Update on botulinum neurotoxin use in aesthetic dermatology Omer Ibrahim, MD,1 Emily C Keller, MD,2 Kenneth A Arndt, MD2
n Abstract
Botulinum toxins are among the most widely studied and versatile drugs in the medicinal market. Since their extraction from Clostridium botulinum, they have been harnessed and incorporated into different formulations with varied properties and actions. These products have been used to treat countless disorders such as musculoskeletal disorders, headaches, and eye disorders, among many others. In the realm of aesthetic cutaneous medicine, the evolution and creativity in the use of botulinum toxins has been swift and ever changing. Knowledge of the science and innovation behind this toxin enables the user to provide the patient with a variety of treatment options founded in evidence-based medicine. This review will highlight the properties and actions of the newer, more recent neurotoxin preparations, as well as some of the latest and novel therapeutic applications of botulinum toxins. Semin Cutan Med Surg 33:152-156 © 2014 Frontline Medical Communications
B
otulinum toxin is a potent neurotoxin that is widely used to treat a myriad of conditions including neuromuscular disorders, pain, eye disorders, and facial rhytides, among many others. OnabotulinumtoxinA (Botox, Allergan, Irvine, California) was the first neurotoxin to be studied extensively. Since its commercial introduction in 1990, it has become one of the leading and most widely researched formulations of botulinum toxin A, and serves as the basis of comparison for subsequent neurotoxin preparations.1 As the applications and patient base have grown dramatically since the introduction of Botox, many companies and researchers have strived to develop their own unique neurotoxin preparations. The following review will catalogue and discuss the newer, more recent neurotoxin formulations, as well as novel therapeutic applications of botulinum toxin. New and emerging botulinum toxin preparations IncobotulinumtoxinA
IncobotulinumtoxinA (Xeomin, Merz Pharmaceuticals, Frankfurt, Germany) is a commercially available botulinum toxin preparation widely used in aesthetic medicine. It is produced from the type A Hall strain of C. botulinum. Unlike other type A botulinum toxins on the market, incobotulinumtoxinA is free of complexing proteins Department of Dermatology, Cleveland Clinic Foundation, Ohio SkinCare Physicians, Chestnut Hill, Massachusetts Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Correspondence: Omer Ibrahim, MD; Cleveland Clinic; 9500 Euclid Ave, A61;Cleveland, OH 44114. Email: [email protected]
1 2
152 Seminars in Cutaneous Medicine and Surgery, Vol. 33, December 2014
and contains only active toxins.2 It is used in all major European markets, South Korea, and Argentina for the treatment of glabellar lines. In July 2011, the Food and Drug Administration (FDA) approved its use for the treatment of glabellar frown lines in the United States.2 The major investigations assessing the efficacy and safety of incobotulinumtoxinA in the treatment of glabellar lines consisted of two identical randomized, multicenter, placebo controlled trials. Over 500 patients were enrolled to receive 20 U of incobotulinumtoxinA to the glabellar area, with the primary efficacy endpoint as the response rate at day 30 posttreatment. Treatment responders were defined as a 2-point or greater improvement on the Facial Wrinkle Scale. At day 30, one of the two trials exhibited a 68% responder rate and the other exhibited a 48% responder rate.3 After the placebo-controlled period, over 100 patients were enrolled into an open-label trial, and 99% of the subjects showed a 1-point or greater improvement on the Facial Wrinkle Scale at 4 weeks posttreatment.1 Further studies incorporating incobotulinumtoxinA compared it to onabotulinumtoxinA. A large phase III international study showed that 24 U of incobotulinumtoxinA was equally as effective and safe as 24 U of onabotulinumtoxinA in the treatment of glabellar frown lines, using a 1:1 dose ratio.4 In 2 smaller studies, identical doses of onabotulinumtoxinA and incobotulinumtoxinA demonstrated comparable efficacy and safety in the treatment of periorbital wrinkles and horizontal forehead lines in men.5,6 Larger studies on cervical dystonia and blepharospasm also showed that incobotulinumtoxinA and onabotulinumtoxinA possessed similar potencies and efficacies.1 In order to compare diffusion capacities of the 2 preparations, a study was designed to measure anhidrotic areas created by the injected toxins. The results showed that incobotulinumtoxinA and onabotulinumtoxinA had similar