Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-08-24
2003-10-21
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S576000
Reexamination Certificate
active
06635678
ABSTRACT:
This Application is a 371 of PCT/GB97/03525 filed Dec. 23, 1987
This invention relates to the treatment of relief of fecal incontinence and anal itch (pruritis ani), particularly for patients who have had a major bowel resection and reanastomosis.
Anal or fecal incontinence is the inability to voluntarily control the passage of feces or gas through the anus. It may occur either as fecal soiling or as rare episodes of incontinence for gas or watery stools. It is a very distressing condition that can result in self-inflicted social isolation and despair.
Conventional treatments for fecal incontinence include drug therapy to improve stool consistency, such as morphine, loperamide and codeine phosphate to reduce gut motility, and laxatives to soften stools and relieve constipation. Biofeedback training is another treatment which involves muscle strengthening exercises to improve anal canal resting pressure, and squeeze pressure, and to teach symmetry of anal canal function. The most common form of treatment however, is surgical repair, such as the creation of a neo-sphincter which involves grafting on muscle from other parts of the anus, or a colostomy. (Gastroenterology in Practice, Summer 1995, p18-21; Dig Dis 1990; 8:179-188; and The New England Journal of Medicine, April 1992, p1002-1004). In mild cases of anal leakage, the patient will often try and plug the anus with a ball of cotton wall.
In Gut, 1991, 32, p. 345-346 it was reported that two thirds of patients with idiopathic faecal incontinence had a decreased anal resting pressure resulting from an abnormal internal sphincter function. In many incontinent patients, the internal anal sphincter was found to be abnormally thin, while others had an external anal sphincter defect.
It has also been reported that in vitro contractile response of the internal anal sphincter to noradrenaline is decreased in incontinence, (Br. J. Surg. 1992, vol 79, August, p829-832; Digestive Diseases and Sciences, vol 38, no. 11, November 1993, p1961-1969). A further discussion of the innervation and control of the internal anal sphincter and drugs which can increase or decrease the normal anal resting pressure, is discussed in the text book Coloproctology and the Pelvic Floor (Butterworths), second edition, 1992, at chapter 3 p37-53; Automic Control of Internal Anal Sphincter; and Journal of Clinical Investigation 1990, 86: p424-429.
In Surgery 1990; 107: p311-315 sodium valproate was found to be useful in the treatment of minor incontinence after ileoanal anastomosis.
It has now surprisingly been found that fecal incontinence and anal itch can be resolved by treatment with &agr; adrenergic agonists, nitric oxide synthase inhibitors, prostaglandins F
2&agr;
, dopamine, morphine, &bgr;-blockers such as propranolol, and 5—Hydroxytryptamine (5—HT).
This is surprising since it was always thought that once an anal sphincter began functioning abnormally, the patient would require major surgery.
In this way the anal leakage is reduced or eliminated without the patient having to undergo major surgery.
Accordingly in a first aspect of the invention there is provided method for the treatment or prophylaxis of fecal incontinence or anal itch by topical application in and/or around the anal canal of a patient, a therapeutically active amount of a physiologically active agent selected from an &agr; adrenergic agonist, nitric oxide synthase inhibitor, prostaglandin F
2&agr;
, dopamine, morphine, &bgr;-blockers, and 5—Hydroxytryptamine
The agents of the invention appear to at least partially treat the incontinence by increasing the resting pressure of the internal anal sphincter.
Preferred agents are al adrenergic agonists, nitric oxide synthase inhibitors, and prostaglandin F
2&agr;
.
Examples of suitable &agr;
1
adrenergic agonists are nor—adrenalin, methoxamine, but particularly preferred is phenylephrine.
Examples of suitable F
2&agr;
prostaglandin are dinoprost and carboprost.
Examples of suitable NO synthase inhibitors are N
G
—monomethyl-L-arginine (L-NMMA), and N
G
—nitro-L-arginine methyl ester (L-NAME).
The medicament can contain a single active agent or a combination of any of the above active agents.
Nitric Oxide (NO) synthase inhibitors such as LNMMA have previously been suggested for the therapeutic treatment of septic shock.
The prostaglandins, along with thromboxanes and leukotrienes are all derived from 20-carbon polyunsaturated fatty acids an are collectively termed eicosanoids. F
2&agr;
prostaglandins derived in vivo from the endoperoxide prostaglandin H
2
which turn derived from leukotrienes. Clinically, F
2&agr;
prostaglandin preparations such as dinoprost and carboprost are used as uterine stimulants in the termination of pregnancy, missed abortion or the induction of labor.
Phenylephrine (an &agr;
1
adrenergic agonist) is used as a mydriatic in ophthalmology, and as a decongestant, for example, in cold and flu remedies.
However there has been no suggestion to the iventors knowledge of using any of these active agents to treat fecal incontinence or anal itch.
As used herein “fecal incontinence” includes all types of anal leakage from minor leakage or ‘spotting’ through moderate leakage, to major instances of faecal incontinence, and includes neurogenic, active, urge and passive incontinence.
More particularly the class of incontinent patients who will benefit most from the present invention are those with idiopathic incontinence and those whose incontinence is at least partly due to a weakness of either the internal or external anal sphincter, especially those with a normal or low maximum anal pressure and a structurally intact internal anal sphincter muscle, such as with an abnormally thin sphincter. However patients with minor structural damage such as a fragmented sphincter would still benefit from the invention. Not only incontinent patients with a damaged or abnormal internal sphincter can be treated, but also patients with a damaged or abnormal external sphincter since the increase in the internal anal resting tone induced by the invention will compensate for a poorly functioning external sphincter.
Another class of patients who particularly benefit from the invention are post-surgical patients who have had major bowel resection and reanastomosis. For example patients with ileoanal pouch (restorative proctocolectomy), coloanal (with or without colonic pouch) anostomosis, lower anterior resection, and colectomy with ileorectal anastomosis.
The damage to the sphincter could be caused by trauma, such as experienced in child birth, surgical operations, or road traffic accidents. Furthermore it is also believed that incontinence caused by primary internal anal degeneration can also be relieved by the invention.
Anal leakage also often leads to pruritis of the anus and therefore by reducing or eliminating the leakage, the pruritis or anal itch is also relieved or prevented.
Furthermore, as a result of the increased anal resting pressure, the patient no longer has the discomfort of distended anal sphincter muscles.
Physiologically acceptable salts of the above active compounds are also within the scope of the invention. Suitable salts include those formed with both organic and inorganic acids, such as those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids.
By salt we also mean to include any complex or pseudo salt wherein the active agent (such as phenylephrine) is associated with, for example, a derivative to an organic or inorganic acid.
Prodrugs and any other bioprecursor which are converted in vivo to the active agents (such as phenylephrine) are also within the scope of the invention.
A particularly preferred salt of phenylephrine is the hydrochloride salt.
Although the medicament can be administered, for example, orally or intravenously to systemically treat the faecal incontinence, it is preferred that the incontinence
Kamm Michael A.
Phillips Robin K. S.
Criares Theodore J.
Kim Jennifer
S.L.A. Pharma AG
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