|Publication number||USRE39300 E1|
|Application number||US 09/880,881|
|Publication date||Sep 19, 2006|
|Filing date||Jun 15, 2001|
|Priority date||Jan 28, 1993|
|Publication number||09880881, 880881, US RE39300 E1, US RE39300E1, US-E1-RE39300, USRE39300 E1, USRE39300E1|
|Inventors||David J. Mayer, Jianren Mao|
|Original Assignee||Virginia Commonwealth University Medical College Of Virginia|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (74), Non-Patent Citations (32), Referenced by (6), Classifications (19), Legal Events (1)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This is a continuation of application Ser. No. 08/043,280 filed Apr. 6, 1993, now U.S. Pat. No. 5,321,012, which is a continuation-in-part of U.S. patent application Ser. No. 08/010,583, filed Jan. 28, 1993, abandoned.
This invention relates to a composition containing an addictive substance and a component which inhibits the development of tolerance to and/or dependence on the addictive substance. More particularly, the invention relates to a composition containing an addictive substance such as morphine or codeine and at least one nontoxic substance that blocks the N-methyl-D-aspartate (NMDA) receptor, e.g., a morphinan such as dextromethorphan or dextrorphan, or that blocks at least one major intracellular consequence of NMDA receptor activation, e.g., a ganglioside such as ganglioside GM1 or GT1b, a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide.
Morphine is a rapid and effective drug for the treatment of severe pain but its long term administration has been limited due to its negative side effects, principally tolerance and dependence, which develop rapidly after administration. In an effort to make morphine of greater use in the treatment of pain, it has been combined with a variety of substances intended to inhibit one or more of its undesirable side effects. U.S. Pat. No. 2,770,569 describes the combination of morphine with the compound levo-d-hydroxy-N-allyl-morphinan which is said to suppress or eliminate such undesirable side reactions of morphine as depression, nausea and vomiting. U.S. Pat. No. 4,126,684 discloses reducing either the addiction liability of an addictive substance such as a narcotic analgesic or a barbiturate or the withdrawal symptoms caused by deprivation of such a substance in an addicted subject by administering the addictive substance, e.g., morphine, with a 4-amino-3-p-halophenylbutyric acid. U.S. Pat. No. 4,415,871 describes the prevention of treatment tolerance and physical dependence in chronic morphine treatment by combining the morphine with any of the specific dipeptides indicated therein. U.S. Pat. No. 5,041,446 discloses inhibiting the development of tolerance to morphine by combining the morphine with dapiprazole. U.S. Pat. No. 5,057,519 achieves a reduction in morphine tolerance by combining the morphine with a benzamide antagonist for a subtype of the serotonin receptor, 5-HT3. Trujillo et al., “Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801”, Science, 251 (4989), pp. 85-87, Jan. 4, 1991; Tanganelli et al., “Glutamate antagonists prevent morphine withdrawal in mice and guinea pigs”, Neuroscience Letters, 122(2), pp. 270-272, Jan. 28, 1991; Marek et al., “Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat”, Brain Research, 547(1), pp. 77-81, Apr. 26, 1991; and, Marek et al., “Delayed application of MK-801 attenuates development of morphine tolerance in rats, Brain Research, 558(1), pp. 163-165, Aug. 30, 1991 discuss the role of MK-801 (the compound 5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine), an NMDA receptor antagonist or blocker, in reducing morphine dependence in laboratory animals. However, MK-801 has been found to be toxic and is therefore unsuitable for pharmaceutical use.
In accordance with the present invention, a composition is provided which comprises an addictive substance and at least one nontoxic substance that blocks the N-methyl-D-aspartate receptor or at least one major intracellular consequence of N-methyl-D-aspartate receptor activation.
Further in accordance with the present invention, a method of inhibiting the development of tolerance to and/or dependence on an addictive substance administered to a mammal which is liable to addiction thereto is provided which comprises administering the addictive substance to the mammal before, with or following administration to the mammal of a tolerance-reducing and/or dependence-reducing amount of at least one non-toxic substance that blocks the N-methyl-D-aspartate receptor or at least one major intracellular consequence of N-methyl-D-aspartate receptor activation.
Still further in accordance with this invention, a method of alleviating withdrawal symptoms in a mammal addicted to an addictive substance is provided which comprises administering to the addicted mammal the addictive substance before, with or following administration to the mammal of a dependence-reducing amount of at least one nontoxic substance that blocks the N-methyl-D-aspartate receptor or the intracellular consequences of N-methyl-D-aspartate receptor activation thereby alleviating withdrawal symptoms when the addictive substance is withdrawn from the mammal.
