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The Science of Botulinum Toxin

Featuring Mark Nestor, MD, PhD | Co-Director |

Director of Center for Clinical and Cosmetic Research
Voluntary Professor, Dermatology
University of Miami, Miller School of Medicine
Miami, FL

| Published February 22, 2024

Mark Nestor, MD, PhD, took us through a rigorous review of key clinical postulates of botulinum toxin type A to optimize results for our patients and assess properties to discern differences between commercially available products. His first postulate states that all the type A toxins have the same mechanism of action: the heavy chain of the 150kDa active molecule irreversibly binds SV2 receptors on presynaptic cholinergic neurons, leading to cellular uptake, disulfphide bond breakage, and cleavage of the SNAP 25 protein by the light chain to prevent acetylcholine vesicles from fusing with the cell membrane. The rate-limiting step of this cascade of events is the first, SV2 receptor binding. Potency, therefore, is defined by the amount, activity, and affinity of toxin to bind to this SV2 receptor. This is not directly proportional to manufacture units, as lyophilized toxins may vary by 20% within each vial, and daxibotulinumtoxin peptide may prevent aggregation thereby increasing affinity. It follows that increasing the potency may be possible by increasing the number of SV2 receptors, and there is technology looking at additive enhancer toxins for this purpose. The light chain remains active in the cytoplasm for up to 10 months, but the recovery of response leaves many investigators with questions. While muscle mass and age may play a role in differences seen among patients, acetylcholine receptor gene upregulation, proliferation of neuronal axon sprouts, and myogenesis are the least understood parts of toxin response and lifecycle.
These myriad factors that influence clinical efficacy are addressed by Postulate II and III, while also bringing in more clinical variables like the distribution of toxin. The efficacy and duration of the effect of botulinum toxin is proportional to the degree of molecular saturation of molecules bound at neuromuscular junctions as well as the time to recovery, but this is difficult to ascertain objectively for commercial products. While each manufacturer uses its own methodology to tout potency results, Dr Nestor recommended comparing independent trial data or results in an individual split-face study. For example, noninferiority trials looking at glabellar lines and the frontalis muscle compare different toxins on contralateral sides of the face. Abobotulinum toxin demonstrated a faster result than onabotulinum toxin for the frontalis, while there was a slight but insignificant preference for prabotulinum toxin compared to onabotulinum toxin for glabellar lines. 

Postulate V states that increased molecular potency will decrease the time to onset and increase the duration of effect, up until a certain point that is. Diffusion, a passive process that is the same for all toxins, and spread, based on anatomy, technique, and reconstitution, should also be considered when administering toxin. The later postulates consider the impact of diffusion and spread on clinical effect, and while increasing injection sites may allow for optimal spread, the technique comes with more risk of bruising and consumes more time. Looking into 2024, Dr Nestor also mentioned 2 new toxins in the process of garnering FDA approval, letibotulinumtoxin A and relabotulinumtoxin A, the latter of which is derived from clostridium botulinum. Overall, this was a thorough evaluation of one of the most commonly administered injections in the aesthetic domain. 


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