US20020052418A1 - Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders - Google Patents

Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders Download PDF

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US20020052418A1
US20020052418A1 US09/932,370 US93237001A US2002052418A1 US 20020052418 A1 US20020052418 A1 US 20020052418A1 US 93237001 A US93237001 A US 93237001A US 2002052418 A1 US2002052418 A1 US 2002052418A1
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pain
effective dose
subject
administration
group
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Mitchell Shirvan
Meir Bialer
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Teva Pharmaceutical Industries Ltd
Yissum Research Development Co of Hebrew University of Jerusalem
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Assigned to TEVA PHARMACEUTICAL INDUSTRIES, LTD. reassignment TEVA PHARMACEUTICAL INDUSTRIES, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SHIRVAN, MITCHELL
Assigned to YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM reassignment YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIALER, MEIR
Publication of US20020052418A1 publication Critical patent/US20020052418A1/en
Priority to US10/826,904 priority patent/US20040204495A1/en
Priority to US12/457,875 priority patent/US8288442B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • Pain is considered to play a basic physiological role in the detection and localization of tissue damage or potentially damaging physiological processes. Pain has been broadly classified as somatogenic, where a physiological explanation can be found, or psychogenic, where the physiological explanation is not known (The Merck Manual of Diagnosis and Therapy).
  • neuropathic pain is described as a pain which results from a dysfunction in the central or peripheral nervous system (Tremont-Lukats, I. et al.; Woolf, C. and Mannion, R.).
  • the pain can be both chronic and acute, and can also be evoked by noxious stimuli, also referred to as hyperalgesia, or by non-noxious stimuli referred to as allodynia (Attal, N.). Allodynia and hyperalgesia can have mechanical causes (dynamic or static), or a thermal cause.
  • neuropathic pain examples include: all the painful peripheral neuropathies and specifically diabetic peripheral neuropathy; postherpetic neuralgia; and trigemincal neuralgia.
  • Trigeminal neuralgia for example, is the most common neuralgic syndrome in the elderly. The initial drug of choice is carbamazepine.
  • amitriptyline is most commonly used.
  • somatogenic pain that may have neuropathic components include cancer pain, postoperative pain, low back pain, complex regional pain syndrome, phantom pain, HIV pain, arthritis (osteo-arthritis and rheumatoid arthritis) pain and migraines.
  • Migraines constitute one of the four major categories of primary headaches (International Headache Society; Silberstein, S.D. et al.). The other three types of primary headaches are tension-type, cluster and a miscellaneous-type (International Headache Society; Silberstein, S.D. et al.).
  • One current view is that there is a continuous spectrum of headache severity ranging from mild tension headaches to severe migraines. Others consider tension headaches and migraines to be distinct entities.
  • Migraines are considered to be a familial disorder characterized by periodic pulsatile headaches. (Principles of Neurology). Migraines are found in about 4% of the male population and 7% of the female population. Migraines can occur in the presence or absence of an aura. An aura is a complex of focal neurological symptoms which may precede or accompany a migraine attack (Silberstein, S. D. et al.). Auras can be characterized by visual, sensory, or motor phenomenon, and may also involve language or brainstem disturbances (Silberstein, S. D. et al.).
  • a major theory regarding the pain of migraines is that it stems from a form of sterile neurogenic inflammation (Moskowitz, M. A. and Cutrer, F. M.).
  • the neurogenic inflammation results in the leakage of plasma proteins into the dura mater, which can be quantified by measuring the leakage of radioactive albumin (Suzzi, M. C. and Moskowitz, M. A.).
  • Drugs used in the treatment of headache disorders originate from a broad range of different drug categories. These include: 5-hydroxytryptamine agonists (5-HT 1 agonists); dihydroergotamine; ergotamine; anti-emetics; anxiolytics; non-steroidal anti-inflammatory drugs; steroids; major tranquilizers; narcotics; beta-blockers; calcium channel blockers; anti-depressants; and anti-epileptic drugs.
