Basic science: Myobloc®

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7 Basic science

Myobloc®

Neil S. Sadick, Nils Krueger

Summary and Key Features

• Myobloc® is the only botulinum toxin product that is based on serotype B

• Botulinum toxin B (BoNT-B) has its own unique mechanism of action, binds specific serotype receptors, and targets specific intracellular proteins

• Myobloc® requires no reconstitution before injecting as it is available in a liquid formulation

• Myobloc® is FDA approved for the treatment of abnormal head position and neck pain that accompanies cervical dystonia in adults

• BoNT-B is an important replacement whenever it comes to immunoresistance in patients treated with BoNT-A

• Myobloc® has a higher rate of adverse effects and the injection can be more painful compared with other BoNT products

• BoNT-B has a rapid onset of effect (within 48 hours after injection). The duration is limited to a maximum of 10–12 weeks

• BoNT-B affects a larger area around the injection point associated with a smoother clinical effect

• The most common side effects when used for the treatment of facial rhytides are xerostomia and headaches as well as dry eyes and brow ptosis

3D basic science: Myobloc®

Myobloc® (Solstice Neurosciences, San Francisco, CA), or Neurobloc® in Europe (Eisai Europe, Hatfield, UK), is the only commercially available drug based on botulinum toxin serotype B (BoNT-B) and was FDA cleared for the treatment of abnormal head position and related pain of cervical dystonia in 2000. Besides this indication, it has been shown to be effective for the treatment of many other diseases like subacromial bursitis, Frey syndrome, spastic trismus, Parkinson disease-related drooling or sialorrhea in children with cerebral palsy. Similar to drugs based on botulinum toxin serotype A (BoNT-A), Myobloc® has also been used in the field of aesthetic dermatology to treat facial rhytides caused by hyperkinetic muscles and for the management of hyperhidrosis.

Myobloc® is contributed as a purified solution packaged in ready-to-use vials and requires no reconstitution. The solution is stabilized at pH 5.6 to ensure that the toxin complex is intact with a single-entity molecular weight of approximately 700 kDa. The liquid preparation form enables the toxin to be injected as a uniform and intact complex, as opposed to partially dissociated subunits. The non-lyophilized and non-vacuum-dried preparation also minimizes the amount of denatured protein and secures an active neurotoxin amount of 65%. Myobloc® is available in vials of 2500, 5000, and 10 000 U, each with a concentration of 5000 U/ml. As the toxic potency depends on several factors and cannot be transferred directly from animals to humans, the equivalency to BoNT-A-based Botox® / Xeomin® units is considered to be in a range from 1 : 20 to more than 1 : 125. Myobloc® can be diluted with saline, as much as sixfold, before injection without loss in total activity and is stable for 9 months when stored at room temperature (25°C) and for >36 months when stored at refrigerated temperatures (2–8°C).

Pharmacology of botulinum toxin B

Botulinum neurotoxins are synthesized as macromolecular complexes of 300–900 kDa and different neurotoxin complex protein structures, depending on the serotype of the clostridial strain that produced it. Every progenitor toxin contains a 150 kDa neurotoxin molecule and one or more non-toxin proteins. At approximately 700 kDa the molecular weight of the BoNT-B complex is in between that of BoNT-A (900 kDa) and all other serotypes, with weights <500 kDa. The neurotoxin complex is composed of associated proteins such as hemagglutinin and a non-toxic, non-hemagglutinin moiety. The active neurotoxin exists in a 150 kDa dichain molecule consisting of a heavy chain of approximately 100 kDA and a light chain of approximately 50 kDA, linked together by a disulfide bond.

Botulinum toxin B affects the nervous system in a similar way to all other botulinum toxins in a series of cellular actions including binding, internalization, and inhibition of acetylcholine release. The heavy chain of the complex contributes to the irreversible binding of the toxin to the serotype-specific protein within the soluble N-ethyl maleimide-sensitive factor attachment protein receptor (SNARE) complex, which is involved in release of acetylcholine-containing vesicles from the presynaptic neuron. The light chain mediates proteolysis of SNARE proteins and subsequent inhibition of synaptic vesicle fusion to the presynaptic membrane of the human motor neurons. This leads to flaccid paralysis associated with botulism. Each serotype cleaves a specific residue on one of the N-ethylmaleimide sensitive factor (NSF) attachment proteins. Botulinum toxin B cleaves the vesicle-associated membrane protein (VAMP) also known as synaptobrevin. VAMP is cleaved by the serotypes F, G, and D too, but at differing locations (Table 7.1). The high specificity of the BoNT light chain cleavage is attributed to the light chain recognizing long SNARE sequences with 30–50 residues indicated by the specific serotype.

