Botulinum Toxin Type A Preparations Research Articles

Botulinum toxin type-A preparations are not the same medications - basic science (Part 1).

Botulinum neurotoxin type A (BoNT/A) formulations are widely used in clinical practice. Although they share a common mechanism of action resulting in presynaptic block in acetylocholine release, their structure and pharmacological properties demonstrate some similarities and many differences. Bioequivalence has been discussed since the onset of the clinical use of BoNT/A. In this review, we provide an update on the studies and compare the molecular structure, mechanisms of action, diffusion and spread, as well as immunogenicity and dose equivalence of onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA.

Electrophysiological study for comparing the effect of biological activity between type A botulinum toxins in rat gastrocnemius muscle

New cosmetic applications and products based on the effects of botulinum toxin (BTX) treatment have stimulated demand for this class of natural compounds. This demand generates the need for appropriate standardized protocols to test and compare the effectiveness of new BTX preparations. Based on the previously described electrophysiological methods, we measured and compared the inhibitory effects of two BTX type A (BTX-A) preparations on neuromuscular transmission through split-body test. The effectiveness was evaluated in terms of the compound muscle action potential (CMAP) and conduction velocity after BTX-A injection. We used a split-body method to compare two different BTX-As in the rat. Based on the changes in the CMAP, the two different BTX-As induced paralytic effect on the rat tibialis anterior muscle. However, the two different BTX-A preparations did not differ significantly in effectiveness and did not induce a delay in conduction velocity. The new BTX-A preparation used in this electrophysiological study had similar effect compared with the previously marketed BTX-A.[AQ: Please approve the edits made to the sentence "The new BTX-A preparation…") We propose that a split-body electrophysiological protocol will be useful in establishing the comparative effectiveness of new BTX products.

Current Aesthetic Use of AbobotulinumtoxinA in Clinical Practice: An Evidence-Based Consensus Review

The amount and complexity of scientific and clinical evidence for aesthetic use of botulinum neurotoxin type A (BoNT-A) has expanded rapidly in recent years, especially for abobotulinumtoxinA, necessitating reassessment of current knowledge about aesthetic use of abobotulinumtoxinA and other BoNT-A preparations. A committee of 13 plastic surgeons, facial plastic surgeons, and dermatologists engaged in a live discussion of information from a systematic literature review and an Internet-based survey of their beliefs and practices. The committee achieved consensus on most issues. It was concluded that doses of different BoNT-A preparations cannot be interconverted with a fixed ratio. The size of the "field of effect" is difficult to measure, and comparisons between preparations have yielded equivocal results. Nonresponse due to neutralizing antibodies appears exceedingly rare with currently available BoNT-A preparations and of little concern clinically. BoNT-A dose, injection depth, and injection technique should be adjusted according to the anatomic area being treated and each patient's individual characteristics and goals. Aesthetic use of BoNT-A has a good safety profile. Most adverse events are minor and related to the trauma of injection, although special care is needed in certain anatomic areas. Detailed recommendations for treatment of different anatomic areas are presented. BoNT-A products are often used in conjunction with other treatment modalities (eg, fillers and resurfacing), but little agreement was reached on best practices. The findings reported in this consensus document may serve as a practical guide for aesthetic practitioners as they apply the latest knowledge about BoNT-A in providing their patients with optimal care.

Antibody-induced secondary treatment failure in a patient treated with botulinum toxin type A for glabellar frown lines

Botulinum toxin type A (BTX-A) preparations are widely used nonsurgical treatments for facial wrinkles. Higher doses of BTX-A are also used for therapeutic purposes in the treatment of conditions involving increased muscle tone, such as cervical dystonia. The phenomenon of antibody-induced treatment failure is well known in the therapeutic setting, but reports are also emerging following cosmetic use of BTX-A. We describe the case of a 41-year-old female nurse who developed secondary treatment failure during 6 years of BTX-A treatment for glabellar lines. After a good response to the first BTX-A injection, the intensity and duration of effect decreased after subsequent treatments. Antibody tests revealed a high titer of neutralizing anti-BTX-A antibodies. This case shows secondary treatment failure due to the production of neutralizing antibodies following administration of BTX-A formulations for cosmetic purposes and demonstrates that immunogenicity of BTX-A preparations is an important consideration, even in the cosmetic setting.

