US2683106A - Analgesic composition - Google Patents
Analgesic composition Download PDFInfo
- Publication number
- US2683106A US2683106A US107389A US10738949A US2683106A US 2683106 A US2683106 A US 2683106A US 107389 A US107389 A US 107389A US 10738949 A US10738949 A US 10738949A US 2683106 A US2683106 A US 2683106A
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- United States
- Prior art keywords
- morphine
- narcotic
- codeine
- group
- narcotics
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 44
- 230000000202 analgesic effect Effects 0.000 title claims description 13
- 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 claims description 52
- 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 claims description 37
- 239000000126 substance Substances 0.000 claims description 29
- 230000003533 narcotic effect Effects 0.000 claims description 28
- 229960005181 morphine Drugs 0.000 claims description 21
- 229960004126 codeine Drugs 0.000 claims description 18
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 18
- 239000000021 stimulant Substances 0.000 claims description 16
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 claims description 14
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 14
- 230000004936 stimulating effect Effects 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 8
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 claims description 8
- MXYUKLILVYORSK-UHFFFAOYSA-N (+/-)-allo-lobeline Natural products C1CCC(CC(=O)C=2C=CC=CC=2)N(C)C1CC(O)C1=CC=CC=C1 MXYUKLILVYORSK-UHFFFAOYSA-N 0.000 claims description 6
- MXYUKLILVYORSK-HBMCJLEFSA-N (-)-lobeline Chemical compound C1([C@@H](O)C[C@H]2N([C@H](CCC2)CC(=O)C=2C=CC=CC=2)C)=CC=CC=C1 MXYUKLILVYORSK-HBMCJLEFSA-N 0.000 claims description 6
- 229960002339 lobeline Drugs 0.000 claims description 6
- 229930013610 lobeline Natural products 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 229960001410 hydromorphone Drugs 0.000 claims description 5
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- DFIYTRTXUYWZSK-UHFFFAOYSA-N 4-cyclohexyl-3-ethyl-1,2,4-triazole Chemical compound CCC1=NN=CN1C1CCCCC1 DFIYTRTXUYWZSK-UHFFFAOYSA-N 0.000 claims 1
- 239000004081 narcotic agent Substances 0.000 description 20
- 230000000694 effects Effects 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 12
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000011287 therapeutic dose Methods 0.000 description 7
- 239000000729 antidote Substances 0.000 description 6
- 230000000954 anitussive effect Effects 0.000 description 5
- -1 4-cyclohexyl Chemical group 0.000 description 4
- ZTVIKZXZYLEVOL-MCOXGKPRSA-N Homatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(O)C1=CC=CC=C1 ZTVIKZXZYLEVOL-MCOXGKPRSA-N 0.000 description 4
- 229940124584 antitussives Drugs 0.000 description 4
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 4
- 229960000857 homatropine Drugs 0.000 description 4
- 206010011224 Cough Diseases 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 3
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 2
- GRZMOSSVIPFGFF-GNJLJDPWSA-N 2-[(2r,6s)-6-[(2s)-2-hydroxy-2-phenylethyl]-1-methylpiperidin-2-yl]-1-phenylethanone;sulfuric acid Chemical compound OS(O)(=O)=O.C1([C@@H](O)C[C@H]2N([C@H](CCC2)CC(=O)C=2C=CC=CC=2)C)=CC=CC=C1.C1([C@@H](O)C[C@H]2N([C@H](CCC2)CC(=O)C=2C=CC=CC=2)C)=CC=CC=C1 GRZMOSSVIPFGFF-GNJLJDPWSA-N 0.000 description 2
- 206010065929 Cardiovascular insufficiency Diseases 0.000 description 2
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
- 206010038678 Respiratory depression Diseases 0.000 description 2
- 206010070863 Toxicity to various agents Diseases 0.000 description 2
- 229940075522 antidotes Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960002319 barbital Drugs 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 229960004415 codeine phosphate Drugs 0.000 description 2
- 230000000881 depressing effect Effects 0.000 description 2
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical class C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229940127240 opiate Drugs 0.000 description 2
