Botulinum toxin pharmacology

Botulinum toxin is used in dermatology to reverse deep wrinkles. Its pharmacological mechanism of action in this use is... 

The pharmacologic basis of these disorders is unknown, and there is no satisfactory medical treatment for them. A subset of patients respond well to levodopa medication (dopa-responsive dystonia), which is therefore worthy of trial. Occasional patients with dystonia may respond to diazepam, amantadine, antimuscarinic drugs (in high dosage), carbamazepine, baclofen, haloperidol, or phenothiazines. A trial of these pharmacologic approaches is worthwhile, though often not successful. Patients with focal dystonias such as blepharospasm or torticollis often benefit from injection of botulinum toxin into the overactive muscles. The role of deep brain stimulation for the treatment of these conditions is being explored. 

Goodman Gilman s The Pharmacological Basis of Therapeutics. New York McGraw Hill, 2005. Simpson LL. Identification of the major steps in botulinum toxin action. Ann Rev Pharmacol Toxicol 2004 44 167-193. 

Aoki KR. Pharmacology and immunology of botulinum toxin type A. Clin Dermatol. 2003 21 476-480. 

Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia evidence-based review including meta-analysis of the effect of botulinum toxin and other cure options. Eur J Neurol. 2004 11 361-370. 

Callaway JE. Botulinum toxin type B (Myobloc) pharmacology and biochemistry. Clin Dermatol. 2004 22 23-28. 

The therapeutic use of botulinum toxin for ophthalmic purposes and for local muscle spasm was mentioned in Chapter 6 Introduction to Autonomic Pharmacology. Local injection of botulinum toxin has become popular for the treatment of generalized spastic disorders (eg, cerebral palsy). Most clinical studies to date have involved administration in one or two limbs, and the benefits appear to persist for weeks to several months after a single treatment. Most studies to date have utilized type A botulinum toxin, but type B is also available. 

Brin MF (1997) Botulinum toxin chemistry, pharmacology, toxicity, and immunology. Muscle Nerve Suppl 6 S146-68... 

Simpson LL, Maksymowych AB, Park J, Bora RS (2004) The role of the interchain disulfide bond in governing the pharmacological actions of botulinum toxin. J Pharmacol Exp Ther 308 857-64... 

Coffield, J., Bakry, N., Zhang, R., Carlson, J., Gomella, L., Simpson, L. (1997). In vitro characterization of botulinum toxin types A, C and D action on human tissues combined electrophysiologic, pharmacologic and molecular biologic approaches. J. Pharmacol. Exp. Ther. 280 1489-98. 

Simpson, L.L. (1986). Molecular pharmacology of botulinum toxin and tetanus toxin. Annu. Rev. Pharmacol. Toxicol. 26 427-53. 

Simpson, L.L. (1981). The origin, structure, and pharmacological activity of botulinum toxin. Pharmacol. Rev. 33 155-88. 

Some patients, perhaps up to 20%, may experience return of normal eye movements after medical control of the thyrotoxicosis. For patients who do not experience improvement, the only pharmacologic interventions shown to be effective for the specific changes associated with class 4 disease are systemic prednisone and local injections of botulinum toxin, though both modalities are rarely used, for motility signs alone, in modern therapy. 

Toxins in general are potent poisons. Nevertheless, the selectivity of action of some of these toxins means they have been harnessed in medical therapeutics (and even more widely in experimental pharmacology and physiology). Toxins that have been, or still are. us in medicine include atropine, botulinum toxin, cardiac glycosides, coichidne, eserine, hyoscine, picrotoxin, morphine, ouabain, strychnine, veratridine, vinca alkaloids and many more. All these work by an action at a defined molecular site, whether ion channel, neurotransmitter receptor, enzyme, pump or intracellular organelle. Those toxins that work at nonneuronal, or not specifically at neuronal sites (e.g. cholera toxin, pertussis toxin, cardiac glycosides, phospholipases) are discussed under TOXINS. 

Choline uptake is inhibited by hemicholinium. Botulinum toxin binds to synaptobrevir and prevents ACh release, and AChE inhibitors slow its rate of breakdown. Several reversible AChE inhibitors are useful pharmacologic agents the irreversible AChE inhibitors are generally poisons. 

Uses The uses of botulinum toxin in Parkinson s disease [54" ], anal fissure [55" ], women with chronic pain [56" ], spasticity after stroke in adults [57", 58 ], and urological conditions [59 have been reviewed. The pharmacology and formulations of botuhnum toxins and data from clinical trials, demonstrating their efficacy in dystonia, spasticity, tics, tremor, dysphonia, and autonomic disorders, have been reviewed [60 ]. 

Simpson, L. L. Pharmacological studies on the subcellular site of action of botulinum toxin type A. J. Pharmacol. Exp. Therapeut. 206, 661—669 (1978). 

Small GTPases of the Rho family are ADP-ribosylated (e.g., at Asn4l of RhoA) and inactivated by C3-like toxins from Clostridium botulinum, Clostridium limosum, and Staphylococcus aureus. These proteins have a molecular mass of 23-30 kDa and consist only of the enzyme domain. Specific inhibition of Rho functions (Rho but not Rac or Cdc42 are targets) is the reason why C3 is widely used as a pharmacological tool [2]. 

The role of C2 toxin in disease is not clear because all C. botulinum strains that produce C2 toxin also synthesize extremely potent neurotoxins, the effector molecules of botulism. When Simpson compared the pharmacological properties of C. botulinum neurotoxin type Cl with C2 toxin in detail, it became obvious that C2 toxin does not cause the flaccid paralysis symptoms attributed to classic botulism. However, isolated C2 toxin is a potent enterotoxin that proves lethal in various animals 2 pmol of C2 toxin readily kill mice, rats, guinea pigs, and chickens within 1 h after application. For mice, the LD50 (i.v.) of C2 toxin is less than 50 ftnol. Ohishi and Odagiri also reported that C2 toxin causes necrotic, hemorrhagic lesions in the intestinal wall, whereas Simpson reported that C2 toxin elicits hypotension as well as fluid accumulation in the lungs. ... 

Simpson LL, Stiles BG, Zapeda HH et al. (1987) Molecular basis for the pathological actions of Clostridium perfringens lota toxin. In Infect. Immun. 55 118-22 Simpson LL (1989) The binary toxin produced by Clostridium botulinum enters cells by receptor-mediated endocytosis to exert its pharmacologic effects. In J. Pharmacol. Exp. Ther. 251 1223-8... 

Reuner KH, Schlegel K, Just I, et al. (1991) Autoregulatory control of actin synthesis in cultured rat hepatocytes. In FEBS Letters. 286 100-4 Schmid A, Benz R, Just I, et al. (1994) Interaction of Olostridium botulinum 02 toxin with lipid bilayer membranes. Formation of cation-selective channels and inhibition of channel function by chloroquine. In J Biol Chem. 269 16706-11 Simpson LL (1982) A comparison of the pharmacological properties of Clostridium botulinum type 01 and 02 toxins. In J Pharmacol Exp Then 223 695-701 Simpson LL (1989a) Botulinum Neurotoxin andTetanus Toxin, pp 1 -422, San Diego Academic Press... 

Simpson LL (1989b) The binary toxin produced by Clostridium botulinum enters cells by receptor-mediated endocytosis to exert its pharmacologic effects. In J Pharmacol Exp Then 251 1223-8... 

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