37 mg of dextro-propoxyphenemagnification is illustrated in Graph I. hydrochloride in pure form are sufficient for an analge- G h I sia lasting approximately 70 minutes, whereas the same rap 5 dosage of dextro-propoxyphene in the mixture dis- Effectiveness magnification factor obtained through closed above assures an equally effective analgesia, mp n of 50 values of and in Table 2 even after 4 hours of elapsed time (see Graph II).
Magnification factor 5.-
l l l l I l I l l l i 15 so 120 1 240 4 minutes Graph ll D-Pro mixt e 1 v I a DProp.-HCL
l l 15 3O 60 v v 240 minute s Table 3 Number of very ineffec-- cases good good fair tive Degenerative spine syndromes, 197 49 1 I with or without radiculitis, I I 19 14 I such as: spondyl-arthrosis morbus Bechterew osteochondrosis HWS-syndrome, occipital syndrome, thoracic syndrome LWS-syndrome, lumbo-sacral syndrome discus prolapse Arthroses 44 9 24 9 2 Arthritides 2 31 l 1 Neuralgias, neuritis 46 14 24 5 I 3 Abdominal rheumatisms 22 8 l2 2 Periarthritides l4 5 5 2 2 Post-traumatic conditions 24 30 l Total 413 111 241 37 24 In 82.2 percent of these cases the results observed by the examining physicians were listed as either very good or good. The extraordinary analgesic effects achieved are particularly evident in the category of post-traumatic conditions. The treatment results obtained in other typical categories of the rheumatoid group indicates that the antirheumatic effects of phenyl butazone in the disclosed combination fully match previously observed effects of treatment with phenyl butazone in its known large dosage, even though its dosage in the disclosed combination is substantially reduced.
It has thus become possible to offer successful antirheumatic therapy, in spite of a reduction of the phenyl butazone dosage to one-third of its previously required dosage.
I claim:
1. Drug composition having an antirheumatic and analgesic indication containing as active ingredients dextropropoxyphene and phenyl butazone in moleratio between 1 to l and l to 8.
2. The drug composition of claim 1 wherein the mole ratio of dextro-propoxyphene to phenyl butazone is between 1 to l and 1 to 4.
3. The drug composition of claim 1 wherein the mole ratio of dextro-propoxyphene to phenyl butazone is l 4. The method of treating rheumatic disorder which
Claims (6)
1. Drug composition having an antirheumatic and analgesic indication containing as active ingredients dextropropoxyphene and phenyl butazone in mole ratio between 1 to 1 and 1 to 8.
2. The drug composition of claim 1 wherein the mole ratio of dextro-propoxyphene to phenyl butazone is between 1 to 1 and 1 to
3. The drug composition of claim 1 wherein the mole ratio of dextro-propoxyphene to phenyl butazone is 1 to 2.
4. THE METHOD OF TREATING RHEUMATIC DISORDER WHICH COMPRISES ADMINISTERING TO A PATIENT SUFERING FROM RHEUMATIC DISORDER AN EFFECTIVE ANTIRHEUMATIC AND ANALGESIC AMOUNT OF DEXTRO-PROPOXYPHENE AND PHENYL BUTAZONE IN MOLE RATIO BETWEEN 1 TO 1 AND 1 TO 8 AS ACTIVE INGREDIENTS.
5. The process of claim 4 wherein the mole ratio of dextro-propoxyphene to phenyl butazone is between 1 to 1 and 1 to 4.
6. The process of claim 4 wherein the mole ratio of dextro-propoxyphene to phenyl butazone is 1 to 2.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2220500A DE2220500C3 (en) | 1972-04-26 | 1972-04-26 | analgesic |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3890444A true US3890444A (en) | 1975-06-17 |
Family
ID=5843353
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US354558A Expired - Lifetime US3890444A (en) | 1972-04-26 | 1973-04-26 | Drug composition |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US3890444A (en) |
| AT (1) | AT331967B (en) |
| AU (1) | AU5504873A (en) |
| BE (1) | BE798758A (en) |
| CA (1) | CA1014473A (en) |
| DD (1) | DD102916A1 (en) |
| DE (1) | DE2220500C3 (en) |
| FR (1) | FR2182249B1 (en) |
| GB (1) | GB1431661A (en) |
| LU (1) | LU67498A1 (en) |
| NL (1) | NL160487C (en) |
| ZA (1) | ZA732847B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3482021A (en) * | 1965-07-01 | 1969-12-02 | Geigy Chem Corp | Anti-phlogistic and analgesic compositions and methods for relieving inflammatory conditions |
| US3749797A (en) * | 1971-07-02 | 1973-07-31 | Lilly Co Eli | Analgesic compositions |
-
1972
- 1972-04-26 DE DE2220500A patent/DE2220500C3/en not_active Expired
-
1973
- 1973-04-24 FR FR7316250*A patent/FR2182249B1/fr not_active Expired
- 1973-04-25 GB GB1952573A patent/GB1431661A/en not_active Expired
- 1973-04-26 ZA ZA732847A patent/ZA732847B/en unknown
- 1973-04-26 AT AT373873A patent/AT331967B/en not_active IP Right Cessation
- 1973-04-26 US US354558A patent/US3890444A/en not_active Expired - Lifetime
- 1973-04-26 LU LU67498A patent/LU67498A1/xx unknown
- 1973-04-26 NL NL7305850.A patent/NL160487C/en not_active IP Right Cessation
- 1973-04-26 DD DD170455A patent/DD102916A1/xx unknown
- 1973-04-26 BE BE130448A patent/BE798758A/en unknown
- 1973-04-26 CA CA170,092A patent/CA1014473A/en not_active Expired
- 1973-05-01 AU AU55048/73A patent/AU5504873A/en not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3482021A (en) * | 1965-07-01 | 1969-12-02 | Geigy Chem Corp | Anti-phlogistic and analgesic compositions and methods for relieving inflammatory conditions |
| US3749797A (en) * | 1971-07-02 | 1973-07-31 | Lilly Co Eli | Analgesic compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| LU67498A1 (en) | 1973-07-13 |
| AU5504873A (en) | 1974-11-07 |
| DE2220500B2 (en) | 1980-06-19 |
| CA1014473A (en) | 1977-07-26 |
| GB1431661A (en) | 1976-04-14 |
| ZA732847B (en) | 1974-03-27 |
| ATA373873A (en) | 1975-12-15 |
| FR2182249B1 (en) | 1976-07-02 |
| AT331967B (en) | 1976-09-10 |
| NL160487C (en) | 1979-11-15 |
| DE2220500A1 (en) | 1973-11-08 |
| DD102916A1 (en) | 1974-01-05 |
| BE798758A (en) | 1973-10-26 |
| NL160487B (en) | 1979-06-15 |
| FR2182249A1 (en) | 1973-12-07 |
| NL7305850A (en) | 1973-10-30 |
| DE2220500C3 (en) | 1981-02-26 |
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