BOTULINUM
TOXIN
History
- Clinical effects of botulinum
toxin have been recognized since 1897- van Ermengem relates bolulism
to a toxim produced by Clostridium botulinum - botulism
- BTX blocks Neuromuscular
transmission (1949)
- BTX-A used to treat strabismus
in non-human primates
- BTX used to treat strabismus
in humans (1981)
- Double blind placebo
controlled study - BTX-A effect in treating Cervical Dystonia
(1986)
- Effectiveness demonstrated
in double blind placebo controlled study of BTX-A for focal dystonia
- Seven antigenically
distinct neurotoxins
- BTX-A is FDA
approved for strabismus, blepharospasm, hemifacial spasm
- Treatment of
choice for blepharospasm, oromandibular dystonia, cervical dystonia,
spasmodic dysphonia
Terminology:
BTX, BT, BoNT, BoTX
- BOTOX® (Allergan, Inc),
- DYSPORT (Speywood Pharmaceuticals
Ltd)
Botulinum toxin acts pre-synaptically
at nerve terminals to prevent the release of acetylcholine ->this
causes a
CHEMICAL DENERVATION
Seven serologically distinct
neuroparalytic toxins (A through G) are produced by Clostridium
botulinum bacteria. The only form of the toxin that has been approved
for clinical use is botulinum toxin type A
CLINICAL
EFFECT
- onset of clinical
effect is 24 - 72 hours
- peak effect
4 - 6 weeks
- average duration
of effect is sustained 3 - 4 months
- nerve sprouts
and reinnervates - new terminal formation
- effect on individual
nerve terminals is effectively irreversible
- the recovery
of neuromuscular control occurs as a result of nerve sprouting
and new terminal formation
SAFETY
- 1 unit = LD50
in mice
- A unit is defined in terms
of its biological activity; 1 unit is equal to the LD50 for intraperitoneal
injections into mice. LD50 is dose needed to kill 50% of the
mice. This is true for both brands of toxin.
- LD50 in monkeys
= 39U/kg
- Implies LD50
in humans = 3,000 units
- In clinical
use, dose range = 60 - 400 units
- No anaphylactic
reactions
Usage
- BTX-A is approved
in most countries for treatment of strabismus, blepharospasm,
focal spasms including hemifacial spasm
- It is widely
used and indicated for many cases of cervical dystonia, spasticity
and other disorders of excess muscle activity
Pharmacology:
Mechanism of Action
- Botulinum toxin
molecule - light & heavy chain linked by a disulfide bond.
(heavy chain is responsible for binding; light chain is intracellular
toxic moiety)
- Like tetanus
toxin, BTX is a zinc endopiptidase. Its 7 serotypes differ in
their cellular targets as well as their potency and duration
of action
- Inhibits release
of acetylcholine
- toxin binding
to presynaptic receptors on the axon terminal
- internalization
of toxin by receptor-mediated endocytosis
- inhibition of
neurotransmitter release by blocking release machinery
- BTX is internalized
by endocytosis at the axon terminal and becomes fully activated
by disulfide reduction once inside the cell
- BTX-A targets
SNAP-25 (25 kDa synaptosome-associated protein). The type A toxin
selectively cleaves a protein called SNAP-25. This protein is
one of several involved in the fusion of vesicles containing
neurotransmitters within the nerve terminal membrane.
- The complexity
of this mechanism may account for the relatively slow onset of
the effect of botulinum toxin:- 24 - 72 hours.
- The existence
of retrograde transport of intact toxin has not been proven,
and is unlikely to be clinically important.
- BTX-A causes
reversible denervation atrophy.
- Axon sprouting
terminates the clinical effect usually in 2 - 6 months.
- Extent of denervation
is determined largely by dose and volume of injection.
|
BTX-A affects the
neuromuscular junction through binding, internalization, and
inhibition of acetylcholine release. It must enter the nerve
endings to exert its chemodenervating effect. Once inside the
cholinergic nerve terminal cell, BTX-A inhibits the docking and
fusion of acetylcholine vesicles at the pre-synaptic membrane.
Duration of effect is usually 3 to 4 months, but can be longer
or shorter. Gradually, muscle function returns by the regeneration
or sprouting of blocked nerves forming new neuromuscular junctions.
BTX-A is dose-dependent and reversible secondary to the regeneration
process. |
