I still remember the first patient I ever treated with Botox (botulinum toxin A, Allergan, Inc.) over a decade ago. A high-ranking official at the Italian Embassy, he requested softening of his frown but retention of the ability to "look angry with my staff when I need to." The results were impressive enough to evoke in my mind the observation of the British science fiction writer, Arthur C. Clarke, that any sufficiently advanced technology is indistinguishable from magic.

It is perhaps fitting that my first experience of botulinum neurotoxin was with a European patient, given that I now count among my patients a considerable number of Europeans and European expatriates. This is due partly to the location of my offices in suburban Washington, DC; partly to my own European roots (though American-born, I was raised in England); and, to a lesser extent, perhaps a consequence of my good command of "English" English and my passable French, which render me somewhat Euro-friendly— albeit that my French is of the schoolgirl variety and rather deficient in medical terminology.

Many of my European patients express surprise at the limited number of injectables available in the US, coming as they do from locales where a plethora of botulinum neurotoxin and dermal filler options is the norm. The FDA approval this April of Dysport (abobotulinum toxin A, Medicis Pharm. Corp.), a new botulinum neurotoxin A for temporary improvement of glabellar lines, brings us a little closer to the European model. And we will draw closer still over the next couple of years as further toxins and fillers are approved and the prospect of a topical botulinum neurotoxin becomes less remote.

With the excitement of a new aesthetic tool, there may also come some inertia. Incorporating a new botulinum neurotoxin into our treatment paradigms takes a little work: There are dilutions to be figured and treatment units to be calculated. Much has been made of the need to devise a conversion factor to translate Botox Units to Dysport Units. There has been pre-approval speculation regarding the perceived benefits and disadvantages of the new product. Botox has served us immeasurably well; it's a gold standard therapy and has so revolutionized our field that it is no exaggeration to speak of facial aesthetics in the US in terms of two eras: Pre-Botox and Post-Botox. How, then, does Dysport fit in?

A new Continuing Medical Education (CME) initiative that launches this summer is designed to answer this question. Entitled "Advances in Cosmetic Therapy—A Focus on Botulinum Neurotoxin A (and abbreviated to ACT)," this educational program comprises regional and local workshops and seminars throughout the country that provide a scientific and clinical overview of Dysport, including consensus recommendations for both on-label and off-label aesthetic use. My experience with Dysport over the past two to three years has been as a Principal Investigator on two FDA studies of Dysport and as a member of the steering committee for the ACT CME initiative.

TWO OPTIONS
The Dysport and Botox toxin molecules have the same primary structure (amino acid sequence) and molecular weight (150 kDaltons). They are produced by two different bacterial strains of Clostridium botulinum type A and purified from culture in different ways, Dysport by column chromatography and Botox by dialysis and a series of acid precipitations. Dysport is then solubilized with lactose and human albumin, while Botox is solubilized with human albumin. After filtering and vial filling, Dysport is freeze-dried and Botox is vacuum-dried. Notwithstanding these distinct manufacturing processes, six clinical trials of Dysport conducted in the US over the past seven years in over 3,100 subjects show that Dysport is the same as Botox in key respects. These include batch-to-batch consistency, efficacy, safety and tolerability, predictability of results and general strategy for placement of injection points. When injected appropriately, both Dysport and Botox produce natural-looking results that can be precisely individualized to suit patient preferences, whether for preservation of mobility or for a near-freeze of muscle action. Although neutralizing antibodies may be produced and potentially reduce treatment efficacy when either product is injected in high doses for the treatment of spasticity, no significant antibody production has occurred with the use of either Dysport or Botox in much lower doses for aesthetic purposes. The most recent of these studies, with Dysport, showed no decrease in treatment efficacy after up to six cycles of treatment over approximately three years.¹

The main clinical difference lies in how treatment units are measured: 1 Dysport Unit is not the same as 1 Botox Unit; hence, one injects different numbers of units of Dysport and Botox into a given facial zone. However, this is not due to inherent differences in the toxin molecules themselves; rather, it is a function of the proprietary assays employed by the respective manufacturers to determine toxin potency and to define a treatment unit.²

Despite their striking similarities, Dysport and Botox have a few unique characteristics that are intriguing enough to bear closer examination, particularly since they may serve as a foundation for individualization of botulinum neurotoxin treatment. Dysport has a quicker onset of effect; study data show a median of three days with some subjects reporting onset of effect within 24 hours of injection.1 And Dysport may have greater longevity: Successive open-label treatment cycles resulted in clinical effects that lasted longer; ultimately, a significant number of study subjects still had sustained improvement of glabellar lines when evaluated 150 days after treatment.^1,3 Dysport's zone of activity, also referred to as its field of effect, may differ from that of Botox in certain situations. It has been speculated that Dysport might diffuse or spread more than Botox. Given that ptosis is an objective measure of undesirable toxin diffusion or spread after glabellar injection, which is the on-label indication for both Dysport and Botox, one can examine ptosis rates to objectively evaluate this speculation. In fact, the rate of temporary eyebrow and/or eyelid ptosis is comparable after either Dysport or Botox injection into the glabella: Combined data from the Dysport studies show a ptosis rate of 2.1 percent and the package insert reports a ptosis rate of two percent from a study of 398 subjects,⁴ while the package insert for Botox Cosmetic reports a ptosis rate of five percent based on literature reports,⁵ and a ptosis rate of 3.2 percent from a study of 405 subjects.⁶ There is no support in these scientific data for concern over unwarranted diffusion or spread with either product when used for aesthetic indications.

