Recovery from botulinum neurotoxin poisoning in vivo.
Botulinum neurotoxins cause the disease botulism, which is characterized by prolonged muscle paralysis. In contrast, injections of low doses of purified botulinum neurotoxins do not cause systemic illness but produce localized muscle paralysis that is beneficial for treating several human medical disorders involving uncontrollable muscle contraction. Optimizing the therapeutic efficacy while diminishing adverse reactions requires precise knowledge of toxin potency as well as a clear understanding of how each toxin causes disease. A novel in vivo mouse assay has been used to correlate toxin dosage with the duration of muscle paralysis. Voluntary running activity performed by mice was proportional to the amount of toxin injected into the hind limbs and the subsequent rate of recovery over the ensuing days or weeks was a function of botulinum neurotoxin serotype A or B concentration. Botulinum neurotoxin A produced longer paralysis than botulinum neurotoxin B consistent with human observations. A third serotype, botulinum neurotoxin E, had the shortest duration of action, but unlike the other two toxins, dosage did not influence recovery time. Botulinum neurotoxin A recovery appeared biphasic with the initial phase about two-fold faster than the final phase. Over four weeks, muscle activity had gradually improved following the highest botulinum neurotoxin A dose, reaching about half of the normal running activity. Lower botulinum neurotoxin A doses led to incrementally faster and complete recovery. Persistence of maximum paralysis was exponentially related to botulinum neurotoxin A dosage, with a doubling of the paralysis time occurring with every 25% increase of the toxin concentration. In contrast, the rate of recovery from botulinum neurotoxin B was monophasic relative to toxin dosage and the duration of maximum paralysis was linear relative to dosage. Combinations of botulinum neurotoxin A and B and botulinum neurotoxin A and E were tested and shown to exacerbate paralysis compared with individually administered serotypes.
Laboratory of Bacterial Toxins, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, HFM 434, Room 122, Bethesda, MD 20892, USA. james.keller@fda.hhs.gov
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D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001905:Botulinum Toxins / Q000506:poisoning*; D019274:Botulinum Toxins, Type A / Q000506:poisoning; D001906:Botulism / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009498:Neurotoxins / Q000506:poisoning*; D020127:Recovery of Function / Q000502:physiology*; D012420:Running; D013997:Time Factors
D000975:Antioxidants; D009498:Neurotoxins; C096323:rimabotulinumtoxinB; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A; C096326:botulinum toxin type E