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Surgery and Cosmetics

Joel L. Cohen, MD

Neurotoxins: Present and Future

Joel Cohen

Wednesday, August 13, 2008

Neurotoxins isolated from Clostridium botulinum bacteria have revolutionized the fields of ophthalmology, neurology and aesthetics. Currently types A and B toxins are clinically available in the US, with Botox (type A) being the only agent approved for cosmetic use (glabella) by the U.S. Food and Drug Administration. The use of Botox to improve facial wrinkles is the most common cosmetic procedure currently performed in the US, with more than 3 million procedures having taken place in 2006.1,2 This review covers Botox and Myobloc/Neurobloc (type B) as well as other neurotoxins on the therapeutic and cosmetic horizon including Dysport/Reloxin, Xeomin, Prosigne, and PurTox.

Botulinum Toxins

Seven different strains of Clostridium have been described (designated A, B, C, D, E, F and G) and each produces a distinct toxin. These toxins are high molecular weight protein complexes that include three key components: a 150 kDa toxin, a non-toxin hemagglutinin protein, and a non-toxin non-hemagglutinin protein. The 150 kDa toxin protein itself is composed of two distinct parts; a 100 kDa heavy-chain and a 50 kDa light-chain which are both required for neurotoxicity. The non-toxin proteins of the complex may provide the overall toxin complex with some degree of protection (particularly against temperature or enzymatic denaturation).

The process of chemical denervation requires that the neurotoxin heavy-chain of the complex binds a specific receptor on the presynaptic nerve terminal, which leads to receptor-toxin mediated endocytosis. Once the complex of the heavy and light chains is inside the nerve terminus, the light-chain becomes separated through vesicle lysis. The toxin light-chain then prevents neural conduction to skeletal muscles by cleaving specific proteins necessary for the docking, fusion and release of acetylcholine at the nerve terminus. Toxins A, C and E cleave synaptosomal associated protein (SNAP-25) and toxins B, D, F and G cleave vesicle associated membrane protein (VAMP, also known as synaptobrevin). Muscle paralysis usually occurs within approximately 3-7 days and synaptic regeneration reverses paralytic effect within 3-6 months. Contraindications to botulinum toxins are few and include Eaton-Lambert syndrome, amyotrophic lateral sclerosis (ALS), myasthenia gravis, hypersensitivity to botulinum toxins or one of its ingredients, and pregnancy.

Botulinum Toxin Type A

Botulinum toxin type A (BTX-A) in the US (originally called "Oculinum") was first used in humans in 1968 by Alan Scott in San Francisco to treat strabismus. By 1989, clinical data from thousands of patients showed efficacy without evidence of systemic adverse effects, which led to the Food and Drug Administration (FDA) approval for the treatment of strabismus as well as blepharospasm. Alastair and Jean Carruthers were the first to report cosmetic efficacy in the adjacent musculature after these therapeutic ophthalmologic injections during the same time period. In 1991, Allergan Inc. purchased this purified BTX-A, and the agent was given the name Botox (Allergan, Inc., Irvine, CA).  

The complex size of Botox is approximately 900 kDa which includes toxin and non-toxin hemagglutinin and nonhemagglutinin proteins. One vial of Botox contains 100 units of toxin, with one unit (U) equal to the median amount necessary to kill 50% of female Swiss-Webster mice after intraperitoneal injection (LD50). Botox is a vacuum-dried product and in addition to 100 U of toxin, each vial contains 500 micrograms (µg) of albumin and 900 µg of sodium chloride.

