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Skeletal Muscle Atrophy Induced by Intramuscular Repeated Dose of Botulinum Toxin Type A in Rats

Botulinum toxin type A was intramuscularly administered to Sprague–Dawley rats once a day for 28 days at doses of 1, 3, and 9 ng kg−1 day−1 to investigate the possibility of unanticipated toxicity of repeated dose. A dose-related decrease in body weight gain was noted and lasted throughout the 4-week recovery period. Paralytic gait was a common clinical sign observed in the animals dosed at ≥3 ng kg−1 day−1 and muscle atrophy at 9 ng kg−1 day−1. Decreased creatinine was monitored in both males and females treated at 9 ng kg−1 day−1. Microscopic examination of the quadriceps femoris muscle, the test article application site, confirmed the muscle atrophy with a decrease in myofiber diameter and an increase of myofiber nuclei and intermyofiber connective tissue. Although antibody against botulinum toxin type A was detected in the sera from both males and females at 9 ng kg−1 day−1, no immunogenicity-related changes or lesions were noted. In conclusion, no other side effects of the botulinum toxin type A injection except the decrease in body weight gain and the muscle atrophy at the administration site were noted in the 28-day intramuscular repeated dose study.