The term “nontoxic” as used herein shall be understood in a relative sense and is intended to designate any substance that has been approved by the United States Food and Drug Administration (“FDA”) for administration to humans or, in keeping with established criteria, is susceptible to approval by the FDA for administration to humans.
A particularly important category of addictive substances with which the present invention is concerned are the narcotic analgesics, e.g., opiates, opiate derivatives, opioids and their pharmaceutically acceptable salts. Specific examples of narcotic analgesics include alfentanyl, alphaprodine, anileridine, bezitramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphanol, metazocine, methadone, metopon, morphine, opium extracts, opium fluid extracts, powdered opium, granulated opium, raw opium, tincture of opium, oxycodone, oxymorphone, pethidine, phenazocine, piminodine, racemethorphan, racemorphan, thebainc and pharmaceutically acceptable salts thereof. For a detailed discussion of these and other narcotic analgesics, reference may be made to Jaffe et al., “Opioid Analgesics and Antagonists” in “Goodman and Gillman's Pharmacological Basis of Therapeutics”, Goodman et al., eds. 7th ed., 1985, MacMillan and Company, New York pp. 491-531.
Other addictive substances that can be utilized herein include acetorphine, acetyldihydrocodeine, acetylmethadol, allylprodine, alphracetylmethadol, alphameprodine, alphamethadol, benzethidine, benzylmorphine, betacetylmethadol, betameprodine, betamethadol, betaprodine, clonitazene, cocaine, codeine, methylbromide, codeine-N-oxide, cyprenorphine, desomorphine, dextromoramide, diampromide, diethylthiambutene, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiamubutene, dioxaphetyl butyrate, dipipanone, drotebanol, ethanol, ethylmethylthiambutene, eton itazene, etorphine, etoxeridine, furethidine, hydromorphinol, hydroxypethidine, ketobemidone, levomoramide, levophenacylmorphan, methyldesorphine, methyldihydromorphine, morpheridine, morphine methylpromide, morphine methylsulfonate, morphine-N-oxide, myrophine, nicocodeine, nicomorphine, nicotine, noracymethadol, norlevorphanol, normethadone, normorphine, norpipanone, phenadoxone, phenampromide, phenomorphtan, phenoperidine, piritramide, pholcodine, proheptazoine, properidine, propiran, racemoramide, thebacon, trimeperidine and the pharmaceutically acceptable salts thereof.
Still other addictive substances that can be utilized in the practice of the invention include the sedatives and hypnotics, e.g., benzodiazepines such as chlordiazepoxide, chlorazepate, diazepam, flurazepam, halazepam, ketazolam, borazepam, oxazepam, prazepam, temazepam, triazolam and the pharmaceutically acceptable salts thereof, barbiturates such as amobarbital, ambobarbital, barbital, butabartital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal and thiopental and the pharmaceutically acceptable salts thereof and other sedatives and hypnotics such as chloral hydrate, meprobamate, methaqualone, methyprylon and the pharmaceutically acceptable salts thereof.
By way of inhibiting the development of tolerance to and/or dependence on any of the foregoing and similarly addictive substances, the addictive substance is administered before, with or following the administration of at least one nontoxic substance that blocks the N-methyl-D-aspartate (NMDA) receptor or the intracellular consequences of N-methyl-D-aspartate receptor activation. Activation of the NMDA receptor, a subtype of excitatory amino acid receptors, induces a number of changes in the functional activity of nerve cells, and in particular, their capacity for excitability or inhibition in the presence of an addictive substance, via an increase in intracellular Ca++ concentration. The major consequences of NMDA receptor activation include the following sequences, or cascades, of events occurring within nerve cells:
A substance that blocks the NMDA receptor will effectively prevent all of the foregoing major intracellular sequences of events from taking place. However, even with activation of the NMDA receptor, it is still possible to inhibit the development of tolerance to and/or dependence on an addictive substance by combining the addictive substance with a substance that blocks at least one of the foregoing major intracellular sequences of events. Thus, e.g., a substance that interferes with translocation and activation of protein kinase C or with calmodulin induced activation of constitutive nitric oxide synthase as well as induction of inducible nitric oxide synthase is also useful for the practice of this invention.