For therapeutic use, Botox is Food and Drug Administration (FDA) approved for the treatment of strabismus, blepharospasm, cervical dystonia and axillary hyperhidrosis. It has FDA approval cosmetically only for the treatment of glabellar rhytides. However, Botox has been shown to be very effective in treating many regions of facial wrinkles as well as various locations of hyperhidrosis. In addition, there have been reports of Botox specifically improving patient self-perception.3

Dysport (Ipsen Limited, Slough, England) is also a BTX-A product, and is currently marketed and sold in over 60 countries worldwide (not including the US). The overall complex size of this product has never been published by Ipsen; although, it is claimed in some papers to be of approximately 500 kDa and in others to be of 900 kDa; like Botox, it includes non-toxin hemagglutinin and nonhemagglutinin proteins in addition to the actual toxin heavy- and light-chains. One vial of Dysport contains 500 U of air-dried toxin, 125 µg of albumin and 2.5 mg of lactose. It is important to emphasize that Dysport comes from a different type A strain of bacteria than Botox, and has been developed differently from Botox; therefore Dysport Units, also called Speywood Units are not equivalent to Botox Units. Attempts at comparisons of Botox and Dysport units in animal and human studies suggest that the equivalence doses for neurological use are 1 U Botox to 2.5-5 U Dysport.4 In aesthetic use, dose-finding studies showed optimal doses closer to a conversion rate of 1:2.5.5,6  Medicis (Scottsdale, AZ) has purchased the rights from Ipsen to distribute Dysport in the US under the name Reloxin and has recently submitted data and filed for approval with the FDA.

One concern regarding the long-term use of botulinum toxins in general is the risk of immunogenicity. Neutralizing antibodies to BTX-A toxins can lead to loss of treatment effect and have certainly been reported in the neurological literature, usually associated with toxins used at high doses (currently at higher risk for doses above 400 U of Botox).4,7 Botox underwent a formulation change in 1997 that decreased the complexing protein load from 25 ng/100 U to 5 ng/100 U and this change was associated with a marked decrease in neutralizing antibody formation.7 Neutralizing antibodies associated with BTX-A in typical cosmetic doses after the late 1990's is mostly anecdotal and considered very rare, but has now been reported and should be suspected in aesthetic patients who fail to respond to previously effective doses.8


Xeomin (NT-201, Merz Pharmaceuticals GmBH, Frankfurt am Main, Germany), packaged as a freeze-dried powder, is a purified BTX-A product which is free of the accessory complexing proteins (hemagglutinin and non-hemagglutinin) found in the other BTX-A products. The lower protein load of this purified agent is purported to be less immunogenic than other BTX-A products.9 Animal studies support this notion but reliable human immunogenicity data is not yet available.9  

Prosigne (Lanzhou Biological Products Institute, China) is a Chinese type A botulinum toxin that has been available for clinical use (not in US) since 1993. Reliable data is lacking to properly assess efficacy and safety but some preliminary studies suggest clinical utility in the treatment of conditions such as focal dystonia, hemifacial spasm and blepharospasm.10,11

PurTox (Mentor Corp., Santa Barbara, CA.) is a purified type A botulinum toxin that began Phase IIIa study in 2007 for the cosmetic treatment of glabellar rhytides. The company is also involved in a Phase I therapeutic study of PurTox for the treatment of pain associated with adult onset cervical dystonia. The toxin is believed to be quite similar to Xeomin in that it is free of non-toxin complexing proteins (hemagglutinin and non-hemagglutinin), and thus may have less risk of immunogenicity (especially for neurologic patients who are likely to receive high doses of botulinum toxin over an anticipated extended period of time). But as for Xeomin, reliable human immunogenicity data is not yet available to support this hypothesis.

Botulinum Toxin Type B

Concern surrounding the potential for type A toxin antigenicity/tolerance originally heightened interest in expanding clinical neurotoxin sub-type variety in the 1990's. The fact that toxin serotypes do not appear to cross-neutralize, led botulinum toxin type B (BTX-B) to be studied in therapeutic arenas, showing clinical efficacy in the treatment of various movement disorders since 1995. BTX-B was FDA approved in the US for the treatment of cervical dystonia and hemifacial spasm in 2001 under the name Myobloc (Solstice, South San Francisco, CA), and marketed as Neurobloc outside of the US.  

Instead of being packaged as a powder, Myobloc comes pre-constituted in vials containing 25 ng (2,500 U)/0.5 cc, 50 ng (5,000 U)/1.0 cc and 100 ng (10,000 U)/2.0 cc of product in solution with 0.05% albumin. The size of this product-complex is 700 kDa and falls between that of Dysport (500 kDa) and Botox (900 kDa).4 Myobloc consists of the 150 kDa type B active toxin and both types of non-toxin proteins, hemagglutinin and nonhemagglutinin. Treatment of patients with cervical dystonia with Botox and Myobloc led to attempts at equivalency doses used in many cosmetic studies (1 U Botox = approximately 50-100 U Myobloc), though the optimal ratio is not yet established.  