diffusion capacities and comparable spread.7 When comparing their respective durations of effect, both products exhibited about 50% effectiveness at 4 months posttreatment, and incobotulinumtoxinA glabellar injections lasted between 3-6 months in comparison to 3-5 months with onabotulinumtoxinA.1 Furthermore, large studies have been conducted to compare the immunoresistance patterns of the more popularly used neurotoxins. During the incobotulinumtoxinA development trial, 12 previously antibody-negative patients (1.1%) had developed neutralizing antibodies after the first treatment.1 In contrast, a large meta-analysis on onabotulinumtoxinA and antibody formation showed that 11 of the 2240 subjects (0.49%) developed neutralizing antibodies. The data on antibody formation cannot be directly compared between incobotulinumtoxinA and onabotulinumtoxinA due to the fact that none of the incobotulinumtoxinA antibody-positive patients were botulinum toxin A naïve prior to treatment with incobotulinumtoxinA, while some of the onabotu1085-5629/13$-see front matter © 2014 Frontline Medical Communications DOI: 10.12788/j.sder.0115
O. Ibrahim, E. C. Keller, and K. A. Arndt linumtoxinA patients were treatment naïve. Therefore, antibody formation and its clinical relevancy remain controversial.1 Neuronox (neu-BoNT/A)
Much controversy and confusion arises when attempting to compare and interconvert between different toxin formulations due to differences in molecular weight and potency units.8 Neuronox (neuBoNT/A, Medytox Inc, Cheonwon-gun, Korea) is a newer serotype A complex toxin that was initially developed to closely resemble features of the most widely known botulinum toxin, onabotulinumtoxinA.8 The aim of the product was to provide an alternative similar to onabotulinumtoxinA, to reduce the cost of treatment, and to eliminate the confusion in dosing.8 Neu-BoNT/A was approved for the treatment of blepharospasm in South Korea in 2006, and has since then been incorporated into the field of aesthetic medicine. Neu-BoNT/A, similar to onabotulinumtoxinA, is developed from the type A Hall strain of Clostridium botulinum.8 In comparing the DNA sequence of neu-BoNT/A to Allergan’s published data,9 there is no difference in amino acid sequence between the two toxins.8 In addition, one 100-U vial of neu-BoNT/A, like onabotulinumtoxinaA, contains 100 U of purified toxin complex, 0.9 mg of sodium chloride, and 0.5 mg of human serum albumin. Furthermore, the molecular weights of the two products are nearly identical. Most believe that onabotulinumtoxinA is a homogenous 900-kDa complex.10 Although the molecular weight and its affect on toxin action is a highly debated topic, some assert that molecular weight affects the diffusion and spread of the toxin.11,12 As such, neu-BoNT/A was developed as a highly homogenous 900-kDa toxin complex to further ease comparability with onabotulinumtoxinA and produce similar diffusion properties.8 The potencies of neu-BoNT/A and onabotulinumtoxinA are also nearly identical, and can be interconverted on a 1:1 ratio.8 Several techniques are used to investigate the comparative efficacies of toxin preparations, including measuring compound muscle action potentials in mice after injection, the digit abduction scoring assay in mice, and measurement of reduction in murine muscle force generation after injection.8 Several preclinical studies incorporating these techniques to compare neu-BoNT/A and onabotulinumtoxinA have shown that their actions are bioequivalent and have a conversion ratio of 1:1.8,13 Clinically, the actions of these two toxins seem to be essentially equal. A double-blind, randomized, controlled study compared neuBoNT/A and onabotulinumtoxinA in the treatment of moderateto-severe glabellar wrinkles in 314 patients. At 4 weeks postinjection, responder rates were 93.7% in the neu-BoNT/A group and 94.5% in the onabotulinumtoxinA group, yielding no significant differences between the two groups. There were no serious adverse events with either product.14 Another double-blind, randomized, comparative study that treated essential blepharospasm showed no differences between the two products in efficacy or safety when administered at a 1:1 dose ratio.15 Although comparative studies are still scant and longer-term follow-up studies are still needed to assess for long-term safety of neu-BoNT/A, it seems to be nearly identical to onabotulinumtoxinA in composition, action, and efficacy. Despite their similarities, neu-BoNT/A offers a more cost-effective option to patients in Korea.8 This product is likely to become a viable competitor in the field of injectable neurotoxins.