Table 7.1 Pharmacology of botulinum toxin serotypes by target / cleavage sizes

Serotype Target size Cleaves at
A SNAP-25* Gln197–Arg198
B VAMP† Glu76–Phe77
C Syntaxin Lys253–Ala254
  Lys252–Ala252
SNAP-25* Arg198–Ala199
D VAMP† Ala67–Asp68
Lys59–Leu60
E SNAP-25* Arg180–Ile181
F VAMP† Gln58–Lys59
G VAMP† Ala81–Ala82

* SNAP-25 is a soluble NSF attachment protein of 25 000 kDa.

† VAMP = vesicle-associated membrane protein (synaptobrevin).

Immunogenicity

Patients treated with any botulinum toxin can develop neutralizing antibodies that reduce or completely eradicate the toxin’s clinical effectiveness. All botulinum serotypes are antigenically distinct and can cause an individual immune response. The formation of antibodies has been linked to high loads of neurotoxin complex protein. Consequently, botulinum toxin preparations with high specific potencies and low total unit doses have the lowest immunogenicity. The incidence of antibody formation with BoNT-A in cervical dystonia was reported by Berman to be less than 5%. In a study by Jankovic and colleagues, the immunoresistance rate for BoNT-B was found to be up to 30% after 42 months when cervical dystonia patients were treated with high doses of Myobloc®. Currently there are no published data on immunoresistance in patients treated for aesthetic purposes, but the incidence is considered to be significantly lower as much lower doses are used and the development of antibodies correlates with the total cumulative dose. Patients becoming resistant to one particular serotype can usually be treated with another serotype. As botulinum toxin serotypes share some sequence homology with one another, a theoretical basis for serum cross-reactivity is given, which can further potentiate resistance to other serotypes with multiple injections. Consequential risk factors associated with the evolution of cross-resistant antibodies include treatment of high doses of toxin, increased frequency of administration, and the amount of neurotoxin protein delivered in each injection.

Pearl 1

Resistance to BoNT-A appears more often in the treatment of movement disorders, but can also appear after aesthetic treatments. Myobloc® may be helpful in people showing resistance to botulinum toxin phenotype A.

Case Study 1

Resistance to BoNT-A

A 38-year-old female presented in the office with a history of treatments with 25 U onabotulinumtoxinA and 75 U abobotulinumtoxinA for upper face rejuvenation. She was unsatisfied because the last treatments had effects for less than 6 weeks.

Due to the apparent BoNT-A resistance, she was switched to BoNT-B. After injection of 2500 U BoNT-B in the upper third of the face, the average duration of effect was 12 weeks.

Myobloc® in the aesthetics practice

Despite its primary indication in the treatment of cervical dystonia, increasing cosmetic demands for the effective treatment of facial rhytids have provided Myobloc® with a platform to expand into the dimension of off-label usage. BoNT-B has been successfully investigated for the treatment of hyperkinetic rhytides as well as for the therapy of palmar and axillar hyperhidrosis.

Efficacy in the treatment of hyperkinetic rhytides

BoNT-B is shown to be efficient in the treatment of hyperkinetic rhytides in the upper third of the face. Studies confirm the denervating effect on orbicularis oculi, frontalis, and corrugator supercilii (Table 7.2). The described efficacy with 2500–3000 U per treatment side is 42–100% after 24–72 hours, 62–78% after 4 weeks, 26–50% after 8 weeks and <5% after 12 weeks. Rhytides in the lower two-thirds of the face have not yet been assessed. Referring to the study by Carruthers et al, a dose of at least 1500 U BoNT-B seems to be ideal for a complete paresis of the frontalis muscle. Direct comparisons with BoNT-A in a 1 : 50 ratio show similar efficacy in the first 4 weeks after injections, but an inferiority of BoNT-B at later timepoints.

