Methods of preventing and reducing the severity of stress-associated conditions

a technology of stress-associated conditions and methods, which is applied in the field of adrenergic agonists, can solve the problems that the treatment of such stress-associated conditions has generally been ineffective or unsatisfactory, and achieve the effects of preventing or reducing the severity of gastrointestinal disease, preventing or reducing the severity of irritable bowel syndrome or dyspepsia, and preventing or reducing the severity of tachycardia

Inactive Publication Date: 2008-08-28
GIL DANIEL W +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]In one embodiment, a method of the invention prevents or reduces the severity of gastrointestinal disease. In other embodiments, a method of the invention prevents or reduces the severity of irritable bowel syndrome or dyspepsia. In another embodiment, a-method of the invention prevents or reduces the severity of tachycardia other than tachycardia associated with myocardial ischemia, for example, tachycardia associated with a pulmonary disorder. In a further embodiment, a method of the invention prevents or reduces the severity of panic attack. In still further embodiments, a method of the invention prevents or reduces the severity of insulin-resistance, or prevents or reduces the severity of type II diabetes. In yet a further embodiment, a method of the invention prevents or reduces the severity of a non-inflammatory dermatological condition. In other embodiments, a

Problems solved by technology

Unfortunately, treatments for such stress-associated conditions have generally been ine

Method used

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  • Methods of preventing and reducing the severity of stress-associated conditions
  • Methods of preventing and reducing the severity of stress-associated conditions
  • Methods of preventing and reducing the severity of stress-associated conditions

Examples

Experimental program
Comparison scheme
Effect test

example i

Preparation of Brimonidine

[0059]This example describes preparation of brimonidine (5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline).

Preparation 6-Amino-5-bromoquinoxaline hydrobromide

[0060]6-Aminoquinoxaline (2.08 g, 14.4 mmol) was dissolved in 11.5 ml glacial acetic acid. The solution was cooled in water while a solution of bromine (0.74 ml, 2.3 g, 14.4 mmol) in 1.5 ml glacial acetic acid was added slowly over 15 minutes. After stirring for an additional 30 minutes, the orange red solid formed was filtered off and washed thoroughly with dry ether. The solid was dried in vacuo overnight to yield 4.44 g crude product (a yield of 100%). The compound, 6-amino-5-bromoquinoxaline hydrobromide, had no definite melting point. A phase change from fine powder to red crystals was observed at about 220° C. Decomposition was observed at about 245° C. The material was used directly for preparation of 6-amino-5-bromoquinoxaline as follows.

6-Amino-5-Bromoquinoxaline

[0061]Crude 6-amino-5-bromoquinox...

example ii

Mouse Models with Different Mechanisms of Sensory Sensitization

[0068]This example demonstrates that the increased sympathetic tone of α-2A and α-2C knockout mice enhances induction of tactile hypersensitivity by α-1 receptor activation.

A. Sulprostone-Induced Tactile Hypersensitivity is Driven by the Sympathetic Nervous System While Phenylephrine-Induced Tactile Hypersensitivity is Independent of Sympathetic Nervous System Input

[0069]To dissect the contribution of the sympathetic nervous system to sensory sensitization, mouse models having different mechanisms of sensory sensitization were developed. Tactile hypersensitivity was measured in mice following intrathecal or intraperitoneal injection of an inducing agent by scoring the response to light stroking of the mouse flank with a paintbrush. To mimic increased sympathetic tone, phenylephrine, an α-1 adrenergic receptor agonist, was injected. As shown in FIGS. 1a and 1b, intrathecal (i.t.) or intraperitoneal (i.p.) dosing of phenyl...

example iii

Comparison of Activity of α-2 Agonists Brimonidine and Clonidine

[0083]This example demonstrates that α-adrenergic agonists differ in their ability to alleviate sensory hypersensitivity that is enhanced by the sympathetic nervous system.

A. Brimonidine, But not Clonidine, Alleviates Sympathetically-Enhanced Tactile Hypersensitivity

[0084]Spinally administered α-2 adrenergic agonists alleviate neuropathic pain through a spinal α-2A receptor. To determine if the increased sympathetic activity in α-2 knockout mice alters the analgesic activity of the α-2 agonists, several agonists were assayed for activity. The α-2 agonists brimonidine and clonidine were first tested in the NMDA model in which sensitization is not influenced by the basal sympathetic tone of the knockout mice. Intrathecal co-administration of NMDA with either clonidine or brimonidine resulted in complete inhibition of tactile hypersensitivity in the wildtype and α-2C (FIGS. 5a and c, respectively) knockout mice. As expecte...

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Abstract

The present invention provides a method of preventing or reducing the severity of a stress-associated condition in a subject by systemically administering to the subject an effective amount of brimonidine or a pharmaceutically acceptable salt, ester, amide, sterioisomer or racemic mixture thereof. Stress-associated conditions that can be treated according to a method of the invention include, but are not limited to, dyspepsia, tachycardias other than tachycardia associated with myocardial ischemia, panic attack, non-inflammatory dermatogical conditions, disorders of muscle contraction, sensory hypersensitivity associated with migraine, and behavioral disorders.

Description

[0001]This application is a continuation of U.S. application Ser. No. 10 / 607,439, the contents of which are incorporated by reference herein.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The invention relates generally to the sympathetic nervous system and various stress-associated conditions and, in particular, to the α-2 adrenergic agonist, brimonidine.[0004]2. Background Information[0005]Conditions that are associated with or exacerbated by stress can be mediated, at least in part, by the sympathetic nervous system. Such stress-associated conditions include, without limitation, gastrointestinal disease; irritable bowel syndrome; dyspepsia; tachycardia; panic attack; insulin-resistance; type II diabetes; dermatogical conditions; disorders of muscle contraction such as tension type headache; sensory hypersensitivity associated with migraine such as nausea, photophobia and phonophobia; and stress-associated behavioral disorders such as overeating and drug dependenc...

Claims

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Application Information

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IPC IPC(8): A61K31/498A61P29/00A61P25/00
CPCA61K31/498A61P1/00A61P1/04A61P1/14A61P11/00A61P13/10A61P17/00A61P21/00A61P25/00A61P25/06A61P25/14A61P29/00A61P37/08A61P3/10
Inventor GIL, DANIEL W.WHITCUP, SCOTTBRIN, MITCHELL F.DONELLO, JOHN E.
Owner GIL DANIEL W
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