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WO1996011680A2 - Utilisation d'agonistes de gaba dans le traitement de vomissements - Google Patents

Utilisation d'agonistes de gaba dans le traitement de vomissements Download PDF

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Publication number
WO1996011680A2
WO1996011680A2 PCT/EP1995/004025 EP9504025W WO9611680A2 WO 1996011680 A2 WO1996011680 A2 WO 1996011680A2 EP 9504025 W EP9504025 W EP 9504025W WO 9611680 A2 WO9611680 A2 WO 9611680A2
Authority
WO
WIPO (PCT)
Prior art keywords
emesis
gaba
acid
use according
induced
Prior art date
Application number
PCT/EP1995/004025
Other languages
English (en)
Other versions
WO1996011680A3 (fr
Inventor
David Edmund Bays
Charanjit Bountra
Original Assignee
Glaxo Group Limited
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 Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU37458/95A priority Critical patent/AU3745895A/en
Publication of WO1996011680A2 publication Critical patent/WO1996011680A2/fr
Publication of WO1996011680A3 publication Critical patent/WO1996011680A3/fr

Links

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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid

Definitions

  • the present invention relates to the use of ⁇ -aminobutyric acid (GABA) agonists having an agonist action at GABA B receptors in the treatment of emesis.
  • GABA ⁇ -aminobutyric acid
  • GABA is an endogenous inhibitory neu retransmitter in the CNS and peripheral nervous systems.
  • Receptors for GABA have been divided into GABA and GABA ⁇ receptor sub-types.
  • GABAB agonists are described as being of use in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome and as prokinetic and anti-tussive agents.
  • the invention accordingly provides, in a first aspect, the novel use of a GABA agonist having an agonist action at GABA B receptors, selected from the compounds ⁇ -phenyl- ⁇ -aminobutyric acid ( ⁇ -phenyl-GABA), 3-amino-2-(4- chorophenyl)-nitropropane, 1-(aminomethyl)cyclohexaneacetic acid
  • a GABA agonist having an agonist action at GABA B receptors, selected from the compounds ⁇ -phenyl- ⁇ -aminobutyric acid ( ⁇ -phenyl-GABA), 3-amino-2-(4- chorophenyl)-nitropropane, 1-(aminomethyl)cyclohexaneacetic acid
  • Patent Specification No. 2185483 such as D-N-(2-pyrrolidone-5-carbonyl)- piperidine, in the treatment of emesis.
  • GABA agonists having an agonist action at GABA B receptors listed above and gene ⁇ cally and specifically disclosed in the above referenced patent specifications in the preparation of a medicament for use in the treatment of emesis.
  • a method for the treatment of a mammal including man, suffering from or susceptible to emesis, comprising administration of an effective amount of a GABA agonist having an agonist action at GABA B receptors listed above or generically or specifically disclosed in the above referenced patent specifications.
  • baclofen reduced the frequency of vomiting due to duodenal ileus in a patient with Duchenne muscular dystrophy.
  • ( ⁇ ) baclofen in the treatment of emesis caused by duodenal ileus is not included within the scope of the instant invention.
  • GABA agonists having an agonist action at GABA B receptors have been shown to have anti-emetic activity as indicated by for example their ability to inhibit emesis induced by a variety of emetogens in the ferret.
  • emesis The treatment of emesis mentioned hereinbefore includes the treatment of nausea, retching and vomiting.
  • Emesis includes acute emesis, delayed or late emesis and anticipatory emesis.
  • GABA agonists having an agonist action at GABA B receptors are useful in the treatment of emesis however induced.
  • emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclop hosp ham id e, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.
  • cytarabine methotrexate and 5-fluorouracil
  • vinca alkaloids e.g. etoposide, vinblastine and vincristine
  • others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof
  • radiation sickness e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g.
  • gastritis or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g.
  • altitude sickness such as morphine
  • opioid analgesics such as morphine
  • gastro-oesophageal reflux disease acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation
  • heartburn such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia.
  • GABA B agonists may be administered as the raw chemical but are preferably presented as a pharmaceutical formulation. Suitable pharmaceutical formulations for GABA B agonists are described in the art, for example as in the above referenced patent specifications.
  • GABA B agonists may be formulated for oral, buccal, parenteral, depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). Oral and parenteral formulations are preferred.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystaliine cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystaliine cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl- p_-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • the GABA B agonists may be formulated for parenteral administration by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the GABA B agonists may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the GABA B agonists may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the GABA B agonists may be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • Suitable dose ranges are described in the art, that is to say that for use as anti- emetics the compounds may be used at doses appropriate for other conditions for which GABA B agonists are known to be useful. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient, and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected.
  • a suitable dose range is for example 0.1 mg/kg to about 200 mg/kg, e.g. 0.1 mg/kg to 10 mg kg, bodyweight per day.
  • GABA B agonists having an agonist action at GABA B receptors useful in the instant invention may, if desired, be administered in combination with one or more other therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art.
  • GABA agonists having an agonist action at GABA B receptors may be administered in combination with a systemic anti-inflammatory corticosteroid such as methyl prednisolone or dexamethasone, a 5HT3 antagonist such as ondansetron, granisetron or metoclopramide, or a tachykinin antagonist, including substance P antagonists and other neurokinin antagonists, such as an NK-* receptor antagonist, or a sympathomimetic such as ephedrine, pseudoephedrine or oxymetazoline.
  • a systemic anti-inflammatory corticosteroid such as methyl prednisolone or dexamethasone
  • a 5HT3 antagonist such as ondansetron, granisetron or metoclopramide
  • a tachykinin antagonist including substance P antagonists and other neurokinin antagonists, such as an NK-* receptor antagonist, or a sympathomimetic such as ephedrine, pseudo
  • the anti-emetic activity of the GABA B agonist ( ⁇ ) baclofen was demonstrated by its ability to inhibit emesis induced by radiation, cisplatin, morphine and ipecacuanha in the ferret.
  • the anti-emetic activity of R(-) baclofen (active isomer) was demonstrated by its ability to inhibit radiation-induced emesis in the ferret.
  • Cisplatin Test In this model of emesis the onset of retching and vomiting occurs approximately 1 hour after the administration of cisplatin (200mg/m 2 i.p.). The test compound was administered (s.c.) 1 hour after the administration of the emetogen and its effect on emesis determined by comparison with appropriate controls (e.g. water).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On décrit l'utilisation d'agonistes de l'acide η-aminobutyrique (GABA) possédant une activité agoniste au niveau des récepteurs de GABAB, dans le traitement des vomissements.
PCT/EP1995/004025 1994-10-14 1995-10-12 Utilisation d'agonistes de gaba dans le traitement de vomissements WO1996011680A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37458/95A AU3745895A (en) 1994-10-14 1995-10-12 Use of gaba antagonists in the treatment of emesis