- 229960002085 oxycodone Drugs 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- IUAXSWPNEQYKDR-GXTZACRKSA-N (4R,4aR,7aR,12bS)-9-methoxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one 2,3-dihydroxybutanedioic acid dihydrate Chemical compound O.O.OC(C(O)C(O)=O)C(O)=O.COc1ccc2C[C@@H]3[C@@H]4CCC(=O)[C@@H]5Oc1c2[C@]45CCN3C IUAXSWPNEQYKDR-GXTZACRKSA-N 0.000 description 1
- LGFMXOTUSSVQJV-NEYUFSEYSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;(4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;1-[(3,4-dimethoxyphenyl)methyl]-6 Chemical compound Cl.Cl.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 LGFMXOTUSSVQJV-NEYUFSEYSA-N 0.000 description 1
- PLXBMOXFGRMADD-UHFFFAOYSA-N 1-methyl-4-phenylpiperidine-4-carboxylic acid;hydrochloride Chemical compound Cl.C1CN(C)CCC1(C(O)=O)C1=CC=CC=C1 PLXBMOXFGRMADD-UHFFFAOYSA-N 0.000 description 1
- ZISAYMMMXRIPMW-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;phenol Chemical compound OC1=CC=CC=C1.OC(=O)C(O)C(O)C(O)=O ZISAYMMMXRIPMW-UHFFFAOYSA-N 0.000 description 1
- AWFYPPSBLUWMFQ-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=C2 AWFYPPSBLUWMFQ-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 206010042464 Suicide attempt Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003179 convulsant agent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- XHILEZUETWRSHC-NRGUFEMZSA-N hydromorphone hydrochloride Chemical compound [H+].[Cl-].O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XHILEZUETWRSHC-NRGUFEMZSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- NPZXCTIHHUUEEJ-CMKMFDCUSA-N metopon Chemical compound O([C@@]1(C)C(=O)CC[C@@H]23)C4=C5[C@@]13CCN(C)[C@@H]2CC5=CC=C4O NPZXCTIHHUUEEJ-CMKMFDCUSA-N 0.000 description 1
- 229950006080 metopon Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- NCYVXEGFNDZQCU-UHFFFAOYSA-N nikethamide Chemical compound CCN(CC)C(=O)C1=CC=CN=C1 NCYVXEGFNDZQCU-UHFFFAOYSA-N 0.000 description 1
- 229960003226 nikethamide Drugs 0.000 description 1
- MUZQPDBAOYKNLO-RKXJKUSZSA-N oxycodone hydrochloride Chemical compound [H+].[Cl-].O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C MUZQPDBAOYKNLO-RKXJKUSZSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 210000001034 respiratory center Anatomy 0.000 description 1
- 239000003169 respiratory stimulant agent Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
Definitions
- This invention relates to analgesic and antitussive compositions. to analgesic and antitussive compositions which contain morphine or substances having a morphine-like effect, in mixture with certain other substances which act prophylactically to prevent or reduce the adverse effects of morphine and similar compounds on respiration and/or on the heart.
- the main object of my present invention is to provide analgesic and antitussive compositions containing morphine and similar drugs, said compositions causing less depression of respiration and heart rate than encountered in the use of known preparations of morphine and the like.
- Another object of my present invention is to provide analgesic and antitussive compositions containing morphine and similar drugs, which can be administered with safety in larger doses .than at present possible, thus producing relief for many of those patients who do not respond at all or do not respond well to the ordinary therapeutic doses of such drugs.
- a further object of my present invention is to provide analgesic compositions in which morphine or other drugs having an analgesic and/or cough relieving effect similar to that of morphine are present in mixtures with substances which have a stimulating effect on respiration and/ or on the heart.
- stimulants like pentamethylenetetrazol, nikethamide, etc., are likewise ad- Fur- It has particular relation 7 thermore, in conditions of circulatory or respiratory depression accompanied by pain or cough stimulants as Well as narcotics have been administered, but the stimulant was then given to treat the pre-existing conditions of circulatory or respiratory depression and not as an antidote to a toxic action of the narcotics.
- stimulants in therapeutic doses do not affect the normal heart rate or normal respiration, but when narcotics are combined with such stimulants in one dose and administered together, the stimulants are absorbed so fast, that they start their stimulating action, as soon as, or before the adverse symptoms of the narcotics ordinarily would appear.
