Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-06
2001-09-11
Huang, Evelyn Mei (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S229200, C514S230200, C514S291000, C514S292000, C514S293000, C514S300000, C544S066000, C544S101000, C546S080000, C546S081000, C546S083000, C546S084000, C546S123000, C546S156000, C548S453000
Reexamination Certificate
active
06288081
ABSTRACT:
This application is a 371 of PCT/EP97/06751 filed on Dec. 3, 1997.
The invention relates to the use of quinolone- and naphthyridonecarboxylic acid derivatives which are substituted in position 7 by a 1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl radical, and of their salts for the therapy of
Helicobacter pylori
infections and associated gastroduodenal disorders.
In the years following the rediscovery of
Helicobacter pylori
(
H. pylori
; old name
Campylo
-
bacter pylori
) by Warren and Marshall in 1983, the pathophysiological ideas on the genesis of gastro-duodenal disorders in man were developed further in a fundamental way.
H. pylori
is considered to be the cause of type B gastritis and seems to play a causative part in the perpetuation of peptic ulcers. Epidemiological and pathological investigations likewise indicate a connection between the long-term colonization of the mucosa of the stomach by the bacterium and the formation of certain forms of stomach carcinoma. Because of this,
H. pylori
was, in 1994, classed as a carcinogen of the first order (most dangerous cancer-causing category). A rare form of stomach cancer, MALT lymphoma (mucosa-associated lymphoid tissue) appears likewise frequently to be caused by the germ. Indeed, in initial casuistries, after
H. pylori
eradication, not only the reactive infiltrates disappeared, but even some of the MALT lymphomas of low malignancy. A connection with Ménétrier's syndrome is also being discussed. The role of
H. pylori
in functional gastropathy (nonulcerous dyspepsia) is still unclear.
Various epidemiological studies reach the conclusion that approximately half of the population of the world is infected with the bacterium. The likelihood of colonization of the stomach by Helicobacter increases as a function of age. The optimum adaptation of Helicobacter to the living conditions in the unusual, low-competition habitat of the stomach seems to be the precondition for successful establishment of the chronic infection and for the wide distribution of this pathogenic species.
The pathogens are, with their flagella, not only highly mobile in liquid media but also in the viscous mucous of the mucosa of the stomach, they adhere to the epithelial cells of the stomach and they multiply best at an oxygen content of 5%, as is prevalent in the mucous of the stomach wall. Moreover, the bacteria produce large amounts of the enzyme urease which cleaves urea into ammonia and carbon dioxide. The “cloud of ammonia” which is formed possibly assists the bacteria in neutralizing the acidic medium in the microenvironment, resulting in protection against the aggressive stomach acid.
Peptic Ulcers
The introduction of the histamine H
2
-receptor antagonists in the 1970s was a milestone in the therapy of peptic ulcers. World-wide, the frequency of surgical interventions for the treatment of the ulcer decreased dramatically. This principle of the acid blockade was improved even more by the development of the more strongly effective proton pump inhibitors.
However, the antacid therapy has a causal effect—i.e. by disinfectant treatment—only on the symptoms of the ulcer, not on the natural cause of the disease which is characterized by the occurrence of relapses. This is because virtually all ulcus duodeni patients and a predominant majority of the patients suffering from ulcus ventriculi have an
H. pylori
infection of the stomach and therefore suffer from infectious diseases. Only ulcerations caused by nonsteroidal antiphlogistics are not associated with an
H. pylori
infection.
Thus, according to the recommendations of a consensus conference which was organized by the American National Institute of Health (NIH) in 1994, all patients suffering from peptic ulcers should, in the case of a positive germ test, undergo eradication therapy directed against
H. pylori
(NIH Consensus Statement 1: 1-23; 1994). The arguments in favour of this came from controlled therapy studies which showed that, after successful germ eradication, the ulcer relapse rates decrease dramatically (0%-29% versus 61%-95%).
H. pylon
Therapy
In practice, the current eradication of
H. pylori
is not particularly simple. There is no simple and nevertheless reliably effective therapy. The germ is located under the layer of mucous, where it is well protected and difficult to attack.
In vitro,
H. pylori
shows sensitivity towards numerous antibiotics. However, these antibiotics are, as a monotherapy, not effective in vivo. They include, inter alia, penicillin, amoxicillin, tetracycline, erythromycin, ciprofloxacin, metronidazole and clarithromycin. Likewise, bismuth salts and to a lesser extent even proton pump inhibitors (omeprazole, lansoprazole) have antibacterial activity in vitro, but not in vivo.
Among all the therapy modalities used hitherto for eradicating
H. pylori
, to date only the triple therapies below are sufficiently effective:
1. classic bismuth triple therapy (bismuth salt plus two antibiotics) and
2. modified triple therapy (antacid plus two antibiotics).
However, these regimes are complicated eradication methods with poor compliance which may in up to 35% of all cases be associated with side effects (stomach aches, sickness, diarrhoea, a dry mouth, impairment of taste and allergic skin reactions, etc.). This makes a broader use more difficult. Another great disadvantage is the large number of medicaments which have to be taken every day (12-16 tablets/day). This is particularly pronounced in the quadruple therapy where an acid secretion inhibitor is administered simultaneously with the classic triple therapy.
However, the dual therapy (combination of amoxicillin with omeprazole), which is better tolerated and is propagated in Germany, has only a low efficacy and even seems to fail substantially in the case of patients who have been pre-treated with omeprazole and in the case of smokers.
The antibiotic components which are generally administered in triple therapies are amoxicillin, nitroimidazole compounds (metronidazole, tinidazole), tetracycline and, more recently, macrolides (clarithromycin) [in 3-4 partial doses].
Throughout the world, eradication rates of 70-90% are achieved. However, this eradication success can be influenced by a variety of factors:
1. Primarily, mention has to be made of the resistance of the germ (developing countries: up to 60%, Germany: up to 10%) towards metronidazole, the antibiotic which is most frequently used in the triple therapy. In the treatment with Clarithromycin, reference is likewise made to the disadvantage of a resistance development of up to 10%.
2. Another factor which has to be mentioned is the abovementioned compliance of the patients.
Animal Model
An
H. felis
mouse model has been described as a suitable animal model [A. Lee et al., Gastroentrology 99: 1315-1323 (1990)] and we modified this model in such a way that it is highly suitable for the screening and the comparative assessment of the abovementioned compounds.
In spite of considerable morphological differences, the corkscrew-like, urease-forming bacterium
H. felis
is very closely related to
H. pylori. H. felis
is a natural inhabitant of the mucosa of the stomach of dogs and cats. After oral inoculation, the pathogens also colonize the stomach of mice, in a similar manner to that in which
H. pylori
colonizes the stomach of humans. The established chronic long-term infection leads to active gastritis in germ-free mice and induces a corresponding immune response.
The therapeutic efficacy of test samples determined in the
H. felis
mouse model is considered to be very predictive for the corresponding clinical activity.
In spite of very good in vitro activity of antibiotics (for example Amoxicillin or erythromycin) against
H. pylori
, these do not show any significant clinical therapeutic effect after having been administered in monotherapy. This fact is also represented by the
H. felis
mouse model. Correspondingly, the clinically accepted eradicative effect of the classic triple therapy could also be confirmed
Baasner Bernd
Bartel Stephan
Endermann Rainer
Himmler Thomas
Jaetsch Thomas
Bayer Aktiengesellschaft
Huang Evelyn Mei
Norris & McLaughlin & Marcus
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