Among the nontoxic substances that block the NMDA receptor and as such are useful in the practice of the present invention are morphinans such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) and dextrorphan ((+)-3-hydroxy-N-methylmorphinan), their mixtures and the pharmaceutically acceptable salts thereof. Other useful nontoxic substances that block the NMDA receptor include ketamine (2-(2-chlorophenyl)-2-(methylamino)cyclohexanone), pyrroloquinoline quinone and cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid.
Nontoxic substances that block a major intracellular consequence of NMDA receptor activation and are therefore useful in the practice of the invention include inhibitors of protein kinase C such as the gangliosides, in particular, ganglioside GM1 (monosialoganglioside) and ganglioside GT1b (trisialoganglioside); amphipathic long chain bases such as sphingosine, N,N,N-trimethylsphingosine, sphinganine and psychosine; quinolyloxazole-2 -ones such as 4-methyl-5-(3-quinolinyl)- 2-(3H)-oxazolone and phenyl-5-(2-quinolinyl)-2-3(3H)-oxazolone; 1,4-bis-(amino-hydroxyalkylamino)anthraquinones such as 1,4-bis-(3-propylamino-2-hydroxypropylamino)-9,10 anthracenedione and 1,4 -bis-(3-benzylamino-2-hydroxypropylamino)-9,10 anthracenedione; and, mixtures and pharmaceutically acceptable salts of any of the foregoing.
Additional nontoxic substances that block a major intracellular consequence of NMDA receptor activation and as such are useful in the practice of the invention include inhibitors of calmodulin such as the phenothiazines, in particular, chlorpromazine, chlorpromazine sulfoxide, prochlorperazine dimaleate, perphenazine, trifluoperazine, fluphenazine, fluphenazine enanthate, fluphenazine decanoate, thioridazine, mesoridazine besylate, piperacetazine, acetophenazine dimaleate, carphenazine dimaleate, butaperazine dimaleate and phenothiazine sulfoxide; naphthalenesulfonamides such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, N-(6-aminohexyl)-5-chloro-2-naphthalenesulfonamide and N-(6-aminohexyl)-5-bromo-2-naphthalenesul fonamide; 4 -substituted-4H,6H-pyrrolo[1, 2-a][4,1] benzoxazepines such as 1,3-dihydro-1-((1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1] benzoxazepin-4-yl)methyl]-4-piperidinyl}-2H-benzimidazol-2-one; benzhydryls such as N- (diphenylmethylthioehtyl]-2-(trifluoromethyl)benzeneethanamine, N-[2 -(bis(4 -fluorophenyl)methylthio)ethyl]-2-(trifluoromethyl)benzenethanamine and N-[2-(bis(4-fluorophenyl)methylthio)ethyl]-3-(trifluoromethyl)benzeneethanamine; tricyclic antidepressant drugs such as imipramine, 2 -chloroimipramine and amitriptyline; penfluridol; haloperidol; pimozide; clozapine; calmidazolin; and, mixtures and pharmaceutically acceptable salts of any of the foregoing.
Administration of the composition of this invention can be in the form of a single dosage unit containing both the addictive substance and the nontoxic substance that blocks the NMDA receptor or a major intracellular consequence of NMDA receptor activation or the two substances can be administered separately provided both are ultimately present in effective amounts in the patient. Introduction of the composition into the patient can be by way of oral administration or by intravenous, intramuscular, subcutanous, intrathecal, epidural or intracerebroventricular injection.
The preferred dosage of addictive substance and the nontoxic substance that blocks the NMDA receptor or a major intracellular consequence of NMDA receptor activation can vary widely, e.g., from about 0.25 to about 250 mg/day, but actual amounts will vary according to the particular active substances being used, the particular formulation containing the active substances and tile state and circumstances of the host being treated. As those skilled in the art recognize, many factors that modify the action of the active substances herein will be taken into account by the treating physician such as the age, body weight, sex, diet and condition of the subject, the time of administration, the rate and route of administration, and so forth. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage determination tests in view of the experimental data provided herein.
In alleviating withdrawal symptoms in addicted subjects deprived of the addictive substance, the substance that blocks the NMDA receptor or a major intracellular consequence of NMDA receptor activation can be administered to the subject, together with the addictive substance, at a dosage rate of about 0.25 to about 250 mg/day, again, specific dosage levels and routes of administration being selected in accordance with the subject's circumstances. As a result of this treatment, the subject will experience a reduced level of dependence on the addictive substance eventually reaching the point where total withdrawal of the substance will result in at most mild withdrawal symptoms.