- the stimulants provide normal or near normal gaseous interchange in the lungs which interchange is in risk of being reduced and the stimulants are instrumental in preventing or lessening slowing down of the circulation by the narcotics.
- the favorable effect of the stimulants is enhanced by the fact that their reaction time, i. e. the time between their administration and the start of the stimulant action, is shorter than the reaction time of the narcotics present in the compositions of my invention.
- the stimulating effect lasts long enough to insure normal or near normal functioning of heart and respiration until the action of the narcotics ebbs off.
- the therapeutic doses of the stimulants usually recommended in narcotic poisoning are not required when the stimulant is given simultaneously with the opiate or compound having a similar action according to the present invention.
- the quick absorption of the stimulants which I have used insures immediate antagonistic action so that the paralyzing effect of the narcotics cannot take hold of the organism.
- the damage caused between the advent of the toxic symptoms and the time required for the antidote to be administered and to take effect is elminated.
- the high solubility of the stimulant provides the presence of the antidote in the circulatory system before the poisoning begins to act thus reducing the required amount of the antidote substantially as compared with the administration of the stimulant once the narcotic has taken effect.
- morphine, morphine-derivatives, and other substances having a morphine-like analgesic and/or antitussive effect such as codeine, codeine derivatives, l-methyl l-phenyl piperidine l-carboxylic acid ethyl ester and its salts, such as the hydrochloride, 2-dimethylamino-4,4-diphenyl heptanone-5, or its salts, pantopon, methyl-dihydro morphinone or its salts and the like are used.
- These substances are administered according to the present invention in mixture with substances which stimulate the heart and/ or the respiratory center and have a high solubility in water, lipoids and other body fluids.
- Examples of such substances are: pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline or its salts, i-cyclohexyl 3-ethyl 1,2,4-triazol, paramethyl-amino-ethanol phenol or its salts.
- Example 1 15 mg. of morphine sulfate is homogeneously mixed with 40 mg. pentamethyle-netetrazol and the mixture is administered preferably in dissolved form by injection.
- Example 2 100 mg. of ethyl l-methyl-4 phenyl-piperidine- 4-carboxylate hydrochloride is dissolved in 1 cc. of a 25% by weight aqueous solution of pyridinebeta-carboxylic acid diethylamide and the mixture is administered orally or parenterally.
- Example 4 4 mg. of dihydromorphinone hydrochloride is mixed with 0.5 mg. of dihydromorphinone homatropine terephthalate and 60 mg. of pentamethylenetetrazol and the mixture injected.
- Example 5 4.5 mg. of dihydroxycodeinone hydrochloride is mixed with 0.75 mg. of dihydrohydroxycodeinone homatropine terephthalate and 25 mg. of pentamethylenetetrazol and by preference administered orally. 7
- Example 6 10 mg. of codeine phosphate is mixed with mg. of codeine-sodium diethylbarbiturate and 50 mg. of para-methylamine-ethanol-phenol tartrate and taken in a capsule.
- compositions embodying my invention are administered by injections of the dissolved compositions or given by mouth or in the form of a suppository rectally.
- narcotic substance or narcotic component is used in the present specification and claims to denote morphine, morphine derivatives and other natural or synthetic compounds having a morphinelike therapeutic effect.
- a new analgesic composition in which a narcotic component selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine is present in mixture with at least one compound selected from the group of substances stimulating respiration and substances stimulating the heart, said stimulants being easily soluble in water and selected from the group consisting of pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline and its salts, 4-cyclohexyl 3-ethyl l,2/i-triazol, paramethylamine-ethanol phenol and its salts said composition containing the narcotic component and the stimulant in a proportion substantially corresponding to the ratio of 3.75 parts by weight of dihydromorphinone to not more than 60 parts by weight of pentamethylenetetrazol.
- a new analgesic composition in which a narcotic component selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine is present in mixture with at least one compound selected from the group of substances stimulating respiration and substances stimulating the heart, said stimulants being easily soluble in water and selected from the group consisting of pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline and its salts, i-cyclohexyl 3-ethy1 1,2,4-triazol, paramethylamine-ethanol phenol and its salts, the amount of stimulant per therapeutic dose of the composition being smaller than the therapeutic dose for the adult patient, of the stimulant.
