Botulinum toxin type B

Botulinum toxin type B is a neuromuscular blocking agent. The mechanism of action of Botulinum toxin type B in blocking neuromuscular conduction occurs by a three-step process:

1. Extracellular binding of the toxin to specific acceptors on motor nerve terminals.
2. Internalisation and release of the toxin into the cytosol of the nerve terminals.
3. Inhibition of acetylcholine release from nerve terminals at the neuromuscular junction.

When injected directly into a muscle, botulinum toxin type B causes a localised paralysis that gradually reverses over time. The mechanism by which muscle paralysis is reversed over time remains unknown, but may be associated with the intraneuronal turnover of the affected protein and/or sprouting of the nerve ending.

Botulinum toxin type B injected intramuscularly produces localised muscle weakness by chemical denervation. Following local intramuscular injection of botulinum toxin type B serious adverse events that may have been due to systemic effects of Botulinum Toxin Type B, were observed in 12% of adverse reaction cases reported during the post-marketing experience (including the following adverse reactions: dry mouth, dysphagia and blurred vision). However, no pharmacokinetic or Absorption, Distribution, Metabolism and Excretion (ADME) studies have been performed.

Single dose pharmacology studies in cynomolgus monkeys have shown no effects other than the anticipated dose-dependent paralysis of injected muscles, together with some diffusion of toxin at high doses producing similar effects in neighbouring non-injected muscles.

Single dose intramuscular toxicology studies have been performed in cynomolgus monkeys. The systemic No Observed Effect Level (NOEL) was shown to be approximately 960 U/kg. The dose resulting in death was 2400 U/kg.

Because of the nature of the product, no animal studies have been carried out to establish the carcinogenic effects of botulinum toxin type B. Standard tests to investigate the mutagenicity of botulinum toxin type B have not been performed.

Development studies in rats and rabbits have shown no evidence of foetal malformations or changes to fertility. In the development studies, the No Observed Adverse Effect Dose Level (NOAEL) in rats was 1000 U/kg/day for maternal effects and 3000 U/kg/day for foetal effects. In rabbits, the NOAEL was 0.1 U/kg/day for maternal effects and 0.3 U/kg/day for foetal effects. In the fertility studies the NOAEL was 300 U/kg/day for general toxicity in both males and females and 1000 U/kg/day for fertility and reproductive performance.