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB9420784A GB9420784D0 (en) 1994-10-14 1994-10-14 Medicaments

Publications (2)

Publication Number Publication Date
WO1996011680A2 true WO1996011680A2 (fr) 1996-04-25
WO1996011680A3 WO1996011680A3 (fr) 1996-06-27

Family

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PCT/EP1995/004025 WO1996011680A2 (fr) 1994-10-14 1995-10-12 Utilisation d'agonistes de gaba dans le traitement de vomissements

Country Status (3)

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AU (1) AU3745895A (fr)
GB (1) GB9420784D0 (fr)
WO (1) WO1996011680A2 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999008671A1 (fr) * 1997-08-20 1999-02-25 Warner-Lambert Company Analogues du gaba pour prevenir et traiter des lesions gastro-intestinales
EP1031350A1 (fr) * 1999-02-23 2000-08-30 Warner-Lambert Company Utilisation d'un analogue de la gabapentine pour la fabrication d'un médicament pour la prevention et le traitement des douleurs viscérales
US6127418A (en) * 1997-08-20 2000-10-03 Warner-Lambert Company GABA analogs to prevent and treat gastrointestinal damage
EP0974351A3 (fr) * 1998-04-24 2000-12-13 Jouveinal Médicament pour la prévention et le traitement des dommages gastrointestinaux
US6576626B2 (en) 1999-12-09 2003-06-10 Astrazeneca Ab Aminopropylphosphinic acids
US6596711B1 (en) 1999-12-09 2003-07-22 Astrazeneca Ab (Aminopropyl)methylphosphinic acids
WO2005025559A1 (fr) * 2003-09-12 2005-03-24 Agi Therapeutics Ltd. Traitement de gastroparesie et de dyspepsie non ulcereuse avec des agonistes de gabab
US6919379B2 (en) 2001-06-08 2005-07-19 Astrazeneca Ab Compounds useful in reflux disease
US7309719B1 (en) * 1998-05-15 2007-12-18 Warner Lambert Company, Llc Stabilized pharmaceutical preparation of gamma-aminobutyric acid derivatives and process for preparing the same
US7319095B2 (en) 1999-12-09 2008-01-15 Astrazeneca Ab Use of GABAB receptor agonists
US10556914B2 (en) 2015-09-15 2020-02-11 Abbvie Inc. Substituted isoxazolopyridazinones and isothiazolopyridazinones and methods of use
CN111603560A (zh) * 2020-06-22 2020-09-01 泉州台商投资区秋鑫茶业有限公司 茶叶γ-氨基丁酸在肿瘤放射治疗上的应用
US10918632B2 (en) * 2016-09-07 2021-02-16 The Children's Hospital Of Philadelphia Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorder

