Therapeutic uses of the botulinum toxins

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1 Therapeutic uses of the botulinum toxins

Summary and Key Features

• Botulinum toxins exzymatically affect the SNARE proteins in neural endings

• Botulinum toxins will reduce and prevent the release of substances exocytosed by SNARE proteins

• Reduction of SNARE function may have therapeutic implications for autonomic, sensory and motor parts of the nervous system

• Reduction of acetyl choline neurotransmitter can reduce the hyperfunction of muscles in various dystonias

• Reduction of acetyl choline neurotransmitter can reduce autonomic nervous system hyperfunction such as hyperhidrosis and sialorrhea

• Reduction of SNARE function can also reduce the release of inflammatory mediators such as substance P, CGRP, glutamate and others

• Reduction of inflammatory mediators can have an affect on pain syndromes

• Pain syndromes such as post-herpetic neuralgia, migraine headaches, TMD can be improved with botulinum toxin

• Inflammatory conditions such as rheumatoid arthritis may be improved with intra-articular injections of botulinum toxin

• Bioengineered toxins may allow precise localization and decrease of exocytosed proteins such as hormones

Introduction

Since the 1970s, when Alan Scott introduced botulinum neurotoxin A as a therapeutic agent, the number of different uses for this drug has increased exponentially. In the 1950s, Arnold Burgen and Vernon Brooks, at McGill, discovered that botulinum toxin presynaptically blocked the release of acetylcholine from motor nerve terminals, thus weakening muscle strength by chemical denervation. Brooks also reported the fact that botulinum toxin could possibly be used therapeutically. The observation that tetanus and botulinum toxins blocked the exocytosis of acetylcholine was further refined with the discovery that these toxins enzymatically degraded different portions of the soluble N-ethyl maleimide-sensitive factor attachment protein receptor (SNARE) proteins. Alan Scott’s original work using botulinum toxin to weaken muscle for the correction of strabismus, and then blepharospasm, led others to begin to investigate the toxins for use with other dystonias and hyperfunctional muscular disorders.

The original observations of Kerner that patients with botulism had dry mouth and eyes suggested that the toxin might be used to control hypersecretory states. With the knowledge that the autonomic nervous system also depended on acetylcholine as the neurotransmitter, it seemed even more likely that botulinum toxin could be used to control disorders of this system. Clinical trials have shown efficacy in autonomic disorders such as hyperhidrosis, sialorrhea, and Frey syndrome.

A number of trials for hyperfunctional muscular disorders such as cervical dystonia and spasticity showed a dramatic reduction of pain, even greater than the reduction of muscle function. Our trials of toxin use for cosmetic indications revealed a number of individuals whose migraine headaches disappeared. These and other studies revealed a pattern that seemed to indicate that the toxin had a role in pain syndromes. Other studies then showed that, even in cases of post-herpetic neuralgia, pain could be decreased or eliminated. This clinical information led to the discovery that inflammatory mediators such as calcitonin gene-related peptide (CGRP), substance P, glutamate and others are also released by SNARE proteins. The toxin will reduce or eliminate the release locally of inflammatory mediators that have the effect of lowering central nervous system pain thresholds and thereby causing central sensitization. Botulinum toxin was found to reverse this effect. Many pain studies are in progress. Toxin treatment of chronic migraine headaches was recently EU and FDA approved after extensive clinical trials.

The newest change to potential toxin treatment has been the ability to change the molecule. The binding site of the molecule has been altered chemically to add specific ligands. This allows a toxin to be created that has an affinity for sensory, but not motor neurons, autonomic neurons, and even certain excretory glands. Keith Foster, of Syntaxin, recently described making a specific ligand for growth hormone secretory cells in the pituitary gland. Growth hormone is also secreted with a SNARE-related exocytosis, and therefore can be modulated with targeted specific botulinum toxin. This treatment could be used for patients with acromegaly. Other glandular secretions should be studied in this new paradigm for hypersecretory control.

The following material will in greater depth describe the use of botulinum toxins for the management of disorders of efferent nerves and muscular hyperfunction; afferent nerves, pain disorders, and inflammatory conditions; autonomic nervous system disorders; and glandular hypersecretion. (See Box 1.1.)

Box 1.1

Therapeutic uses of botulinum toxins

I. Hyperfunctional muscular use:

a. Cervical dystonia

b. Blepharospasm

c. Oromandibular dystonia

d. Spasmodic dysphonia

e. Occupational writer’s cramp

f. Foot dystonia

g. Musician’s dystonia

h. Facial dystonia

i. Meige syndrome

j. Tic disorders and stuttering

2. Hyperfunctional facial lines (cosmetic)

3. Hemifacial spasm / facial synkinesis

5. Esotropia / exotropia

7. Post-stroke and cerebral palsy spasticity

8. Tremor disorders: limb, neck, vocal

10. Other laryngeal disorders: puberophonia, vocalis process granulomas

II. Autonomic nervous system use

1. Hyperhidrosis: axillary, palmar, plantar, and facial

2. Benign prostatic hypertrophy

3. Sialorrhea / sialocele / drooling

5. UES / LES achalasia

6. Neurogenic hyperactive bladder

7. Frey syndrome

8. Anal fissures

9. Vaginismus / anismus

III. Afferent nervous system / pain syndromes / anti-inflammatory:

1. Tension headaches

2. Migraine headaches

3. Temporomandibular disorders / bruxism

4. Myofascial pain

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