Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1995-10-23
1998-02-17
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
A61K 31195
Patent
active
057191859
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP94/01319 filed Apr. 21, 1994.
The present invention relates to the use of .gamma.-aminobutyric acid (GABA) agonists having an agonist action at GABA.sub.B receptors in the treatment of emesis.
GABA is an endogenous inhibitory neurotransmitter in the CNS and peripheral nervous systems. Receptors for GABA have been divided into GABA.sub.A and GABA.sub.B receptor sub-types. GABA.sub.B 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.
It has now been found that GABA agonists having an agonist action at GABA.sub.B receptors are useful in the treatment of emesis.
The invention accordingly provides, in a first aspect, the novel use of GABA agonists having an agonist action at GABA.sub.B receptors in the treatment of emesis.
There is also provided as a further aspect of the invention the use of GABA agonists having an agonist action at GABA.sub.B receptors in the preparation of a medicament for use in the treatment of emesis.
In an alternative or further aspect there is provided 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.sub.B receptors.
There is an isolated report (The Lancet, Jul. 23, 1983, pg. 227) that baclofen reduced the frequency of vomiting due to duodenal ileus in a patient with Duchenne muscular dystrophy. It is submitted that the use of (.+-.) baclofen in the treatment of emesis caused by duodenal ileus is not included within the scope of the instant invention.
Thus, according to a further aspect the invention provides the use of GABA agonists having an agonist action of GABA.sub.B receptors in the treatment of emesis with the proviso that, when the emesis is caused by duodenal ileus, the GABA agonist is other than (.+-.) baclofen.
It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
GABA agonists having an agonist action at GABA.sub.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.
The treatment of emesis mentioned hereinbefore includes the treatment of nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis. GABA agonists having an agonist action at GABA.sub.B receptors are useful in the treatment of emesis however induced. For example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, 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; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, 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; pregnancy; vestibular disorders, such as motion sickness or vertigo; 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); and opioid analgesics, such as morphine.
Specific GABA agonists having an agonist action at GABA.sub.B receptors for use in the present invention include 4-amino-3-(5-chloro-2-thienyl)butyric acid and those compounds generically and specifically disclosed in GB 1017439, e.g. baclofen, U.S. Pat. No. 4,656,298, e.g. 3-aminopropylphosphonous acid (3-aminopropylphosphinic acid)
REFERENCES:
patent: 5091184 (1992-02-01), Khanna
Dickson et al., The Lancet, 23 Jul. 1983, p. 227.
Hillier, R., British Medical Bulletin, vol. 46, No. 1, 1990, pp. 271-291.
Hanks et al., The Lancet, vol. 339, 25 Apr. 1992, pp. 1031-1036.
Wyant, Drugs, vol. 26, 1983, pp. 262-267.
Bays David Edmund
Bountra Charanjit
Glaxo Group Limited
Henley III Raymond
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