EP0346445A1 - Potentialisateur de dextrorphane pour compositions antispasmodiques et procedes - Google Patents

Potentialisateur de dextrorphane pour compositions antispasmodiques et procedes

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Publication number
EP0346445A1
EP0346445A1 EP89901396A EP89901396A EP0346445A1 EP 0346445 A1 EP0346445 A1 EP 0346445A1 EP 89901396 A EP89901396 A EP 89901396A EP 89901396 A EP89901396 A EP 89901396A EP 0346445 A1 EP0346445 A1 EP 0346445A1
Authority
EP
European Patent Office
Prior art keywords
anticonvulsant
dextromethorphan
dextrorphan
metabolite
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP89901396A
Other languages
German (de)
English (en)
Other versions
EP0346445A4 (fr
Inventor
John W. FERKANY
Michael Pontecorvo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP0346445A1 publication Critical patent/EP0346445A1/fr
Publication of EP0346445A4 publication Critical patent/EP0346445A4/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • 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
    • A61K31/42—Oxazoles
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to a novel composition and a method for the treatment of epilepsy and other forms of convulsions. More specifically, the invention is directed to a pharmaceutical composition comprising the metabolites of dextromethorphan as a potentiating agent for an anticonvulsant drug.
  • DPH diphenylhydantoin
  • Phenytoin stems from its ability to Inhibit epileptic activity without causing a general depression of the central nervous system. Phenytoin also has the advantage in that it can limit the development of maximal seizure activity and reduce the spread of the seizure process from an active focus.
  • the dose-dependent toxic effects associated with the continued use of phenytoin as well as other anticonvulsant hydantoins include cerebellar vestibular effects (nystagmus, ataxia and diplopia vertigo) and central nervous system disturbances such as blurred vision, mydriasis and hyperactive tendon reflexes.
  • Behavioral changes that have been associated with the use of phenytoin include hyperactivity, confusion, dullness, drowsiness and hallucination.
  • Further adverse toxic effects include increased frequency of seizures, peripheral neuropathy, gastrointestinal distress, gingival hyperplasia, osteomalacia, megaloblastic anemia, hirsutism, endocrine effects and lymphadenopathy.
  • phenytoin can cause cardiovascular collapse and depression of the central nervous system.
  • Tortella showed that 30 mg/kg dextromethorphan administered s.c. to rats could provide complete protection against transauricular maximal electroshock seizures.
  • the anticonvulsant potency of phenytoin was potentiated by co-administration of dextromethorphan and that this potentiating effect was present even at sub-threshold levels of dextromethorphan (e.g., 15 rag/kg s.c).
  • Tortella was based, in part, on earlier findings reported by Craviso and Musacchio in Mol. Pharmacol.. 23:619-628 and 23:629-640 (1983). This study was conducted in part to determine whether dextro ⁇ methorphan binds at a subset of opiate receptors. Craviso and Musacchio demonstrated high affinity binding of [ 3 H]dextromethorphan to homogenates of guinea pig, mouse and rat lower brainstem (K ⁇ less than 20 nM) .
  • Tortella and Musacchio U.S. Patent No. 4,694,010 of the potentiating characteristics of dextromethorphan as an anticonvulsant was based on the binding site of [ 3 H]dextromethorphan, and on the compounds, like dextromethorphan, which inhibited binding at the same site at concen ⁇ trations considered reasonable to those skilled in the art (IC50 ⁇ 500 nM) .
  • Tortella and Musacchio were, however, rather narrow since I R]dextromethorphan and the related non-opiate compounds were believed to be able to potentiate only the anti-epileptic hydantoin anticonvulsants which enhanced binding to the dextromethorphan site in the central nervous system.
  • anticonvulsants such as carbamazepine, phenobarbital, diazepam and ketamine which were specifically shown not to Inhibit or enhance [ • ]dextromethorphan binding.
  • potentiating compounds were also limited by the require ⁇ ments that the potentiators are non-opioid compounds that act at the same binding site as dextromethorphan. Thus, related compounds that do not inhibit or enhance [ ** ⁇ ]dextromethorphan binding were excluded.
  • dextromethorphan is rapidly metabolized in vivo via oxidative O-demethylation to yield dextrorphan (DEX) and two lesser metabolites.
  • the minor N- and N,O-demethylation metabolite products are (+) D-(3) methoxymorphinan and (+) D-hydroxymorphinan respectively.