While I don't wish to subvert this article into a high school physics term paper, it is perhaps worth noting that all toxins diffuse after injection, at a rate mathematically elucidated by the First and Second (Ficks') Laws of Diffusion.^7,8 Diffusion has been elegantly defined as the random walk of an ensemble of particles from regions of high concentration to regions of lower concentration. In this case, toxin molecules will move outwards from the injection site, where they are highly concentrated, until they are bound by neuromuscular junction receptors and the concentration of free, unbound toxin molecules is no higher at the injection site than in other areas—that is, until equilibrium is reached. As an everyday example of diffusion, think of the outward movement of an ink drop after it is placed in water. All toxins also spread after injection, partly due to diffusion and partly due to physical factors that don't depend on concentration, such as injection volume and pressure, needle depth and angle, and tissue massage or manipulation after injection. When evaluating studies that purport to show spread of either Dysport or Botox, it's important to consider whether the reported results might be influenced by these aspects of injection technique, which have nothing to do with the toxins themselves. The analogy here is to think of the ink drop being injected through a syringe onto the water; some of its outward movement is due to diffusion and some is due to the injection method. Clinically speaking, it's equally important to understand that some toxin spread is desirable as this is what produces natural-looking results—provided that there is no increase in rate of ptosis.

Based on my experience with both Dysport and Botox, I feel it is most clinically accurate to think of these two toxins as having slightly different fields of clinical effect and to develop an understanding of how these can be harnessed to optimize patient results. If the Dysport and Botox toxin molecules are the same, why should they behave differently in a few respects? The answer may lie in the different accessory proteins that exist in a complex with each toxin molecule after synthesis and as it passes through the manufacturing process. The chemical bonds between each toxin molecule and its accessory proteins are of the noncovalent variety—the type of bond that is crucial to maintaining three-dimensional, or tertiary, molecular structure. (As a point of interest, noncovalent bonds also hold together the two strands of a DNA molecule in a double helix). These accessory proteins are believed to dissociate from the toxin molecule shortly after injection, probably within one minute of exposure to physiologic pH conditions.⁹ While there is currently no direct evidence that accessory proteins influence the behavior of Dysport and Botox after injection, there is some fascinating circumstantial evidence from the basic science literature that this may be the case.

In vitro studies show that the presence of a single accessory protein is sufficient to enhance the enzymatic activity of botulinum neurotoxin A.¹⁰ Accessory proteins also increase the rate at which botulinum neurotoxin is absorbed through cell membranes, a process that is essential in order for it to exert its clinical effects¹¹ and impact the bioavailability of botulinum neurotoxin A.¹² Finally, there is evidence that accessory proteins form a three-dimensional delivery vehicle for another type of botulinum neurotoxin (type D) to increase cell membrane binding and prevent toxin breakdown,¹³ and that three-dimensional structure profoundly impacts the biological activity of botulinum toxin A.¹⁴ The picture that emerges is that accessory proteins may influence three dimensional structure and other features of the toxin molecule after injection, thereby determining its mobility and biological activity. This, in turn, could control onset of action of the toxin, clinical effects including its field of effect, and possibly its longevity.

CLINICAL IMPLICATIONS
Fortunately, we don't need an in-depth understanding of basic science in order to utilize the unique characteristics of Dysport and Botox to our patients' advantages. I have found that patients tend to appreciate a quicker time to onset. I believe there are emotional factors at play here: the shorter the time that elapses between treatment and results, the more comfortable patients feel about the philosophical and financial decisions that they have made. It is precisely for this reason that patients who undergo radiofrequency skin tightening, ablative laser resurfacing or other procedures where there is a significant time lag between "the pain" (of the procedure) and "the gain" (of the results) often require more emotional hand-holding than patients having procedures that confer more immediate gratification. A wider field of effect sometimes allows me to reduce the number of injection points necessary to achieve the desired clinical results, particularly when treating the forehead and the crow's feet. And it has allowed me on occasion to reduce the number of residual lines post-treatment, most notably the tenacious line that lies immediately above the middle and lateral one-thirds of the eyebrow.