International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood Unit) – part II: wrinkles on the middle and lower face, neck and chest

Azzalure® (Galderma SA), a newly approved European botulinum neurotoxin type A (BoNT-A), is derived from Dysport™ (Ipsen Ltd.), which has a 20-year history of product consistency and has been widely used for various aesthetic and therapeutic applications. Azzalure® and Dysport™ are collectively referred to as BoNT-A (Speywood Unit) after the unit of their activity, and are distinct from other commercial BoNT-A preparations. Consensus has been developed for the treatment of upper facial wrinkles with BoNT-A (Speywood Unit). To provide consensus recommendations on the treatment with BoNT-A (Speywood Unit) for wrinkles on the middle and lower face, neck and chest region. The members of the International Board on Botulinum toxin Azzalure (IBBA) convened to develop consensus based on their extensive experience. The recommended final concentration of BoNT-A (Speywood Unit) is 200 Speywood Units/ml after reconstitution. The consensus recommendations were provided for nine indications, including lower eyelid wrinkles, bunny lines, drooping nasal tip, perioral wrinkles, masseter hypertrophy, drooping mouth corners, dimpled chin, platysmal bands and décolleté wrinkles. For each indication, anatomy of the region to be treated was discussed, as were potential side-effects. The consensus recommendations included the number and location of the injection points, dose range of each point and the total injection, as well as specific injection technique. These recommendations provide a guideline for physicians who wish to perform safe and efficacious treatment with BoNT-A (Speywood Unit) on the less commonly treated middle and lower face, neck and chest region.

International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood Unit) – part I: upper facial wrinkles

Azzalure (Galderma SA) is a newly approved European botulinum neurotoxin type A (BoNT-A). It is derived from Dysport (Ipsen Pharma), which has a long history of usages in various applications. Azzalure and Dysport are collectively referred to as BoNT-A (Speywood Unit) and are different from other BoNT-A preparations. To provide consensus recommendations on the treatment of upper face wrinkles with BoNT-A (Speywood Unit). The members of the International Board on Botulinum toxin Azzalure (IBBA) convened to develop consensus on the treatment of upper facial wrinkles based on their own extensive experience. The consensus recommendations address the general issues regarding treatment and provide specific guidelines on the anatomy, injection points, dose, injection technique and safety precautions concerning each common upper face indication. The recommended final concentration of BoNT-A (Speywood Unit) is 200 s.U/mL (10 s.U/0.05 mL) after reconstitution. For glabellar lines, the members recommend a total of five injection points with 10 s.U/point. For forehead wrinkles, the members recommend four to six injections into the frontalis with 5-10 s.U/point. For crow's feet, the members recommend three injections per side with 5-10 s.U/point at the lateral part of the orbicularis oculi. For lateral eyebrow lift, the members recommend one point at each eyebrow tail and an additional one in each side of the frontalis with 5-10 s.U/point. This guideline provides a framework for physicians who wish to perform safe and efficacious injection of BoNT-A (Speywood Unit).

Treatment of glabellar lines with botulinum toxin type A (Speywood Unit): a clinical overview

Azzalure (Galderma) is a newly approved European botulinum neurotoxin type A (BoNT-A) specifically designed for aesthetic usages. It is sourced from Dysport (Ipsen Ltd.), which has a 20-year product consistency and has been used widely for various therapeutic and aesthetic applications. Azzalure and Dysport are collectively referred to as BoNT-A (Speywood Unit; s.U) (or abobotulinumtoxinA in the U.S.) after their biological activity unit, which is unique and not interchangeable with units of other commercial BoNT-A preparations. Azzalure is approved for the treatment of moderate-to-severe glabellar lines, with a total dose of 50 s.U distributed evenly among 5 injection points. To ensure optimal treatment outcomes with BoNT-A (s.U), it is crucial for injectors to adopt proper methods of reconstitution and injection, which can be acquired through training. We review here the method of reconstitution for BoNT-A (s.U), as well as the injection dose, points and techniques for glabellar line treatment. We also review the efficacy and safety results of BoNT-A (s.U) demonstrated in 11 clinical studies, most of which were randomized, double-blind and placebo-controlled. The studies included assessments after single injections as well as after up to 6 repeated treatment sessions. We summarize the clinical efficacy results, which include the responder rate 1 month post-injection, onset of response and duration of action, as well as safety results, which include incidence of treatment-emergent adverse events and specifically eyelid ptosis. The efficacy and safety profiles reported here are unique to BoNT-A (s.U) and cannot be generalized to other BoNT-A products.