  • 5-hydroxytryptamine agonists 5-HT 1 agonists
  • dihydroergotamine ergotamine
  • anti-emetics anxiolytics
  • non-steroidal anti-inflammatory drugs steroids
  • major tranquilizers narcotics
  • beta-blockers calcium channel blockers
  • anti-depressants anti-epileptic drugs
  • U.S. Pat. No. 5,585,358 describes a series of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment of epilepsy and other neurological disorders.
  • U.S. Pat. No. 5,585,358 does not teach or suggest the use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain or headache disorders.
  • the subject invention provides a method of treating or preventing pain and/or a headache disorder in a subject comprising the administration of a therapeutically effective amount of a derivative of a valproic acid amide or a 2-valproenic acid amide, to thereby treat or prevent the pain and/or headache disorder.
  • the subject invention contains pharmaceutical compositions comprising these derivatives.
  • FIG. 1 presents the effects of the administration of VGD (valproylglycine amide or Compound 1) versus MC (methyl cellulose or vehicle) in the Chung model of neuropathic pain.
  • the subject invention provides a method of treating subject suffering from pain comprising periodically administering to the subject a therapeutically effective amount of a compound having the following structure:
  • R 1 , R 2 , R 3 and R 4 are independently the same or different and are hydrogen, a linear or branched C 1 -C 6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, so as to thereby treat the subject's pain.
  • the subject invention also provides a method of preventing pain in a subject predisposed to suffering from pain comprising periodically administering to the subject a prophylactically effective dose of a compound having the following structure:
  • R 1 , R 2 , R 3 and R 4 are independently the same or different and are hydrogen, a linear or branched C 1 -C 6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, so as to thereby prevent pain in the subject.
  • the subject invention provides a method of treating a subject suffering from a headache disorder comprising periodically administering to the subject a therapeutically effective dose of a compound having the following structure:
  • R 1 , R 2 , R 3 and R 4 are independently the same or different and are hydrogen, a linear or branched C 1 -C 6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, so as to thereby treat the headache disorder.
  • the subject invention further provides a method of preventing a headache disorder in a subject predisposed to suffering from a headache disorder comprising periodically administering to the subject a prophylactically effective dose of a compound having the following structure:
  • R 1 , R 2 , R 3 and R4 are independently the same or different and are hydrogen, a linear or branched C 1 -C 6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, so as to thereby prevent the headache disorder in the subject.
  • the compound has the following structure:
  • the compound is N-(2-n-propylpentanoyl)-glycinamide and has the structure:
  • the compound is N-(2-n-propylpent-2-enoyl)-glycinamide and has the structure:
  • the pain is acute. In another embodiment, the pain is chronic. In a further embodiment, the pain is somatogenic pain. In a preferred embodiment, the pain is neuropathic pain.
  • the headache disorder may be a migraine.
  • the headache disorder may be a cluster headache.
  • the headache disorder may be a tension-type headache.
  • the headache disorder may be a miscellaneous-type headache.
  • the subject may be a human being.
  • one or more of R 1 , R 2 , R 3 , or R 4 is a linear chain C 1 -C 6 alkyl group. In another embodiment, one or more of R 1 , R 2 , R 3 , or R 4 is a branched chain C 1 -C6 alkyl group. In yet another embodiment, one or more of R 1 , R 2 , R 3 , or R 4 is a benzyl, alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl, aryloxycarbonylbenzyl, carboxybenzyl, nitrobenzyl, cyanobenzyl, or halobenzyl group.
  • one or more of R 1 , R 2 , R 3 , or R 4 is a phenyl, naphthyl, anthracenyl, pyridinyl, indolyl, furanyl, alkylphenyl, hydroxyphenyl, alkoxycarbonylphenyl, aryloxycarbonylphenyl, nitrophenyl, cyanophenyl, halophenyl group, mercaptophenyl, or aminophenyl group.
  • the subject invention also provides a method of treating a subject suffering from neuropathic pain comprising administering to the subject 500 mg of N-(2-n-propylpentanoyl)glycinamide six times per day so as to thereby treat the subject's neuropathic pain.