Studies comparing the cosmetic efficacies of BTX-A with BTX-B report interesting findings in several respects. The rate of onset (usually within 72 hours) of Myobloc seems to precede that of Botox by about 1-3 days, but seems to have a shorter duration of action and a greater radius of diffusion compared with type A botulinum toxins.4  A double-blind, randomized comparison study found the mean duration of Myobloc and Botox to be 6.4 and 12.7 weeks, respectively, when injected into lateral canthal rhytides.4 In addition, the lower pH (5.6) of Myobloc is thought to cause the increased amount of pain associated with injection when compared to the more physiologically buffered BTX-A agents (pH 6-7.3).4 Despite the pain, shorter action and seemingly less predictable diffusion pattern, BTX-B could potentially be useful for situations where rapid onset is desirable (such as asymmetry or an imminent event) or if concerns of antibody production to BTX-A toxins exist.

Discussion

Several clinical botulinum toxins in development will likely be available in the US in the coming years. Ongoing work with these neurotoxins focuses on identifying potential benefits of each agent, and studies continue to refine their dosage conversions with current formulations. The market share associated with the arrival of new products will likely foster a competitive atmosphere. The future of botulinum toxins, in my opinion, is also likely to have an expanded use in various combination therapies (including fillers, intense pulsed light, laser modalities, dermabrasion, chemical peels and surgery).  

Disclaimer: Relevant to this review article, Dr. Cohen is a consultant for Allergan, Medicis and Merz.  He is also a clinical trial participant for Allergan and Medicis.

References

  1. Flynn, TC. Update on botulinum toxin. Semin Cutan Med Surg. 2006;25:115-121.
  2. Physicians coalition for injectable safety. Accessed 1-1-2008, available at: http://www.injectablesafety.org/
  3. Fagien S, Cox SE, Finn JC, et al. Patient-reported outcomes with botulinum toxin type A treatment of glabellar rhytids: a double-blind, randomized, placebo-controlled study. Dermatol Surg. 2007;33:S2-9.
  4. Matarasso SL. Comparison of botulinum toxin types A and B: a bilateral and double-blind randomized evaluation in the treatment of canthal rhytides. Dermatol Surg. 2003;29:7-13.
  5. Monheit G, Carruthers A, Brandt F, et al. A randomized, double-blind, placebo-controlled study of botulinum toxin type A for the treatment of glabellar lines: determination of optimal dose. Dermatol Surg. 2007;33:S51-59.
  6. Ascher B, Zakine B, Kestemont P, et al. A multicenter, randomized, double-blind, placebo-controlled study of efficacy and  safety of 3 doses of botulinum toxin A in the treatment of glabellar lines. J Am Acad Dermatol. 2004;51:223-33. Erratum in: J Am Acad Dermatol. 2005;52:156.
  7. Yablon SA, Brashear A, Gordon MF, et al. Formation of neutralizing antibodies in patients receiving botulinum toxin type A for treatment of poststroke spasticity: a pooled-data analysis of three clinical trials. Clin Ther. 2007;29:683-690.
  8. Lee S. Antibody-induced failure of botulinum toxin type A therapy in a patient with masseteric hypertrophy. Dermatol Surg. 2007;33:S105-110.
  9. Jost WH, Blumel J, Grafe S. Botulinum neurotoxin type A free of complexing proteins (XEOMIN) in focal dystonia. Drugs. 2007;67:669-683.
  10. Tang X, Wan X. Comparison of Botox with a Chinese type A botulinum toxin. Chin Med J (Engl). 2000;113:794-798.
  11. Rieder CRM, Schestatsky P, Socal MP, et al. A double-blind, randomized, crossover study of prosigne versus botox in patients with blepharospasm and hemifacial spasm. Clin Neuropharmacol. 2007;30:39-42.
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