Several years ago in Pharmacy Times, I described 2 drugs that I considered to be ?wonder drugs.?1 To be included in this category, a drug should have a number of uses and/or be the drug of choice available for those uses. My first selection, aspirin, was an obvious choice, considering its analgesic, antipyretic, and anti-inflammatory effects. Recently, that drug has become widely used for antithrombotic prophylaxis in patients who have had angina pectoris or a myocardial infarction. Aspirin also may reduce the risk of mental illness. Many other attributes of aspirin are still in the discovery phase, including its ability to reduce the risk of colorectal cancer.
My second choice was less obvious. I chose thalidomide, despite its painful past history of teratogenic effects and the fact that it was in part responsible for the 1962 Drug Amendments. Thalidomide has been used for years as the drug of choice under special conditions to treat certain forms of leprosy. It also has been indicated for erythema multiforme, lupus, and Weber- Christian disease. Other diseases that may be amenable to treatment with thalidomide include AIDS, inflammatory bowel disorder, rheumatoid arthritis, multiple sclerosis, macular degeneration, diabetic retinopathy, and pyoderma gangrenosum. In addition, thalidomide is now being investigated for potential use in cancer treatment because of its antiangiogenic effects.2
Now there is a third drug to consider?botulinum toxin. This toxin would appear to be even less likely than thalidomide to be deemed a wonder drug. It is the deadliest toxin known to humans, and it is often referred to as the most poisonous poison.3 Despite its toxicity, botulinum toxin has been compared with penicillin because of its versatility against a wide range of ills, and because it is an organic product derived from a common bacterium.
This neurotoxin is produced by the anaerobic bacterium Clostridium botulinum, and extremely small amounts can lead to botulism. The condition can occur in 2 ways. It can result from infection with bacterial spores that produce and release the toxin in the body. Examples include enteric infectious botulism and wound botulism. Botulism also can occur after ingestion of the toxin (foodborne botulism).4 The term botulism is derived from the Latin botulus (sausage). It was introduced in 1870 to describe a fatal food-poisoning syndrome associated with eating sausage. Fish and other animal proteins also transmit the disease, however. In the United States, plant rather than animal products are common transmission vehicles. 5 Although death rates from botulism poisoning are just a fraction of what they were 30 years ago, botulism continues to strike dozens of people each year?most of them children.6
Strains of C botulinum produce 7 antigenically distinct neurotoxins. They all interfere with neural transmission by decreasing the frequency of acetylcholine release. Acetylcholine is the principal neurotransmitter at the neuromuscular junction. When the synaptic transmission is blocked, muscles become clinically weak and atrophic. Paralysis and a nearly complete decline of end-plate potentials occur within a few hours after the injection of botulinum toxin. The affected nerve terminals do not degenerate, but the blockage of neurotransmitter release is irreversible. Function can be recovered by the sprouting of nerve terminals and formation of new synaptic contacts, a process that takes 2 to 3 months.7
Botulinum toxin has a number of advantages over other paralyzing and painkilling agents. First, it is specific, acting only where injected, and the toxin can be used to weaken a muscle rather than paralyzing it. The second advantage is its long duration of action. The toxin lasts for months, but the effects eventually dissipate.8
The idea of using botulinum toxin had been considered for several years, but it seemed too wild to take seriously. This situation changed with a publication in 1971 that demonstrated that local changes in animal muscles could be induced using the toxin.9 Alan Scott, MD, an ophthalmologist from the Smith-Ketterwell Eye Research Institute in San Francisco, Calif, and others shortly thereafter began using the toxin for experiments in animals on extraocular muscle. These studies showed that paralysis could be localized to the target muscle and its duration and depth controlled by dose, and all without systemic side effects.7 Dr. Scott thus paved the way for clinical research in a number of specialties.
Clinical trials in human patients began in 1977 to study the treatment for strabismus (as an alternative to incisional surgery) and for blepharospasm. Both conditions are characterized by excessive muscle contractions. Strabismus is also known as cross-eye or walleye. Blepharospasm is a rare disorder manifested by overactive blinking or locked-shut eyelids. It can lead to functional blindness.
The product sold under the trade name Botox (botulinum toxin type A) proved to be safe and effective, and it was finally approved in December 1989. It was the first bacterial toxin to be used as a medicine. Since then, Botox has become the treatment of choice for primary blepharospasm.8
In December 2000, the FDA approved Botox to treat cervical dystonia (torticollis), a neurologic movement disorder causing severe neck and shoulder contractions. Some improvement in pain relief, head position, and disability occurs in 90% of patients, and three quarters achieve considerable improvement. The toxin is now the treatment of choice for this condition as well.
In April 2002, Botox was approved to treat frown lines. Using the toxin cosmetically arose serendipitously from the observation that therapy for facial dystonias markedly decreased lines and wrinkles in the treated areas. Allergan, the manufacturer, conducted a placebo-controlled, multicenter, randomized clinical trial involving a total of 405 patients with moderate-tosevere glabellar lines. Data from both investigators? and patients? ratings of the improvement of the frown lines were evaluated. After 30 days, the great majority of investigators and patients rated frown lines improved or nonexistent. Very few placebo patients saw similar improvement. Botox treatment is now widely advertised in direct-toconsumer advertisements.
Other Possible Uses
Local infiltration of botulinum toxin into the internal anal sphincter appears to be an effective treatment for chronic anal fissure (a tear in the lower half of the anal canal that results in severe pain and bright red rectal bleeding). The drug may replace sphincterotomy, a widely used surgical procedure.10
Botulinum toxin also may be useful in patients with other forms of dystonia and in those with certain focal repetitive involuntary movements, including tremor, tics, segmental myoclonus, and other hyperkinetic movement disorders. The effects of botulinum toxin on spasticity in children with cerebral palsy are being studied, as well as its use in relaxing a spastic bladder in patients with multiple sclerosis.8 Injections of the toxin may safely and effectively treat axillary hyperhidrosis, which causes profuse sweating.11 According to a recent news report, the toxin will be increasingly used to end underarm sweating and may someday be used as a personal grooming agent.12
Botulinum toxin has been used to treat headaches, backaches, myofascial and other severe pain, clubfoot, obesity, and tennis elbow. The toxin also has been employed for disorders of the ear, nose, and throat. Conditions treated include bruxism, temporomandibular joint dysfunction, laryngeal disorders, and stuttering with glottal blocking.8
Most patients treated with botulinum toxin require repeated injections over many years. Some patients who respond well initially may develop tolerance to the drug. Neutralizing antibodies may be developing to the toxin, and higher doses or frequent injections may increase the risk of antibody formation. Injections, therefore, should be given at the lowest effective dose.8
The astounding number of indications for using aspirin, thalidomide, and botulinum toxin is evidence of the dynamic processes inherent in drug discovery. The ?wonder drug? designation can be unexpectedly and even miraculously bestowed on old drugs, teratogens, or neurotoxins. The next candidate may be a new drug. Gleevec (imatinib mesylate) inactivates a gene that is hyperactive in chronic myelogenous leukemia. It appears that many other cancers may be caused by the same kind of genetic defect the drug singles out. This discovery would be a major breakthrough, and Gleevec would indeed be another wonder drug.
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