- a composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and pentamethylenetetrazol.
- a composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and pyridine-beta-carboxylic acid diethylamide.
- a composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and a substance selected from the group consisting of lobeline and salts thereof.
- a composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and a substance. selected from the group consisting of para-methylamino-ethano1phenol and salts thereof.
- composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and 4-cyclohexyl 3-ethy1 1,2,4-tria'zol.
- composition as claimed in claim 1, in which a morphine salt is used as the narcotic component.
- composition as claimed in claim 1 in which a mixture of a simple salt of dihydromorphinone with dihydromorphinone homatropine weight of morphine to about 40 parts 'by weight of pentamethylenetetrazol.
- a composition as claimed in claim 1 containing as the narcotic ingredient 1-methyl-4 phenyl-piperidine 4-carboxylate hydrochloride and as the stimulant pyridine-beta-carboxylic acid diethylamide, in the proportion of about 87.14 parts by weight of 1-methyl-4 phenylpiperidineA-carboxylate to about 25 parts by weight of pyridine-beta-carboxylic acid diethylamide.
- a composition as claimed in claim 1, containing as the narcotic compound dihydrohydroxycodeinone hydrochloride, and dihydrohydroxycodeinone homatropine terephthalate and as the stimulant pentamethylenetetrazol, in the proportion of a total amount of about 4.65 parts by Weight of dihydrohydroaycodeinone to about 25 parts by weight of pentamethylenetetrazol.
Description
ministered as restoratives and antidotes.
Patented July 6, 1 954 ANALGESIC COMPOSITION Mozes J uda Lewenstein, Kew Gardens, N. Y.
No Drawing.
Application July 28, 1949,
Serial No. 107,389
16 Claims. 1
This invention relates to analgesic and antitussive compositions. to analgesic and antitussive compositions which contain morphine or substances having a morphine-like effect, in mixture with certain other substances which act prophylactically to prevent or reduce the adverse effects of morphine and similar compounds on respiration and/or on the heart.
The main object of my present invention is to provide analgesic and antitussive compositions containing morphine and similar drugs, said compositions causing less depression of respiration and heart rate than encountered in the use of known preparations of morphine and the like.
Another object of my present invention is to provide analgesic and antitussive compositions containing morphine and similar drugs, which can be administered with safety in larger doses .than at present possible, thus producing relief for many of those patients who do not respond at all or do not respond well to the ordinary therapeutic doses of such drugs.
A further object of my present invention is to provide analgesic compositions in which morphine or other drugs having an analgesic and/or cough relieving effect similar to that of morphine are present in mixtures with substances which have a stimulating effect on respiration and/ or on the heart.
Other objects and the advantages of the invention will be apparent from the appended claims and the following specification, which describes some embodiments of the invention.
It is known that in addition to their clinical, useful effects, morphine and drugs having similar action have a depressing effect on respiration anda slowing effect on the heart. These effects represent serious drawbacksin the clinical use of morphine and similar drugs and have often caused dangerous complications in cases of overdoses.
To counteract such dangerous complications, it is a well known practice to administer substances stimulating respiration and/or the heart as antidotes in cases of drug poisoning (barbiturates, opiates, etc). This action is followed when too large a dose of narcotics, etc., has been taken by patients inadvertently; or advertently in suicide attempts. However, it also frequently happens that heart rate or respiration will respond unfavorably to therapeutic doses of narcotics. In such instances, stimulants like pentamethylenetetrazol, nikethamide, etc., are likewise ad- Fur- It has particular relation 7 thermore, in conditions of circulatory or respiratory depression accompanied by pain or cough stimulants as Well as narcotics have been administered, but the stimulant was then given to treat the pre-existing conditions of circulatory or respiratory depression and not as an antidote to a toxic action of the narcotics.
The need for narcotics with less depressing influence on heart rate and respiration has been urgently felt. Many compounds have been synthesized with this purpose in mind and many combinations tried without achieving the desired result.
