Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-09-13
1996-08-13
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144
Patent
active
055456480
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/CA93/00554 filed Dec. 20, 1993.
1. Field of the Invention
The present invention relates to the use of 4-aminopyridine (4-AP) in the treatment of neurological diseases. In particular, the=present invention relates to the use of 4-aminopyridine in spinal cord injured individuals to increase motor control and sensory ability and to reduce chronic pain and spasticity.
2. Background of the Invention
Neurological deficits resulting from traumatic injury to the spinal cord are traditionally ascribed to transection of axons in white matter pathways, which normally mediate interaction between regions of the neuraxis above and below the site of direct damage. Clinical pathological studies of spinal cord injury confirm that there is extensive loss of white matter, although the most severe damage usually occurs within central gray matter (Kakulas and Bedbrook, 1969; Jellinger, 1976; Kakulas, 1984). Complete transection of the spinal cord is relatively rare, but the extent of axonal survival is not usually determined, even in the small minority of cases where postmortem examination is performed. The completeness of the lesion is an important issue, however, since conduction failure in any surviving pathways may contribute to losses of sensory and motor function. Experimental studies in animals (e.g. Eidelberg et al., 1977; Eidelberg et al., 1981a; Eidelberg et al., 1981b; Blight, 1983a; Blight and DeCrescito, 1986; Bresnahan et al., 1987; Noble and Wrathall, 1989; Blight, 1991), and a very few clinical observations (Noordenbos and Wall, 1976) have shown that complex neurological functions can be mediated by a small proportion of surviving axonal pathways.
Electrophysiological recordings from isolated spinal cord have shown chronic failure of action potential conduction in surviving myelinated axons, following a blunt contusion injury (Blight, 1983b). Some of this conduction block can be overcome, at the level of single nerve fibers, using the drug 4-aminopyridine (4-AP) (Blight, 1989). Intravenous injection of this compound in animals with experimental or naturally occurring spinal cord injuries, produces significant improvements in electrophysiological (Blight and Gruner, 1987) and behavioral function (Blight et at., 1991). An initial study in spinal cord injury patients was organized by Dr. Keith Hayes, and indicated a potential for modest therapeutic benefit, mostly at the electrophysiological level, combined with a lack of serious side effects (Hayes et at., 1991 and submitted for publication).
SUMMARY OF THE INVENTION
In accordance with the present invention, a clinical trial was designed to examine the potential functional benefits of 4-AP in patients with chronic spinal cord injury: A placebo-controlled, double-blind, crossover design was used to allow for possible effects of patient expectation, and to minimize observational bias. A wide range of injury types were examined, based on the expectation that this approach to treating conduction failure would vary in its effectiveness with differences in the severity and distribution of damage to the spinal cord.
The results of the study demonstrated that 4-aminopyridine is useful in increasing motor control and sensory ability in spinal cord injured individuals. Surprisingly, 4-aminopyridine was also shown to reduce chronic pain and spasticity in certain individuals. The latter effect was unexpected based on the known properties of 4-aminopyridine.
Accordingly, the present invention provides the use of 4-aminopyridine in the treatment of a condition that affects the nervous system.
The present invention also provides the use of 4-aminopyridine to reduce pain, in particular in a spinal cord injured individual.
The present invention also provides the use of 4-aminopyridine to reduce spasticity, in particular in a spinal cord injured individual.
The present invention further provides a commercial package, containing as active ingredient, 4-aminopyridine, together with instructions for the use thereof to treat a spinal cord injured in
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Brain Res. Bull., vol. 22, No. 1, 1989, pp. 47-52, Andrew R. Blight `Effect of 4-aminopyridine on axonal conduction-block in chronic spinal cord injury` cited in the application see abstract.
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Blight Andrew R.
Hansebout Robert R.
Canadian Spinal Research Organization
Cintins Marianne M.
Jarvis William R. A.
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