Introduction

Botulinum toxin is a naturally occurring protein produced by the anaerobic bacterium Clostridium botulinum. The protein acts as a neurotoxin by blocking the release of acetylcholine at the neuromuscular junction of striated muscle, thereby blocking neuromuscular motor transmission. This unique property has been found to have great clinical utility, treating such diverse medical conditions as blepharospasm, hyperhidrosis, and dynamic rhytides.

Seven serologically distinct types of botulinum toxin have been identified – designated as types A, B, C1, D, E, F, and G. Only botulinum toxin A and B are used clinically, with serotype A being the most potent. At this time, rimabotulinumtoxinB or Myobloc^® (Solstice Neurosciences, Inc; South San Francisco, CA) is the only commercially available botulinum toxin B. Initially approved by the FDA in 2000 for the treatment of cervical dystonia, its use in cosmetic applications has been limited by systemic anticholinergic adverse effects and high antigenicity. Therefore the following discussion will focus solely on botulinum toxin A (BoNT-A).

BoNT-A, like all the botulinum toxin serotypes, causes flaccid muscle paralysis by blocking acetylcholine release at neuromuscular junctions. The compound, first purified in 1946 by Dr Edward Shantz, was first found to have a cosmetic application in 1988 when Drs Jean and Alastair Carruthers observed improvement in the appearance of periorbital rhytides in patients treated for blepharospasm. In 1992, the Carruthers published their first study describing its cosmetic use in the treatment of glabellar frown lines. Subsequent randomized controlled studies provided evidence for its safety and efficacy leading to FDA approval of BoNT-A for cosmetic procedures in 2003. Today BoNT-A is considered a vital component of non-invasive facial rejuvenation and is the most common non-surgical cosmetic procedure performed.

Types of botulinum toxin A

There are multiple formulations of BoNT-A available in the US and internationally; however, the practitioner must be aware that these products are not interchangeable and important differences exist. As such, in 2009 the US FDA established unique drug names to ‘help ensure patient safety and reduce confusion’ (Table 9.1). What follows is a review of available products and their known and theoretical differences.

There are currently three formulations of BoNT-A available in the US today for cosmetic applications: onabotulinumtoxinA or Botox^® (Allergan, Inc, Irvine, California, USA), abobotulinumtoxinA or Dysport^® (Ipsen Biofarm Ltd, Berkshire, UK) and incobotulinumtoxinA or Xeomin^®® (Merz Pharmaceuticals, Frankfurt am Main, Germany). For ease of discussion, the products will be referenced by their trade names moving forward. Botox^® (Fig. 9.1) was the first to become available and continues to dominate the worldwide cosmetic market. In the USA it is approved for the treatment of glabellar lines and hyperhidrosis. It has also been shown to be highly effective for such ‘off-label’ uses as the treatment of dynamic rhytides of the forehead, periorbital area, midface, perioral area, and neck.

Figure 9.1 Vial of Botox, botulinum toxin A with the unreconstituted product seen as the small white ring of powder visible around the base of the vial. Each vial contains 100 units of botulinum exotoxin A in lyophilized form, as well as a small amount of sodium chloride (0.9 mg) and human albumin (0.5 mg).

Dysport^® (Fig. 9.2), another preparation of BoNT-A, is approved for the treatment of glabellar lines. It has become increasingly popular worldwide since its introduction and has been shown to have similar cosmetic applications to Botox^®.

Figure 9.2 Vial of Dysport^® supplied as sterile, single-use, 3 mL glass vial. Each vial contains either 300 or 500 units of lyophilized form of the botulinum toxin type.

A third product, Xeomin^® (Merz Pharmaceuticals, Frankfurt am Main, Germany) was previously indicated only for treatment of cervical dystonia and blepharospasm. However, as of July 2011, it also gained FDA approval for the treatment of glabellar rhytides. Xeomin^® has become available in the United States in the spring of 2012.

Other BoNT-A products currently in development include Purtox^® (Mentor Corporation, Santa Barbara, California, USA), Neuronox^® (Medy-Tox, Chung-cheongbuk-do, Korea), and Prosigne^® (Lanzhou, China). Purtox^® recently completed the first of three Phase III clinical trials with promising results. Clinical trial data in the United States are still pending on the other BoNT-A formulations, some of which are currently available outside the United States. In the future it will be interesting to see how the addition of other BoNT-A products to the market will affect product pricing and patient access to them.

Mechanism of action

All botulinum toxin serotypes produce their clinical effect by blocking neuromuscular transmission. Specifically, BoNT-A acts through the cleavage of SNAP-25 (synaptosomal-associated protein of 25 kDa), a protein required for the release of acetylcholine at the neuromuscular junction. The toxin anchors to motoneuronal synapses and becomes internalized via its heavy chain. The light chain of the toxin then catalyzes the cleavage of SNAP-25 with the resultant inhibition of acetylcholine release. All BoNT-A products act through this mechanism.

Compositional differences

The botulinum neurotoxin molecule is a 150 kDa single-chain polypeptide consisting of a 100 kDa heavy chain and a 50 kDa light chain. These chains are held together by a disulfide bond and are associated with a zinc atom (Fig. 9.3). In its native state the 150 kDa toxin is found complexed with large protective proteins. These complexing proteins, which are primarily hemagluttinins, act to protect ingested toxin from degradation within the gastrointestinal tract. In neutral to basic pH environments the BoNT-A complex dissociates into the free 150 kDa neurotoxin and high-molecular-weight hemagglutinin components.

Figure 9.3 The structure of the 150 kDa botulinum toxin A: it is composed of a 100 kDa heavy chain (responsible for the high-affinity, irreversible, docking on the presynaptic nerve membrane) on the left and a 50 kDa light chain (responsible for the cleavage of proteins in the synaptic fusion complex) on the right. The heavy and light chains are held together by a disulfide bond.

The complexing proteins of the native molecule seem to have evolved as a clever mechanism to protect the toxin when ingested by the host. However, the role that these proteins play, if any, in cutaneous injection of BoNT-A is unclear and remains a subject of debate. It has been argued that the proteins help to stabilize the core toxin or that they may help to enhance activity; however, these hypotheses have not been substantiated.

The three available formulations of BoNT-A vary in the presence, absence, and amount of complexing proteins. Botox^® is the largest of the available preparations at 900 kDA (Fig. 9.4) and is associated with the most complexing proteins. Due to the method employed in its production, Dysport^® may be associated with a variable number of proteins with a molecular weight ranging from 500 to 900 kDa. Uniquely in the group, Xeomin^® is composed only of the 150 kDa neurotoxin, free of any complexing proteins. Purtox^® will also be a non-complexed formulation of botulinum toxin A.

Figure 9.4 The structure of the large 900 kDa botulinum toxin A: note that the actual botulinum toxin itself makes up only 150 kDa of the structure; the rest is made up of large protective hemagglutinin (HA) and non-toxic non-hemagglutinin (NTNH) proteins. The complex is held together by non-covalent bonds that are stable in the acidic environment of the gastrointestinal tract, but dissociate as the pH increases in the blood stream and releases the free toxin. (LC = light chain; HC = heavy chain; SS = disulfide bond; Zn = zinc.)

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