Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-08-11
1999-11-23
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514651, A61K 3134, A61K 31135
Patent
active
059901594
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns the use of antagonists of the 5HT4 receptor for avoiding, alleviating, suppressing or overcoming the gastrointestinal side-effects of (selective) serotonin reuptake inhibitors. The present invention also concerns pharmaceutical formulations comprising 5HT4-receptor antagonists and serotonin reuptake inhibitors for avoiding, alleviating, suppressing or overcoming the gastrointestinal side-effects of serotonin reuptake inhibitors.
Depression in its many variations has recently become much more visible to the general public than it has previously been. It is now recognized as an extremely damaging disorder, and one that afflicts a surprisingly large fraction of the population. Suicide is the most extreme symptom of depression, but many people, not so drastically afflicted, live in misery and partial or complete uselessness, which may also afflict their family.
Depression is often associated with other diseases or conditions, or caused by such other conditions. For example, it is associated with Parkinson's disease; with HIV infection; with Alzheimer disease; and with abuse of anabolic steroids. Depression may also be associated with abuse of any substance, or may be associated with behavioral problems resulting from or occuring in combination with head injuries, mental retardation or stroke (EP 0714663).
During the last two decades, the treatment of depression with antidepressants has moved from the treatment of hospitalised melancholic inpatients to the outpatient setting. During the last few years, the majority of depressed patients, including patients with moderate or mild depressive symptoms, are now treated in primary care. Recent studies have shown that mild depression is a serious condition, representing social and economical liability to the patient and a high cost to society. Such patient clearly benefits from therapy with antidepressants. One of the main contributing factors to this evolution in therapeutic practice has been the introduction of new antidepressants, among which the selective serotonin reuptake inhibitors (SSRIs) are the most important and most widely prescribed. Although the SSRIs are said to have a lesser incidence of side effects, still the use of SSRIs is hampered by a number of adverse effects. The adverse effects occurring most frequently during treatment with SSRIs are gastrointestinal disturbances, such as, for example nausea, diarrhoea/loose stools, constipation, with an incidence of 6 to 37% (Drugs 43 (Suppl. 2), 1992). Nausea is the main adverse effect in terms of incidence. These adverse effects, although mild to moderate in severity, shy some patients away from treatment with SSRIs. The percentage of patients withdrawing because of nausea ranges from 3 to 8% of the patients. Moreover it has been frequently observed that after administration of SSRIs, patients suffer from dyspepsia.
We discovered that the gastrointestinal disturbances associated with the administration of SSRIs is mainly due to a diminished compliance of the stomach. The "compliance of the stomach" can be expressed as the ratio of the volume of the stomach over the pressure exerted by the stomach wall. The compliance of the stomach relates to the gastric tone, which is the result of the tonic contraction of muscle fibers of the proximal stomach. This proximal part, by exerting a regulated tonic contraction (gastric tone), accomplishes the reservoir function of the stomach, namely gastric accommodation and emptying. Impairment of adaptive relaxation as a response to food intake may be the pathophysiological basis of some gastrointestinal disturbances or disorders associated with the use of SSRIs.
Patients suffering from dyspepsia after the intake of SSRIs feel hungry but cannot finish a normal meal. This is explained by this diminished stomach compliance. Normally when a subject starts eating, the stomach will show an adaptive relaxation, i.e the stomach will relax to accept the food that is ingested. This adaptive relaxation is not possible when the stomach compliance is hamp
REFERENCES:
Chemical Abstracts, vol. 122, No. 15, Apr. 10, 1995, Abstract No. 178309, A. Lucchelli et al.: "The interaction of antidepressant drugs with central and peripherical enteric 5-HT3 and 5-HT4 receptors".
Bosmans Jean-Paul Rene Marie Andre
Meulemans Ann Louise Gabrielle
Ciambrone Coletti Ellen
Henley III Raymond
Janssen Pharmaceutica N.V.
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