Table 7.2 Systematic overview of studies evaluating the effect of BoNT-B on hyperkinetic wrinkles

image image

Dose response

All studies assessing the dose response show a clear increase of duration with higher doses. While Kim et al approved increasing duration with doses from 400 to 1600 U BoNT-B per treated side, Spencer et al found this correlation for higher doses from 1875 to 3750 U to be effective, too. Carruthers et al confirmed these findings in one study with 139 subjects for six different doses from 500 to 3000 U, but did not find a significant difference between 250 and 500 U.

Onset and duration

Onset and duration of effect of BoNT-B have been assessed in several studies. The agent is described as taking effect rapidly after injection. Near-complete paresis of the treated muscle is usually seen within 24–72 hours after injection. In direct comparison to BoNT-A, the onset of BoNT-B is quicker and the clinical result is smoother. The duration of effect depends on the dosage used, but seems to be limited to a maximum of 10–12 weeks. Sadick (in 2003) specified the duration of effect with 2400 U BoNT-B to be 9.6 weeks, while it was 10.1 weeks with 3000 U. Bauman et al found an average wear-off time of 7 weeks after injection of 1500 U BoNT-B into each orbicularis oculi. While studies by Comella et al and Tintner et al show a superior duration of BoNT-A in patients treated for cervical dystonia, a study by Pappert et al shows no difference. The non-inferiority is supported by an animal study by Arezzo, which shows a consistent duration of the direct effects on the treated muscle when equivalent doses of BoNT-A or BoNT-B were injected.

Pearl 2

BoNT-B is known to be the botulinum toxin phenotype with the fastest onset time. It usually takes effect in the first 48 hours after injection. Myobloc® may therefore be helpful for people who want a more rapid onset.

Case Study 2

Fast Onset

A 42-year-old female presented in the office for forehead and glabella rejuvenation, in preparation for her daughter’s wedding 2 days later. Because the onset of BoNT-A is delayed, she was treated instead with a total of 3125 U BoNT-B for the interglabellar complex and 2500 U BoNT-B for the frontalis BoNT-B. The treatment effect was apparent in time for the ceremony.

Diffusion and spreading

The effect of botulinum toxin is not limited to the injection site. As the muscle fascia is a relatively ineffective boundary the unbound toxin can, driven by the concentration gradient and the dynamics of the injection, diffuse to nearby cholinergic neurons through the extracellular space. The spreading is not limited to tissue in close proximity, as distant muscles can be affected due to vascular or lymphatic transport of the toxin. Because of the smoother and less precise clinical effect, BoNT-B is assumed to diffuse more widely than does BoNT-A. This theory is supported by the high rate of dry mouth or dry eyes after injections with BoNT-B, reported in studies by Baumann et al and Kim et al, as well as the finding by Chapman et al of dysphagia as a common adverse effect in the treatment of cervical dystonia with BoNT-B. Doubts on the higher diffusion potential come from Arezzo’s animal studies, as his studies show that BoNT-A can cause a paralysis up to 40% in non-treated, contralateral muscles compared with 0% with BoNT-B at equivalent doses. These data indicate that differences in the pattern of side effects for BoNT-A and BoNT-B may be more related to differences in receptor distribution on autonomic neurons than to greater spread of paralysis from an injection site.

Pearl 3

BoNT-B is known to be effective in a larger area around the injection site. The effect is smoother and more natural. Myobloc® should therefore be used where a greater spread and more natural appearance is wanted.

Tolerability and safety

Injections with BoNT-B are mainly reported to be more painful than injections with other botulinum toxins. It is understood that the increased pain is not related to the toxin itself, but rather to the acidic pH of 5.6. Overall, the injection pain is described to be mild to moderate and for most patients no reason to discontinue the therapy. However, a double-blind study by Carruthers et al showed no difference in pain between BoNT-B and placebo.

The safety of botulinum toxin B is well examined. The most common side effects, when used in aesthetic medicine, are dry mouth (13–45%), headaches (3–25%), dry eyes (5%), as well as heavy brows and lid ptosis (5–7%). Furthermore, two studies (by Baumann et al and Carruthers et al) describe flu-like symptoms after the injection of BoNT-B, but relate it to the seasonal context. The described side effects are comparable to those seen in the treatment of chronic neurological movement disorders, where doses of up to 25 000 U BoNT-B are not uncommon.

Pearl 4

Due to the larger area of effect of BoNT-B, Myobloc® should be used with caution in elderly people where the risk of brow ptosis is higher.

