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Surgery and Cosmetics

James M. Spencer, MD, MS

Alternatives to Botox (Botulinum Toxin)

James M. Spencer, MD, MS

Wednesday, January 12, 2005

In this commentary:
How Botox Works
Treatment With BTX A
Treatment With BTX B
Treatment With Topicals

How Botox Works

The use of botulinum toxin (BTX) for cosmetic enhancement was introduced a little over 12 years ago1, and has rapidly become one of the most popular cosmetic procedures performed today. It is a relatively easy technique with an excellent safety profile that produces an outstanding cosmetic result. BTX itself is a natural, well-described protein and is thus unpatentable. However, for a variety of reasons, most notably the secrecy and difficulty encountered in the manufacturing process, there has been only one commercial preparation available in the United States. However, alternative preparations and approaches to producing a "Botox effect" are now becoming available.

BTX is a protein produced by the anaerobic spore-forming bacterium Clostridium botulinum. These bacteria are widely distributed in the environment, principally as spores. Under the proper conditions, the spores can germinate and produce infection. Typically, spore-contaminated food is ingested, and then the spores germinate in the digestive tract and elaborate one of a series of highly potent neurotoxins (BTX). The toxin itself is rather small but is complexed noncovalently with a group of additional proteins that protect the neurotoxin from the acidic environment of the gut. Once absorbed from the gut, the multiprotein complex dissociates in response to the higher pH, and free neurotoxin is released. There are 7 antigenically distinct serotypes of BTX, labeled A-G. One strain of bacteria produces only 1 serotype.

All cholinergic nerves have receptors for BTX, and thus are potential targets for BTX therapy. The principal use has been to temporarily disrupt cholinergic nerve transmission to skeletal muscle and thus produce a flaccid paralysis. This has been highly effective in treating conditions characterized by hyperfunctional muscles. When a cholinergic nerve fires, the action potential is carried distally toward the neuromuscular junction. Preformed vesicles containing the neurotransmitter acetylcholine are within the terminal portion of the neuronal axon. In response to an action potential, these vesicles dock and fuse with the membrane of the terminal axon and release their content of acetylcholine into the synaptic cleft, where it will cause muscle contracture. The docking, fusing, and release of these acetylcholine vesicles are orchestrated by a group of proteins known as the SNARE complex. The BTX binds to specific membrane receptors on the neuronal axon, are internalized, and then enzymatically inactivate a component of the SNARE complex. For example, BTX A, the serotype currently in commercial use, cleaves the protein SNAP-25, thus inactivating the SNARE complex. BTX B cleaves an entirely different protein, synaptobrevin, but the end result is the same: the inactivation of the SNARE complex. With time, new sprouts from the axon re-establish functional contact with the muscle. However, ultimately the original motor end plate regains function, and the sprouts regress. Thus the effects of BTX are temporary.

BTX is a well-described bacterial protein that was first isolated and purified in the 1920s. It therefore cannot be patented in the way that a new medication can. However, it is also considered a potential biologic weapon, and thus the manufacturing process is somewhat guarded. Furthermore, the manufacturing process is a difficult one. In the United States, only 1 commercial preparation of BTX was available for the first decade of use: BTX A marketed as Botox (Allergan Inc., Irvine, California), approved for use in 1989 and initially marketed under the name Oculinum. An alternative preparation of BTX A has been marketed in Europe and South America since 1991 under the name Dysport (Beaufour Ipsen Pharmaceuticals, France). Phase III clinical trials are now under way in the United States, and American physicians may expect to have a choice of BTX A preparations in the future. In December 2000, a commercial preparation of BTX B (Myobloc in the United States or Neurobloc in Europe, both from Solstice Neurosciences in Ireland) was approved for therapy of cervical dystonia and has been investigated for off-label cosmetic use. Physicians in the United States now have a choice between BTX A and BTX B, and may soon have an alternative preparation of BTX A as well. A comparison of these products is warranted to guide clinical use.

Treatment With BTX A

There are more than 10 years' experience in the cosmetic use of Dysport in both Europe and South America. At this point, it seems clear that it is safe and effective in cosmetic therapy. The only FDA-approved cosmetic use of Botox is in the treatment of glabellar rhytides. In a similar approach, a recent published trial of 119 patients treated with various doses of Dysport in the same injection pattern used for the Botox FDA trial showed that Dysport was both safe and effective in the treatment of glabellar rhytides.2

However, it is becoming apparent that there are differences between Dysport and Botox. Although the toxin itself is the same, there are differences in the manufacturing process that may produce differences in clinical results. Dysport and Botox are derived from different bacterial strains and purified by different chemical means. As previously mentioned, naturally BTX is noncovalently associated with nontoxin proteins. These proteins are important in protecting the toxin during drying, reconstitution, and injection. It is not clear to what extent the 2 preparations have the same degree of intact multiprotein complex. Both require reconstitution with sterile saline, but Botox is vacuum-dried while Dysport is freeze-dried. One vial of Botox contains 100 units of toxin, 500 g albumin, and 0.9 mg NaCl, while 1 vial of Dysport contains 500 units of toxin, 125 g albumin, and 2.5 mg lactose.

