The therapeutic window in rats of botulinum neurotoxin subtype A2 is wider than that of subtype A1, regardless of the presence of nontoxic proteins

Abstract

Introduction : The botulinum neurotoxin complex type A1 (A1LL) is widely used in the world for neurological disorders. Improved safety is hoped for when large-dose administrations of the neurotoxin product are needed. In this study, we examined whether the removal of nontoxic proteins from A1LL and a difference in the subtype of neurotoxin has any impact on the efficacy, side effects, and therapeutic window (TW). Methods : Rats received an injection into the left gastrocnemius of 0.05–13.6 U of botulinum neurotoxin subtype A2 or A1, both being free of nontoxic proteins (A2NTX and A1NTX, respectively), or A1LL. The amplitude of the compound muscle action potential (CMAP) of both legs was periodically measured after injection. The TWs for each preparation were calculated as the ratio of the dose producing a 50% reduction in the CMAP amplitude in the left (ED50) and right (SD50) legs. Results and discussion : No significant difference was noted among the three preparations in ED50. There was also no significant difference between A1NTX and A1LL in SD50. However, the SD50 of A2NTX was higher than that of both A1NTX and A1LL. Furthermore, the TW of A2NTX was wider than that of both A1NTX and A1LL, while, on the other hand, the TWs were not significantly different between A1NTX and A1LL. These findings suggest that A2NTX may be safer for large-dose administrations into skeletal muscle than both A1LL and A1NTX, regardless of the presence of nontoxic proteins.