  • the absolute plasma levels of dextro ⁇ methorphan following administration of 20 to 60 mg p.o. in humans rarely exceeds five nanograms per milliliter whereas the dextrorphan levels are 380 nanograms per milliliter.
  • dextrorphan represents the major metabolite since, in eight hours, the other demethylation products in urine account for less than 15% of the dose of dextromethorphan administered. More importantly, the major metabolite, dextrorphan, has a relatively low affinity (> 2000 nM) for the [ ** ⁇ ]dextromethorphan receptor but a relatively high affinity for the [ 3 H]TCP-labeled-NMDA-linked receptor ( ⁇ 10 nM) .
  • dextromethorphan is rapidly converted to dextrorphan jLn vivo these data raise the possibility that dextromethorphan's anticonvulsant effects may not be directly related to the [ 3 H]dextromethorphan binding site as suggested by Tortella and Musacchio, but may result from the action of metabolites at other (e.g., PCP/NMDA) receptors.
  • PCP/NMDA PCP/NMDA
  • the present invention is directed primarily to the discovery that the metabolites of dextromethorphan which do not bind with reasonable affinity at the dextromethorphan receptor site (IC50 > 100 nM) can act as an effective potentiator for anticonvulsants, including both those like phenytoin, chat enhance [ K]dextromethorphan binding and those that do not inhibit or enhance [*- ⁇ ]dextromethorphan binding (e.g., carbamazepine, phenobarbital, diazepam, ketamine) .
  • the present invention relates to a composition of matter and a method of treating epilepsy using the metabolite of dextromethorphan as a potentiating agent for anticonvulsants.
  • the present invention is directed primarily to a composition of matter including at least one metabolite of dextromethorphan as a pote ⁇ tiator for an anticonvulsant agent. More particularly the invention relates to a pharmaceutical composition which utilizes the metabolites of dextromethorphan as the potentiating agent for any anticonvulsant. The invention further relates to a method of treating epilepsy using the composition including an effective amount of potentiating agent of one of the metabolites of dextromethorphan and an anticonvulsant agent.
  • the present invention is directed to the discovery that the metabolites of dextromethorphan and In particular the major metabolite, dextrorphan, are useful as anticonvulsants in the treatment of epilepsy. Moreover, the present invention relates to the discovery that the metabolites of dextro ⁇ methorphan are effective potentiating agents for other anticonvulsant compounds. Specifically the metabolites of dextromethorphan have been shown to potentiate and increase the effectiveness of anticonvulsants and also to interact with PCP-linked-NMDA receptors.
  • the dextromethorphan metabolite is intermixed in a potentiating amount, or administered separately as an adjunct, with a suitable anticonvulsant.
  • the compounds are introduced to the patient in an amount necessary to treat epilepsy and prevent or control convulsions.
  • Dextromethorphan [(+) 3-methoxy-17-methylmorphinan] is a widely used non- opiate antitulich which has recently been shown to possess anticonvulsant activity against electrical seizure in laboratory animals.
  • Dextromethorphan is known to have has a high affinity for the [ ** ⁇ ]dextromethorphan labeled receptor but a relatively low affinity for the PCP receptor sites.
  • Dextromethorphan when introduced to the human body rapidly metabolizes into three metabolites.
  • the major O-demethylated metabolite is dextrorphan (DEX) , D(+)-17-methylmorphinan-3-ol.
  • the minor metabolites by the N, and N,0-deraethylation process are (+)D-3 methoxymorphinan, and (+)D- hydroxymorphinan.
  • Dextrorphan demonstrates a low affinity for the [ 3 H]dextromethorphan receptor (IC 50 - 140 - 5000 nM) but a very high affinity for the PCP-labeled NMDA-linked receptor (IC50 ⁇ 10 nM) . Since dextrorphan functions by a different mechanism, and binds at different sites than dextromethorphan, dextrorphan provides an additional approach to control and prevent convulsions in patients affected with seizure disorders. Additionally, we have discovered that dextrorphan can be used in a manner by which the anticonvulsant properties of other anticonvulsants can be improved or potentiated at lower dosages thereby providing a lowering of the chronic toxicity of the drugs.
  • anticonvulsants examples include phenytoin, amobarbital sodium (sodium 5-ethyl-5-isopentylbarbiturate) , methsuximide (N,2-Dimethyl-2-phenylsuccinimide), clonazepam (5-(2 chloro ⁇ henyl)-l, 3- dihydro-7-nitro 2H-1.4, benzodiazepine-2-one) , valproic acid, metharbital (5,5 diethyl-1-methylbarbituric acid), mephobarbital (5-ethyl-l-methyl-5- phenylbarbituric acid, ephenytoin (3-methyl 5,5-phenyl-ethyl-hydantoin) , primidone, paramethadione (5-ethyl-3,5-demethyl-2,4-oxazolidinedione, phenacemide (N-aminocarbonyl)-benzeneacetamide,
