10.1.1 The History

Clostridium botulinum is an anaerobic, spore-forming bacterium that creates a toxin under the appropriate conditions (Carruthers and Carruthers 2005a). Clostridium botulinum was first identified in 1895 by Professor Emile Pierre Marie van Ermengem when an illness broke out at a picnic in Belgium after people ate salted, raw ham. Subsequently, in 1920, Dr. Herman Sommer began the isolation and development process of the toxin and in 1946 it was finally isolated by Edward Shantz for the US Army. The function of the molecule was discovered by A.S.V. Burgen in 1949 (Burgen et al. 1949). In 1952, Burgen urged Vernon Brooks to continue his studies on botulinum toxin while Brooks was working toward a PhD. Then, in 1953, medical application of the botulinum toxin ensued when Dr. Vernon Brooks inadvertently became the “godfather for the Botox^® treatment of many dystonias and other involuntary muscle movements” after discovering the mechanism of action of the botulinum toxin (Brooks 2001).

It wasn’t until 1977 when Alan B. Scott and colleagues injected the first patients with botulinum toxin type A by applying principles discovered by Dr. Vernon. These first patients were suffering with strabismus and had relief from Dr. Scott’s novel treatments using botulinum toxin. Dr. Scott then reported his findings in 1980 and he named the substance Oculinum (eye aligner). In 1989, Allergan obtained approval by the FDA to market Oculinum as Botox ^® (US Dept. of Health 2009 docket # FDA-2008-P-0061).

There are three major commercial brands of BoNT/A products available worldwide: onabotulinumtoxinA (ONA) marketed as Botox^®/Vistabel^® by Allergan Inc. (Irvine, CA), abobotulinumtoxinA (ABO) marketed as Dysport^®/Azzalure^® by Ipsen (Paris, France), and incobotulinumtoxinA (INCO) marketed as Xeomin^®/Bocouture^® by Merz Pharmaceutical Gmbh (Frankfurt, Germany). The fourth US FDA approved BoNT/A, prabobotulinumtoxin-xvfs (PRABO) marketed as Jeuveau™ by Evolus (Korea), was released in the US market mid-2019. Three other manufacturers based in Korea and China produce three additional BoNT/A brands marketed mainly in Asia: Medy-Tox (Korea) owns Meditoxin/Neuronox/Siax brands, Hugel Inc. (Korea) has Botulax (also Zentox or Regenox in other countries), and Lanzhou Institute for Biologic Products (Lanzhou, China) produces a BoNT/A called BTXA and is distributed by local/regional companies under different brand names.

Botulinumtoxin type B (BoNT/B) (rimabotulinumtoxinB) was approved by the US FDA in 2000 with the trade name Myobloc/Neurobloc for the treatment of cervical dystonia. The product is presently marketed by US WorldMeds in the USA and by Eisai Europe Limited in Europe (Aoki and Guyer 2001). BoNT/B is not currently used in aesthetics due to the different mechanism of action and higher side effect profile and so is beyond the scope of this text.

10.1.2 Types of BoNT/A Used in Aesthetics

In 2009, the United States Food and Drug Administration mandated non-trade names for all approved BoNT/A. The mandated names are in attempt to clarify differences of the formulations. The chemical formulations of the three BoNT/A differ slightly, cannot be substituted, and have different dosing curves (Sundaram et al. 2016). The variations of the formulations depend on the production and process of each manufacturer.

The potency of each BoNT/A is different, and the medications are not interchangeable. For example, the dose of BoNT/A is measured in units. A unit is defined as the median dose, administered by intraperitoneal injection, needed to kill 50% of mice in a test sample after a specified test duration. Each manufacturer creates individual assays for their product (Fonfria et al. 2018). The concentration of onabotulinumtoxinA (Botox^®) , incobotulinumtoxinA (Xeomin^®) , and prabotulinumtoxin-xvfs (Jeuveau™) is 4 units per 0.1 mL and sold as 100 units in 2.5 mL solution per vial (Evolus 2019; Allergan 2017; Merz Pharmaceuticals LLC 2018). Whereas dosing of abobotolulinumtoxinA (Dysport^®) , is 10 units per 0.1 mL and sold as 300 units in 3.0 mL per vial (Ipsen Biopharmaceuticals Inc 2017).

Of the four types of BoNT/A, onabotulinumtoxinA (Botox^®) has 39 indications in 40 countries for treatment of a variety of conditions including bladder spasms, cervical dystonia, facial spasms, migraine headaches, blepharospasm, and depression. OnabotulinumtoxinA is also the most widely studied neurotoxin for therapeutic and cosmetic purposes, with over 2800 articles and over 400 peer-reviewed articles worldwide between 1986 and 2013 (Mohindru et al. 2013).

Currently, BoNT/A is the most popular non-surgical cosmetic procedure in the world (ISAPS 2016; Frevert 2015; Botox 2018). The safety and efficacy profile of BoNT/A is excellent when used appropriately in patients. The data on abobotulinumtoxinA (Dysport^®) and incobotulinumtoxinA (Xeomin^®) are also growing as more practitioners use and recommend these products (Sundaram et al. 2016).

10.2.1 Mechanism of Action

To comprehend how BoNT/A works in the musculature of the face and neck, an understanding of the synaptic communication and neurotransmitter relationship is necessary. All four commercial brands of BoNT/A for cosmetic indications work in similar ways . Soluble N-ethylmaleimide sensitive factor adaptor proteins (SNAPs) and SNAP receptors (SNAREs) are the main targets of BoNT/A (Rizo and Sudhof 2012). Injection of the BoNT/A molecule into the muscle blocks neuromuscular transmission by binding to surface receptors on motor nerve terminals thereby entering the nerve terminals, and inhibiting the release of the neurotransmitter, acetylcholine (Frevert 2015). This inhibition occurs as the pH-induced translocation of the toxin light chain to the cell cytosol cleaves SNAP-25, a pre-synaptic protein that is crucial in the successful docking and release of acetylcholine from vesicles within nerve endings (Frevert 2015; Aoki and Guyer 2001). The result is a decrease in the target muscle activity (see Figs. 10.1 and 10.2).