  • the subject invention provides a method of preventing neuropathic pain in a subject predisposed to suffering from neuropathic pain comprising administering to the subject 500 mg of N-(2-n-propylpentanoyl)glycinamide six times per day so as to thereby prevent neuropathic pain in the subject.
  • compounds used in this invention possess chiral centers. It is a further embodiment of this invention that these compounds may comprise substantially pure D or L enantiomers or racemic mixtures. It is to be understood that compounds of this invention may be of the E-(trans) or Z-(cis) geometric configuration, or a mixture thereof.
  • the amount of the compound incorporated in the pharmaceutical composition may vary widely. Factors considered when determining the precise dose are well known to those skilled in the art. Examples of such factors include, but are not limited to, the subject being treated and the specific pharmaceutical carrier, as well as the route and frequency of administration.
  • a therapeutically effective dose of the compound may comprise about 10 to about 6,000 mg of the active ingredient. In one embodiment, the therapeutically effective dose comprises about 10 to about 3,000 mg. In another embodiment, the therapeutically effective dose comprises about 10 to about 2,000 mg. In a preferred embodiment, the therapeutically effective dose comprises about 10 to about 1,000 mg of the active ingredient. In another embodiment, the therapeutically effective dose comprises about 50 mg to about 500 mg. In a further embodiment, the therapeutically effective dose comprises about 500 to about 4000 mg. In another embodiment, the therapeutically effective dose comprises about 1000 to about 3000 mg. In yet another embodiment, the therapeutically effective dose comprises about 2000 to about 3000 mg. In a preferred embodiment, the therapeutically effective dose comprises about 3000 mg.
  • a prophylactically effective dose of the compound may comprise about 10 to about 6,000 mg of the active ingredient.
  • the prophylactically effective dose comprises about 10 to about 3,000 mg.
  • the prophylactically effective dose comprises about 10 to about 2,000 mg.
  • the prophylactically effective dose comprises about 10 to about 1,000 mg of the active ingredient.
  • the prophylactically effective dose comprises about 50 mg to about 500 mg.
  • the prophylactically effective dose comprises about 500 to about 4000 mg.
  • the prophylactically effective dose comprises about 1000 to about 3000 mg.
  • the prophylactically effective dose comprises about 2000 to about 3000 mg.
  • the prophylactically effective dose comprises about 3000 mg.
  • the administration of the compound may be effected once daily or up to 6 times per day.
  • the administration of the compound may be effected twice a day.
  • the administration of the compound may be effected 3 times a day.
  • the administration of the compound may be effected 4 times a day.
  • the administration of the compound may be effected 5 times a day.
  • the administration of the compound may be effected 6 times a day.
  • the subject invention also provides a method of treating a subject suffering from pain comprising periodically administering to the subject a therapeutically effective dose of composition comprising a compound having the following structure:
  • R 1 , R 2 , R 3 and R 4 are independently the same or different and are hydrogen, a linear or branched C 1 -C 6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, so as to thereby treat the subject's pain.
  • the subject invention provides a method of preventing pain in a subject predisposed to suffering from pain comprising periodically administering to the subject a prophylactically effective dose of composition comprising a compound having the following structure:
  • R 1 , R 2 , R 3 and R 4 are independently the same or different and are hydrogen, a linear or branched C 1 -C6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, so as to thereby prevent pain in the subject.
  • the subject invention also provides compounds containing a valproic acid moiety or a 2-valproenic acid moiety, as well as pharmaceutical compositions comprising these compounds.
  • the subject invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier encompasses any of the standard pharmaceutically accepted carriers, such as a phosphate-buffered saline solution, water, suspen sions, powders, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets, dissolvable tablets and capsules.
  • An example of an acceptable triglyceride emulsion useful in the intravenous and intraperitoneal administration of the compounds is the triglyceride emulsion commercially known as Intralipid®.
  • pharmaceutically acceptable carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, glycols, or other known excipients. These carriers may also include flavor and color additives or other ingredients.
  • the administration of the pharmaceutical composition may be effected by any of the well known methods including, but not limited to, by inhalation, rectal, oral, intravenous, intraperitoneal, parenteral, intramuscular, transdermal, subcutaneous, sublingual, nasal, buccal, pulmonary, vaginal or topical administration.
