Botulinum toxin type A is a protein complex derived from Clostridium botulinum. The protein consists of type A neurotoxin and several other proteins. Under physiological conditions it is presumed that the complex dissociates and releases the pure neurotoxin.
Clostridium botulinum toxin type A neurotoxin complex blocks peripheral acetyl choline release at presynaptic cholinergic nerve terminals.
Intramuscular injection of the neurotoxin complex blocks cholinergic transport at the neuromuscular junction by preventing the release of acetylcholine. The nerve endings of the neuromuscular junction no longer respond to nerve impulses and secretion of the chemotransmitter is prevented (chemical denervation). Re-establishment of impulse transmission is by newly formed nerve endings and motor end plates. Clinical evidence suggests that botulinum toxin type A reduces pain and neurogenic inflammation and elevates cutaneous heat pain thresholds in a capsaicin induced trigeminal sensitization model. Recovery after intramuscular injection takes place normally within 12 weeks of injection as nerve terminals sprout and reconnect with the endplates.
After intradermal injection, where the target is the eccrine sweat glands, the effect lasted for about 4-7 months in patients treated with 50 Units per axilla.
There is limited clinical trial experience of the use of botulinum toxin type A in primary axillary hyperhidrosis in adolescents between the ages of 12 and 18. A single, year long, uncontrolled, repeat dose, safety study was conducted in US paediatric patients 12 to 17 years of age (N=144) with severe primary hyperhidrosis of the axillae. Participants were primarily female (86.1%) and Caucasian (82.6%). Participants were treated with a dose of 50 Units per axilla for a total dose of 100 Units per patient per treatment. However, no dose finding studies have been conducted in adolescents so no recommendation on posology can be made. Efficacy and safety of botulinum toxin type A in this group have not been established.
Botulinum toxin type A blocks the release of neurotransmitters associated with the genesis of pain. The presumed mechanism for headache prophylaxis is by blocking peripheral signals to the central nervous system, which inhibits central sensitisation, as suggested by pre-clinical and clinical pharmacodynamic studies.
Following intradetrusor injection, botulinum toxin type A affects the efferent pathways of detrusor activity via inhibition of acetylcholine release. In addition botulinum toxin type A inhibits afferent neurotransmitters and sensory pathways.
Classical absorption, distribution, biotransformation and elimination studies on the active substance have not been performed due to the extreme toxicity of botulinum toxin type A.
Human ADME studies have not been performed due to the nature of the product. It is believed that little systemic distribution of therapeutic doses of botulinum toxin type A occurs. Botulinum toxin type A is probably metabolised by proteases and the molecular components recycled through normal metabolic pathways.
Non-clinical data based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity reveal no special hazard for humans other than exaggerated pharmacological effects predictable at high doses, given the neurotoxic nature of botulinum toxin type A. Carcinogenicity studies have not been conducted.
In monkeys receiving a single intramuscular (i.m.) injection of botulinum toxin type A, the No Observed Effect Level (NOEL) ranged from 4 to 24 Units/kg. The i.m. LD50 was reported to be 39 Units/kg.
In three different studies (six months in rats; 20 weeks in juvenile monkeys; 1 year in monkeys) where the animals received i.m. injections, the NOEL was at the following respective botulinum toxin type A dosage levels: < 4 Units/kg, 8 Units/kg and 4 Units/kg. The main systemic effect was a transient decrease in body weight gain.
In a study in which juvenile rats received intramuscular injection of botulinum toxin type A every other week from postnatal day 21 for 3 months at the doses of 8, 16, or 24 units/kg, changes in bone size/geometry associated with decreased bone density and bone mass secondary to the limb disuse, lack of muscle contraction and decrease in body weight gain observed. The changes were less severe at the lowest dose tested, with signs of reversibility at all dose levels. The no-observed adverse effect dose in juvenile animals (8 Units/kg) is similar to the maximum adult dose (400 Units) and lower than the maximum paediatric dose (340 Units) on a body weight (kg) basis.
There was no indication of a cumulative effect in the animal studies when botulinum toxin type A was given at dosage intervals of 1 month or greater.
Decrease in bodyweight was observed following a single intradetrusor injection of <10 Units/kg botulinum toxin type A in rats. To simulate inadvertent injection, a single dose of botulinum toxin type A (~7 Units/kg) was administered into the prostatic urethra and proximal rectum, the seminal vesicle and urinary bladder wall, or the uterus of monkeys (~3 Units/kg) without adverse clinical effects. However, bladder stones have been observed in monkeys given a single dose of botulinum toxin type A to the prostatic urethra and proximal rectum, and in a repeated dose intraprostatic study. Due to anatomical differences the clinical relevance of these findings is unknown. In a 9 month repeat dose intradetrusor study (4 injections), eyelid ptosis was observed at 24 Units/kg, and mortality was observed at doses ≥24 Units/kg. No adverse effects were observed in monkeys at 12 Units/kg, which corresponds to a 3-fold greater exposure than the recommended clinical dose of 200 Units for urinary incontinence due to neurogenic detrusor overactivity (based on a 50 kg person).
Botulinum toxin type A was shown not to cause ocular or dermal irritation, or give rise to toxicity when injected into the vitreous body in rabbits.
Allergic or inflammatory reactions in the area of the injection sites are rarely observed after botulinum toxin type A administration. However, formation of haematoma may occur.
When pregnant mice and rats were injected intramuscularly during the period of organogenesis, the developmental NOEL of botulinum toxin type A was at 4 Units/kg. Reductions in ossification were observed at 8 and 16 Units/kg (mice) and reduced ossification of the hyoid bone at 16 Units/kg (rats). Reduced foetal body weights were observed at 8 and 16 Units/kg (rats).
In a range-finding study in rabbits, daily injections at dosages of 0.5 Units/kg/day (days 6 to 18 of gestation), and 4 and 6 Units/kg (administered on days 6 and 13 of gestation), caused death and abortions among surviving dams. External malformations were observed in one foetus each in the 0.125 Units/kg/day and the 2 Units/kg dosage groups. The rabbit appears to be a very sensitive species to botulinum toxin type A treatment.
The reproductive NOEL following i.m. injection of botulinum toxin type A was 4 Units/kg in male rats and 8 Units/kg in female rats. Higher dosages were associated with dose-dependent reductions in fertility. Provided impregnation occurred, there were no adverse effects on the numbers or viability of the embryos sired or conceived by treated male or female rats.
In female rats, the reproductive NOEL was 16 Units/kg. The developmental NOEL was 4 Units/kg.
Botulinum toxin type A showed antigenicity in mice only in the presence of adjuvant. Botulinum toxin type A was found to be slightly antigenic in the guinea pig.
No haemolysis was detected up to 100 Units/ml of botulinum toxin type A in normal human blood.
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