The composition herein can be formulated as a liquid, powder, elixir, injectable solution, etc. Formulations for oral use can be provided as hard gelatin capsules wherein the composition is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the composition is mixed with an oleaginous medium, e.g., liquid paraffin or olive oil.
Aqueous suspensions can contain the composition in admixture with pharmaceutically acceptable excipients such as suspensing agents, e.g., sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrol idone, gum tragacanth and gum acacia, dispersing or wetting agents such as naturally occurring phosphatide, e.g., lecithin, or condensation products of an alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain al iphatic alcohols, e.g., heptadecaethyleneoxycetanol, or condensation products of ethylene exide with partial esters derived from fatty acids and a hexitol, e.g., polyoxyethylene sorbitol monoleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitan monooleate. Such aqueous suspensions can also contain one or more preservatives, e.g., ethyl- or n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or sodium or calcium cyclamate.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the composition in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, e.g., sweetening, flavoring and coloring agents, can also be present. Syrups and elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents.
The composition of this invention or either of its principal active ingredients can be provided in sustained release dosage form of which many kinds are known, e.g., as described in U.S. Pat. Nos. 4,788,055; 4,816,264; 4,828,836; 4,834,965; 4,834,985; 4,996,047; 5,071,646; and, 5,133,974, the contents of which are incorporated by reference herein.
The examples that follow are illustrative of the invention.
The effect of systemic dextrorphan on prevention of the development of morphine tolerance and dependence was examined in Sprague-Dawley rats weighing 350-400 gm. Morphine tolerance was developed in the rats by twice daily subcutaneous injection of 10 mg/kg morphine sulfate. The analgesic effect of the morphine was examined by using the well known tail-flick test which measures the latency of tail-flick upon radiant heat stimulation. The latency of tail-flick test is defined as the time elapsed from the onset of radiant heat to the flick of the rat's tail. In order to examine the effect of dextrorphan on the development of morphine tolerance, each morphine-treated rat also received intraperitoneal administration of either dextrorphan (1.56, 3.13, 6.25, 12.5 mg/kg, n=5/group) or saline (n=6) given 30 minutes prior to each morphine administration.
The effects of ganglioside GM1 in inhibiting morphine tolerance and dependence utilizing both systemic and intrathecal treatment were evaluated. The systemic treatment procedure, including both morphine and ganglioside GM1 administration, was exactly the same as that used in the experimental work presented in Example 1 except that ganglioside GM1 was given 1 hour before each morphine administration.
As shown in
This example demonstrates the effectiveness of ganglioside GM1 in preventing the development of morphine tolerance at the site of the spinal cord. Morphine sulfate 10 μg was delivered once daily through an intrathecal (spinal) canula implanted 5 days before the first morphine injection. Ganglioside GM1 or saline also was delivered intrathecally 30 minutes before each morphine injection.
The effects of ganglioside GM1 and the toxic NMDA receptor antagonist MK 801 on morphine tolerance were evaluated.
As shown in
These examples illustrate the effects of the phenothiazine trifluoperazine (Example 5) and the naphthalenesulfonamide N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (Example 6) in preventing the development of morphine tolerance in rats.
