| Hazard Information | Back Directory | [Indications]
Botulinum toxin purified neurotoxin complex (Botox) is a
purified form of botulinum toxin type A, produced from a
culture of Clostridium botulinum. Injection of botulinum
toxin into muscle induces paralysis by inhibiting the release
of acetylcholine from motor neurons, thereby blocking
neuromuscular conduction. It is approved for the
treatment of blepharospasm, strabismus, and excessive
sweating. Botox is also approved for use in dermatology
to induce paralysis of the muscles of facial expression to
reverse deep wrinkles. The effect of an individual treatment
usually becomes apparent within 3 days and lasts
approximately 3 months. The effect may persist for a
longer period after a series of treatments because the
muscles atrophy. The major adverse effect is temporary
loss of function of a muscle required for normal social
functioning, as may occur after inadvertent injection of
muscles required for smiling or raising the upper eyelids. | [Biological Functions]
Botulism is most commonly caused by ingestion of a
neurotoxin produced by Clostridium botulinum in improperly
canned food. Poisoning may also occur after
wound contamination with the organism. Infant botulism
may occur when spores of the organism germinate
and manufacture the toxin in the intestinal tract of infants.
Botulinum toxin works by inhibiting ACh release
at all cholinergic synapses.
Botulinum toxins are classified into seven antigenically
distinct types, A through G. Each consists of a
polypeptide chain of about 150,000 daltons. All but one
is nicked by trypsin-type enzymes to yield a light and
heavy chain linked by a disulfide bridge.One end of the
heavy chain mediates binding to the nerve terminal, and
the other initiates internalization of the toxin. The light
chain produces the intracellular inhibition of ACh release.
This involves a Zn-dependent endopeptidase
action to cleave synaptic target proteins that control
vesicle docking and fusion with the prejunctional membrane. | [Clinical Use]
Botulinum toxin is used clinically in the treatment of
blepharospasm, writer’s cramp, spasticities of various
origins, and rigidity due to extrapyramidal disorders. It
is also used to treat gustatory sweating and cosmetically
to decrease facial wrinkles. Botulinum toxin A (Botox,
Oculinum) injected intramuscularly produces functional
denervation that lasts about 3 months. Clinical
benefit is seen within 1 to 3 days.Adverse effects range
from diplopia and irritation with blepharospasm to
muscle weakness with dystonias. | [Side effects]
Botulinum toxin is the most toxic substance known.
One gram of crystalline toxin adequately dispersed can
kill a population of a million people, so its use in bioterrorism
is a possibility. The toxin can be introduced
through inhalation or ingestion but not through dermal exposure. The threat of mass inhalation poisoning is
limited by the ability or inability to aerosolize the toxin
for widespread dispersion. Contaminating the water or
food supply is also a possibility, although the toxin is
degraded by standard water treatment and by heating
of foods to 85°C (185°F) for 5 minutes. Prior immunization
with toxoid vaccine is advisable for personnel at
risk, but prophylactic administration of trivalent equine
antitoxin is not recommended. | [Enzyme inhibitor]
This bacterial toxin and neurotoxin (FW = 149.3 kDa; CAS 93384-43-1;
abbreviated as BTX or BoNT) from Gram-positive Clostridium botulinum
are ADP-ribosyltransferases and proteases that give rise to the clinical
manifestations of botulism. Classification: BTX consists of seven
antigenically and serologically distinct neurotoxins (types A, B, C1, C2, C3,
D, E, F, and G) that are otherwise functionally and structurally similar.
Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C
and D cause toxicity only in animals. Each botulinum toxin possesses
individual potencies, necessitating special care to avoid medication errors.
Recent changes to the established drug names by the FDA were intended to
reinforce these differences and prevent medication errors. They include the
following: exotoxins, which inhibit the release of catecholamines from the
adrenal medulla and block the release of acetylcholine at neuromuscular
junctions. The seven distinct types of exotoxin are now labeled A through G,
each consisting of two peptide chains linked by a disulfide bond. Chain I of
botulinum toxin C2 catalyzes the ADP-ribosylation of G-actin and prevents
actin polymerization. Neurotoxic Effects: Following the attachment of the
botulinum toxin’s heavy chain to one or more proteins on the exterior
surface of axon terminals, the toxin is taken by neurons via endocytosis. The
light chain cleaves endocytotic vesicles and enters the cytoplasm, where it
proteolytically degrades the SNAP-25 protein, a type of SNARE protein
involved in vesicle trafficking. SNAP-25 is essential for vesicle fusion, a
step that is required for release of neurotransmitters, particular acetylcholine,
from the axon endings Botulinum toxin thereby prevents neurosecretory
vesicles from docking/fusing with the nerve synapse plasma membrane and
releasing their neurotransmitters. Clinical Applications: Injectable
formulations of OnabotulinumtoxinA (INN generic name) are now used to
treat blepharospasm or strabismus, to relieve neck pain, resulting from
cervical dystonia, and for muscle stiffness in the elbow, wrist, and finger
muscles in adult patients with upper limb spasticity. Botox is often
employed to prevent chronic migraine and cosmetically to improve the
appearance of deep facial lines or furrows between eyebrows and creases in
the skin around the eyes. Patients with urinary incontinence and overactive
bladder can also benefit from appropriate application. Target (s) :
catecholamine release; acetylcholine release; actin polymerization
. |
|
|