  • the preferred anticonvulsants according to the invention are phenytoin or carbamazepine. It has been discovered that by simultaneously administering these different types of anticonvulsants with the metabolites of dextro ⁇ methorphan the effects of the anticonvulsants can be potentiated to reduce the required amount for effective treatment.
  • Ethosuximide was determined to be ineffective in protecting against these seizures since only one in five mice was protected at one half hour and none was protected one hour after i.p. injections of 500 mg/kg. At this dose all mice injected showed signs of sedation, ataxia and gross toxicity.
  • the first study compared the effects of dextrorphan, dextromethorphan and phenytoin.
  • Dextrorphan and dextromethorphan were dissolved in saline.
  • Phenytoin was dissolved in 30% propylene glycol in distilled water.
  • Dextrorphan and dextromethorphan were administered 30 min and phenytoin 1 hr prior to the MES test. . All injections were i.p. in a volume of 0.01 ml/g.
  • Dextrorphan like phenytoin and dextromethorphan, is shown in Table 1 to be a potent and efficacious anticonvulsant against MES seizures.
  • the anticonvulsant effects of the dextrorphan were dose-related having an ED50 of 12.7 mg/kg. At higher doses, dextrorphan decreased the incidence of tonic hindlimb extension to 0%. When compared on the basis of molecular weight, dextrorphan was 2.2 times more potent than dextromethorphan as an anticonvulsant against MES seizures.
  • mice Based on at least 8 doses for each drug, covering the entire range from 0 to 100% protection, n > 8 mice per dose. Values in parenthesis are 95% confidence limits calculated according to the method of Litchfield and Wilcoxon (1949, J. Pharmacol. EXP. Thera .. 49:99). All values are reported as mg/kg.
  • mice Male CF-1 mice weighing 25 - 30 grams were used for all studies. All of the test animals were naive to drug and seizure exposure and were used only once. Compounds of interest were dissolved in saline (0.9%; w/v) and administered i.p. in a final volume of 1 percent of body weight. Test compounds (anticonvulsants) were administered 30 minutes prior to the induction of seizures. Seizures were induced by the administration of NMDA (250 mg/kg) and animals were observed for a period of thirty minutes. Typically, control animals responded with seizure activity consisting of initial staring followed in rapid order by hindlimb scratching, increased locomotor activity, rearing behavior, clonic seizures, tonic extension and death.
  • NMDA 250 mg/kg
  • M 801 was the most effective compound evaluated to antagonize NMDA-induced seizures and, on a mole basis was 7-fold more potent than PCP.
  • the order of potency of the remaining compounds was PCP > 3-(2- carboxypiperazin-4-yl)propyl-l-phosphonic acid (CPP) > ketamine - dextrorphan
  • dextromethorphan > DL( ⁇ )2-amino-7-phosphonoheptanoic acid (AP7) .
  • AP7 DL( ⁇ )2-amino-7-phosphonoheptanoic acid
  • NMDA receptor antagonist AP7.
  • PCP phencyclidine
  • CPP 3-(2 carboxy-piperazin- 4-yl)propyl-l-phosphono acid
  • KET ketamine
  • DEX dextrorphan
  • DM dextromethorphan.
  • GABA ⁇ receptor agonists muscimol 5 mg/kg and THIP (15 mg/kg), the GABA ⁇ receptor agonist, baclofen (20 mg/kg), as well as the antlcholinerglc, atropine sulfate (10 mg/kg).
  • Other compounds which inhibit seizures but were not able to inhibit NMDA- induced convulsions were two antitussives agents including the dextro ⁇ methorphan receptor active agents, caramiphen (100 - 500 mg/kg) and noscapine (100 - 400 mg/kg).
  • dextrorphan was examined using the MES seizure model described in Example I, above.
  • Male CF-1 mice weighing approximately 27-34 grams were randomly assigned to control or drug treatment groups. All of the test animals were naive to drug and seizure exposure and used only once.
  • Dextrorphan was dissolved in saline and phenytoin in 30% propylene glycol in distilled water as described above. For combination studies phenytoin was administered 1 hr and dextrorphan 30 min prior to the test.
  • Table 3 shows that dextrorphan potentiated the anticonvulsant effects of phenytoin.
  • the amount of protection (% animals without seizures) at any given dose of phenytoin was increased by co-administration of dextrorphan.
  • 9 mg/kg dextrorphan (a dose marginally effective when administered alone) increased the % protection from 0 to 37.5 at 0.25 mg/kg phenytoin, from 4.2 to 50 at 1 mg/kg phenytoin, and from 8.3 to 100 at 3.5 mg/kg phenytoin.
  • the median effective dose (ED50) of phenytoin was decreased almost 7-fold from 5.5 to 0.81 mg/kg.
