However paradoxical it may seem, botulinum toxin has over the past decade risen to the status of 'wonder drug'.47'48 It is used to treat a variety of diseases characterized by spasm or overactivity of a particular muscle or group of muscles. In many of these illnesses the muscular hyperactivity is the primary disorder (e.g., cervical dystonia), while in others, it is secondary to another disease (e.g., rigidity and tremor in Parkinson's disease). In most of these conditions intramuscular injection of botulinum toxin has become the treatment of choice and has replaced previous and much less satisfactory surgical or pharmacological alternatives. Clinically effective paralysis with type A botulinum toxin typically lasts three or four months, but it can be longer.47'48
The widespread applicability of botulinum toxin's ability to relax tense muscles originates in the work of two investigators. Alan Scott was an ophthalmologist who pioneered preclinical evaluation of botulinum toxin in monkeys and its subsequent clinical use in patients with strabismus (wandering eye) and blepharospasm;49 Edward Schantz was a protein chemist who had crystallized botulinum toxin type A and provided it on request to Scott.50 Botulinum toxin type A was licensed by the US Food and Drug Administration on December 1989 for the treatment of blepharospasm and strabismus, thus culminating more than a decade of collaborative effort by Scott and Schantz.
Once the effectiveness of botulinum toxin had become evident to clinicians, its application to other disorders or muscle contraction and movement quickly followed.47'48 The list of disorders for which botulinum toxin is being evaluated continues to lengthen and now includes smooth muscle (gastrointestinal) disorders and also a variety of skeletal muscle conditions that include cerebral palsy and extremity spasms after injury to the central nervous system. Botulinum toxin has even been used cosmetically for the removal of frown lines and 'crow's feet' wrinkles on the face.47
At present, there are two commercial preparations of botulinum toxin type A in use, one made in the United States (BOTOX®, Allergan) and one made in England (Dysport®, Speywood Pharmaceuticals): The potency of the two toxin preparations are not identical; 1 ng of BOTOX® contain approximately 2.5 units of toxin, whereas 1 ng of Dysport® contains 40 units (one unit of toxin is defined as the mouse LD50 dose).48
The clinical use of botulinum toxin is not without its problems. Several side-effects have been noted. Unwanted paralysis of adjacent muscles (e.g., ptosis obscuring vision, dysphagia resulting in aspiration) is caused by the diffusion of toxin away from the injection site. This complication limits the amount of toxin that can be injected at a given treatment session. Other side-effects include a transient influenza-like syndrome suggestive of an allergic reaction and the development of neutralizing antibodies that render the patient resistant to further treatment with botulinum toxin type A.46^18'51
Clinical experience with botulinum toxin has accumulated rapidly, and international conferences on its use now occur with regularity.51-53 Even so, the therapeutic application of botulinum toxin remains in its infancy. Much refinement and improvement in its usefulness can be expected in the years ahead. It is likely that additional botulinum toxin serotypes will come into widespread use (types B and F toxins have already been studied25'47'50'51), including type C toxin which, uniquely among the eight clostridial neurotoxins, has syntaxin as its substrate. Various combinations of toxins will likely be tried in order to prolong the duration of desired weakening or of frank paralysis (e.g., a mixture of toxins A, B, and C would cleave the three different protease substrates), and the problem of neutralizing antibody formation will also probably be solved 43 Tetanus toxin's retrograde axonal transport may be harnessed as a means to deliver various medications to the spinal cord and perhaps beyond. Finally, molecular engineering of the toxins may improve their duration of action or permit delivery of the light chain to other cell types, where it could block unwanted secretory activity.53 The paradoxical emergence of the world's most poisonous substance as a wonder drug at the very time that at least one nation was preparing to use it as a weapon of mass destruction illustrates once again the constant potential for the perversion of scientific knowledge. This paradox re-emphasizes the need for humanitarian principles, as well as humanitarians, always to prevail in the use of such knowledge.
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