Chinese type A botulinum toxin
Chinese type A botulinum toxin (CBTX-A, Lanzhou Biological Products Institute, Lanzhou, China) is also a serotype A botulinum toxin developed from the type A Hall strain of C. botulinum. In 1993, the Chinese Ministry of Health approved CBTX-A for use in a multitude of neurological and musculoskeletal disorders.16 The product was approved in 2012 by the Chinese Food and Drug Administration for the treatment of glabellar lines. It has since been widely used in China in aesthetic dermatology at a fraction of the cost of onabotulinumtoxinA.17 CBTX-A has not been widely investigated, and therefore, specific information regarding molecular weight and conversion ratios between CBTX-A and more well-known botulinum toxins is scant. Each vial of CBTX-A contains 100 U of purified neurotoxin, 5 mg of gelatin, 25 mg of dextran, and 25 mg of sucrose.16 Gelatin is a potent skin sensitizer, theoretically making CBTX-A more allergenic than onabotulinumtoxinA. In one study investigating CBTX-A in the treatment of hemifacial spasm and blepharospasm, erythema at injection sites was reported up to a few days after injection, which the investigators postulated might have been due to the composition of the product.16 In another study comparing onabotulinumtoxinA to CBTX-A in the treatment of hemifacial spasm and blepharospasm, CTBX-A and onabotulinumtoxinA appeared to provide equivalent rates of improvement, onset of action, and duration of response.18 In a similar investigation, it was noted that when administering the same units of onabotulinumtoxinA and CBTX-A, the onabotulinumtoxinA group experienced higher rates of complications due to neurotoxin overdose.16 In concordance with previous observations, this suggests that although the comparative potencies of both products have not been investigated; unit-to-unit, onabotulinumtoxinA may have a higher potency than CBTX-A.19 With injectable neurotoxins, the anatomic proximity and functional complexity of facial muscles demand accuracy and precision. Therefore, it is imperative to understand the diffusion properties of the injected toxin and be able to predict its action in order to avoid untoward effects in patients. A study conducted by Jiang et al sought to compare the diffusion properties of CBTXA and onabotulinumtoxinA.17 In the double-blinded, randomized, controlled study, CBTX-A and onabotulinumtoxinA were injected intradermally and subcutaneously into the foreheads of the study subjects. The Minor’s starch iodine test was then performed on the subjects’ foreheads in order to assess the area of anhidrosis created by the toxin, as an indirect measurement of its diffusion area. The study concluded that with both intradermal and subcutaneous injections, CBTX-A consistently demonstrated a greater area of diffusion when compared with onabotulinumtoxinA.17 Larger and longer-term studies are needed to characterize the inherent properties, potency, efficacy, and side-effect profile of CBTX-A. In time, CBTX-A may eventually provide patients with yet another alternative product with similar results as other neurotoxins, and at a much lower cost.19 NABOTA (DWP450)
NABOTA (DWP450, Daewoong, Co Ltd, Seoul, Korea) is a type A botulinum toxin that is almost identical to onabotulinumtoxinA. Similar to onabotulinumtoxinA, this complexed toxin weighs 900 kDa, is packaged in a 100-U vial, and each vial’s excipients are human serum Vol. 33, December 2014, Seminars in Cutaneous Medicine and Surgery 153
n n n Update on botulinum neurotoxin use in aesthetic dermatology
n TablE 1 Summary of recent botulinum toxin formulations Agent
Company
City
Country
Approval
IncobotulinumtoxinA (Xeomin)
Merz Pharmaceuticals
Frankfurt
Germany
United States, Europe, South Korea, Argentina for glabellar lines
Neuronox
Medytox Inc.
Cheonwon-gun
Korea
South Korea for blepharospasm
Chinese botulinum toxin A
Lanzhou Biological Products Institute
Lanzhou
China
China for glabellar lines
NABOTA (DWP450)
Daewoong, Co. Ltd.
Seoul
Korea
Pending
Botulinum toxin A gel (RT001)
Revance Therapeutics Inc.
Newark, California
US
Pending
albumin and sodium chloride.20 In a comparative trial by Kim and colleagues, onabotulinumtoxinA and DWP450 were injected into rats in a split-body fashion, and compound muscle action potentials were measured postinjection. The trial showed that there were no differences in paralytic effects between the 2 formulations.20 Another trial by Ko and colleagues compared the diffusion behaviors of 3 toxins: onabotulinumtoxinA, DWP450, and abobotulinumtoxinA.21 AbobotulinumtoxinA (Dysport, Medicis Aesthetics, Inc, Scottsdale, Arizona) is another type A botulinum neurotoxin that was FDA approved in the United States in 2009 for the treatment of glabellar lines.1 The results of this comparative trial demonstrated that 3.3 U of DWP450 and 3.3 U of onabotulinumtoxinA injected into the forehead exhibited almost identical anhidrotic halos on Minor’s starch iodine test 2 weeks posttreatment, suggesting that these 2 formulations may have similar diffusion properties. The anhidrotic halo of a bioequivalent 8.3 U of abobotulinumtoxinA was almost 3 times as large as those of the other 2 toxins, suggesting a greater diffusion capacity in comparison to onabotulinumtoxinA and DWP450.21 No other descriptive or comparative clinical trials exist that explore DWP450 further; however this product may soon expand in the literature and in the international market. Botulinum toxin type A topical gel (RT001)
