Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-04-24
2004-05-25
Kumar, Shailendra (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S616000
Reexamination Certificate
active
06740667
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an antimicrobial agent for preventing, ameliorating and treating diseases caused by the microaerophilic Gram-negative spiral and short bacillus
Helicobacter pylori
(
H. pylori
), for example peptic ulcer and gastritis, particularly recurring peptic ulcer and gastritis.
PRIOR ART
Conventionally, a large number of medicines have been used as anti-ulcer agents for preventing, ameliorating and treating peptic ulcer such as gastric ulcer and duodenal ulcer, and recently, histamine H
2
-receptor antagonists among these medicines are mainly used. By the advent of histamine H
2
-receptor antagonists, it became possible to rapidly ameliorate and treat peptic ulcer and gastritis, particularly with respect to subjective symptoms. However, in the treatment of peptic ulcer or gastritis by the conventional anti-ulcer agents containing histamine H
2
-receptor antagonists, there is the problem that ulcer recurs highly frequently when chemotherapy is suspended after the recovery. Because the reason for this recurrence has not been revealed for a long time, none of effective prophylactic and therapeutic methods have been established.
Meanwhile, it was shown from 1979 onward that the microaerophilic Gram-negative spiral and short bacillus
H. pylori
is present in gastric mucosa of patients suffering from peptic ulcer and bacterium has a close relationship with gastritis and gastric ulcer. It, formerly classified as
Campylobacter pylori
(
C. pylori
), was newly designated
H. pylori
in re-consideration in microbial taxonomy in 1989, and thus
C. pylori
and
H. pylori
are the same bacterium although it may be referred to as
C. pylori
in some literatures.
As literatures showing the relationship between
H. pylori
and gastric ulcer or gastritis, e.g. Med. J. Aust., 142, 436-439, 1985 and Am. J. Gastroentel., 82, 192-199, 1987 reported that acute gastritis occurred upon oral administration of
H. pylori
to healthy volunteers.
Further, the attention has been directed to the relationship between
H. pylori
and gastritis or peptic ulcer, since it was also reported in Gastroentel., 94, 33-40, 1988 that when an antibiotic is administered to patients suffering from peptic ulcer to eradicate
H. pylori
, the improvement of an image of gastric tissues is recognized.
In addition, Lancet, 1437-1442, 1988 reported that the frequency of recurrence of peptic ulcer is high in
H. pylori
—positive patients suffering from peptic ulcer as compared with
H. pylori
—negative patients, and it was thus revealed that the eradication of
H. pylori
is essential for prevention and treatment of recurring peptic ulcer.
Further, recently, the relationship between
H. pylori
and the generation of gastric cancer has been discussed enthusiastically, and the importance of eradication of
H. pylori
came to be recognized more strongly.
As medicines capable of eradicating
H. pylori
, antibiotics such as penicillin, cephalosporin, tetracycline, neuquinolone, and macrolide antibiotics, and some anti-ulcer agents such as praunotol, sofalcone, benexate hydrochloride (betadex), bismuth preparations, and a proton pump inhibitor (referred to hereinafter as PPI) may be proposed.
Among the above-mentioned known medicines capable of eradicating
H. pylori
, anti-ulcer agents other than PPI have a very weak action for eradication of
H. pylori
, and thus the effect of these anti-ulcer agents in eradication could not be expected in clinically ordinary doses.
On the other hand, PPI is recognized to have stronger efficacy, but the eradication of
H. pylori
by PPI alone is difficult.
Further, the in vitro action of the antibiotics in eradication is very strong, but they are rapidly degraded in gastric acid because of very weak physical properties against acid, so there is the problem that their in vivo or clinical effect could not be recognized to be so significant as expected. Further, the antibiotics are administered for eradicating
H. pylori
in larger doses than clinically ordinary doses, thus causing frequently occurring side effects such as anaphylaxis and diarrhea, and when used for a long period of time, the antibiotics bring about many problems such as occurrence of non-recovering severe side effects such as impediments of organs and blood, and generation of resistant bacteria.
As described above, medicines by which recurring peptic ulcer and gastritis attributable to
H. pylori
can be clinically prevented and treated reliably and safely for a prolonged period of time, have never been found yet and there has been demand for a new medicine.
The study during this period is described in e.g. Pharmacia, 32 (7), 828-831, 1996, that is:
(1) The H
2
-receptor antagonist did not have an antimicrobial action on
H. pylori.
(2) The degree of efficacy for
H. pylori
therapy by PPI alone (lansoprazole, 30 mg/day, 8 weeks) was as very low as 5%.
(3) The effect of a single antibiotic in eradication was also very low.
(4) Accordingly, combined therapy by multiple drugs and combined therapy by PPI are considered to be effective, and particular attention is paid to combined therapy by PPI and an antibiotic; however, even combined therapy using 2 drugs, that is, lansoprazole+clarithromycin or omeprazole+amoxicillin, did not achieve any satisfactory effect for eradication of the microorganism.
(5) Accordingly, combined therapy simultaneously using 3 medicines, that is, PPI plus 2 antibiotics, has also been attempted recently.
Such extreme combined therapy by multiple drugs has many disadvantages that administration for a long time is cumbersome and difficult and occurrence of side effects is increased significantly, and thus it cannot be said that such therapy is preferable for the patient.
Under these circumstances, the development of a medicine which in an ordinary dose, exhibits a satisfactory action on eradication of
H. pylori
and is highly safe even when used for a long time has been continued.
DISCLOSURE OF THE INVENTION
Accordingly, the present inventors have conducted extensive studies for a medicine which satisfies such requirements i.e. a clinically more potent action on eradication of
H. pylori
and high safety even when administered for a prolonged period of time. As a result, they unexpectedly found that oxethazaine, which is used clinically widely as a local anesthetic for digestive-tract mucosa, achieved the desired object as an antimicrobial agent. Further, they found that a combination of oxethazaine and PPI brings about synergism or additive effect on eradication of
H. pylori
, thus achieving further preferable therapeutic effects, while a combination of oxethazaine and an antibiotic or a H
2
-receptor antagonist can lead to a reduction of the dose of the antibiotic or H
2
-receptor antagonist administered, and thus completed the present invention.
Accordingly, the object of the present invention is to provide an antimicrobial agent which is clinically highly effective against
H. pylori
, specifically a prophylactic, therapeutic and ameliorating agent for peptic ulcer and gastritis, particularly a prophylactic, therapeutic and ameliorating agent for recurring ulcer and recurring gastritis, consequently enabling prevention of gastric cancer.
Oxethazaine according to the present invention has the chemical name 2,2′-[(2-hydroxyethyl)amino]bis[N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide], which is represented by the following formula:
Oxethazaine is used pharmacologically as a local anesthetic for digestive-tract mucosa to treat pains, acid symptoms, nausea, emesis, stomach discomfort, an impending need to defecate etc., which are accompanied by esophagitis, gastritis, gastric and duodenal ulcer, and colon hypersensitivity.
Further, oxethazaine unlike antibiotics does not permit appearance of resistant bacteria, and thus it can be expected that its therapeutic effect is stable for a prolonged period of time.
Oxethazaine can be produced by a method described in U.S. Pat. No. 2,780,646.
The present invention provides an ant
Hadano Makoto
Sato Masaru
Eisai Co. Ltd.
Kumar Shailendra
Nixon & Vanderhye P.C.
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