Calmodulin is an intracellular colactor necessary for the nitric oxide pathway that can be initiated upon NMDA receptor activation.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US2770569||Oct 15, 1952||Nov 13, 1956||Hoffmann La Roche||Analgesic compositions|
|US4126684||Dec 8, 1976||Nov 21, 1978||Ciba-Geigy Corporation||4-amino-3-p-halophenylbutyric acids and their derivatives used in the control of narcotic abuse|
|US4316888||Apr 15, 1980||Feb 23, 1982||Nelson Research & Development Co.||Method and composition of reducing pain|
|US4362870||Mar 19, 1981||Dec 7, 1982||Regents Of The University Of Minnesota||Selective opioid receptor alkylating agents|
|US4416871||Jan 11, 1982||Nov 22, 1983||The United States Of America As Represented By The Department Of Health And Human Services||Inhibition by peptides of tolerance to and physical dependence on morphine|
|US4446140||Mar 29, 1982||May 1, 1984||Nelson Research & Development Company||Method and composition for treating mouth pain|
|US4464378||Apr 28, 1981||Aug 7, 1984||University Of Kentucky Research Foundation||Method of administering narcotic antagonists and analgesics and novel dosage forms containing same|
|US4476141||Oct 27, 1983||Oct 9, 1984||University Of Georgia Research Foundation, Inc.||Use of N-(6 aminohexyl)-5-chloro-1-naphthalenesulfonamide, N-(6 aminohexyl)-5-chloro-2-naphthalenesulfonamide, and N-(6 aminohexyl)-5-bromo-2-naphthalenesulfonamide as vaginal contraceptives|
|US4602909||Feb 7, 1983||Jul 29, 1986||Richter Gedeon Vegyeszeti Gyar Rt||Iontophoresis intermediary material and contact solution for the treatment of chronic pain syndromes|
|US4758559||Jan 21, 1986||Jul 19, 1988||Ciba-Geigy Corporation||Pyrrolo[1,2-a] [4,1]benzoxazepine derivatives useful as calmodulin and histamine inhibitors|
|US4769372||Jun 18, 1986||Sep 6, 1988||The Rockefeller University||Method of treating patients suffering from chronic pain or chronic cough|
|US4785000||Nov 16, 1987||Nov 15, 1988||The Rockefeller University||Method of treating patients suffering from chronic pain or chronic cough|
|US4788055||Dec 9, 1985||Nov 29, 1988||Ciba-Geigy Corporation||Resinate sustained release dextromethorphan composition|
|US4806543||Nov 25, 1986||Feb 21, 1989||Board Of Trustees Of The Leland Stanford Junior University||Method and compositions for reducing neurotoxic injury|
|US4816264||Jun 6, 1986||Mar 28, 1989||Warner-Lambert Company||Sustained release formulations|
|US4816450||Sep 15, 1986||Mar 28, 1989||Duke University||Inhibition of protein kinase C by long-chain bases|
|US4828836||May 19, 1987||May 9, 1989||Euroceltique S.A.||Controlled release pharmaceutical composition|
|US4834965||Nov 12, 1987||May 30, 1989||Euroceltique, S.A.||Controlled release pharmaceutical composition|
|US4834985||May 19, 1987||May 30, 1989||Euroceltique S.A.||Controlled release pharmaceutical composition|
|US4876276||Oct 26, 1987||Oct 24, 1989||Yissum Research Development Co. Of The Hebrew University Of Jerusalem||(3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols|
|US4888347||Dec 24, 1986||Dec 19, 1989||Merck Sharp & Dohme Limited||Use of specific N-methyl-D-aspartate receptor antagonists in the prevention and treatment of neurodegeneration|
|US4906779||Aug 29, 1988||Mar 6, 1990||State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University||N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists|
|US4912114||Apr 14, 1989||Mar 27, 1990||Sandoz Ltd.||Morphinan derivatives|
|US4919916||Nov 21, 1988||Apr 24, 1990||Golwyn Daniel H||Treatment of neurotransmitter-linked drug abuse|
|US4924008||May 4, 1989||May 8, 1990||American Home Products Corporation||Benzobicycloalkane derivatives as anticonvulsant neuroprotective agents|
|US4937232||May 17, 1988||Jun 26, 1990||Duke University||Inhibition of protein kinase C by long-chain bases|
|US4942182||Mar 1, 1989||Jul 17, 1990||Weiss Susan R B||Treatment for cocaine addiction|
|US4959493||Apr 22, 1988||Sep 25, 1990||Suntory Limited||Carboxycyclopropylglycine and process for producing the same|