There is an apparent difference in potency when 1 unit of Botox is compared to 1 unit of Dysport. How "units" are measured, as well as additives to the preparations, may explain this discrepancy. Botulinum toxins are extraordinarily potent, and an entire vial contains toxin measured in the nanogram range. Although it is customary to measure medications in units of mass (grams or milligrams), BTX is measured in units of biologic activity. One unit of BTX activity is the LD50 (lethal dose 50%) following intraperitoneal injection of mice. However, the mice used to measure the 2 preparations are not the same, and thus a discrepancy is introduced. Furthermore, Botox contains a higher concentration of albumin. It seems that albumin may block nonspecific binding of the toxin, and thus Botox, with a higher albumin concentration, may therefore be more potent. Clinical use has indicated 1 unit of Botox has the potency of about 3-5 units of Dysport. However, it does not seem that Dysport is exactly the same as Botox if the dose is simply multiplied by 3-5 times. In animal studies, although the therapeutic ratio is 1:3-5, the lethal doses of the 2 preparations have a ratio of around 1:2. Further studies will better delineate proper dosing and the duration of the 2 preparations in comparison to each other.

Treatment With BTX B

BTX B (Myobloc) has become available as an alternative to BTX A. Myobloc comes as an intact multiprotein complex already as a liquid at pH 5.6. It does not require reconstitution, and is stable for months to years. It is FDA-approved for the treatment of cervical dystonia, but preliminary studies have investigated its cosmetic use. As with BTX A, "units" are defined as the LD50 in standardized mice, and 1 unit of BTX A should equal 1 unit of BTX B. However, response to BTX is species-specific, and the response of mice cannot be used to assess the response of humans. Based on data from treating cervical dystonia, it appears that 1 unit of Botox has the potency of 50-100 units of Myobloc. Therefore, Myobloc comes as a solution of 5000 units/mL in 0.5-mL, 1-mL, or 2-mL vials. Initial testing for cosmetic use assumed a 1:50 "conversion factor" for Botox to Myobloc. Myobloc was injected into the glabella and forehead3 and the lateral canthus4 in the pattern and with the dosing typically used for Botox, with a 1:50 dosing conversion factor. Both investigators noted a more rapid onset than with Botox, and perhaps a superior cosmetic effect. However, the effect wore off in about half the duration of action of Botox - that is, in about 8 weeks. It is not clear if BTX B simply has a shorter duration of action, or if the 1:50 conversion is inaccurate and the patients were underdosed.

Spencer and colleagues tested escalating doses of Myobloc (conversion ratios of 1:75, 1:100, and 1:125) and found the highest dose did have a longer duration of action.5 However, even the longer duration was not as long as with Botox (12 weeks vs 16 weeks). Perhaps higher doses will last even longer. However, Myobloc is a liquid at a fixed concentration: As the dose escalates, the volume injected increases and diffusion may become an issue. Reformulating the product to a more concentrated liquid would require additional FDA testing.

Treatment With Topicals

Perhaps owing to the success of BTX, some over-the-counter cosmeceuticals are advertising themselves as alternatives to Botox. Pentapeptides are protein fragments 5 amino acids long that are thought to perhaps stimulate collagen synthesis. One such preparation of a pentapeptide (StriVectin-SD) has been advertising at cosmetic counters that it is "better than Botox." If this product works at all, it does not do so by muscle paralysis and thus in no way is a topical BTX. There is, however, a hexapeptide (6-amino-acid chain), Argeriline, that has been promoted as actually functioning as a topical BTX. There is a paper in the cosmetic literature6 reporting a "30% improvement in wrinkle depth after 30 days of use." It is difficult to imagine that this preparation could penetrate to the level of the neuromuscular junction and inhibit cholinergic nerve transmission, but, as with many unproven cosmeceuticals, it is widely available to consumers.

BTX has been an extraordinarily successful cosmetic treatment. Physicians in the United States have essentially had only a single choice in using muscle weakening for cosmetic benefit, and that is Botox. It is quite likely that the idea of muscle weakening as cosmetic therapy will lead to novel medications or devices and thus offer patients and physicians alike a choice in therapy.

References

  1. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum A exotoxin. J Dermatol Surg. 1992;18:17.
  2. Ascher B, Zakine B, Kestemont P, et al. A multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of 3 doses of botulinum toxin A in the treatment of glabellar lines. J Am Acad Dermatol. 2004;51(2):223-233.
  3. Sadick NS. Botulinum toxin type B for glabellar rhytides: a prospective open-label response study. Dermatol Surg. 2002;28(9):817-821.
  4. Mattarraso SL. Comparison of botulinum toxins type A and B: a bilateral and double-blind randomized evaluation in the treatment of canthal rhytides. Dermatol Surg. 2003;29(1):7-13.
  5. Spencer JM, Gordon M, Goldberg DJ. Botulinum B treatment of the glabella and frontalis region: a dose response analysis. J Cosmetic Laser Ther. 2002;4(1):19-23.
  6. Mira-Blanes C, et al. A synthetic hexapeptide (Argeriline) with anti-wrinkle activity. Int J Cometic Sci. 2002;24(5):303.
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