Myobloc® in the treatment of hyperhidrosis

Beside its use for the treatment of hyperkinetic facial lines, BoNT-B is effective for the treatment of hyperhidrosis. The eccrine sweat glands are innervated by sympathetic nerves that use acetylcholine. As botulinum toxin has the ability to block the release of this neurotransmitter in the postganglionic sympathetic fibers of the glands, it can be used to stop the excessive sweat production for several weeks (Table 7.3).

Table 7.3 Systematic overview of studies evaluating the effect of BoNT-B on hyperhidrosis

image

For the treatment of focal palmar or axillary hyperhidrosis, injected botulinum toxin has to be evenly distributed every 2 cm2 in the areas in which a starch iodine test indicated sweating. A sweat reduction of 95–100% with a mean duration of 3–5 months can be expected when doses of 2000–5000 U BoNT-B are used. Hechtel et al showed an extremely low-dose treatment with only 250 U BoNT-B per axilla to be effective for 1–3 months. However, there seems to be no correlation between dosage and duration or efficacy, when higher doses (2000 U per side) are used.

Pearl 5

The larger area of effect of BoNT-B is particularly useful in the treatment of hyperhidrosis as fewer injections per treatment area are needed.

The information on safety is highly variable. The most commonly described adverse effect is xerostomia, occurring in 5–90% of subjects. Other common side effects are heartburn, excessively dry hands, muscle weakness, decreased grip strength, dry eyes, acne, headache, and flu-like symptoms. However, there are also studies (by Hecht et al and Frasson et al) where no side effects other than mild pain at the injection side occurred. In direct comparison with BoNT-A, BoNT-B seems to have a faster onset and a shorter duration of effect.

Treatment considerations for Myobloc®

A good rule of thumb to produce Myobloc® results comparable to BoNT-A is to use the established total of Botox® / Xeomin® units and multiply it by 100 to find the number of Myobloc® units needed. As the clinical effect of Myobloc® is wider than that of BoNT-A, the number of injection points can be reduced in most cases (Table 7.4). According to this rule, to eradicate glabellar lines the procerus complex and corrugators supercilii muscles have to be treated with 2000–3000 U Myobloc® in three or four injection sites instead of 20–30 U Botox® / Xeomin® units in five injection sites. The injection of the frontalis utilizes 1500–3000 U of Myobloc®, distributed evenly over three or four injection sites to provide satisfactory results. A dose of 1500 U of Myobloc® has to be injected on each side of the face, into the corrugator supercilii, the procerus complex, and the medial portion of the orbicularis oculi muscle, to achieve effective results in the lifting of the brow. It is found that, for the treatment of crow’s feet, 1000–2000 U of Myobloc® per side have to be injected into two to three sites of each orbicularis oculi muscle.

Table 7.4 Provisional dosing guidelines for botulinum toxin B injections for facial rhytids

Muscle site BoNT-B (Myobloc®)
Units No. of injections
Glabella 2000–3000 3
Frontalis 1500–3000 3–4
Brow lift 1500 total 2–4 per side
Periorbital 1000–2000 per side 2–3 per side

Summary

Myobloc® is the only commercial available drug based on botulinum toxin serotype B. It is FDA cleared for the treatment of cervical dystonia, but also applicable for the treatment of hyperkinetic facial rhytides and focal hyperhidrosis of the palms and axillae. In contrast to other botulinum toxin products, Myobloc® is available as a purified solution packaged in ready-to-use vials of 2500, 5000, and 10 000 U each, requiring no reconstitution. The liquid preparation ensures the integrity of the toxin as uniform and intact complex and minimizes the amount of denatured protein. The equivalency of Myobloc® units to the widely used Botox® / Xeomin® units is reported to be in a range between 1 : 20 and 1 : 125 and mostly said to be 1 : 100.

Myobloc® is shown to be efficient in the treatment of hyperkinetic rhytides of the upper third of the face in several clinical studies. It is described to have a faster onset and a smoother and less narrow effect, but also a shorter duration of effect, when compared with BoNT-A. However, the duration increases with higher doses, but seems to be limited to a maximum of 10–12 weeks. The diffusion potential of Myobloc® is unclear. Due to the wider effect and the higher rate of side effects, BoNT-B is assumed to exhibit more diffusion and spread. However, these findings can also be related to differences in receptor distribution on autonomic neurons.

