Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-20
2002-12-03
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S192000, C514S278000, C514S338000, C514S395000, C514S503000, C514S619000, C514S819000, C514S925000, C514S926000, C514S927000, C514S928000, C424S653000
Reexamination Certificate
active
06489317
ABSTRACT:
TECHNICAL FIELD
This invention relates to pharmaceutical compositions and therapeutic methods for the treatment and/or prevention of recurrence of gastrointestinal disorders associated with infection by
Helicobacter pylori
(
H. pylori
).
BACKGROUND
Helicobacter pylori
has been found to cause chronic histological gastritis and peptic ulcer disease, such as gastric and duodenal ulcer. It also appears to cause a condition called non-ulcer dyspepsia where
Helicobacter pylori
causes inflammation in the stomach which is histologically associated with indigestion and epigastric pain.
Helicobacter pylori
is also thought to have a role in the causation of stomach cancer and its eradication may be instrumental in causing cure of ulcer disease, a reversal of a proportion of patients with non-ulcer dyspepsia, and prevention of gastric cancer development in those who may be predisposed to it.
Until recent times,
H. pylori
has been found to be difficult to eradicate using known chemotherapeutic agents. Although many antibiotics can suppress
H. pylori
growth in vivo the mucosal concentration appears to be inadequate and penetration of the usual gastric mucus layer is poor. Furthermore, there is frequently more than one infecting agent within the mucosa and hence, sensitivities of the various bacteria may vary within one patient and within one region of the mucosa. The development of adequate in vivo eradication methods for chronic
H. pylori
infection has therefore been difficult. Furthermore, single antibiotics are almost never adequate for use and double antibiotic combinations have also resulted in poor eradication rates. A further major looming problem progressively affecting current eradication therapies is the rapid development of clarithromycin resistance worldwide. The proportion of
H. pylori
infections which are resistant to clarithromycin is increasing by from 2-5% per year. Resistance is developing faster in the countries where clarithromycin is being used frequently; in particular, USA and Europe. Hence, new methods for eradication of
H. pylori
are urgently required. In addition, salvage therapies for patients who have failed first time therapy are also unavailable and such treatments are becoming in demand as more and more patients undergo therapy and fail initial eradication attempts.
It is therefore an object of the present invention to provide a novel pharmaceutical composition for the treatment and/or prevention of recurrence of gastrointestinal disorders associated with
H. pylori.
It is a further object of the invention to provide methods for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with
H. pylori
in a patient.
DISCLOSURE OF THE INVENTION
The present inventor has found that the use of a novel combination antibiotic therapy not only results in high initial eradication rates of
H. pylori
but also can be used as a salvage therapy. There is a large volume of literature describing numerous and varying combinations of antimicrobial agents for
H. pylori
eradication, to a large extent due to the fact that it is difficult to predict clinically which combination might work and which will be unsuccessful. Indeed, persons skilled in the art cannot—from in vitro studies or from their previous experience—simply predict the success or failure of a particular regime.
Rifampicin is an antimycobacterial antibiotic used in the treatment of tuberculosis. Recently, its semi-synthetic derivative, an ansamycin called rifabutin which is currently indicated for the treatment of tuberculosis or
Mycobactenium avium
complex infection, has been described as having in vitro activity against
Helicobacter pylori
when tested in culture. In the present invention combinations containing an ansamycin have been found to be clinically effective in eradicating
H. pylori.
In a first embodiment, the present invention provides a pharmaceutical composition for the treatment of gastrointestinal disorders associated with
H. pylori
infection including a first antibiotic which is an ansamycin, at least one second antibiotic or antimicrobial agent selected from amoxycillin, tetracycline and bismuth compounds, and a proton pump inhibitor, together with at least one pharmaceutical acceptable carrier, diluent, adjuvant or excipient; wherein said ansamycin is rifabutin.
In a second embodiment, the invention provides a method for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with
H. pylori
in a patient requiring said treatment and/or prevention, which method comprises administering to said patient sequentially or simultaneously a therapeutically effective amount of a first antibiotic which is an ansamycin, a therapeutically effective amount of at least one second antibiotic or antimicrobial agent selected from amoxycillin, tetracycline and bismuth compounds, and a therapeutically effective amount of a proton pump inhibit; wherein said ansamycin is rifabutin.
Typically, a method of treatment in accordance with the invention results in the eradication of
H. pylori
from the patient who is treated.
In a third embodiment, the invention further provides the of a therapeutically effective amount of a first antibiotic which is an ansamycin, a therapeutically effective amount of at least one second antibiotic or antimicrobial agent selected from amoxycillin, tetracycline and bismuth compounds, and a therapeutically effective amount of a proton pump inhibitor for the manufacture of a medicament for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with
H. pylori
in a patent; wherein said ansamycin is rifabutin.
In a fourth embodiment, the invention still further provides a therapeutically effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least one second antibiotic or antimicrobial agent selected from amoxycillin, tetracycline and bismuth compounds, and a therapeutically effective amount of a proton pump inhibitor when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with
H. pylori
in a patient; wherein said ansamycin is rifabutin.
The pharmaceutical composition of the invention includes, in addition to the ansamycin, one or more other antibiotics or antimicrobial agents. Typically, where the patient to whom the pharmaceutical composition is to be administered has previously not been treated for
H. pylori
infection, the pharmaceutical composition of the invention includes rifabutin, and just one other antibiotic or antimicrobial agent. In other cases, the pharmaceutical composition typically includes rifabutin, and two different antibiotics or antimicrobial agents.
Similarly, in the method of the second embodiment and in the third and fourth embodiments of the invention the ansamycin and a single other antibiotic or antimicrobial agent may be used, but more typically the ansamycin and two different other antibiotics or antimicrobial agents may be used.
In the method of the second embodiment, the active agents, namely the ansamycin, the one or more other antibiotics or antimicrobial agents, and the proton pump inhibitor may be administered simultaneously or sequentially, in any order.
The pharmaceutical composition of the first embodiment includes a proton pump inhibitor (PPI). Similarly, a method of the second embodiment includes the administration of a proton pump inhibitor. The inclusion of a PPI can help to enhance the eradication rate of
H. pylori
and can improve the patient's symptoms, since patients are often dyspeptic at the beginning of the treatment. The administration of the PPI in the method of the second embodiment may be separate from the administration of the ansamycin and other antibiotic(s) or antimicrobial agent(s), or the PPI may be co-administered with the ansamycin and/or one or more other antibiotics or antimicrobial agents. Suitable PPIs include omeprazole, pantoprazole, Iansoprazole and rabeprazole.
The antibiotic(s) or antimicrobial age
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