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Botulinum toxins are potent neurotoxins produced by the bacteria
Clostridium botulinum. The most widely studied effect of botulinum
toxins is at the neuromuscular junction where they block the release
of acetylcholine preventing muscle contraction and causing local
flaccid paralysis (rather than rigid, or tetanic, paralysis caused
by a related clostridial protein, tetanus toxin). This results in
a temporary (months) chemodenervation and the loss or reduction
in activity in the target organ (muscle, sweat gland, or sphincter)
with minimal risk of systemic adverse effects. However, botulinum
toxins work not only at the neuromuscular junction but also alter
the sensory input, producing secondary changes at the central level.
The broadening clinical role of botulinum toxins depends on the
multiple direct and indirect effects that the toxin exerts in both
the peripheral nervous system and in the central nervous system
(CNS).
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In 1989, the FDA approved botulinum toxin type A (BTX-A) for
use in treating strabismus, blepharospasm and hemifacial spasm.
In 2000–2001, both BTX-A (Allergan, Inc.) and botulinum toxin
type B (BTX-B; Elan Pharmaceuticals) were FDA-approved for use in
treating cervical dystonia, and in 2002, BTX-A was approved by the
FDA for treatment of glabellar frown lines. Besides the FDA-approved
indications, botulinum toxins have been used in a vast array of
clinical problems, including achalasia; anismus; benign prostatic
hypertrophy; dysphonia; dystonias; essential tremor; hyperhidrosis;
kyphoscoliosis; low back pain; migraine and tension-type headache;
myofascial pain; pancreatitis; pelvic floor disorders; rectal fissures;
sialorrhea; spasticity; temporomandibular joint syndrome; urinary
sphincter dysfunction; wrinkles; and various other movement disorders.
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Clostridium botulinum was first identified as a causative agent
in food poisoning by Van Ermengem following a fatal outbreak in
1895.1 In the 1920s, additional outbreaks lead
to the isolation of a relatively crude form of botulinum toxin (BTX),2 the
neurotoxin responsible for food-borne botulism.
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Early development of BTX began during WW II in the course of
studying the nature of certain toxins, including BTX, and the means
for protecting against them.3 Although much of
this initial work was carried out on BTX-A, other types of botulinum
toxin were also studied, including types B, C, D, and E. The purpose
was to develop a polyvalent toxoid for immunization purposes. After
the war, a crystallized form of BTX-A became available and stimulated
considerable scientific interest. Dr. Alan B. Scott, of the Smith-Kettlewell
Eye Research Foundation, initiated efforts to study BTX in a monkey
model of strabismus in the late 1960s.4 Sufficient
data was collected by 1978 to file an investigational new drug (IND)
application for human clinical studies.5 The passage
of the Orphan Drug Act of 1983 and FDA approval aided clinical development
of BTX-A as an orphan drug in December 1989.
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There are two types of commercial botulinum toxins presently
available in the United States: Botox (Botulinum toxin type A Purified
Neurotoxin Complex, Allergan, Inc., 2525 Dupont Drive, Irvine, CA)
and BTX-B (Myobloc, Elan Pharmaceuticals, ...