Efficacy and safety of botulinum neurotoxin type A free of complexing proteins (NT 201) in cervical dystonia and blepharospasm

Botulinum neurotoxin type A (BTX-A) weakens voluntary muscle power and is an effective therapy for focal dystonia, including cervical dystonia (CD) and benign essential blepharospasm (BEB). Antibody formation against BTX-A may lead to failure of treatment. NT 201 (XEOMIN®) is a formulation of pure BTX-A that is free of complexing proteins and therefore may have a reduced immunogenic potential in comparison with other BTX-A preparations. In clinical trials, NT 201 was found to be effective, well-tolerated and at least noninferior to a BTX-A preparation containing complexing proteins in the treatment of CD and BEB. There were no differences between the two therapies in terms of onset of action, duration and waning of effect. Future research is aimed at evaluating the benefits of NT 201.

Botulinum Neurotoxin Type A Free of Complexing Proteins (XEOMIN??) in Focal Dystonia

Botulinum neurotoxin type A (BTX-A) weakens voluntary muscle strength and is an effective therapy for focal dystonia, including cervical dystonia (CD) and benign essential blepharospasm (BEB). It is also known to relieve hemifacial spasm and focal spasticity in children and adults. In addition, BTX-A has been shown to be effective in a wide range of other indications, such as gastrointestinal disorders, hyperhidrosis and cosmetic wrinkle correction (e.g. glabellar frown lines). A new formulation of BTX-A, NT 201 (XEOMIN((R))) has been developed. NT 201 is a formulation of pure BTX-A free of complexing proteins and, therefore, may have a reduced immunogenic potential compared with other BTX-A preparations. The pre-clinical and clinical development of NT 201 is reviewed in this article.A total of five clinical trials were completed in Europe and Israel. Two studies were conducted in 46 healthy volunteers. A further three studies in 816 patients were conducted to provide data on the safety and efficacy of NT 201 in the treatment of CD and BEB. NT 201 was found to provide non-inferior efficacy and safety profiles in the treatment of CD and BEB compared with a BTX-A preparation containing complexing proteins (BOT [BOTOX((R))]). The clinical development programme of NT 201 showed a 1 : 1 NT 201 to BOT dose ratio. The pre-clinical studies conducted with NT 201 showed an acceptable safety profile and support the use of NT 201 in an intramuscular administration regimen for patients with CD and BEB. NT 201 was effective, well tolerated and non-inferior to BOT in the treatment of both CD and BEB. In addition, there were no differences between the two therapies in terms of onset of action, duration and waning of effect. Further research is required to determine the long-term efficacy and safety profile of NT 201.

The evolution of botulinum neurotoxin type A for cosmetic applications

Very few pharmaceutical preparations share an evolutionary history as remarkable as that of botulinum neurotoxin (BoNT). The exotoxin of the organism Clostridium botulinum, once feared as a terrible poison, has been reborn as a highly regarded and widely used therapeutic and aesthetic agent. In less than two decades since the report of the success of BoNT type A (BoNTA) in reducing glabellar lines, injection of this product has become the most common non‐surgical cosmetic procedure performed in the USA and worldwide. In addition to temporarily eliminating rhytids by muscle weakening, other dermatologic applications of BoNTA include correcting facial asymmetries and treating hyperhidrosis. Although BOTOX is the most clinically substantiated and published of the BoNTA preparations, other BoNTA products, as well as a BoNT type B product, are available in some parts of the world, and others are in development.