In studying this problem I tried to find another solution. I did not look for new narcotics Without the undesirable side effects, but I concentrated on the possibility of neutralizing such effects in our existing drugs. I reasoned that once the narcotics are administered, the untoward reactions are bound to occur unless a substance is present in the body, which will not affect the therapeutically useful action of the narcotics, but which may hamper or inhibit the unwished for effects. In addition such a substance should otherwise not exert any action. In looking for such a compound I have now found that the high solubility in water, lipoids,
and other body fluids of a number of heart and respiration stimulants enables me to prevent completely or to a great extent the mentioned adverse effects on the respiration and the heart rate of therapeutic doses of morphine and substances having a similar effect. Such stimulants in therapeutic doses do not affect the normal heart rate or normal respiration, but when narcotics are combined with such stimulants in one dose and administered together, the stimulants are absorbed so fast, that they start their stimulating action, as soon as, or before the adverse symptoms of the narcotics ordinarily would appear. The stimulants provide normal or near normal gaseous interchange in the lungs which interchange is in risk of being reduced and the stimulants are instrumental in preventing or lessening slowing down of the circulation by the narcotics. The favorable effect of the stimulants is enhanced by the fact that their reaction time, i. e. the time between their administration and the start of the stimulant action, is shorter than the reaction time of the narcotics present in the compositions of my invention. The stimulating effect lasts long enough to insure normal or near normal functioning of heart and respiration until the action of the narcotics ebbs off.
In severe cases of pain and cough the relief obtained from the usual maximum doses of narcotics often is quite insuflicient. It has now been found possible to increase the doses of narcotics considerably without endangering the lives of the patients, provided the narcotics are administered in mixtures according to my invention. Thus it is possible to provide much more profound relief than was possible hitherto.
In animal experiments it was found that the lethal dose of such mixtures does not depend upon the amount of narcotics but is determined by the convulsant amount of the stimulant. In clinical use on human beings many thousands of doses of combinations of narcotics and stimulants according to this invention have been given without any serious depression of heart rate or respiration having been reported by any of the numerous hospitals and clinics, where these mixtures have been investigated.
Quite unexpectedly I found that the therapeutic doses of the stimulants usually recommended in narcotic poisoning are not required when the stimulant is given simultaneously with the opiate or compound having a similar action according to the present invention. The quick absorption of the stimulants which I have used insures immediate antagonistic action so that the paralyzing effect of the narcotics cannot take hold of the organism. In addition, the damage caused between the advent of the toxic symptoms and the time required for the antidote to be administered and to take effect is elminated. With simultaneous administration the high solubility of the stimulant provides the presence of the antidote in the circulatory system before the poisoning begins to act thus reducing the required amount of the antidote substantially as compared with the administration of the stimulant once the narcotic has taken effect.
In carrying out the present invention, morphine, morphine-derivatives, and other substances having a morphine-like analgesic and/or antitussive effect, such as codeine, codeine derivatives, l-methyl l-phenyl piperidine l-carboxylic acid ethyl ester and its salts, such as the hydrochloride, 2-dimethylamino-4,4-diphenyl heptanone-5, or its salts, pantopon, methyl-dihydro morphinone or its salts and the like are used. These substances are administered according to the present invention in mixture with substances which stimulate the heart and/ or the respiratory center and have a high solubility in water, lipoids and other body fluids. Examples of such substances are: pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline or its salts, i-cyclohexyl 3-ethyl 1,2,4-triazol, paramethyl-amino-ethanol phenol or its salts.
Example 1 15 mg. of morphine sulfate is homogeneously mixed with 40 mg. pentamethyle-netetrazol and the mixture is administered preferably in dissolved form by injection.
Example 2 100 mg. of ethyl l-methyl-4 phenyl-piperidine- 4-carboxylate hydrochloride is dissolved in 1 cc. of a 25% by weight aqueous solution of pyridinebeta-carboxylic acid diethylamide and the mixture is administered orally or parenterally.
Eatample 3 5 mg. of dihydrocodeinone bitartrate is di"- solved in 1 cc. of an aqueous solution containing 5 mg. lobeline sulfate and preferably given by mouth.
Example 4 4 mg. of dihydromorphinone hydrochloride is mixed with 0.5 mg. of dihydromorphinone homatropine terephthalate and 60 mg. of pentamethylenetetrazol and the mixture injected.