  • Topical administration can be effected by any method commonly known to those skilled in the art. These methods include, but are not limited to, incorporation of the pharmaceutical composition into creams, gels, ointments, transdermal patches or other topical formulations and delivery systems.
  • the compound When the compound is introduced orally, it may be mixed with other food forms and consumed in solid, semi-solid, suspension or emulsion form.
  • the compound may be administered as sprinkles.
  • the oral composition may be enterically-coated.
  • enteric coatings are well known in the art. Commonly known enteric coatings include Eudragit S and Eudragit L (Lehman, K., 1971; Lehman, K. 1973; Handbook of Pharmaceutical Excipients, 2 nd ed.).
  • the invention encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a solid and the composition is a tablet.
  • the invention also encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a gel and the composition is a suppository.
  • the invention further encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a liquid and the composition is a solution.
  • Compound 1 was prepared as disclosed by U.S. Pat. No. 5,585,358.
  • Compound 2 was prepared as disclosed by U.S. Pat. No. 5,585,358.
  • the anti-pain effects of Compounds 1 and 2 are evaluated in a model for traumatic nerve injury.
  • the specific model is the rat constriction injury model, a commonly accepted model for the evaluation of the potential of a compound to treat chronic neuropathic pain.
  • the end point is whether a compound can reverse cold allodynia in rats following a neuropathic injury.
  • MC may be used as the control.
  • Compounds 1 and 2 reverse cold allodynia in the chronic constriction injury model of neuropathic pain with ED 50 values of less than 500 mg/kg.
  • the effective dose is below that which has been previously found to be the median ataxic dose (also referred to as the minimal neurotoxic dose).
  • MC may be used as the control.
  • Compound 1 to serve as an anti-pain agent was studied in the Chung model (Kim, S. H. and Chung, J. M.). This model is known as a reliable model, predictive for human pain. (Kim, S. H. and Chung, J. M.). In this model, spinal nerves L5 and L6 of the rat are tightly ligated and cut in order to induce neuropathic pain. Male Sabra rats weighing 250-275 g were used throughout the study. Under xylazine-ketamine anesthesia, both the L5 and L6 spinal nerves of one side of the rat were tightly ligated and cut.
  • Pain behavior was measured following operation in all groups using withdrawal latencies of the hind paw to mechanical stimulation with von Frey filaments (tactile allodynia).
  • the mechanical sensitivity of the foot was quantified by the occurrence of foot withdrawal in response to normally innocuous mechanical stimuli.
  • Eight different von Frey filaments ranging from 0.6 to 26 g were used.
  • the efficacy (antiallodynic effect) of the compound was evaluated (300 mg/kg, per os (oral)) in eight rats at days 7 and 14 postoperation in a double-blind randomized crossover manner.
  • the testing included estimation of time of peak effect following drug administration and measurement of the ability of the compound to decrease tactile allodynia.
  • the Moskowitz model which is a well-accepted model of migraines (Suzzi, M. C. and Moskowitz, M. A.), shows that Compounds 1 and 2 inhibit plasma protein extravasation.
  • the disclosed valproic acid amides and 2-valproenic acid amides are effective for the treatment or prevention of headache disorders, such as migraines.
