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Use of an opioid receptor antagonist for the treatment or prevention of gastrointestinal tract disorders

A technology for the use of opioid substances, which is applied in the field of use of opioid receptor antagonists for gastrointestinal diseases, and can solve problems such as aggravating postoperative intestinal obstruction

Inactive Publication Date: 2015-10-07
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Exogenous opioid analgesics are believed to cause or exacerbate postoperative ileus at least in part

Method used

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  • Use of an opioid receptor antagonist for the treatment or prevention of gastrointestinal tract disorders
  • Use of an opioid receptor antagonist for the treatment or prevention of gastrointestinal tract disorders
  • Use of an opioid receptor antagonist for the treatment or prevention of gastrointestinal tract disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: Pharmacokinetics and pharmacology of compound I in non-clinical models

[0074] Efficacy of Compound I in the CNS compared to naltrexone

[0075] Rats were injected subcutaneously with stimulating formalin and with 10 mg / kg morphine. The analgesic effect was determined by the number of times (events) in which rats reduced licking or paying attention to the site of formalin injection. Rats were dosed with 0.02 mg / kg naltrexone (subcutaneous administration) or 1, 3 or 10 mg / kg compound I (oral administration) to determine the compound's ability to reverse the analgesic effect of morphine. Naltrexone was found to be approximately 100-fold more potent than compound I in reversing the effects of morphine in the rat CNS ( figure 1 ). Naltrexone and Compound I have similar affinities for μ-opioid receptors. Different experiments showed that Compound I has high oral bioavailability in rats. The analgesic effects induced by reversal of morphine by opioid receptor...

Embodiment 2

[0080] Example 2: Calculation of an effective dose of Compound I for the treatment of OIC or OBD in humans and determination of a sufficient amount to act peripherally without compromising central analgesia or producing central opioid withdrawal symptoms

[0081] The nonclinical animal studies described above showed that Compound I exhibited some peripheral effects in mice and rats, and further described the main mechanism by which Compound I was excreted from the CNS (i.e., the transporter P- gp substrate). However, the key question is whether these data are relevant to humans and what impact they have on the therapeutic utility of Compound I for the treatment of disorders in humans.

[0082] The main question is whether Compound I can act sufficiently peripherally in humans to treat conditions, particularly OIC or OBD, which depends on its selectivity for peripheral opioid receptors versus antagonism of opioid receptors in the CNS Antagonism may otherwise impair centrally m...

Embodiment 3

[0099] Example 3: Phase I Multiple Escalating Dose Clinical Study with Compound I; Preliminary Results

[0100] The purpose of the phase I multiple escalating dose clinical study was to evaluate the safety, tolerability, pharmacokinetics, and clinical effects of multiple escalating doses of Compound I administered twice daily (BID) due to the Pain Subjects with opioid-induced constipation (OIC) on long-term opioid therapy. The first part of the study was a randomized, double-blind, placebo-controlled, multiple escalating dose study, during which subjects received 4 oral doses of the study drug over 2 days while confined to the study unit. ). Each of the 0.10 mg, 0.25 mg, 0.35 mg, 0.50 mg, and 0.75 mg BID dose groups included 4 subjects, and randomization was unbalanced, with Compound I treatment groups (n=3) versus placebo treatment groups (n=1) The ratio was 3:1. Only 2 subjects were included in the 0.75 mg BID group. Evaluation of clinical effects included the following m...

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Abstract

The disclosure relates to a method of treating or preventing a condition in a subject associated with the activation of an opioid receptor in the periphery by administering an effective amount of 5-(2-methoxy-4-{[2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl}-phenoxy)-pyrazine-2-carboxamide (Compound I). In particular, the disclosure relates to a method of treating or preventing opioid-induced constipation or opioid-induced bowel dysfunction in a human without reducing centrally-mediated opioid analgesia or producing central opioid withdrawal symptoms by administering an effective amount of Compound I. The disclosure further relates to the use of Compound I for the preparation of a medicament for the treatment or prevention of a condition in a subject associated with the activation of an opioid receptor in the periphery.

Description

[0001] This application is a Chinese invention patent application (application date: September 17, 2010; application number: 201080052209.2 (international application number: PCT / US2010 / 049311); invention name: opioid receptor antagonist for gastrointestinal diseases purposes) divisional application. [0002] 1. Cross references to related applications [0003] This application claims the benefit of US Provisional Application 61 / 243,616, filed September 18, 2009, the contents of which are incorporated herein by reference under 35 U.S.C. § 119(e). 2. Background technology [0004] Pain is the most common reason people seek medical attention. Mild to moderate pain is usually treated with acetaminophen and nonsteroidal anti-inflammatory drugs. Opioid analgesics are prescribed for moderate to severe acute and chronic pain, primarily as receptors for endogenous mu-, delta- and / or kappa-opioid receptors in the central nervous system ("CNS"). agonist. Long-term use of opioid anal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/497A61P1/10A61K31/137A61K31/4535
CPCA61K31/497A61P1/00A61P1/04A61P1/08A61P1/10A61P11/00A61P43/00A61K9/0053A61K2121/00
Inventor R.M.伍德沃德
Owner MERCK & CO INC
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