Although the cosmetic use of botulinum toxin injections provides patients with desired results with an acceptable safety profile, adverse events still do occur. The lateral canthal area (LCA) is of particular concern due to the anatomic proximity of the orbicularis oris muscle to the globe of the eye, as well as to the zygomaticus major, contributing to the elevation of the lateral upper cutaneous lip.22 Misplaced injections in the LCA targeting lateral canthal lines (LCLs) can lead to partial lip ptosis or uncomfortably dry eyes.23-25 Complications have been reported involving light sensitivity and pupillary reflexes when injected at the LCA.26,27 In addition to expected injection-related pain, erythema, and swelling, bruising in the LCA is of particular concern due to thin skin and superficial blood vessels in the area.22 In attempts to minimize the risk of these complications, a novel botulinum toxin type A gel (RT001, Revance Therapeutics, Inc, Newark, CA) has been developed. The product contains an albumin-free 150-kDa toxin and a novel peptide that facilitates transcutaneous flux of the toxin.22 This product was specifically created to treat moderate-to-severe LCLs. In one of the first reported clinical 154 Seminars in Cutaneous Medicine and Surgery, Vol. 33, December 2014
experiments evaluating the product, investigators set out to determine the efficacy and safety of 2 sequential applications of RT001 in treating moderate-to-severe LCLs.22 Thirty-six subjects were randomized to receive either RT001 or placebo to bilateral LCAs at baseline and again at 4 weeks. Outcomes were measured using the Investigator’s Global Assessment of Lateral Canthal Line at Rest (IGA-LCL) Severity Scale. At 8 weeks, 50% of LCAs treated with RT001 demonstrated a 2-point or more improvement in baseline IGA-LCL versus none of the placebo subjects, and 94.7% of LCAs treated with RT001 demonstrated a 1-point or greater improvement in baseline IGA-LCL severity at 8 weeks posttreatment. Subjects reported significant improvements in LCLs after treatment with RT001. Of note, there were no treatment-related adverse events.22 In a similar study by Glogau et al, the investigators sought to assess the efficacy and safety of a single application of RT001 in the treatment LCLs. Subjects were randomized to receive either one treatment of RT001 or placebo. At 4 weeks posttreatment, 44.4% of the RT001 study group demonstrated a 2-point or greater improvement in baseline IGA-LCL versus 0% of the placebo. Furthermore, 88.9% of the RT001 study group achieved clinically relevant improvement by investigator assessment.28 In both studies combined, one subject exhibited mild, transient posttreatment erythema. None of the RT001 treated subjects experienced stinging, burning, scaling, ocular symptoms, or unwanted diffusion beyond the treated areas.22,28 In the near future, RT001 may come to the forefront as a viable noninvasive treatment of LCLs. Injection-associated pain, erythema, edema, and swelling would most likely be evaded, and most importantly, precision in treatment could be achieved. In recent years, the goal of neurotoxin injections has shifted towards a softer, more natural look, focusing more on eliminating wrinkles at rest while preserving normal facial movement. Aggressive treatment of LCLs can result in elimination of LCLs during active smiling, resulting in what patients deem as an unnatural, insincere, and undesirable smile.28 With further comparative and analytical studies, RT001 may soon become a staple in the gentler treatment of LCLs. Table 1 summarizes in detail the newer and upcoming botulinum toxin formulations. Novel uses of injectable neurotoxins Botulinum toxin and keloids
Keloids can be aesthetically displeasing and, depending on size and location, can have profound psychological and social conse-
O. Ibrahim, E. C. Keller, and K. A. Arndt quences on the patient. More than just cosmetically disfiguring, keloids can also be tender, sensitive, or pruritic. Many treatment modalities including intralesional corticosteroids or 5-fluorouracil, silicone sheets and gels, lasers, and cryotherapy have been attempted with varying degrees of success.29 Injection of botulinum toxin A (BTA) has been implemented in attempts to prevent keloid formation after surgery, and more recently, to treat keloids after trauma or surgery.30 In one study, injection of 15 U of onabotulinumtoxinA per 2 cm into the musculature adjacent to a surgical wound within 24 hours resulted in less noticeable scar formation compared with placebo.31 Another study showed similar results when BTA was injected 4-7 days prior to surgery. These investigations suggest that reduction of tension during the wound healing process may result in less noticeable scars.30 Recently, a prospective, uncontrolled study suggested the therapeutic use of BTA in the treatment of established keloids.32 Twelve subjects’ keloids (varying from 1 to 3 per subject) were injected at 3-month intervals for 3 total injections, and dosages ranged from 70 to 140 U per session. At 1-year follow-up, 3 subjects reported excellent results, 5 subjects reported good results, and 4 subjects reported fair results. Overall, some degree of improvement was noted in all subjects and there were no signs of recurrence within the follow-up period.32 The suggested mechanism of action of BTA was the toxin-induced decrease in fibroblast proliferation and reduction in fibrogenic factors like transforming growth factor b-1.33 Nevertheless, subsequent in vitro observations have contradicted this theory.30 The theory of reducing wound tension peri-operatively to prophylactically improve the cosmetic appearance of scars makes sense; however, the clinical efficacy and mechanism by which BTA acts on established keloids still merits further exploration. Preliminary findings suggest its efficacy in treating these lesions, but further in-depth, controlled studies are needed to characterize the effects of BTA on keloids. Botulinum toxin and skin texture
