Novel methods for the treatment and prevention of ileus

Inactive Publication Date: 2005-07-21
APOLOR CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0010] Accordingly, the present invention is directed, in part, to novel methods for treating and/or preventing ileus. Specifically, in one embodiment, there ar

Problems solved by technology

For example, administration of mu opioid agonists often results in intestinal dysfunction due to the large number of receptors in the wall of the gut (Wittert, G., Hope, P. and Pyle, D., Biochemical and Biophysical Research Communications 1996, 218, 877-881; Bagnol, D., Mansour, A., Akil, A. and Watson, S. J., Neuroscience 1997, 81, 579-591).
Specifically, opioids are generally known to cause nausea and vomiting as well as inhibition of normal propulsive gastrointestinal function in animals and man (Reisine, T., and Pastemak, G., Goodman &Gilman's The Pharmacological Basis of Therapeutics Ninth Edition 1996, 521-555) resulting in side effects such as, for example, constipation.
The presence of endogenous opioid compounds associated with the GI tract suggests that an abnormal physiological level of these compounds may lead to bowel dysfunction.
It is a common problem for patients having undergone surgical procedures, especially surgery of the abdomen, to suffer from a particular bowel dysfunction called post-surgical (or post-operative) ileus.
Ileus may be diagnosed by the disruption of normal coordinated movements of the gut, resulting in failure of the propulsion of intestinal contents.
In some instances, particularly following surgery, including surgery of the abdomen, the bowel dysfunction may become quite severe, lasting for more than a week and affecting more than one portion of the GI tract.
Similarly, post-partum ileus is a common problem for women in the period following childbirth, and is thought to be caused by similar fluctuations in natural opioid levels as a result of birthing stress.
The administration of opioid analgesics to a patient after surgery may often contribute to bowel dysfunction, thereby delaying recovery of normal bowel function.
Since virtually all patients receive opioid analgesics, such as morphine or other narcotics for pain relief after surgery, particularly major surgery, current post-surgical pain treatment may actually slow recovery of normal bowel function, resulting in a delay in hospital discharge and increasing the cost of medical care.
These prior art methods suffer from drawbacks, for example, as lacking specificity for post-surgical or post-partum ileus.
And these prior art methods offer no means for prevention.
However, it is well known that activity of naloxone and related drugs is not limited to peripheral Systems and may interfere with the analgesic effects of opioid narcotics.
The majority of currently known opioid antagonist therapies are not peripherally selective and have the potential for undesirable side effects resulting from penetration into the CNS.

Method used

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  • Novel methods for the treatment and prevention of ileus
  • Novel methods for the treatment and prevention of ileus

Examples

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example

[0212] This example is directed to in vivo experiments in humans which demonstrate the effectiveness of the methods of the present invention.

[0213] A 78 patient Phase II clinical study was conducted which compared two doses (2 mg and 12 mg) of the compound of formula (II) versus placebo in patients undergoing partial colectomy or simple or radical hysterectomy surgical procedures. The results of this study are set forth in the following Tables 1 5o 4 and are depicted graphically in FIGS. 1 to 5.

TABLE 1MEAN TIME TO FIRST FLATUSDosageDaysSEM (days)Hours12 mg2.230.15153.438 2 mg2.620.19262.967Placebo2.860.27568.675

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Abstract

Novel methods for the treatment and / or prevention of ileus. The methods may comprise administering to a patient an effective amount of a peripheral mu opioid antagonist compound. Preferred compounds for use in the methods include piperidine-N-alkylcarboxylates, quaternary morphinans, opium alkaloid derivatives and quaterary benzomorphans. The methods are particularly suitable for treating and / or preventing postsurgical ileus and postpartum ileus.

Description

FIELD OF THE INVENTION [0001] The present invention relates to novel methods for the treatment and prevention of ileus. More particularly, the present invention relates to novel methods for the treatment and prevention of ileus by using peripheral mu opioid antagonist compounds. BACKGROUND OF THE INVENTION [0002] It is well known that opioid drugs target three types of endogenous opioid receptors (ie., mu, delta and kappa receptors) in biological systems. Many opiates, such as morphine, are mu opioid agonists that are often used as analgesics for the treatment of severe pain due to their activation of mu opioid receptors in the brain and central nervous system (CNS). Opioid receptors are, however, not limited to the CNS, and may be found in other tissues throughout the body. A number of side effects of opioid drugs may be caused by activation of these peripheral receptors. For example, administration of mu opioid agonists often results in intestinal dysfunction due to the large numb...

Claims

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Application Information

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IPC IPC(8): A61K31/439A61K31/445A61K31/451A61K31/453A61K31/454
CPCA61K31/439A61K31/445A61K31/454A61K31/453A61K31/451
InventorFARRAR, JOHN J.SCHIED, PETER J.SCHMIDT, WILLIAM K.CARPENTER, RANDALL L.
OwnerAPOLOR CORP