Example 5 4.5 mg. of dihydroxycodeinone hydrochloride is mixed with 0.75 mg. of dihydrohydroxycodeinone homatropine terephthalate and 25 mg. of pentamethylenetetrazol and by preference administered orally. 7
Example 6 10 mg. of codeine phosphate is mixed with mg. of codeine-sodium diethylbarbiturate and 50 mg. of para-methylamine-ethanol-phenol tartrate and taken in a capsule.
The compositions embodying my invention are administered by injections of the dissolved compositions or given by mouth or in the form of a suppository rectally.
It will be understood from the above description that the invention is not limited to the specific substances and process steps described above and may be carried out with various modifications without departing from the scope of the invention as defined in the appended claims. For example, instead of the analgesic substances and the stimulants specifically mentioned in the examples, other substances having a substantially similar eiiect, or mixtures of several such sub stances may be used, and compounds having no adverse effects on the therapeutically useful action of the narcotics and the stimulants used, for example, antispasmodics, may be added to the mixtures embodying the invention.
It is to be understood that the term narcotic substance or narcotic component is used in the present specification and claims to denote morphine, morphine derivatives and other natural or synthetic compounds having a morphinelike therapeutic effect.
What I claim is:
1. A new analgesic composition in which a narcotic component selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine is present in mixture with at least one compound selected from the group of substances stimulating respiration and substances stimulating the heart, said stimulants being easily soluble in water and selected from the group consisting of pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline and its salts, 4-cyclohexyl 3-ethyl l,2/i-triazol, paramethylamine-ethanol phenol and its salts said composition containing the narcotic component and the stimulant in a proportion substantially corresponding to the ratio of 3.75 parts by weight of dihydromorphinone to not more than 60 parts by weight of pentamethylenetetrazol.
2. A new analgesic composition in which a narcotic component selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine is present in mixture with at least one compound selected from the group of substances stimulating respiration and substances stimulating the heart, said stimulants being easily soluble in water and selected from the group consisting of pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline and its salts, i-cyclohexyl 3-ethy1 1,2,4-triazol, paramethylamine-ethanol phenol and its salts, the amount of stimulant per therapeutic dose of the composition being smaller than the therapeutic dose for the adult patient, of the stimulant.
3. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and pentamethylenetetrazol.
4. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and pyridine-beta-carboxylic acid diethylamide.
5. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and a substance selected from the group consisting of lobeline and salts thereof.
6. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and a substance. selected from the group consisting of para-methylamino-ethano1phenol and salts thereof.
7. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and 4-cyclohexyl 3-ethy1 1,2,4-tria'zol.
8. A composition, as claimed in claim 1, in which a morphine salt is used as the narcotic component.
9. A' composition as claimed in claim 1, in which a dihydrocodeinone salt is used as the narcotic component.
10. A composition as claimed in claim 1, in which a mixture of a simple salt of dihydromorphinone with dihydromorphinone homatropine weight of morphine to about 40 parts 'by weight of pentamethylenetetrazol.
13. A composition as claimed in claim 1 containing as the narcotic ingredient 1-methyl-4 phenyl-piperidine 4-carboxylate hydrochloride and as the stimulant pyridine-beta-carboxylic acid diethylamide, in the proportion of about 87.14 parts by weight of 1-methyl-4 phenylpiperidineA-carboxylate to about 25 parts by weight of pyridine-beta-carboxylic acid diethylamide.
14. A composition as claimed in claim 1, containing as the narcotic compound dihydrocodeinone bitartrate and as the stimulant lobeline sulfate, in the proportion of about 302 parts by weight of dihydrocodeinone to about 4.3 parts by weight of lobeline.
15. A composition as claimed in claim 1,containing as the narcotic compound dihydrohydroxycodeinone hydrochloride, and dihydrohydroxycodeinone homatropine terephthalate and as the stimulant pentamethylenetetrazol, in the proportion of a total amount of about 4.65 parts by Weight of dihydrohydroaycodeinone to about 25 parts by weight of pentamethylenetetrazol.
16. A composition as claimed in claim 1, containing as the narcotic component codeine phosphate and codeine sodium diethylbarbiturate and as the stimulant para-methylamine-ethanol phenol tartrate, in the proportion of a total amount of about 14.40 parts of codeine to about 50.0 parts by weight or" para-methylamine-ethanol phenol.