US09/932,370 2000-08-17 2001-08-17 Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders Abandoned US20020052418A1 (en)

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US09/932,370 US20020052418A1 (en) 2000-08-17 2001-08-17 Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders
US10/826,904 US20040204495A1 (en) 2000-08-17 2004-04-16 Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment of prevention of pain and/or headache disorders
US12/457,875 US8288442B2 (en) 2000-08-17 2009-06-24 Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders

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US22597700P 2000-08-17 2000-08-17
US22597300P 2000-08-17 2000-08-17
US09/932,370 US20020052418A1 (en) 2000-08-17 2001-08-17 Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders

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US10/826,904 Abandoned US20040204495A1 (en) 2000-08-17 2004-04-16 Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment of prevention of pain and/or headache disorders
US12/457,875 Expired - Fee Related US8288442B2 (en) 2000-08-17 2009-06-24 Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders

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US12/457,875 Expired - Fee Related US8288442B2 (en) 2000-08-17 2009-06-24 Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040175423A1 (en) * 2003-02-05 2004-09-09 Daniella Licht Sustained release formulation of N- (2-propylpentanoyl) glycinamide and related compounds
US20040176463A1 (en) * 2003-02-05 2004-09-09 Daniella Licht Immediate release formulation of n-(2-propylpentanoyl)glycinamide
US20050209163A1 (en) * 2003-12-02 2005-09-22 Thomas Stoehr Novel use of peptide compounds for treating central neuropathic pain
US20060025477A1 (en) * 2004-07-22 2006-02-02 Artman Linda D Analogs of isovaleramide, a pharmaceutical composition including the same, and a method of treating central nervous system conditions or diseases
US20060100157A1 (en) * 2004-03-26 2006-05-11 Schwarz Pharma Ag Novel use of peptide compounds for treating pain in painful diabetic neuropathy
US20060135437A1 (en) * 2004-06-09 2006-06-22 Schwarz Pharma Ag Novel use of peptide compounds for treating pain in trigeminal neuralgia
US20060148861A1 (en) * 2003-02-28 2006-07-06 Yissum Research Developement Co. Of The Hebrew University Of Jerusalem Amide derivatives of 2,2,3,3-tetramethylcyclopropane carboxylic acid
US20060252749A1 (en) * 2005-01-28 2006-11-09 Srz Properties, Inc. Lacosamide for add-on therapy of psychosis
US20070042969A1 (en) * 2004-03-26 2007-02-22 Srz Properties, Inc. Combination therapy for pain in painful diabetic neuropathy
US20070043120A1 (en) * 2005-08-18 2007-02-22 Bettina Beyreuther Therapeutic combination for painful medical conditions
US20070054962A1 (en) * 2001-03-20 2007-03-08 Norma Selve Method for treating acute or chronic pain
US20070197657A1 (en) * 2005-08-18 2007-08-23 Srz Properties, Inc. Method for treating non-inflammatory musculoskeletal pain
US20080287545A1 (en) * 2004-04-16 2008-11-20 Schwarz Pharma Ag Use of Peptide Compounds For the Prophylaxis and Treatment of Chronic Headache
US20090018197A1 (en) * 2003-12-05 2009-01-15 David Rudd Methods for treating status epilepticus and related conditions
US20100029543A1 (en) * 2004-08-27 2010-02-04 Schwarz Pharma Ag Methods for treating nucleoside-induced pain
US20100099770A1 (en) * 2001-03-21 2010-04-22 Schwarz Pharma Ag Method for treating diabetic peripheral neuropathic pain
US20100160443A1 (en) * 2003-07-28 2010-06-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compounds useful for treating neurological disorders
US20100240576A1 (en) * 2006-06-15 2010-09-23 Thomas Stoehr Anticonvulsant combination therapy
US20100256179A1 (en) * 2004-03-26 2010-10-07 Ucb Pharma Gmbh Combination therapy for pain in painful diabetic neuropathy
US20100273714A1 (en) * 2006-06-15 2010-10-28 Schwarz Pharma Ag Peptide compounds for treating refractory status epilepticus
US20110130350A1 (en) * 2004-10-02 2011-06-02 Ucb Pharma Gmbh Synthesis scheme for lacosamide
US9308183B2 (en) 2006-06-30 2016-04-12 Ucb Pharma Gmbh Therapy for hyperexcitability disorders
US10149818B2 (en) 2010-12-02 2018-12-11 Ucb Pharma Gmbh Daily formulation of lacosamide

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1491188A1 (de) * 2003-06-25 2004-12-29 G2M Cancer Drugs AG Topische Verwendung von Valproinsäure zur Behandlung von Hauterkrankungen
US7427601B2 (en) * 2004-06-24 2008-09-23 Schwarz Pharma Ag Method for treating tremor
ES2326355B1 (es) * 2008-02-25 2010-08-10 Centro Atlantico Del Medicamento, S.A. Acido 1-(di-n-propilacetilaminometil)-ciclohexilacetico.
