Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-10-30
2001-01-30
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S428000
Reexamination Certificate
active
06180658
ABSTRACT:
The present invention relates to a method for treating an inflammatory pathological condition in a patient in need thereof, comprising administering on empty stomach an anti-inflammatory effective amount of 2-methoxyphenyl-1-methyl-5p-methylbenzoyl-pyrrol-2-acetamido acetate (known also as amtolmetin guacyl and indicated in the present description also as MED 15).
BACKGROUND ART
Non-steroidal anti-inflammatory drugs (NSAIDs) . have been used for many years in therapy. It is also well known that NSAIDs produce lesions to gastrointestinal apparatus depending on the length of the treatment and on the type of drug. This problem has a dramatic importance in cases where the therapy must be protracted for a long time. An example is rheumatoid arthritis in old people, where a chronic treatment is needed to keep under control the inflammatory state and the pain and make acceptable the quality of life.
At present there is a pharmacological dogma establishing a mandatory connection between anti-inflammatory effect and gastric lesions. This dogma has been recently shaken by the availability of newly synthesised anti-inflammatory drugs showing gastrolesive effects lower than those of old ones. Notwithstanding that equiactive doses of drug could produce lesions of different seriousness, it was settled that an anti-inflammatory drug showed, in any case, a gastrolesive effect. From this fact it followed that it could not be expected that these drugs known in the art could show a gastroprotective effect.
It is also well known, and this has a pharmacological relevance too, that the administration of NSAIDs reflects negatively on renal function, in particular by provoking a remarkable decrease in diuresis. This effect is due to prostaglandin blockade; in fact, prostaglandin physiologically dilate the renal vascular system. The blocking effects of traditional NSAIDs lead to vasoconstriction and to the consequent inhibition of diuresis. From this fact it followed that it could not be expected that these drugs known in the art could be administered without negatively affecting the renal function.
Even more so in view of the above, it could not be expected that a NSAID could simultaneously show a gastroprotective effect without negatively affecting the renal function while at the same time maintaining a high anti-inflammatory activity.
It is also well known that in view of their side-effects on gastric mucosa, NSAIDs are invariably administered after meals or, in general, when the stomach is not empty. The generality of this pharmacological principle finds a practical confirmation in the recommendations found in the packagings of the drugs in commerce. Basically the idea is that the effects of the hypersecretion of hydrochloric acid provoked by the administration of NSAIDs may be, at least partially, counteracted by the presence of food.
It has been now surprisingly found that the compound 2-methoxyphenyl-1-methyl-5p-methylbenzoyl-pyrrol-2-acetamido acetate, which is an effective anti-inflammatory non-steroidal drug as already known in the art, shows a remarkable atisecretory activity on gastric secretion in mammals without affecting the renal function, but, on the contrary, increasing the diuresis. This increase in diuresis is linked to its mechanism of action; in fact, the overflow of neuropeptides (in particular CGRP) produced in the stomach by MED 15 and flowing from the stomach into the bloodstream, produces renal capillary vasodilatation, with reversal of its effect on prostaglandin.
Additionally, and more than unexpectedly for a NSAID, it has been found that amtolmetin guacyl, in order to show its efficacy (gastroprotection and renal tolerability together with an anti-inflammatory effect unchanged), has to be administered on empty stomach in view of the peculiarity of its action mechanism.
The compound 2-methoxyphenyl-1-methyl-5p-methylbenzoyl-pyrrol-2-acetamido acetate is already known in the art and is for instance disclosed in Italian patent application no. 47881A/82 and in U.S. Pat. No. 4,578,481 issued on Mar. 25, 1986.
Both the documents of the state of the art disclose that the above compound shows anti-inflammatory, analgesic, antipyretic, antitussive and antisecretive (on the mucus of the respiratory airway) properties. No mention, either direct or indirect, is made about a possible antisecretive effect on the gastric secretion in mammals.
It is therefore the subject matter of the present invention a method for treating an inflammatory pathological condition in a patient in need thereof, comprising administering on empty stomach an anti-inflammatory effective amount of 2-methoxyphenyl-1-methyl-5p-methylbenzoyl-pyrrol-2-acetamido acetate.
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patent: 4882349 (1989-11-01), Baglioni
patent: 5478481 (1995-12-01), Kazama et al.
patent: 0 755 679 (1997-01-01), None
E. Tubaro et al, “Studies on the gastric tolerability of the new non-sterodidal anti-inflammatory drug amtolmetin guacy1”, Arzneimittelforschung, vol. 45 No. 12, pp. 1298-1302, Dec. 1995.
A. Caruso et al, “Pharmacological properties and toxicology of MED-15, a prodrug of tolmetin”, Drugs under Experimental and Clinical Research, vol. 18, No. 11/12, pp. 481-485 No Date of Publication.
Dialog File Supplier: File 129: PHIND; AN=560550; SCRIP 2290, p. 9, XP002061890, 1997.
M. Delfino, et al, “Evaluation of the Therapeutic Activity and Gastrolesive Effects of a New NSAID vs Placebo in Patients with Osteroarticular Diseases”; Clin Ter., 147:3, pp. 113-116, XP002061891.
M. Lingetti et al, An Evaluation of the Therapeutic Activity of ST-679 in Patients with Osteoarthritis at Different Sites, Clin. Ter., 142:1, p. 2, 1993, No Date of Publication.
G. Donati et al, “A Clinical Study Intended to Establish the Optimum Dosage of St-679 in Rheumatic Disorders”, Clin Ter., 142:1, pp. 19-28, 1993.
Browdy and Neimark
Geist Gary
Medosan Ricerca S.R.L.
White Everett
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