The safety profile of Myobloc® is well examined. The most common side effects when used for the treatment of facial rhytides are xerostomia and headaches as well as dry eyes and brow ptosis. Injections with Myobloc® are mainly reported to be more painful than injections with other botulinum toxins. Patients describe the injection pain as mild to moderate. It is assumed that the increased pain is related not to the toxin itself, but to the solution’s acidic pH of 5.6.

In addition to Myobloc’s application for muscle denervation, it is also effective for the treatment of focal hyperhidrosis, due to its ability to block the sweat glands’ neurotransmitter, acetylcholine. A near-complete sweat reduction with a duration of 3–5 months can be expected, when doses of 2000 Myobloc® units per palm or axilla are injected. In direct comparison with products based on BoNT-A, Myobloc® is reported to have a faster onset and a longer duration of effect. The safety profile for the treatment of hyperhidrosis is generally equivalent to that for the treatment of facial rhytides. Additionally, reported effects are excessively dry hands, muscle weakness, and decreased grip strength.

Conclusion

In times where the average life expectancy is increasing greater than ever in history, a young and beautiful appearance is not only associated with fertility and good health, but can also go with social and economic advantages. Recognition of this fact has created a strong public demand for safe and effective aesthetic solutions for the treatment of wrinkles. One of them is the treatment of overactive facial muscles that cause hyperkinetic rhytides with botulinum toxin to decrease the muscles’ activity and cause paralysis.

Among the botulinum toxins available in the United States, Myobloc® is the only product that is based on botulinum toxin serotype B. It has its own unique mechanism of action, binds specific serotype receptors, and targets specific intracellular proteins. It is also the only botulinum toxin product that is available in a liquid formulation and therefore requires no reconstitution before injecting.

Its unique characteristics and clinical profile, including its very fast onset, smooth result, and superiority in the treatment of hyperhidrosis, make Myobloc® an interesting alternative to BoNT-A-based products. Furthermore, it is an important replacement whenever there is immunoresistance found to be in patients treated with BoNT-A. However, it should be remembered that Myobloc® has a higher rate of adverse effects and the injection can be more painful compared with other BoNT products.

Although the likelihood of serious adverse events is low, all botulinum toxins are considered to be highly potent neurotoxins and extreme care should be taken, especially in increasing doses in patients with any indications including off-label usage. Of course, as physicians become more vigorous with toxin usage for aesthetic treatments (especially in the lower face), the side effects become prevalent and troublesome. For a physician in the aesthetic arena, not only is patient satisfaction important but also patient safety is imperative – especially a thorough understanding of practice and procedure and so avoidance of post-treatment complications.

Further reading

Alster TS, Lupton JR. Botulinum toxin type B for dynamic glabellar rhytides refractory to botulinum toxin type A. Dermatologic Surgery. 2003;29(5):516–518.

Aoki KR, Guyer B. Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions. European Journal of Neurology. 2001;8(suppl 5):21–29.

Arezzo JC. NeuroBloc / Myobloc: unique features and findings. Toxicon. 2009;54(5):690–696.

Baumann L, Slezinger A, Halem M, et al. Pilot study of the safety and efficacy of Myobloc (botulinum toxin type B) for treatment of axillary hyperhidrosis. International Journal of Dermatology. 2005;44(5):418–424.

Baumann L, Slezinger A, Halem M, et al. Double-blind, randomized, placebo-controlled pilot study of the safety and efficacy of Myobloc (botulinum toxin type B) for the treatment of palmar hyperhidrosis. Dermatologic Surgery. 2005;31(3):263–270.

Baumann L, Slezinger A, Vujevich J, et al. A double-blinded, randomized, placebo-controlled pilot study of the safety and efficacy of Myobloc (botulinum toxin type B)-purified neurotoxin complex for the treatment of crow’s feet: a double-blinded, placebo-controlled trial. Dermatologic Surgery. 2003;29(5):508–515.

Berman B, Seeberger L, Kumar R. Long-term safety, efficacy, dosing, and development of resistance with botulinum toxin type B in cervical dystonia. Movement Disorders. 2005;20(2):233–237.

Callaway JE. Botulinum toxin type B (Myobloc): pharmacology and biochemistry. Clinical Dermatology. 2004;22(1):23–28.

Carruthers A, Carruthers J, Flynn TC, et al. Dose-finding, safety, and tolerability study of botulinum toxin type B for the treatment of hyperfunctional glabellar lines. Dermatologic Surgery. 2007;33(1 spec no.):S60–S68.