Subjective reports and observations have described improvement in skin texture, appearance of pores, and oiliness after treatment with botulinum toxin for rhytids.34 Patients have noted smoother, tighter skin with smaller pores and less oil. Oily skin not only gives the skin a shiny, greasy appearance, but is related to the activity of acne.34 Rose and Goldberg sought to prospectively investigate the efficacy and safety of intradermal injections of abobotulinumtoxinA in the treatment of oily skin.34 Twenty-three subjects with mild-to-moderate oiliness of their forehead were treated with 30-
45 U of intradermal abobotulinumtoxinA. Sebum levels before and after treatment were measured with a sebometer. Sebum production decreased by 75%, 80%, 73%, and 59% at 1 week, 1 month, 2 months, and 3 months posttreatment, respectively. Subjective improvement in pore size was also noted. Twenty-one patients reported 50%-75% improvement in skin oiliness, one patient reported >75% improvement, and one patient reported 25%-50% improvement. Two subjects exhibited decreased tone of the frontalis muscle after treatment; otherwise no other side effects were noted.34 The mechanism by which botulinum toxin improves oiliness and texture is not completely understood; however, a recent study by Li and colleagues helped elucidate the pathophysiology.35 Using immunohistochemistry and immunocytofluorescence, the investigators showed that sebaceous glands and sebocytes express acetylcholine receptors, and that stimulating these receptors leads to increased lipid synthesis. Further, when sebocytes were incubated with a-bungarotoxin, an acetylcholine receptor antagonist, lipid synthesis was inhibited.35 The findings of these studies suggest that botulinum toxin may aid in the treatment of sebum-induced conditions like acne vulgaris, as well as the improvement in skin texture and clarity. Botulinum toxin and menopausal hot flashes
Menopausal women commonly exhibit uncomfortable and sometimes debilitating hot flashes characterized by intense heat and diaphoresis. These episodes can also be accompanied by sleep disturbances, irritability, and depressed mood.36 In a randomized, controlled trial, investigators showed that intradermal injections of abobotulinumtoxinA into the glabella, mid- and lateral-forehead, tip of the nose, chin, scalp, chest, and neck, objectively decreased perspiration using the Minor’s starch iodine test. The authors suggest that decreased sweating reduces the intensity of hot flashes and reduces the perceived number of hot flashes possibly by making them less noticeable to patients. With decreased numbers of perceived hot flashes and less intense breakthrough episodes, subjects exhibited improvements in mood disturbances, night sweats, and irritability.36 Botulinum toxin and Raynaud phenomenon
Raynaud phenomenon is a potentially debilitating condition in which patients exhibit marked arterial constriction in response to cold, leading to pale or blue fingers, numbness, and even digital ulceration. Raynaud phenomenon affects nearly 3% of the US population and is more common in women.37 This condition,
n TablE 2 Experimental therapeutic uses of botulinum toxin Agent
Therapeutic Indication
Level of Evidence
References
OnabotulinumtoxinA
Pre- and intra-operative keloid prevention
Level 2c
31
OnabotulinumtoxinA
Keloid treatment
Level 2c
32
AbobotulinumtoxinA
Oily skin
Level 2c
34
AbobotulinumtoxinA
Menopausal hot flashes
Level 2b
36
OnabotulinumtoxinA
Raynaud phenomenon
Level 2b
38
Vol. 33, December 2014, Seminars in Cutaneous Medicine and Surgery 155
n n n Update on botulinum neurotoxin use in aesthetic dermatology whether primary or secondary to autoimmune disease, is notoriously difficult to treat. In recent years, investigators and clinicians have implemented botulinum toxin injections in the treatment of Raynaud phenomenon. In the pilot study, around 10 U of onabotulinumtoxinA were injected into each of 4 sites on the palmar aspect of the hand, subadjacent to the palmar fascia, targeting the superficial palmar arch. At 6 weeks posttreatment, toxin-treated hands demonstrated increased digital pulp temperatures when compared to saline-treated hands.38 Other reports and reviews also demonstrated that treatments with botulinum toxin led to reduction in pain, improvement in digital oxygenation, and dramatic healing of chronic ulcers.37 With further investigation and larger studies, botulinum toxin may prove to be a leading contender in the treatment of Raynaud phenomenon.Table 2 summarizes some of the more recent therapeutic applications of botulinum toxin injections. Conclusion Botulinum toxin has proved over the last 2 decades to be one of the most versatile and widely applicable medications in modern medicine. Knowledge of the new formulations, as well as some of the novel uses, is essential in order to offer patients a variety of treatments options in an innovative and safe manner founded in evidence-based medicine. Although much evolution and advancement has already occurred with these toxins, there is much more research that has yet to transpire. The future applications and indications of neurotoxins in aesthetic cutaneous medicine remains bright. References
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32. 33.
