Kevin C. Smith, MD, FRCPC (Dermatology)
Private practice, Niagara Falls, ON, Canada
Now that several formulations of botulinum toxin type-A (BoNT-A) are on the market in North America and throughout the world, it is of great practical importance for those who administer these medications to be familiar with the differences between the formulations. These differences pertain to the stability of the medications, in particular during the period of time between reconstitution and administration, which may affect the degree of diffusion through various tissues after injection. A variety of relatively new uses of BoNT-A for dermatological conditions will be discussed.
botulinum toxin type-A, BoNT-A, abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, neuromodulator, BOTOX®, Dysport®, XEOMIN®
Medicines formulated from the highly purified, naturally occurring protein known as botulinum toxin type-A (BoNT-A) have been in use since 1980, when ophthalmologist Alan Scott used an injectable formulation of BoNT-A to treat strabismus and blepharospasm in humans. The first formulation of BoNT-A to become commercially available was onabotulinumtoxinA (BOTOX®), licensed in the United States in 1989 for treatment of three conditions: strabismus, blepharospasm, and hemifacial spasm. In recent years, two other formulations of BoNT-A have been licensed for use in the United States and a number of other countries: abobotulinumtoxinA (Dysport®) and incobotulinumtoxinA (XEOMIN®).
Those interested in BoNT-A should become familiar with the non-proprietary names for the various formulations of BoNT-A, because increasingly, presentations at meetings and in scientific publications are using the non-proprietary rather than the trade names for these products.1 A different non-proprietary name was assigned to each formulation of BoNT-A to reflect the fact that while the active ingredient in all three formulations is BoNT-A, the biological activity, in particular the stability and diffusion kinetics,2,3 of the active ingredient is modulated by the other components of the formulation, notably the protective proteins (hemagglutinins and non-hemagglutinins, which are associated with BoNT-A in onabotulinumtoxinA and abobotulinumtoxinA) and the amount and type of human serum albumin (added to the formulations to keep the BoNT-A in solution after reconstitution). Biological activity is also affected by the manufacturing process (as each BoNT-A formulation is manufactured differently), as well as other excipients in the vial (e.g., sodium chloride and sucrose). The effects (if any) on stability after reconstitution caused by the presence of trypsin-like proteolytic activity in incobotulinumtoxinA4 remain to be elucidated.
Non-interchangeability of Products
There is no consensus on how to switch patients between the three formulations. Each formulation is dosed using units specific to the product, which are determined in a manner that is proprietary to the manufacturer. It is important to note that because the dosing units are unique to each formulation, the products are considered to be non-interchangeable.5
While it is possible to construct test systems in which various dose ratios can be compared under standard conditions (e.g., hyperhidrosis on the forehead6 or frontalis muscle contractions7), there is no simple ratio that can be used to facilitate conversion of patients from one formulation of BoNT-A to another.8,9
Since Alan Scott’s pioneering use of BoNT-A for the treatment of blepharospasm and strabismus, various formulations of this versatile biological product have been reported to be useful in the management of over 140 medical, surgical, and aesthetic indications. Of interest to dermatologists, indications that regulatory authorities have approved for marketing and advertising in Canada include (for onabotulinumtoxinA) treatment of upper facial rhytides, including forehead, lateral canthus and glabellar lines,10 as well as for the treatment of hyperhidrosis of the axillae in patients 18 years of age and older.10 It is expected that other formulations of BoNT-A could receive similar regulatory approval for marketing and advertising in Canada in the future.
When they were first introduced, medicines incorporating BoNT-A were used to block the vesicle-mediated release of the neurotransmitter acetylcholine, and so produce for a period of several months very precise and localized relaxation of the striated muscles to which it was applied by injection.
The first suggestion that BoNT-A could be used for purposes other than muscle relaxation came from Bushara and Park in 1994, who observed reduced sweating in the treated area when BoNT-A was used for treatment of hemifacial spasm.11 Based on observations that BoNT-A was useful for controlling excessive sweating, it was found to also be beneficial for the control of persistent facial flushing,12 gustatory sweating (Frey’s syndrome),13 and for conditions made worse by excessive sweating and associated maceration (e.g., familial benign pemphigus (Hailey-Hailey disease),14 dishydrotic eczema,15 and inverse psoriasis16). Its use was even extended to the treatment of facial chromhidrosis17 where part of its mechanism of action was thought to come from inhibition of the release of substance-P.18 Excessive lacrimation,19,20 chronic rhinitis,21,22 sialorrhea,23 and parotid fistulas resulting from skin cancer surgery24,25 have also been reported to respond to treatment with BoNT-A.