KR101733189B1 (ko) * 2010-10-06 2017-05-08 (주)아모레퍼시픽 손톱 또는 발톱 성장 촉진용 조성물

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3050800C2 (de) * 1979-03-22 1989-06-22 Continental Pharma Inc., Bruessel/Bruxelles, Be
US4301176A (en) * 1980-08-18 1981-11-17 Warner-Lambert Company Method of administering calcium valproate
LU83729A1 (fr) * 1981-11-04 1983-09-01 Galephar Sels d'acide valproique,leur preparation et leur utilisation
US4913906B1 (en) * 1985-02-28 2000-06-06 Yissum Res Dev Co Controlled release dosage form of valproic acid
US5169642A (en) * 1988-06-24 1992-12-08 Abbott Laboratories Sustained-release drug dosage units
US6287598B1 (en) * 1993-05-28 2001-09-11 Alza Corporation Method for providing sustained antiepileptic therapy
US5585358A (en) * 1993-07-06 1996-12-17 Yissum Research Development Corporation Of The Hebrew University Of Jerusalem Derivatives of valproic acid amides and 2-valproenoic acid amides, method of making and use thereof as anticonvulsant agents
CZ296263B6 (cs) * 1996-03-25 2006-02-15 Eli Lilly And Company Farmaceutická kompozice pro lécení bolesti a jejípouzití
JP2000504035A (ja) * 1996-08-30 2000-04-04 エヌピーエス パーマシューティカルズ インク． イソ吉草酸ｃｎｓ抑制剤による痙縮、痙攣の治療
IL121268A0 (en) * 1997-07-09 1998-01-04 Dpharm Ltd Branched chain fatty acids their derivatives and use in the treatment of central nervous system disorders
US5760007A (en) * 1997-07-16 1998-06-02 Ortho Pharmaceutical Corporation Anticonvulsant derivatives useful in treating neuropathic pain
AU752192B2 (en) * 1998-06-22 2002-09-12 American Biogenetic Sciences, Inc. The use of valproic acid analog for the treatment and prevention of migraine and affective illness
DE60015070T2 (de) * 1999-01-19 2006-01-05 Ortho-Mcneil Pharmaceutical, Inc. Verwendung von antikonvulsiven derivaten zur behandlung der cluster headache

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8053476B2 (en) * 2001-03-20 2011-11-08 Ucb Pharma Gmbh Method for treating peripheral neuropathic pain
US20070054962A1 (en) * 2001-03-20 2007-03-08 Norma Selve Method for treating acute or chronic pain
US7875652B2 (en) 2001-03-21 2011-01-25 Ucb Pharma Gmbh Method and composition for treating pain or tinnitus aureum
US20110082211A1 (en) * 2001-03-21 2011-04-07 Ucb Pharma Gmbh Method for treating tinnitus aureum
US20100099770A1 (en) * 2001-03-21 2010-04-22 Schwarz Pharma Ag Method for treating diabetic peripheral neuropathic pain
US20040175423A1 (en) * 2003-02-05 2004-09-09 Daniella Licht Sustained release formulation of N- (2-propylpentanoyl) glycinamide and related compounds
US20040176463A1 (en) * 2003-02-05 2004-09-09 Daniella Licht Immediate release formulation of n-(2-propylpentanoyl)glycinamide
US20060148861A1 (en) * 2003-02-28 2006-07-06 Yissum Research Developement Co. Of The Hebrew University Of Jerusalem Amide derivatives of 2,2,3,3-tetramethylcyclopropane carboxylic acid
US7232929B2 (en) 2003-02-28 2007-06-19 Yissum Research Development Company Of The Hebrew University Of Jerusalem Amide derivatives of 2,2,3,3-tetramethylcyclopropane carboxylic acid
US20100160443A1 (en) * 2003-07-28 2010-06-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compounds useful for treating neurological disorders
