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Comparison of type a botulinum toxin products in clinical use

To the Editor, Type A botulinum toxin products are being increasingly used in a range of debilitating clinical conditions, notably head and neck dystonias, cerebral palsy and post-stroke spasticities. The main products, Dysport (Ipsen Ltd., Slough, Berkshire, UK) and Botox (Allergan Inc., Irvine, CA, USA), are licensed for these applications in many countries throughout the world. Clinicians and pharmacists are therefore faced with important choices as to which product to select and need accurate and reliable data in order to make successful assessments. In particular, the information to be used must be unbiased and balanced, especially when reviewing the physicochemical properties or clinical applications of any product. The recent publication by Wenzel and colleagues (1) is based upon current Summary of Product Characteristics (SmPC) or country-equivalent data. Their contribution could significantly assist clinicians and pharmacists in providing an overall view of the two main Type A toxin products in use. However, the authors have chosen to cite a number of old and, regrettably, outdated references with regard to one of the products reviewed, Dysport. For example, the description of the origin and manufacture of Dysport cites a 1981 publication, which was almost 10 years before Dysport was first licensed. The details in that publication do not relate to the licensed product and this reference is not a suitable citation for Dysport characteristics and manufacture. In addition, numerous batches of Dysport bulk toxin have been manufactured and used over the years, as we have published on several occasions (2–4). The authors discuss the size of the Dysport toxin complex and state that the product ‘most likely comprises both 500 and 900 kDa BoNTA complexes’. In fact, the authors go on to state that ‘differences in complex size between Botox and Dysport may in part explain differences in their respective AE (Adverse Event) profiles through the mechanism of migration’. These statements, about complex size and migration, have been repeated so often that they have become an urban legend, but there is no scientific evidence for either statement or conclusion. Certain animal studies cited (5) have not used equivalent doses of each toxin product, have been contradicted by similar studies carried out independently (6) and cannot therefore be used for clinical product comparisons. The size of the toxin complex, determined using rigorous, scientifically sound methodology, has not been published for either product. Scientifically justified reasons for toxin spread have already been shown by other workers to have foundation in aspects such as injection volume, toxin concentration and site of injection [see, for example, (7)]. Indeed, these aspects of the toxin products are not included in the SmPC or equivalent documents and therefore have no bearing on a comparison of the products. The most important and clinically relevant aspect of the toxin complex was noted by Wagman and Bateman over 50 years ago (8) and has been described in the classic review papers of Schantz and Johnson (9, 10): the Type A toxin complex is highly sensitive to pH. The complex is stable at acid pH values, such as seen in the stomach, but dissociates at physiological pH values. The dissociation of the complex at physiological pH 7Æ4 is both rapid and complete in vitro (11) and radioactive tracer experiments have shown no difference in diffusion away from the injection site between pure toxin and toxin complex (12). These data imply that, once injected, the complex dissociates, releasing the toxin. The complex components play no further role in the diffusion or spread of the active neurotoxin. This is supported by human data from head to head trials of a complex-free toxin against Botox, in the extensor digitorum brevis muscle and in patients with cervical dystonia (13,14). In neither case was there a difference in diffusion measured directly in neighboring muscles (13) or a difference in side effect profile (14) respectively. Unless compelling experimental evidence to the contrary becomes available, we Journal of Clinical Pharmacy and Therapeutics (2008) 33, 327–328