|US4975430||Jun 16, 1989||Dec 4, 1990||The State Of Oregon Acting By And Through The State Board Of Education On Behalf Of The Oregon Health Sciences University||CNQX and its analogs as therapeutics for degenerative neural diseases|
|US4990519||Feb 23, 1990||Feb 5, 1991||Merrell Dow Pharmaceuticals||Method of using quinolyloxazole-2-ones as proteinkinase C inhibitors|
|US4994446||Jan 3, 1989||Feb 19, 1991||Ramot - University Authority For Applied Research And Industrial Development Ltd.||Drug system|
|US4994467||May 31, 1989||Feb 19, 1991||Zimmerman Andrew W||Treating autism and other developmental disorders in children with NMDA receptor antagonists|
|US4996047||Nov 2, 1988||Feb 26, 1991||Richardson-Vicks, Inc.||Sustained release drug-resin complexes|
|US5006510||Jun 20, 1989||Apr 9, 1991||Ellis Wladislaw V||Method for relieving chronic pain with a somatostatin analog composition|
|US5013540||Nov 30, 1989||May 7, 1991||Board Of Regents, The University Of Texas System||Using NMDA receptor antagonists to reduce damage due to laser treatment|
|US5023239||May 11, 1987||Jun 11, 1991||Mect Corporation||Sialosyl cholesterol, process for producing the same, and neuropathy remedy comprising the same|
|US5028611||Jun 29, 1989||Jul 2, 1991||The Regents Of The University Of Minnesota||Treatment for cocaine use|
|US5028707||Nov 20, 1989||Jul 2, 1991||Board Of Regents, University Of Texas||4-hydroxyquinaldic acid derivatives|
|US5034395||Feb 24, 1987||Jul 23, 1991||Otsuka Pharmaceutical Co., Ltd.||Novel dihydropyridine derivatives|
|US5034400||Oct 20, 1989||Jul 23, 1991||Olney John W||Method for preventing neurotoxic side effects of NMDA antagonists|
|US5041446||Jun 6, 1989||Aug 20, 1991||Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.||Method for inhibiting the development of tolerance in the analgesic treatment with morphine|
|US5047229||Dec 17, 1986||Sep 10, 1991||Miles, Inc.||Treatment of cardiovascular and cerebral toxicity using calcium modulators|
|US5051426||Mar 27, 1990||Sep 24, 1991||Parnell Pharmaceuticals, Inc.||Method for effecting withdrawal from drug dependency|
|US5051442||Apr 25, 1990||Sep 24, 1991||Merrell Dow Pharmaceuticals Inc.||3-indolyl thioacetate derivatives and NMDA receptor antagonistic use thereof|
|US5055481||Mar 22, 1990||Oct 8, 1991||Wakamoto Pharmaceutical Co., Ltd.||Tetrazole derivatives and aldose reductase inhibition therewith|
|US5057519||Jun 11, 1990||Oct 15, 1991||Bristol-Myers Squibb Company||5-HT3 antagonists: use in reducing opiate tolerance|
|US5068228||Aug 11, 1988||Nov 26, 1991||Koehler Gernot||Use of a metal chelate of an alkylaminoester of phosphoric acid for prophytlaxis or therapy of a neuropathy|
|US5071646||Nov 9, 1989||Dec 10, 1991||Euroceltique, S.A.||Pharmaceutical ion exchange resin composition|
|US5075341||Dec 1, 1989||Dec 24, 1991||The Mclean Hospital Corporation||Treatment for cocaine abuse|
|US5091391||Aug 16, 1990||Feb 25, 1992||University Of Pittsburgh Of The Commonwealth System Of Higher Education||Method of resisting neurodegenerative disorders|
|US5093129||Jan 30, 1989||Mar 3, 1992||E. R. Squibb & Sons, Inc.||Method for treating addiction to a drug of abuse employing an ace inhibitor|
|US5093525||Mar 2, 1990||Mar 3, 1992||State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University||N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists|
|US5095009||Jul 20, 1990||Mar 10, 1992||Merrell Dow Pharmaceuticals Inc.||NMDA antagonists|
|US5106847||Aug 1, 1991||Apr 21, 1992||Merrell Dow Pharmaceuticals Inc.||Excitatory amino acid antagonists, compositions and use|
|US5109017||Sep 26, 1990||Apr 28, 1992||Fisons Corporation||(2-thienyl)alkylamine derivatives having neuroprotective properties|
|US5118675||Feb 15, 1991||Jun 2, 1992||American Home Products Corporation||Quinoxaline phosphono-amino acids|
|US5124319||Oct 11, 1991||Jun 23, 1992||American Home Products Corporation||Benzimidazole phosphono-amino acids|
|US5124340||Jun 28, 1989||Jun 23, 1992||The United States Of America As Represented By The Department Of Health And Human Services||Use of calcium channel blocker to prevent cocaine induced craving and reinforcement|