Basic science research has shown that BoNT-A blocks the vesiclemediated release of neurotransmitters other than acetylcholine, including substance-P,26 glutamate,27 and calcitonin-gene related peptide.28 These properties of BoNT-A may account for its neuromodulating effect on autonomic nerves,29 which makes possible the use of BoNT-A as a therapeutic option for Raynaud’s phenomenon, where treatment with BoNT-A can be safer and simpler than sympathectomy. Onset of action occurs within days and lasts for months, controlling rest pain, shortening and reducing the severity and frequency of attacks, and speeding the healing of ischemic ulcerations.30-33
The observation that BoNT-A inhibits the release of some painmediating neurotransmitters, such as substance-P, helps to explain why BoNT-A has proven useful in the management of a variety of painful conditions, including headache,34-36 multiple cutaneous piloleiomyomas,37 notalgia paresthetica,38 and postherpetic neuralgia in the trigeminal distribution, but not on the trunk or extremities.33
BoNT-A has even proven to be of value in athletes, for example as a treatment for an intention tremor known as “the yips,” afflicting up to 30% of golfers.39 Similar dystonias and occupational cramps that can occasionally trouble dermatologic surgeons might also benefit from treatment with BoNT-A.
Systems for the topical administration of BoNT-A are in development,40,41 and may turn out to be useful for certain medical and aesthetic indications.
The N-terminal light chain component of BoNT-A (known as LC) is the part that cleaves SNAP-25, resulting in the blockade of vesicle-mediated release of a variety of neurotransmitters. This component (or the corresponding LC element from other botulinum neurotoxins) can be attached to a variety of ligands, which are proteins that bind to various glycoproteins that are specific for certain cell types or can be produced by recombinant techniques.42,43
It is likely that such derivatives of BoNT-A and other clostridial neurotoxins, which are now emerging from the labs and in some cases entering clinical trials, will become commercially available. These advances are poised to extend the utility of this class of medications to tissues that are currently unresponsive to BoNT-A, improve tissue specificity, modulate durations of action, and benefit our patients in ways that remain to be explored.
Medications formulated with BoNT-A as their active ingredient have a long record of safety and efficacy for a very wide and growing spectrum of medical and aesthetic indications. Future medications based on derivatives of BoNT-A are likely to further expand the range of utility and improve the risk/benefit ratio of this class of agents.
It is important for those interested in BoNT-A to become familiar with the non-proprietary names for the various formulations of BoNT-A, because non-proprietary nomenclature is being used exclusively in a growing number of academic and educational settings. Additionally, the use of non-proprietary names have been mandated by the US FDA to differentiate between the various formulations of BoNT-A.
It is important for those interested in BoNT-A to realize that each formulation of BoNT-A has unique pharmacologic and pharmacokinetic properties, and may behave differently in various clinical situations and indications, e.g., depending on the dosage, degree of dilution when the product is reconstituted, and the anatomic area being treated. For these reasons, there are no simple “universal” conversion ratios between the various formulations of BoNT-A.
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- de Almeida AT, De Boulle K. Diffusion characteristics of botulinum neurotoxin products and their clinical significance in cosmetic applications. J Cosmet Laser Ther 9(Suppl 1):17-22 (2007).
- de Boulle K, de Almeida AT. Addressing recent concerns in comparative studies of botulinum toxin type A. J Cosmet Laser Ther 12(5):246-8 (2010 Oct).
- Hunt T, Rupp D, Shimizu G, et al. Characterization of SNARE cleavage products generated by formulated botulinum neurotoxin type-A drug products. Toxins 2:2198-212 (2010).
- Albanese A. Discussion of unique properties of botulinum toxins. Toxicon 54(5):702-8 (2009 Oct).
- Trindade de Almeida AR, Marques E, de Almeida J, et al. Pilot study comparing the diffusion of two formulations of botulinum toxin type A in patients with forehead hyperhidrosis. Dermatol Surg 33(1 Spec No.):S37-43 (2007 Jan).
- de Boulle K, Smuts J, van Coller R, et al. An electrophysiological study to demonstrate in vivo differences between two formulations of botulinum toxin type A (BOTOX® and Dysport®). Poster presented at: Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins International Conference 2005 (Toxins 2005). Denver, CO, 23-25 June 2005.
- De Boulle K, Fagien S, Sommer B, et al. Treating glabellar lines with botulinum toxin type A-hemagglutinin complex: a review of the science, the clinical data, and patient satisfaction. Clin Interv Aging 5:101-18 (2010).
- Marchetti A, Magar R, Findley L, et al. Retrospective evaluation of the dose of Dysport and BOTOX in the management of cervical dystonia and blepharospasm: the REAL DOSE study. Mov Disord 20(8):937-44 (2005 Aug).
- BOTOX Cosmetic® product monograph. In: Compendium of Pharmaceuticals and Specialties (CPS) 2011: The Canadian Drug Reference for Health Professionals. Ottawa: Canadian Pharmacists Association, p426-31 (2011).