US20050209163A1 (en) * 2003-12-02 2005-09-22 Thomas Stoehr Novel use of peptide compounds for treating central neuropathic pain
US7794987B2 (en) 2003-12-02 2010-09-14 Ucb Pharma Gmbh Method for treating central neuropathic pain
US20090018197A1 (en) * 2003-12-05 2009-01-15 David Rudd Methods for treating status epilepticus and related conditions
US20070042969A1 (en) * 2004-03-26 2007-02-22 Srz Properties, Inc. Combination therapy for pain in painful diabetic neuropathy
US20100256179A1 (en) * 2004-03-26 2010-10-07 Ucb Pharma Gmbh Combination therapy for pain in painful diabetic neuropathy
US20060100157A1 (en) * 2004-03-26 2006-05-11 Schwarz Pharma Ag Novel use of peptide compounds for treating pain in painful diabetic neuropathy
US8008351B2 (en) 2004-04-16 2011-08-30 Ucb Pharma Gmbh Methods for prophylaxis or treatment of conditions associated with cortical spreading depression
US20080287545A1 (en) * 2004-04-16 2008-11-20 Schwarz Pharma Ag Use of Peptide Compounds For the Prophylaxis and Treatment of Chronic Headache
US20060135437A1 (en) * 2004-06-09 2006-06-22 Schwarz Pharma Ag Novel use of peptide compounds for treating pain in trigeminal neuralgia
US7820857B2 (en) 2004-06-09 2010-10-26 Ucb Pharma Gmbh Method for treating pain in trigeminal neuralgia
US8338641B2 (en) 2004-06-09 2012-12-25 Ucb Pharma Gmbh Method for treating atypical facial pain
US20060025477A1 (en) * 2004-07-22 2006-02-02 Artman Linda D Analogs of isovaleramide, a pharmaceutical composition including the same, and a method of treating central nervous system conditions or diseases
US8536137B2 (en) 2004-08-27 2013-09-17 Ucb Pharma Gmbh Methods for treating nucleoside-induced pain
US20100029543A1 (en) * 2004-08-27 2010-02-04 Schwarz Pharma Ag Methods for treating nucleoside-induced pain
US20110130350A1 (en) * 2004-10-02 2011-06-02 Ucb Pharma Gmbh Synthesis scheme for lacosamide
US8809585B2 (en) 2004-10-02 2014-08-19 Ucb Pharma Gmbh Synthesis scheme for lacosamide
US20060252749A1 (en) * 2005-01-28 2006-11-09 Srz Properties, Inc. Lacosamide for add-on therapy of psychosis
US20070197657A1 (en) * 2005-08-18 2007-08-23 Srz Properties, Inc. Method for treating non-inflammatory musculoskeletal pain
US20070043120A1 (en) * 2005-08-18 2007-02-22 Bettina Beyreuther Therapeutic combination for painful medical conditions
US20080280835A1 (en) * 2005-08-18 2008-11-13 Bettina Beyreuther Novel Use of Peptide Compounds For Treating Muscle Pain
US8735356B2 (en) 2006-06-15 2014-05-27 Ucb Pharma Gmbh Anticonvulsant combination therapy
US8828943B2 (en) 2006-06-15 2014-09-09 Ucb Pharma Gmbh Anticonvulsant combination therapy
US9095557B2 (en) 2006-06-15 2015-08-04 Ucb Pharma Gmbh Anticonvulsant combination therapy
US20100273714A1 (en) * 2006-06-15 2010-10-28 Schwarz Pharma Ag Peptide compounds for treating refractory status epilepticus
US9446011B2 (en) 2006-06-15 2016-09-20 Ucb Pharma Gmbh Anticonvulsant combination therapy
US20100240576A1 (en) * 2006-06-15 2010-09-23 Thomas Stoehr Anticonvulsant combination therapy
US9308183B2 (en) 2006-06-30 2016-04-12 Ucb Pharma Gmbh Therapy for hyperexcitability disorders
US10149818B2 (en) 2010-12-02 2018-12-11 Ucb Pharma Gmbh Daily formulation of lacosamide

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