|US5126330||Feb 1, 1991||Jun 30, 1992||Mect Corporation||Sialosyl cholesterol and neuropathy remedy comprising the same|
|US5133974||Jan 24, 1990||Jul 28, 1992||Kv Pharmaceutical Company||Extended release pharmaceutical formulations|
|US5137889||May 23, 1991||Aug 11, 1992||Otsuka Pharmaceutical Co., Ltd.||Dihydropyridine derivatives and process for preparing the same|
|US5137919||Dec 31, 1990||Aug 11, 1992||Biomembrane Institute||Effect of N,N,N,-trimethylsphingosine on protein kinase C activity melanoma cell growth in vitro; metastatic potential in vivo and human platelet aggregation|
|US5141957||Nov 5, 1990||Aug 25, 1992||Sphinx Pharmaceuticals Corporation||1,4-bis-(amino-hydroxyalkylamino)-anthraquinones for inhibiting protein kinase c|
|US5145842||Jul 30, 1990||Sep 8, 1992||Alder Research Center Limited Partnership||Protein kinase c. modulators. d.|
|US5151360||Jul 2, 1991||Sep 29, 1992||Biomembrane Institute||Effect of n,n,n-trimethylsphingosine on protein kinase-c activity, melanoma cell growth in vitro, metastatic potential in vivo and human platelet aggregation|
|US5166207||Jun 17, 1991||Nov 24, 1992||Neurotherapeutics, Inc.||Method for enhancing the systemic delivery of dextromethorphan for the treatment of neurological disorders|
|US5171752||Jul 19, 1991||Dec 15, 1992||Akzo N.V.||Benzhydryl derivatives having calmodulin inhibitor properties|
|US5183807||Jun 28, 1991||Feb 2, 1993||Fidia S.P.A.||Use of monosialoganglioside gm, to prevent the development of tolerance to the analgesic effect of morphine and related drugs|
|US5185329||Nov 14, 1991||Feb 9, 1993||Bristol-Myers Squibb Company||Method for treatment of substance addiction|
|US5190925||Feb 3, 1992||Mar 2, 1993||Fidia, S.P.A.||Use of gangliosides in the treatment of autonomic dysfunction in Chagas' disease|
|US5321012||Apr 6, 1993||Jun 14, 1994||Virginia Commonwealth University Medical College||Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance|
|US5352683||Mar 5, 1993||Oct 4, 1994||Virginia Commonwealth University Medical College Of Virginia||Method for the treatment of chronic pain|
|US5441982||Sep 24, 1993||Aug 15, 1995||Itzhak; Yossef||Therapeutics for management of cocaine induced toxicity|
|US5654281||Apr 26, 1995||Aug 5, 1997||Virginia Commonwealth University||Inhibiting the development of tolerance to and/or dependence on an addictive substance|
|1||Adams et al., "Emergency Intravenous Sedation of the Delirious, Medically Ill Patient," J. Clin. Psychiatry, 49:12 Suppl., pp. 23-27 (1988).|
|2||Ben-Eliyahu et al., "The NMDA receptor antagonist MK-801 prevents long-lasting non-associative morphine tolerance in the rat," Brain Research, vol. 575, pp. 304-308 (1991).|
|3||Bristow et al., "Subcutaneous ketamine analgesia: postoperative analgesia using subcutaneous infusions of ketamine and morphine," Annals of the Royal College of Surgeons of England, vol. 71 (1989).|
|4||Chapman et al., "The Combination of NMDA Antagonism and Morphine Produces Profound Antinociception in the Rat Dorsal Horn," Brain Research, vol. 573, pp. 321-323 (1991).|
|5||Dickenson et al., "Dextromethorphan and Levorphanol on Dorsal Horn Nociceptive Neurones in the Rat," Neuropharmacology, vol. 30, No. 12A, pp. 1303-1308 (1991).|
|6||*||Disch. Apoth.-Zig. vol. 119, No. 21 (1979), p. 821, "Opiat-Rezeptoren und Endorphine".|
|7||Haley et al., "Evidence for spinal N-Methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat," Brain Research, vol. 518, pp. 218-226 (1989).|
|8||Hayes et al., "Pretreatment with gangliosides reduces abnormal nociceptive responses associated with a rodent peripheral mononeuropathy," Pain, vol. 48, pp. 391-396 (1992).|
|9||Itzhak et al. "Sensitization to the Toxic Effects of Cocaine in Mice is Associated with the Regulation of N-Methyl-D-Aspartate Receptors in the Cortex", The Journal of Pharmacology and Experimental Therapeutics, vol. 262, No. 2, pp. 464-470 (1992).|
|10||Kamei et al., "Subsensitivity to the Cough-Depressant Effects of Opioid and Nonopiod Antitussives in Morphine-Dependent Rats: Relationship to Central Serotonin Function," Pharmacology Biochemistry & Behavior, vol. 34, pp. 595-598 (1988).|