34. 35. 36. 37. 38.
comparing the diffusion of two formulations of botulinum toxin type A in patients with forehead hyperhidrosis. Dermatol Surg. 2007;33(1 Spec No.):S37-S43. Stone AV, Ma J, Whitlock PW, et al. Effects of Botox and Neuronox on muscle force generation in mice. J Orthop Res. 2007;25(12):1658-1664. Won CH, Lee HM, Lee WS, et al. Efficacy and safety of a novel botulinum toxin type A product for the treatment of moderate to severe glabellar lines: a randomized, double-blind, active-controlled multicenter study. Dermatol Surg. 2013;39(1 Pt 2):171-178. Yoon JS, Kim JC, Lee SY. Double-blind, randomized, comparative study of meditoxin versus botox in the treatment of essential blepharospasm. Korean J Ophthalmol. 2009;23(3):137-141. Wu CJ, Shen JH, Chen Y, Lian YJ. Comparison of two different formulations of botulinum toxin A for the treatment of blepharospasm and hemifacial spasm. Turk Neurosurg. 2011;21(4):625-629. Jiang HY, Chen S, Zhou J, Leung KK, Yu P. Diffusion of two botulinum toxins type A on the forehead: double-blinded, randomized, controlled study. Dermatol Surg. 2014;40(2):184-192. Rieder CR, Schestatsky P, Socal MP, et al. A double-blind, randomized, crossover study of prosigne versus botox in patients with blepharospasm and hemifacial spasm. Clin Neuropharmacol. 2007;30(1):39-42. Tang X, Wan X. Comparison of Botox with a Chinese type A botulinum toxin. Chin Med J (Engl). 2000;113(9):794-798. Kim CS, Jang WS, Son IP, et al. Electrophysiological study for comparing the effect of biological activity between type A botulinum toxins in rat gastrocnemius muscle. Hum Exp Toxicol. 2013;32(9):914-920. Ko EJ, Mun SK, Oh IY, Kwon TR, Kim BJ, Kim MN. Comparison of efficacy and diffusion of three formulations of botulinum toxin type A in two patients with forehead hyperhidrosis. Clin Exp Dermatol. 2014;39(5):673-675. Brandt F, O’Connell C, Cazzaniga A, Waugh JM. Efficacy and safety evaluation of a novel botulinum toxin topical gel for the treatment of moderate to severe lateral canthal lines. Dermatol Surg. 2010;36(Suppl 4):2111-2118. Matarasso SL, Matarasso A. Treatment guidelines for botulinum toxin type A for the periocular region and a report on partial upper lip ptosis following injections to the lateral canthal rhytids. Plast Reconstr Surg. 2001;108(1):208-214; discussion 215-217. Matarasso SL. Decreased tear expression with an abnormal Schirmer’s test following botulinum toxin type A for the treatment of lateral canthal rhytides. Dermatol Surg. 2002;28(2):149-152. Arat YO, Yen MT. Effect of botulinum toxin type a on tear production after treatment of lateral canthal rhytids. Ophthal Plast Reconstr Surg. 2007;23(1):22-24. Racette BA, Lopate G, Good L, Sagitto S, Perlmutter JS. Ptosis as a remote effect of therapeutic botulinum toxin B injection. Neurology. 2002;59(9):1445-1447. Rowe FJ, Noonan CP. Botulinum toxin for the treatment of strabismus. Cochrane Database Syst Rev. 2012;2:CD006499. Glogau R, Blitzer A, Brandt F, Kane M, Monheit GD, Waugh JM. Results of a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a botulinum toxin type A topical gel for the treatment of moderate-to-severe lateral canthal lines. J Drugs Dermatol. 2012;11(1):38-45. Monstrey S, Middelkoop E, Vranckx JJ, et al. Updated scar management practical guidelines: non-invasive and invasive measures. J Plast Reconstr Aesthet Surg. 2014;67(8):1017-1025. Gauglitz GG. Management of keloids and hypertrophic scars: current and emerging options. Clin Cosmet Investig Dermatol. 2013;6:103-114. Gassner HG, Brissett AE, Otley CC, et al. Botulinum toxin to improve facial wound healing: A prospective, blinded, placebo-controlled study. Mayo Clin Proc. 2006;81(8):1023-1028. Zhibo X, Miaobo Z. Intralesional botulinum toxin type A injection as a new treatment measure for keloids. Plast Reconstr Surg. 2009;124(5):275e-277e. Xiao Z, Zhang F, Lin W, Zhang M, Liu Y. Effect of botulinum toxin type A on transforming growth factor beta1 in fibroblasts derived from hypertrophic scar: a preliminary report. Aesthetic Plast Surg. 2010;34(4):424-427. Rose AE, Goldberg DJ. Safety and efficacy of intradermal injection of botulinum toxin for the treatment of oily skin. Dermatol Surg. 2013;39(3 Pt 1):443-448. Li ZJ, Park SB, Sohn KC, et al. Regulation of lipid production by acetylcholine signalling in human sebaceous glands. J Dermatol Sci. 2013;72(2):116-122. Odo ME, Odo LM, Farias RV, et al. Botulinum toxin for the treatment of menopausal hot flushes: a pilot study. Dermatol Surg. 2011;37(11):1579-1583. Neumeister MW, Webb KN, Romanelli M. Minimally invasive treatment of Raynaud phenomenon: the role of botulinum type A. Hand Clin. 2014;30(1):17-24. Jenkins SN, Neyman KM, Veledar E, Chen SC. A pilot study evaluating the efficacy of botulinum toxin A in the treatment of raynaud phenomenon. J Am Acad Dermatol. 2013 Nov;69(5):834-5.
