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Myobloc™ :: Mode of Action
Botulinum toxin (BTX) induces chemical denervation of striated muscles by cleaving proteins required for the release of acetylcholine. The result is temporary flaccid paralysis of the injected muscles, which lasts approximately three to five months. As new neuromuscular junctions form, muscle function returns. There are seven serotypes (A-G) of BTX. Of these, type A was the first to be made available in the United States for medical uses (BOTOX®™). BTX-A is FDA approved for the treatment of blepharospasm, strabismus, and cervical dystonia. A common off-label use is for the treatment of wrinkles. BTX- B, now available in the United States as Myobloc™, provides another option for the treatment of facial wrinkling.
Each of the seven serotypes of BTX are composed of three domains: the binding domain, the translocation domain, and the enzymatic domain. The binding domain, located on the heavy chain of the BTX molecule, is responsible for attaching to the acceptor on the presynaptic nerve terminal. The binding domain of Myobloc™ is distinct from the binding domain of BOTOX®™, therefore these agents bind to different acceptors. Binding of botulinum toxin to its proper acceptor initiates endocytosis and internalization of the toxin heavy chain and light chain. Although the mechanisms of action of the translocation domain are not completely understood, it is responsible for getting the toxin into the endosome of the nerve terminal that contains ACh. Once inside the endosome, the acidic environment is believed to cause a change in the conformation of the toxin that allows the molecule to cross into the cytosol.i
The enzymatic domain of the light chain becomes functional in the cytosol and cleaves a protein in the SNARE complex that incapacitates this complex, preventing the fusion of acetylcholine vesicles, thus blocking extrusion of their contents. The SNARE complex is composed of synaptobrevin, SNAP-25 and syntaxin. (fig. 9) Myobloc™ cleaves a component of the SNARE complex called synaptobrevin, while BOTOX®™ cleaves a component known as SNAP -25.
Antibodies to the critical binding site on the heavy chain of the BTX molecule will prevent binding of the toxin to its receptor, thereby crippling the actions of the toxin. These "neutralizing antibodies" have been reported in patients treated with high doses of botulinum toxin for neurologic disorders such as cerebral palsy, but have not been reported in BOTOX®™ patients treated with cosmetic doses ranging from 12 units to 100 units. Because Myobloc™ has a binding domain that is distinct and different than the binding domain of BOTOX®™, antibodies that neutralize BTX-A would not neutralize BTX-B and vice versa. Therefore, if patients develop antibodies to BTX-A, then they would still be able to use BTX-B.
i Finkelstein A: Channels formed in phospholipid bilayer membranes by diphtheria, tetanus, botulinum and anthrax toxin. J Physiol 1990; 84:188.
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