|11||Kanamaru et al., "Ketamine infusion for Control of Pain in Patients with Advanced Cancer," pp. 1368-1371 (1990) (see English translation of abstact).|
|12||Koyunchoglu et al., "The treatment of heroin addicts with dextromethorphan: A double-blind comparison of dextromethorphan with Chlorpromazine," International Journal of clinical Pharmacology, Therapy and Toxicology, vol. 28, No. 4 pp. 147-152 (1990).|
|13||Koyuncuoglu et al., "Effects of MK 801 on Morphine Physical Dependence: Attenuation and Intensification," Pharmacology Biochemistry & Behavior, vol. 43, pp. 487-490 (1992).|
|14||Koyuncuoglu et al., "Previous Chronic Blockade of NMDA Receptors Intensifies Morphine Dependence in Rats," Pharmacology Biochemistry & Behavior, vol. 39, pp. 575-579 (1991).|
|15||Koyuncuoglu et al., "Suppression by Ketamine and Dextromethorphan of Precipitated Abstinence Syndrome in Rats", Pharmacology Biochemistry and Behavior, vol. 35, No. 4, pp. 829-832 (1990).|
|16||Mankowitz et al., "Epidural Ketamine," SA Medical Journal, vol. 20, pp. 441-442 (1982).|
|17||Mao et al., "Intrathecal GM1 ganglioside and local ganglioside and local nerve anesthesia reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy," Brain Research, vol. 584, pp. 28-35 (1992).|
|18||Mao et al., "Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy," Brain Research, vol. 576, pp. 254-262 (1992).|
|19||Mao et al., "Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury," Brain Research, vol. 588, pp. 144-149 (1992).|
|20||Mao et al., "Post-injury treatent with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in rats with experimental peripheral mononeuropathy," Brain Research, vol. 584, pp. 18-27 (1992).|
|21||Marek et al., "Delayed application of MK-801 attenuates development of morphine tolerance in rats," Brain Research, vol. 558, pp. 163-165 (1991).|
|22||Marek et al., "Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat", Brain Research, vol. 547, pp. 77-81 (1991).|
|23||*||Marek et al; "Brain Research, Delayed application of MIC801 . . . in rats."; vol. 558, pp. 163-165.|
|24||Oshima et al., "Continuous subcutaneous injection of ketamine for cancer pain," Can. J. Anaesth., vol. 37:3, pp. 385-392, (1994).|
|25||Pharma Projects, 1561 (May 1994).|
|26||*||Pharmacol. Biochem. Behav. vol. 35, No. 4 (1990), pp. 829-832.|
|27||*||Pharmacol. Biochem. Behav. vol. 43, No. 2 (1992), pp. 487-490.|
|28||Sadee, "Opiat-Rezeptoren und Endorphine," Deutsche Apotheker-Zeitung, vol. 119, p. 821 (1979).|
|29||Tanganelli et al., "Glutamate antagonists prevent morphine withdrawal in mice and guinea pigs," Neuroscience-Letter., vol. 122, pp. 270-272, 1991.|
|30||*||Truillo et al.; "Inhibition of Morphine . . . MIC801"; Science; vol. 251, pp. 84-87.|
|31||Trujillo et al., "Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801," Science, vol. 251, pp. 85-87 (1991).|
|32||Ventafridda et al., "Studies on the effects of antidepressant drugs on the antinociceptive action of morphine and on plasma morphine in rat and man," Pain, vol. 43, pp. 155-162 (1990).|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US20060111307 *||Nov 16, 2005||May 25, 2006||Wendye Robbins||Methods and compositions for treating pain|
|US20060111308 *||Nov 16, 2005||May 25, 2006||Wendye Robbins||Methods and compositions for therapeutic treatment|
|US20070087977 *||Oct 27, 2006||Apr 19, 2007||Wendye Robbins||Methods and compositions for treating pain|
|US20080241121 *||Apr 2, 2007||Oct 2, 2008||Daniela Salvemini||Inhibitors of the ceramide metabolic pathway as adjuncts to opiates for pain|
|US20090088394 *||Sep 4, 2008||Apr 2, 2009||Wendye Robbins||Methods and compositions for therapeutic treatment|
|US20100086543 *||Sep 23, 2009||Apr 8, 2010||Saint Louis University||Compositions and methods for treating conditions associated with ceramide biosynthesis|
|U.S. Classification||514/25, 514/223.5, 514/306, 514/224.5, 514/812, 514/225.5, 514/216, 514/307, 514/282, 514/304, 514/231.2, 514/305|
|International Classification||A61K31/54, A61K31/44, A61K31/445, A61K31/485, A61K31/70|