Chapman MA, Barron R, Tanis DC, et al. Comparison of botulinum neurotoxin preparations for the treatment of cervical dystonia. Clinical Therapeutics. 2007;29(7):1325–1337.

Choi J-W, Youn C-S, An H-T, et al. Combined use of botulinum toxin type A and B for forehead rhytides: a randomized, double-blind, split-face study. Journal of Dermatological Treatment. 2011. Online. Available http://www.ncbi.nlm.nih.gov/pubmed/21801115 20 October 2011 [Epub ahead of print]

Comella CL, Jankovic J, Shannon KM, et al. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology. 2005;65(9):1423–1429.

Dressler D, Adib Saberi F, Benecke R. Botulinum toxin type B for treatment of axillar hyperhidrosis. Journal of Neurology. 2002;249(12):1729–1732.

Flynn TC, Clark RE, 2nd. Botulinum toxin type B (MYOBLOC) versus botulinum toxin type A (BOTOX) frontalis study: rate of onset and radius of diffusion. Dermatologic Surgery. 2003;29(5):519–522. discussion 522

Frasson E, Brigo F, Acler M, et al. Botulinum toxin type A vs type B for axillary hyperhidrosis in a case series of patients observed for 6 months. Archives of Dermatology. 2011;147(1):122–123.

Halpern JL, Smith LA, Seamon KB, et al. Sequence homology between tetanus and botulinum toxins detected by an antipeptide antibody. Infection and Immunity. 1989;57(1):18–22.

Hecht MJ, Birklein F, Winterholler M. Successful treatment of axillary hyperhidrosis with very low doses of botulinum toxin B: a pilot study. Archives of Dermatological Research. 2004;295(8-9):318–319.

Jankovic J, Hunter C, Dolimbek BZ, et al. Clinico-immunologic aspects of botulinum toxin type B treatment of cervical dystonia. Neurology. 2006;67(12):2233–2235.

Kim EJ, Ramirez AL, Reeck JB, et al. The role of botulinum toxin type B (Myobloc) in the treatment of hyperkinetic facial lines. Plastic and Reconstructive Surgery. 2003;112(5 suppl):88S–93S. discussion 94S–97S

Kranz G, Paul A, Voller B, et al. Long-term efficacy and respective potencies of botulinum toxin A and B: a randomized, double-blind study. British Journal of Dermatology. 2011;164(1):176–181.

Lowe NJ, Yamauchi PS, Lask GP, et al. Botulinum toxins types A and B for brow furrows: preliminary experiences with type B toxin dosing. Journal of Cosmetic and Laser Therapy. 2002;4(1):15–18.

Matarasso SL. Comparison of botulinum toxin types A and B: a bilateral and double-blind randomized evaluation in the treatment of canthal rhytides. Dermatologic Surgery. 2003;29(1):7–13. discussion 13

Nelson L, Bachoo P, Holmes J. Botulinum toxin type B: a new therapy for axillary hyperhidrosis. British Journal of Plastic Surgery. 2005;58(2):228–232.

Oh YJ, Lee NY, Suh DH, et al. A split-face study using botulinum toxin type B to decrease facial erythema index. Journal of Cosmetic and Laser Therapy. 2011;13(5):243–248.

Pappert EJ, Germanson T. Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia: randomized, double-blind, noninferiority trial. Movement Disorders. 2008;23(4):510–517.

Ramirez AL, Reeck J, Maas CS. Botulinum toxin type B (MyoBloc) in the management of hyperkinetic facial lines. Otolaryngology Head and Neck Surgery. 2002;126(5):459–467.

Sadick NS. Prospective open-label study of botulinum toxin type B (Myobloc) at doses of 2,400 and 3,000 U for the treatment of glabellar wrinkles. Dermatologic Surgery. 2003;29(5):501–507. discussion 507

Sadick NS. Botulinum toxin type B for glabellar wrinkles: a prospective open-label response study. Dermatologic Surgery. 2002;28(9):817–821.

Spencer JM, Gordon M, Goldberg DJ. Botulinum B treatment of the glabellar and frontalis regions: a dose response analysis. Journal of Cosmetic and Laser Therapy. 2002;4(1):19–23.

Tintner R, Gross R, Winzer UF, et al. Autonomic function after botulinum toxin type A or B: a double-blind, randomized trial. Neurology. 2005;65(5):765–767.

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