n Abstract
Botulinum toxins are among the most widely studied and versatile drugs in the medicinal market. Since their extraction from Clostridium botulinum, they have been harnessed and incorporated into different formulations with varied properties and actions. These products have been used to treat countless disorders such as musculoskeletal disorders, headaches, and eye disorders, among many others. In the realm of aesthetic cutaneous medicine, the evolution and creativity in the use of botulinum toxins has been swift and ever changing. Knowledge of the science and innovation behind this toxin enables the user to provide the patient with a variety of treatment options founded in evidence-based medicine. This review will highlight the properties and actions of the newer, more recent neurotoxin preparations, as well as some of the latest and novel therapeutic applications of botulinum toxins. Semin Cutan Med Surg 33:152-156 © 2014 Frontline Medical Communications
B
otulinum toxin is a potent neurotoxin that is widely used to treat a myriad of conditions including neuromuscular disorders, pain, eye disorders, and facial rhytides, among many others. OnabotulinumtoxinA (Botox, Allergan, Irvine, California) was the first neurotoxin to be studied extensively. Since its commercial introduction in 1990, it has become one of the leading and most widely researched formulations of botulinum toxin A, and serves as the basis of comparison for subsequent neurotoxin preparations.1 As the applications and patient base have grown dramatically since the introduction of Botox, many companies and researchers have strived to develop their own unique neurotoxin preparations. The following review will catalogue and discuss the newer, more recent neurotoxin formulations, as well as novel therapeutic applications of botulinum toxin. New and emerging botulinum toxin preparations IncobotulinumtoxinA
IncobotulinumtoxinA (Xeomin, Merz Pharmaceuticals, Frankfurt, Germany) is a commercially available botulinum toxin preparation widely used in aesthetic medicine. It is produced from the type A Hall strain of C. botulinum. Unlike other type A botulinum toxins on the market, incobotulinumtoxinA is free of complexing proteins Department of Dermatology, Cleveland Clinic Foundation, Ohio SkinCare Physicians, Chestnut Hill, Massachusetts Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Correspondence: Omer Ibrahim, MD; Cleveland Clinic; 9500 Euclid Ave, A61;Cleveland, OH 44114. Email: [email protected]
1 2
152 Seminars in Cutaneous Medicine and Surgery, Vol. 33, December 2014
and contains only active toxins.2 It is used in all major European markets, South Korea, and Argentina for the treatment of glabellar lines. In July 2011, the Food and Drug Administration (FDA) approved its use for the treatment of glabellar frown lines in the United States.2 The major investigations assessing the efficacy and safety of incobotulinumtoxinA in the treatment of glabellar lines consisted of two identical randomized, multicenter, placebo controlled trials. Over 500 patients were enrolled to receive 20 U of incobotulinumtoxinA to the glabellar area, with the primary efficacy endpoint as the response rate at day 30 posttreatment. Treatment responders were defined as a 2-point or greater improvement on the Facial Wrinkle Scale. At day 30, one of the two trials exhibited a 68% responder rate and the other exhibited a 48% responder rate.3 After the placebo-controlled period, over 100 patients were enrolled into an open-label trial, and 99% of the subjects showed a 1-point or greater improvement on the Facial Wrinkle Scale at 4 weeks posttreatment.1 Further studies incorporating incobotulinumtoxinA compared it to onabotulinumtoxinA. A large phase III international study showed that 24 U of incobotulinumtoxinA was equally as effective and safe as 24 U of onabotulinumtoxinA in the treatment of glabellar frown lines, using a 1:1 dose ratio.4 In 2 smaller studies, identical doses of onabotulinumtoxinA and incobotulinumtoxinA demonstrated comparable efficacy and safety in the treatment of periorbital wrinkles and horizontal forehead lines in men.5,6 Larger studies on cervical dystonia and blepharospasm also showed that incobotulinumtoxinA and onabotulinumtoxinA possessed similar potencies and efficacies.1 In order to compare diffusion capacities of the 2 preparations, a study was designed to measure anhidrotic areas created by the injected toxins. The results showed that incobotulinumtoxinA and onabotulinumtoxinA had similar diffusion capacities and comparable spread.7 When comparing their respective durations of effect, both products exhibited about 50% effectiveness at 4 months posttreatment, and incobotulinumtoxinA glabellar injections lasted between 3-6 months in comparison to 3-5 months with onabotulinumtoxinA.1 Furthermore, large studies have been conducted to compare the immunoresistance patterns of the more popularly used neurotoxins. During the incobotulinumtoxinA development trial, 12 previously antibody-negative patients (1.1%) had developed neutralizing antibodies after the first treatment.1 In contrast, a large meta-analysis on onabotulinumtoxinA and antibody formation showed that 11 of the 2240 subjects (0.49%) developed neutralizing antibodies. The data on antibody formation cannot be directly compared between incobotulinumtoxinA and onabotulinumtoxinA due to the fact that none of the incobotulinumtoxinA antibody-positive patients were botulinum toxin A naïve prior to treatment with incobotulinumtoxinA, while some of the onabotu1085-5629/13$-see front matter © 2014 Frontline Medical Communications DOI: 10.12788/j.sder.0115