- Bushara KO, Park DM. Botulinum toxin and sweating. J Neurol Neurosurg Psychiatry 57(11):1437-8 (1994 Nov).
- Yuraitis M, Jacob CI. Botulinum toxin for the treatment of facial flushing. Dermatol Surg 30(1):102-4 (2004 Jan).
- Martos Diaz P, Bances del Castillo R, Mancha de la Plata M, et al. Clinical results in the management of Frey’s syndrome with injections of Botulinum toxin. Med Oral Patol Oral Cir Bucal 13(4):E248-52 (2008 Apr).
- Kang NG, Yoon TJ, Kim TH. Botulinum toxin type A as an effective adjuvant therapy for Hailey-Hailey disease. Dermatol Surg 28(6):543 (2002 Jun).
- Swartling C, Naver H, Lindberg M, et al. Treatment of dyshidrotic hand dermatitis with intradermal botulinum toxin. J Am Acad Dermatol 47(5):667-71 (2002 Nov).
- Zanchi M, Favot F, Bizzarini M, et al. Botulinum toxin type-A for the treatment of inverse psoriasis. J Eur Acad Dermatol Venereol 22(4):431-6 (2008 Apr).
- Matarasso SL. Treatment of facial chromhidrosis with botulinum toxin type A. J Am Acad Dermatol 52(1):89-91 (2005 Jan).
- Wu JM, Mamelak AJ, Nussbaum R, et al. Botulinum toxin a in the treatment of chromhidrosis. Dermatol Surg 31(8 Pt 1):963-5 (2005 Aug).
- Owecki MK, Kapelusiak-Pielok M, Kowal P, et al. [Bilateral “crocodile tears syndrome” associated with Melkersson-Rosenthal syndrome–case report]. Neurol Neurochir Pol 40(5):450-545 (2006 Sep-Oct).
- Laing TA, Laing ME, O’Sullivan ST. Botulinum toxin for treatment of glandular hypersecretory disorders. J Plast Reconstr Aesthet Surg 61(9):1024-8 (2008 Sep).
- Braun T, Gurkov R, Kramer MF, et al. Septal injection of botulinum neurotoxin A for idiopathic rhinitis: a pilot study. Am J Otolaryngol. 2011 Mar 16. [Epub ahead of print]
- Rohrbach S, Junghans K, Kohler S, et al. Minimally invasive application of botulinum toxin A in patients with idiopathic rhinitis. Head Face Med 5:18 (2009).
- Reddihough D, Erasmus CE, Johnson H, et al. Botulinum toxin assessment, intervention and aftercare for paediatric and adult drooling: international consensus statement. Eur J Neurol 17(Suppl 2):109-21 (2010 Aug).
- Hill SE, Mortimer NJ, Hitchcock B, et al. Parotid fistula complicating surgical excision of a basal cell carcinoma: successful treatment with botulinum toxin type A. Dermatol Surg 33(11):1365-7 (2007 Nov).
- Hatzis GP, Finn R. Using botox to treat a mohs defect repair complicated by a parotid fistula. J Oral Maxillofac Surg 65(11):2357-60 (2007 Nov).
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- Rapp DE, Turk KW, Bales GT, et al. Botulinum toxin type a inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol 175(3 Pt 1): 1138-42 (2006 Mar).
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- Stadlmaier E, Mueller T, Hermann J, et al. Raynaud’s phenomenon: treatment with botulinum toxin. Ann Rheum Dis 64(Suppl 3):275 (2005).
- Sycha T, Graninger M, Auff E, et al. Botulinum toxin in the treatment of Raynaud’s phenomenon: a pilot study. Eur J Clin Invest 34(4):312-3 (2004 Apr).
- Kossintseva I, Barankin B. Improvement in both Raynaud disease and hyperhidrosis in response to botulinum toxin type A treatment. J Cutan Med Surg 12(4):189-93 (2008 Jul-Aug).
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- Sifaki MK, Krueger-Krasagakis S, Koutsopoulos A, et al. Botulinum toxin type A–treatment of a patient with multiple cutaneous piloleiomyomas. Dermatology 218(1):44-7 (2009).
- Weinfeld PK. Successful treatment of notalgia paresthetica with botulinum toxin type A. Arch Dermatol 143(8):980-2 (2007 Aug).
- Adler CH, Caviness JN, Crews D, et al. The yips: a focal, task-specific dystonia. Available at: http://mayoresearch.mayo.edu/adler_lab/project2.cfm. Accessed: 15 May 2011.
- Brandt F, O’Connell C, Cazzaniga A, et al. Efficacy and safety evaluation of a novel botulinum toxin topical gel for the treatment of moderate to severe lateral canthal lines. Dermatol Surg 36 Suppl 4:2111-8 (2010 Dec).
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