Our injection strategies have been refined by years of experience with Botox. Rather than simply follow pre-set templates for the sites and dosages of our injection points, we are now guided by each patient's individual facial anatomy, pattern of muscle activity, muscle mass, and treatment objectives. The ACT CME initiative builds upon this solid foundation with interactive, case-based treatment paradigms that encourage the development of an instinct for botulinum neurotoxin injection, rather than a reliance on fixed injection patterns and toxin-to-toxin conversion ratios. The inclusion of synchronized before-and-after patient videos is a novel and informative method of furthering our understanding of the nuances of neurotoxin treatment. Conversion ratios may be comforting at the outset of one's clinical experience with a new product. However, we do not seek conversion ratios from collagen to hyaluronic acid fillers, nor between the various laser devices we have in our offices. Instead, our focus is on mastering the specifics of the treatment we have selected to address patient objectives. Having worked with Dysport and Botox for some time, now I think directly in Dysport or Botox Units rather than convert one to the other.

By analogy with the European scenario, it is likely that different treatment paradigms will emerge following the FDA approval of Dysport. One is that either Dysport or Botox may be selected for a patient as the most appropriate treatment. Another is that both toxins may be used for the same patient, with each being injected into a different facial area. In making these decisions, it is imperative for us as the custodians of our patients' welfare to look beyond the media and marketing efforts that inevitably accompany a profound change to a highly lucrative genre of aesthetic medicine and, instead, to focus on the scientific and clinical facts as they pertain to each product.

The development of botulinum neurotoxin for aesthetic use must surely rank as one of the ultimate examples of serendipity, and a vivid illustration of another of Arthur C. Clarke's observations—that new ideas pass through three periods. The first, "It can't be done," is followed by the second, "It probably can be done, but it's not worth doing," with culmination in the third and final period, "I knew it was a good idea all along!" Based on my experiences with both Dysport and Botox, I believe that it is most definitely "a good idea" that we now have two gold standard botulinum neurotoxin therapies at our disposal, as this situation undoubtedly benefits both us and our patients.

Dr. Sundaram has performed media work for Allergan, Inc, has served as a Consultant and Speaker for ColBar Life Science Ltd./Ortho Dermatologics and has served as a Clinical Investigator, Consultant and Speaker for Medicis Pharmaceutical Corp. She has no stocks, shares, or other financial interests in these or in any other pharmaceutical or device companies.

The PharmAdura Continuing Medical Education initiative, "Advances in Cosmetic Therapy - A Focus on Botulinum Neurotoxin A"(ACT) is supported by independent educational funding from Medicis Pharmaceutical Corp. Physicians may register to attend a local ACT progam by calling 1-877-252-5100 ext. 29 or by faxing information to PharmAdura, LLC. at 1-845-398-5108.

1. The Efficacy and Safety of a New U.S. Botulinum Toxin Type A in the Retreatment of Glabellar Lines Following Open-Label Treatment. Rubin M, Dover J, Glogau R et al. (2009) J Drugs Dermatol vol. 8 issue 5: 439
2. Panjwani N, O'Keefe R, & Pickett A. Biochemical, functional and potency characteristics of type A botulinum toxin in clinical use. The Botulinum Journal , 1, 153-166.
3. Moy R, Maas C, Monheit G, Huber MB; Reloxin Investigational Group. Long-term safety and efficacy of a new botulinum toxin type A in treating glabellar lines. Arch Facial Plast Surg. 2009 Mar-Apr;11(2):77-83.
4. Dysport Summary of Product Characteristics. Ipsen, Ltd. June 2007
5. Botox Cosmetic Package Insert, Allergan, Inc. 2008
6. Botox Cosmetic Product Monograph, Allergan, Inc. Revised March 2002. Accessible online at www.fda.gov/cder/foi/label/2002/botuall041202LB.pdf
7. Fick A, Poggendorff's Annel. Physik. (1855), 94, 59.
8. Fick A, Phil. Mag. (1855), 10, 30. (in English).
9. Eisele, K H.Dissociation of the 900 kDa neurotoxin complex from C. Botulinum under physiological conditions. Presentation at Toxins 2008. Baveno, Lake Maggiore, Italy.
10. Sharma S. K. and Singh B. R. (2004) Enhancement of the Endopeptidase Activity of Purified Botulinum Neurotoxins A and E by an Isolated Component of the Native Neurotoxin Associated Proteins, Biochemistry, 43, 4791-4798
11. Matsumura T, Jin Y, Kabumoto Y, et al. The HA proteins of botulinum toxin disrupt intestinal epithelial intercellular junctions to increase toxin absorption.Cellular Microbiology, Volume 10, Number 2, February 2008, pp. 355-364(10).
12. Cheng, LW, Onisko BC, Johnson EA, et al. Effects of purification on the bioavailability of botulinum neurotoxin type A. Toxicology. 249(2008):123-129.
13. Hasegawa K, Watanabe T, Suzuki T, et al. A Novel Subunit Structure of Clostridium botulinum Serotype D Toxin Complex with Three Extended Arms. J. Biol. Chem., Vol. 282, Issue 34, 24777-24783, August 24, 2007
14. Zhou B, Pellett S, Tepp W et al. Delineating the susceptibility of botulinum neurotoxins to denaturation through thermal effects. FEBS Letters, 2008;582(10):1526-31).