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Methods for the treatment of a traumatic central nervous system injury via a tapered administration protocol

Inactive Publication Date: 2009-09-03
EMORY UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]Methods for the treatment or the prevention of neuronal damage in the CNS are provided. In particular, the present invention provides a method of administration of a therapeutically effective amount of a progestin or progestin metabolite following a traumatic or ischemic injury to the CNS such that, prior to termination of the progestin or progestin metabolite administration is tapered to avoid withdrawal. The drug taper employed can involve a line

Problems solved by technology

In addition, the traumatic CNS injury is frequently followed by brain and / or spinal cord edema that enhances the cascade of injury and leads to further secondary cell death and increased patient mortality.
During ischemia, consumed cellular ATP usually cannot be adequately replenished in the absence of a supply of oxygen.
Significant ischemia in the CNS occurs with stroke, leading to rapid cell death in the core regions of the stroke where blood flow is reduced to about 20% of normal levels.

Method used

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  • Methods for the treatment of a traumatic central nervous system injury via a tapered administration protocol
  • Methods for the treatment of a traumatic central nervous system injury via a tapered administration protocol
  • Methods for the treatment of a traumatic central nervous system injury via a tapered administration protocol

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effects of Progesterone on Necrotic-Damage and Behavioral Abnormalities Caused by TBI

Methods:

[0088]Male Sprague-Dawley rats (300 g) were housed individually in wire cages and kept on a reverse light-dark cycle (0800-2000 h). Animals were assigned to one of four groups: (1) lesion (n=7); (2) lesion+3 days progesterone (LP3; n=7); (3) lesion+5 days progesterone (LP5; n=7); and (4) Sham (n=8). All procedures involving animals conformed to guidelines set forth in the Guide for the Care and Use of Laboratory Animals (U.S. Department of Health and Human Services, Pub no. 85-23, 1985) and were approved by the Emory University Institutional Animal Care and Use Committee.

[0089]Bilateral contusions of the medial prefrontal cortex were created by a pneumatic impactor device as previously described [40]. Briefly, rats were given anesthetized with ketamine / xylazine (90 mg / kg; 10 mg / kg) and placed in a stereotaxic apparatus. A craniectomy (diameter 6 nm u) was made over the midline of the prefron...

example 2

Dosage Response Curves for Behavioral Recovery Following TBI Upon Administration of Progesterone in a Cylcodextrin Vehicle

Methods:

[0106]Surgery to induce a traumatic brain injury was performed as outlined in Example 1. Behavior testing using the Morris Water Maize was performed as outlined in Example 1 and the methods for the tactical adhesive removal were performed.

Results:

[0107]FIGS. 1A and 1B demonstrate that low and moderate doses of progesterone (8 mg / kg & 16 mg / kg in a cyclodextrin-containing vehicle) produced consistent improvement in Morris water maze performance, whereas the high dose of progesterone (32 mg / kg in a cyclodextrin-containing vehicle) did not show any beneficial effect.

[0108]The sticker removal task is a test for sensory neglect which is a primary deficit for frontal injury. In this task all doses initially produce behavioral recovery, however, the group receiving the high dose of progesterone degraded to lesion control levels and the moderate dose, which was i...

example 3

Tapered Progesterone Withdrawal Enhances Recovery after Traumatic Brain Injury

Methods:

[0109]Male Sprague-Dawley rats received either medial frontal cortex injury or sham surgery. Injections were given 1 and 6 hours post-injury, and every 24 hours for 7 days. Treatment groups (n=8) encompassed injured (1) and sham (S) acute withdrawal (AW), tapered withdrawal (TW) and vehicle (V) treatments. TW injections were progressively halved over the final two treatments. Behavioral testing was conducted post-surgery, mid- and post-withdrawal. Activity boxes were used to investigate vertical movements and exploration. Sensory neglect and anxiety behaviors were also analyzed. Brain harvesting was performed at 8 days or 3 weeks post-injury. Perfused tissue sections were analyzed for lesion volume and immunohistochemical response. Fresh brain tissue was flash frozen in chilled 2-methyl butane, and then homogenized for Western blot analysis.

Results:

[0110]Acute withdrawal and injury (AWI) interacted...

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PUM

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Abstract

The present invention provides methods for the treatment or the prevention of neuronal damage in the CNS. Specifically, the methods of the invention provide for the administration of a therapeutically effective amount of a progestin or progestin metabolite following a traumatic or ischemic injury to the CNS such that, prior to termination of administration of the progestin or progestin metabolite the administration is tapered to avoid withdrawal. The drug taper employed can involve a linear taper, an exponential taper, progressively dividing administered doses by 50%, or can be determined based on the treating physician's assessment of the patient's response to therapy. The tapered administration methods of the present invention may be used in combination with any therapeutic protocol or regimen for the administration of a therapeutically effective amount of a progestin or progestin metabolite to treat a traumatic or ischemic CNS injury.

Description

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0001]This invention was made with United States Government support under grant numbers R01 N5038664-04 and R01N5040825-03 awarded by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health. The United States Government has certain rights in the invention.FIELD OF THE INVENTION[0002]The invention relates to methods for treating a traumatic or ischemic injury to the central nervous system.BACKGROUND OF THE INVENTION[0003]There is growing experimental evidence that progesterone, its metabolites and other gonadal steroids such as estrogen and possibly testosterone, are effective neuroprotective agents; although the specific, physiological mechanisms by which these hormones act in the central nervous system to enhance repair are not completely understood. In addition to being a gonadal steroid, progesterone also belongs to a family of autocrine / paracrine hormones called neurosteroids. Neurosteroi...

Claims

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Application Information

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IPC IPC(8): A61K31/57
CPCA61K31/57A61P25/00A61P25/28A61P9/00
Inventor STEIN, DONALD G.CUTLER, SARAH
Owner EMORY UNIVERSITY
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