Pharmacology of botulinum toxin: differences between type A preparations

Different types of botulinum neurotoxin (BoNT) block different proteins of the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) protein complex within cholinergic nerve terminals, producing blockade of cholinergic neuromuscular and autonomic synapses. Animal studies indicate the longest duration of action for BoNT type A (BoNTA) followed by types B, F, and E. Diffusion to adjacent and remote muscles may be related to protein composition, dilutions, volume, target muscle selection, and injection technique. A review of head-to-head, randomized, controlled trials of BoNTA preparations (Botox and Dysport) suggests that Dysport tends to have higher efficacy, longer duration, and higher frequency of adverse effects. Conversion factors between the preparations varied, however, and remain controversial. In clinical settings, a Botox:Dysport conversion ratio of 1:3 may be appropriate. Animal studies suggest a conversion ratio of 1:2.5-3. When therapeutic effects between these preparations are attempting to be equalized, Dysport seems to produce more adverse effects. In mice, Botox appears to have a better safety margin than Dysport and BoNTB. In rats, diffusion margins are similar for Botox and Dysport. Jitter derived from stimulation single-fiber EMG of injected and remote muscles show no differences between Botox and Dysport. Atrophy of extrafusal muscle fibers of injected and remote muscles do not differ between the BoNTA preparations.

A randomized, double-masked, crossover comparison of the efficacy and safety of botulinum toxin type A produced from the original bulk toxin source and current bulk toxin source for the treatment of cervical dystonia

In 1997, the US FDA approved a new bulk toxin source (now referred to as current) for the manufacture of botulinum toxin type A (BTX-A). The current BTX-A preparation has a lower neurotoxin complex protein load than the original BTX-A preparation, which may reduce antigenic potential. The present double-masked, multicenter study compared the efficacy and safety of BTX-A (BOTOX) produced from both original and current bulk toxin sources for the treatment of cervical dystonia. Patients (N = 133) were injected with BTX-A produced from original and current bulk toxin sources using a crossover design. Adverse events were assessed at each visit. Efficacy was assessed at 2 and 6 weeks post-injection using the severity and pain-disability subscales of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Mean BTX-A doses were comparable (original: 155 U, current: 156 U). Both BTX-A preparations produced similar, statistically significant reductions in TWSTRS severity and pain-disability scores at weeks 2 and 6 post-injection. The original and current BTX-A preparations showed no significant differences in adverse events, including both treatment-related (34%, 31%) and treatment-unrelated (27%, 32%), respectively. BTX-A produced from the original and current bulk toxin sources showed comparable efficacy and safety in the treatment of cervical dystonia; both significantly reduced dystonia severity and pain.

Botulinum toxin antibody type A titres after cessation of botulinum toxin therapy.

In some patients, therapy with botulinum toxin type A (BT-A) becomes ineffective due to formation of antibodies (BT-A-AB). The time course of BT-A-AB titres after cessation of BT-A therapy was quantitatively studied to determine whether and when they might drop. Thirteen patients (eight women, five men) with various dystonic syndromes and complete secondary therapy failure (CSTF) were included in this study (age at initiation of BT-A therapy, 48.2 +/- 11.3 years; number of injection series, 7.7 +/- 2.9; treatment time, 678.8 +/- 385.6 days; mean interinjection interval, 90.4 +/- 35.5 days; mean single dose, 546.7 +/- 336.9 EMU; cumulative dose, 4185.1 +/- 3375.7 EMU [1 EMU = 1 botox MU = 3 dysport MU]). During a monitoring period of at least 750 days after occurrence of CSTF, two or more BT-A-AB tests using the quantitative mouse diaphragm assay were performed. Eight of 13 BT-A-AB titres decreased. The onset of decrease could be detected after between approximately 500 and 1,750 days. After 1,250 to 2,250 days they had dropped below a level of 0.002 U/ml, where CSTF is unlikely. Five of 13 BT-A-AB titres did not decrease. For three of these five, the monitoring period was less than 1,500 days; a chance to drop remained. The other two were monitored for up to 2,400 days. Patients with decreasing and nondecreasing BT-A-AB titres did not exhibit statistically significant differences in either clinical characteristics or treatment parameters. When BT-A therapy was stopped the majority of BT-A-AB titres eventually decreased, allowing reinitiation of BT-A therapy. Application of new BT-A preparations with low antigenic potency might then become an interesting treatment option.