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE41920E1 (en) 1996-07-24 2010-11-09 Warner-Lambert Company Llc Isobutylgaba and its derivatives for the treatment of pain

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JPS5015793B2 (fr) * 1972-06-07 1975-06-07
DE3150486A1 (de) * 1981-12-19 1983-08-25 Merck Patent Gmbh, 6100 Darmstadt Imidazo(4,5-c)pyridine, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung
FR2597100A1 (fr) * 1986-01-21 1987-10-16 Nippon Shinyaku Co Ltd Derives du pyroglutamide
US4952573A (en) * 1988-03-23 1990-08-28 Laboratoirs Alcon S.A. Compounds having GABA like activity, and use of same in tissue irrigating solutions
US5281747A (en) * 1989-05-13 1994-01-25 Ciba-Geigy Corporation Substituted aminoalkylphosphinic acids
US5182290A (en) * 1991-08-27 1993-01-26 Neurogen Corporation Certain oxazoloquinolinones; a new class of GABA brain receptor ligands
GB9125615D0 (en) * 1991-12-02 1992-01-29 Wyeth John & Brother Ltd Amines
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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001515033A (ja) * 1997-08-20 2001-09-18 ワーナー−ランバート・カンパニー 胃腸損傷を防止および治療するためのｇａｂａ類縁体
WO1999008670A1 (fr) * 1997-08-20 1999-02-25 Guglietta, Antonio Analogues de gaba utilises pour prevenir et traiter des lesions gastro-intestinales
WO1999008671A1 (fr) * 1997-08-20 1999-02-25 Warner-Lambert Company Analogues du gaba pour prevenir et traiter des lesions gastro-intestinales
US6426368B2 (en) 1997-08-20 2002-07-30 Warner-Lambert Company Method for preventing and treating alcoholism
US6127418A (en) * 1997-08-20 2000-10-03 Warner-Lambert Company GABA analogs to prevent and treat gastrointestinal damage
US6242488B1 (en) 1997-08-20 2001-06-05 University Of Oklahoma Method for preventing and treating pain
EP0974351A3 (fr) * 1998-04-24 2000-12-13 Jouveinal Médicament pour la prévention et le traitement des dommages gastrointestinaux
US7309719B1 (en) * 1998-05-15 2007-12-18 Warner Lambert Company, Llc Stabilized pharmaceutical preparation of gamma-aminobutyric acid derivatives and process for preparing the same
WO2000050027A1 (fr) * 1999-02-23 2000-08-31 Warner-Lambert Company Derive de gabapentin pour la prevention et le traitement de douleurs viscerales
EP1031350A1 (fr) * 1999-02-23 2000-08-30 Warner-Lambert Company Utilisation d'un analogue de la gabapentine pour la fabrication d'un médicament pour la prevention et le traitement des douleurs viscérales
US7034176B2 (en) 1999-12-09 2006-04-25 Astrazeneca Ab Aminopropylphosphinic acids
US6841698B2 (en) 1999-12-09 2005-01-11 Astrazeneca Ab Aminopropylphosphinic acids
US6596711B1 (en) 1999-12-09 2003-07-22 Astrazeneca Ab (Aminopropyl)methylphosphinic acids
US6576626B2 (en) 1999-12-09 2003-06-10 Astrazeneca Ab Aminopropylphosphinic acids
US7319095B2 (en) 1999-12-09 2008-01-15 Astrazeneca Ab Use of GABAB receptor agonists
US7807658B2 (en) 1999-12-09 2010-10-05 Astrazeneca Ab Use of GabaB receptor agonists
US6919379B2 (en) 2001-06-08 2005-07-19 Astrazeneca Ab Compounds useful in reflux disease
WO2005025559A1 (fr) * 2003-09-12 2005-03-24 Agi Therapeutics Ltd. Traitement de gastroparesie et de dyspepsie non ulcereuse avec des agonistes de gabab
US10556914B2 (en) 2015-09-15 2020-02-11 Abbvie Inc. Substituted isoxazolopyridazinones and isothiazolopyridazinones and methods of use
US10918632B2 (en) * 2016-09-07 2021-02-16 The Children's Hospital Of Philadelphia Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorder
CN111603560A (zh) * 2020-06-22 2020-09-01 泉州台商投资区秋鑫茶业有限公司 茶叶γ-氨基丁酸在肿瘤放射治疗上的应用

Also Published As

Publication number Publication date
AU3745895A (en) 1996-05-06
WO1996011680A3 (fr) 1996-06-27
GB9420784D0 (en) 1994-11-30

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