  • the foregoing examples demonstrate that the dextromethorphan metabolite dextrorphan is a potent anticonvulsant when administered alone in both the MES and N-methyl-D-aspartate models, and effectively potentiates the anticonvulsant effects of phenytoin in the MES model.
  • dextromethorphan metabolites may also be effective anticonvulsants, regardless of whether they compete at dextromethorphan receptors, and also suggests that the range of anticonvulsants that can be potentiated by dextromethorphan or its metabolites may include compounds like carbamazepine that do not interact with dextromethorphan receptors.
  • a metabolite of dextro ⁇ methorphan is administered as the potentiating agent with an anticonvulsant drug.
  • an anticonvulsant drug Any anticonvulsant may be used but phenytoin or carbamazepine are preferred.
  • simultaneous administration in one dosage form is preferred, the compounds may be introduced sequentially or in any order necessary to achieve the optimal control of seizures.
  • the preferred form of administration is oral but any medically accepted route of administration may be employed.
  • the novel composition according to the present invention is used primarily for treatment of convulsions and in particular epilepsy.
  • at least one of the metabolites of dextromethorphan is combined with an anticonvulsant in a proportion whereby the effectiveness of the anticonvulsant is potentiated.
  • potentiating the anticonvulsant effects the amount of the anticonvulsant can be reduced which reduces the dose-related side effects associated with continued use of standard anti ⁇ convulsants without sacrificing the efficacy.
  • the type and severity of the convulsions experienced by the patient will determine the amount of the combination administered.
  • the ratio of the potentiating agent to the anticonvulsant and the effectiveness of the anticonvulsant will determine the amount and form of the composition to be administered to the patient.
  • the form of the anticonvulsants according to the present invention can be a liquid oral dose in the form of solutions and suspensions.
  • the active ingredients are generally dissolved or suspended in distilled water containing a small amount of alcohol to facili ⁇ tate suspension.
  • conventional syrup formulations or any other pharmaceutically acceptable liquid carrier may be employed.
  • parenteral administration is the preferred method of introducing the anticonvulsants to the patient the compounds are dissolved in a suitable liquid carrier.
  • suitable liquid carrier is polyethylene glycol and alcohol although others may be used which are known by those skilled in the art.
  • the anticonvulsants may be introduced as an oral dose in a solid form such as a tablet, pill or capsule.
  • the tablets or capsules may be coated as desired to allow the tablets to be easily swallowed and to provide flavoring.
  • Coatings commonly employed in the pharmaceutical industry may be applied from aqueous suspensions of sugar and insoluble powders such as starch, calcium carbonate, talc and titanium dioxide suspended with a suitable mixing agent such as gelatin. Additional coatings may be applied as desired including water soluble dispersible material such as hydroxy- methylcellulose, cellulose, methylcellulose, carboxymethyl cellulose and mixtures of cellulose acetate and polyethylene glycol.
  • the suitable dosage form may be a capsule formed from commonly employed materials.
  • the components are generally compounded with inert fillers such as talc, lactose, starch, bentonite, diatomaceous earth, lubricants and food flavorings.
  • inert fillers such as talc, lactose, starch, bentonite, diatomaceous earth, lubricants and food flavorings.
  • the tablets are generally formed by conventional procedures including compression molding.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Une composition pharmaceutique comprend un médicament actif antispasmodique et une quantité efficace d'au moins un métabolite de dextrométhorphane, suffisante pour potentialiser l'effet antispasmodique du médicament antispasmodique. Ces métabolites, en particulier le dextrorphane, potentialisent efficacement l'effet d'antispasmodiques, y compris de la phénytoïne et de la carbamazépine. Selon un procédé de traitement de l'épilepsie et d'autres formes de convulsions, on administre simultanément ou successivement une quantité efficace du médicament antispasmodique et une quantité d'au moins un des métabolites de dextrométhorphane suffisante pour potentialiser l'action du médicament antispasmodique.
EP19890901396 1987-12-22 1988-12-19 Potentialisateur de dextrorphane pour compositions antispasmodiques et procedes. Withdrawn EP0346445A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13656487A 1987-12-22 1987-12-22
US136564 1987-12-22

