Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-06-14
2000-10-17
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544105, C07D26528, A61K 315365
Patent
active
061332607
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the use of quinolone- and naphthyridonecarboxylic acid derivatives which are substituted in the 7-position by a 2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl radical, and their salts for the therapy of Helicobacter pylori infections and the gastroduodenal disorders associated therewith.
With the rediscovery of Helicobacter pylori (H. pylori; formally Campylobacter pylori) by Warren and Marshall in 1983, in the following years it was possible to fundamentally further develop the pathophysiological ideas about the origin of gastroduodenal disorders of man.
H. pylori is regarded as a cause of type B gastritis and appears to play a causal role in the perpetuation of peptic ulcer. Epidemiological and pathological investigations likewise point to a relationship between long-term colonization of the gastric mucosa with the bacterium and the origin of certain forms of carcinoma of the stomach. H. pylori was therefore classified in 1994 as a carcinogen of the first class (most dangerous carcinogenic category). A rare stomach cancer, MALT lymphoma (mucosa-associated lymphoid tissue), likewise often appears to be caused by the bacterium. In initial case reports, after H. pylori eradication not only the reactive infiltrates actually disappeared, but also a part of the poorly malignant MALT lymphoma. Relationships with hypertrophic gastritis are also discussed. The role of H. pylori in functional gastropathy (nonulcerative dyspepsia) is still unclear.
Various epidemiological studies come to the conclusion that about half the world population is infected with the bacterium. The probability of the colonization of the stomach with Helicobacter increases with age. The optimum adaptation of Helicobacter to the living conditions in the unusual, low-competition habitat [lacuna] stomach appears to be the prerequisite for the successful establishment of the chronic infection and for the wide distribution of this pathogenic species.
The pathogenic organisms with their flagella are very mobile not only in the liquid medium, but also in the viscous mucus of the gastric mucous membrane, adhere to the gastric epithelial cells and proliferate best at an oxygen content of 5%, as prevails in the mucus of the gastric wall. Moreover, the bacteria form large amounts of the enzyme urease, which splits urea into ammonia and carbon dioxide. Possibly, the resulting `ammonia cloud` helps to neutralize the acidic medium in the microenvironment and thus to protect from the aggressive gastric acid.
The introduction of the histamine H.sub.2 receptor antagonists in the 70s was a milestone in the therapy of peptic ulcer. The frequency of surgical interventions for treatment of the ulcer sufferer thus decreased dramatically worldwide. This principle of acid blockage was improved still further by the development of the even more strongly active proton pump inhibitors
As a result of the antacid therapy, however, only the symptoms of the ulcer, not the natural course of the disorder, which is characterized by the occurrence of relapses, can be influenced causally--say due to bactericidal treatment. Since virtually all duodenal ulcer patients and the predominant majority of patients with stomach ulcer have an H. pylori infection of the stomach and thus suffer from infectious diseases. Only ulcerations which are caused by non-steroidal anti-inflammatories are not associated with an H. pylori infection.
Therefore, according to the recommendations of a consensus conference, which was organized in 1994 by the American Public Health Authority (NIH), in the case of positive detection of bacteria all patients with peptic ulcers should be subjected to eradication therapy directed against H. pylori (NIH Consensus Statement 1: 1-23; 1994). The arguments were supplied by controlled therapy studies, in which it was possible to show that after successful eradication of bacteria the ulcer recurrence rates fall drastically (0%-29% versus 61%-95%).
The present eradication of H. pylori turns out to be problematic in practice. A simple and yet reliably ef
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Baasner Bernd
Bartel Stephan
Himmler Thomas
Jaetsch Thomas
Labischinski Harald
Bayer Aktiengesellschaft
Shah Mukund J.
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