References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,027,722 Diehl Jan. 14, 1936 2,369,711 Blythe Feb. 20, 1945 FOREIGN PATENTS Number Country Date 14,961 Great Britain of 1895 OTHER REFERENCES A., Mar. 19, 1949, pages
Claims (1)
1. A NEW ANALGESIC COMPOSITION IN WHICH A NARCOTIC COMPONENT SELECTED FROM THE GROUP CONSISTING OF MORPHINE, CODEINE AND NARCOTIC DERIVATIVES OF MORPHINE AND CODIENE IS PRESENT IN MIXTURE WITH AT LEAST ONE COMPOUND SELECTED FROM THE GROUP OF SUBSTANCES STIMULATING RESPIRATION AND SUBSTANCES STIMULATING THE HEART, SAID STIMULANTS BEING EASILY SOLUBLE IN WATER AND SELECTED FROM THE GROUP CONSISTING OF PENTAMETHYLENETETRAZOL, PYRIDINE BETA-CARBOXYLIC ACID DIETHYLAMIDE, LOBELINE AND ITS SALTS, 4-CYCLOHEXYL 3-ETHYL 1,2,4-TRIAZOL, PARAMETHYLAMINE-ETHANOL PHENOL AND ITS SALTS SAID COMPOSITION CONTAINING THE NARCOTIC COMPONENT AND THE STIMULANT IN A PROPORTION SUBSTANTIALLY CORRESPONDING TO THE RATIO OF 3.75 PARTS BY WEIGHT OF DIHYDROMORPHINONE TO NOT MORE THAN 60 PARTS BY WEIGHT OF PENTAMETHYLENETETRAZOL.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US107389A US2683106A (en) | 1949-07-28 | 1949-07-28 | Analgesic composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US107389A US2683106A (en) | 1949-07-28 | 1949-07-28 | Analgesic composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2683106A true US2683106A (en) | 1954-07-06 |
Family
ID=22316397
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US107389A Expired - Lifetime US2683106A (en) | 1949-07-28 | 1949-07-28 | Analgesic composition |
Country Status (1)
| Country | Link |
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| US (1) | US2683106A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2770569A (en) * | 1952-08-01 | 1956-11-13 | Hoffmann La Roche | Analgesic compositions |
| DE1067549B (en) * | 1957-10-01 | 1959-10-22 | Bayer Ag | Lacquer solutions, especially stoving or wire lacquers |
| US3203962A (en) * | 1962-10-11 | 1965-08-31 | Ciba Geigy Corp | Alpha-phenyl-beta pyrrolidino-propiophenones |
| US3493657A (en) * | 1961-03-14 | 1970-02-03 | Mozes Juda Lewenstein | Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB189514961A (en) * | 1895-08-08 | 1895-10-12 | Otto Pfennig | Remedy against Sea-sickness. |
| US2027722A (en) * | 1934-04-04 | 1936-01-14 | Univ Minnesota Board Of | Therapeutic agent |
| US2369711A (en) * | 1942-03-17 | 1945-02-20 | Smith Kline French Lab | Medicinal preparation |
-
1949
- 1949-07-28 US US107389A patent/US2683106A/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB189514961A (en) * | 1895-08-08 | 1895-10-12 | Otto Pfennig | Remedy against Sea-sickness. |
| US2027722A (en) * | 1934-04-04 | 1936-01-14 | Univ Minnesota Board Of | Therapeutic agent |
| US2369711A (en) * | 1942-03-17 | 1945-02-20 | Smith Kline French Lab | Medicinal preparation |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2770569A (en) * | 1952-08-01 | 1956-11-13 | Hoffmann La Roche | Analgesic compositions |
| DE1067549B (en) * | 1957-10-01 | 1959-10-22 | Bayer Ag | Lacquer solutions, especially stoving or wire lacquers |
| US3493657A (en) * | 1961-03-14 | 1970-02-03 | Mozes Juda Lewenstein | Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine |
| US3203962A (en) * | 1962-10-11 | 1965-08-31 | Ciba Geigy Corp | Alpha-phenyl-beta pyrrolidino-propiophenones |
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