Publications (2)

Publication Number Publication Date
EP0346445A1 true EP0346445A1 (fr) 1989-12-20
EP0346445A4 EP0346445A4 (fr) 1990-03-28

Family

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Family Applications (1)

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EP19890901396 Withdrawn EP0346445A4 (fr) 1987-12-22 1988-12-19 Potentialisateur de dextrorphane pour compositions antispasmodiques et procedes.

Country Status (4)

Country Link
EP (1) EP0346445A4 (fr)
JP (1) JPH02502546A (fr)
AU (1) AU2929489A (fr)
WO (1) WO1989005642A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5686086A (en) * 1992-07-13 1997-11-11 Shiseido Co., Ltd. External skin treatment composition
US5798109A (en) * 1992-07-13 1998-08-25 Shiseido Company, Ltd. External skin treatment composition
US5962000A (en) * 1992-07-13 1999-10-05 Shiseido Company, Ltd. External skin treatment composition
CA2264182A1 (fr) 1996-08-23 1998-02-26 Algos Pharmaceutical Corporation Anticonvulsivant renfermant une composition pour traiter la douleur neurogene
WO1999008670A1 (fr) 1997-08-20 1999-02-25 Guglietta, Antonio Analogues de gaba utilises pour prevenir et traiter des lesions gastro-intestinales
DK1011658T3 (da) 1997-09-08 2006-04-03 Warner Lambert Co Analgesiske præparater, der omfatter antiepileptiske forbindelser, og fremgangsmåder til anvendelse af samme
AU2002301365B2 (en) * 1997-09-08 2005-11-24 Warner-Lambert Company Analgesic compositions comprising anti-epileptic compounds and methods of using same
EP1471909A4 (fr) * 2002-01-16 2007-07-25 Endo Pharmaceuticals Inc Composition pharmaceutique et methode de traitement de troubles du systeme nerveux central
GB0307860D0 (en) * 2003-04-04 2003-05-14 Novartis Ag Organic compounds
HUP0300929A3 (en) * 2003-04-09 2005-06-28 Richter Gedeon Vegyeszet Analgetic and/or muscle relaxant pharmaceutical composition
US20060252745A1 (en) 2005-05-06 2006-11-09 Almeida Jose L D Methods of preparing pharmaceutical compositions comprising eslicarbazepine acetate and methods of use
GB0700773D0 (en) 2007-01-15 2007-02-21 Portela & Ca Sa Drug therapies
WO2014173900A1 (fr) * 2013-04-22 2014-10-30 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique pour l'utilisation dans le traitement de crises épileptiques

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* Cited by examiner, † Cited by third party
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US4380548A (en) * 1981-08-27 1983-04-19 Warner-Lambert Company N-(2,6-Dimethylphenyl)-4,5-dihydro-4,4-dialkyl-2-methylthio-1H-imidazole-1-carboxamides, anticonvulsive composition and method
US4694010A (en) * 1985-08-16 1987-09-15 New York University Anticonvulsant compositions and method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No relevant documents have been disclosed. *
See also references of WO8905642A1 *

Also Published As

Publication number Publication date
EP0346445A4 (fr) 1990-03-28
WO1989005642A1 (fr) 1989-06-29
JPH02502546A (ja) 1990-08-16
AU2929489A (en) 1989-07-19

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