O. Ibrahim, E. C. Keller, and K. A. Arndt linumtoxinA patients were treatment naïve. Therefore, antibody formation and its clinical relevancy remain controversial.1 Neuronox (neu-BoNT/A)
Much controversy and confusion arises when attempting to compare and interconvert between different toxin formulations due to differences in molecular weight and potency units.8 Neuronox (neuBoNT/A, Medytox Inc, Cheonwon-gun, Korea) is a newer serotype A complex toxin that was initially developed to closely resemble features of the most widely known botulinum toxin, onabotulinumtoxinA.8 The aim of the product was to provide an alternative similar to onabotulinumtoxinA, to reduce the cost of treatment, and to eliminate the confusion in dosing.8 Neu-BoNT/A was approved for the treatment of blepharospasm in South Korea in 2006, and has since then been incorporated into the field of aesthetic medicine. Neu-BoNT/A, similar to onabotulinumtoxinA, is developed from the type A Hall strain of Clostridium botulinum.8 In comparing the DNA sequence of neu-BoNT/A to Allergan’s published data,9 there is no difference in amino acid sequence between the two toxins.8 In addition, one 100-U vial of neu-BoNT/A, like onabotulinumtoxinaA, contains 100 U of purified toxin complex, 0.9 mg of sodium chloride, and 0.5 mg of human serum albumin. Furthermore, the molecular weights of the two products are nearly identical. Most believe that onabotulinumtoxinA is a homogenous 900-kDa complex.10 Although the molecular weight and its affect on toxin action is a highly debated topic, some assert that molecular weight affects the diffusion and spread of the toxin.11,12 As such, neu-BoNT/A was developed as a highly homogenous 900-kDa toxin complex to further ease comparability with onabotulinumtoxinA and produce similar diffusion properties.8 The potencies of neu-BoNT/A and onabotulinumtoxinA are also nearly identical, and can be interconverted on a 1:1 ratio.8 Several techniques are used to investigate the comparative efficacies of toxin preparations, including measuring compound muscle action potentials in mice after injection, the digit abduction scoring assay in mice, and measurement of reduction in murine muscle force generation after injection.8 Several preclinical studies incorporating these techniques to compare neu-BoNT/A and onabotulinumtoxinA have shown that their actions are bioequivalent and have a conversion ratio of 1:1.8,13 Clinically, the actions of these two toxins seem to be essentially equal. A double-blind, randomized, controlled study compared neuBoNT/A and onabotulinumtoxinA in the treatment of moderateto-severe glabellar wrinkles in 314 patients. At 4 weeks postinjection, responder rates were 93.7% in the neu-BoNT/A group and 94.5% in the onabotulinumtoxinA group, yielding no significant differences between the two groups. There were no serious adverse events with either product.14 Another double-blind, randomized, comparative study that treated essential blepharospasm showed no differences between the two products in efficacy or safety when administered at a 1:1 dose ratio.15 Although comparative studies are still scant and longer-term follow-up studies are still needed to assess for long-term safety of neu-BoNT/A, it seems to be nearly identical to onabotulinumtoxinA in composition, action, and efficacy. Despite their similarities, neu-BoNT/A offers a more cost-effective option to patients in Korea.8 This product is likely to become a viable competitor in the field of injectable neurotoxins.
Chinese type A botulinum toxin
Chinese type A botulinum toxin (CBTX-A, Lanzhou Biological Products Institute, Lanzhou, China) is also a serotype A botulinum toxin developed from the type A Hall strain of C. botulinum. In 1993, the Chinese Ministry of Health approved CBTX-A for use in a multitude of neurological and musculoskeletal disorders.16 The product was approved in 2012 by the Chinese Food and Drug Administration for the treatment of glabellar lines. It has since been widely used in China in aesthetic dermatology at a fraction of the cost of onabotulinumtoxinA.17 CBTX-A has not been widely investigated, and therefore, specific information regarding molecular weight and conversion ratios between CBTX-A and more well-known botulinum toxins is scant. Each vial of CBTX-A contains 100 U of purified neurotoxin, 5 mg of gelatin, 25 mg of dextran, and 25 mg of sucrose.16 Gelatin is a potent skin sensitizer, theoretically making CBTX-A more allergenic than onabotulinumtoxinA. In one study investigating CBTX-A in the treatment of hemifacial spasm and blepharospasm, erythema at injection sites was reported up to a few days after injection, which the investigators postulated might have been due to the composition of the product.16 In another study comparing onabotulinumtoxinA to CBTX-A in the treatment of hemifacial spasm and blepharospasm, CTBX-A and onabotulinumtoxinA appeared to provide equivalent rates of improvement, onset of action, and duration of response.18 In a similar investigation, it was noted that when administering the same units of onabotulinumtoxinA and CBTX-A, the onabotulinumtoxinA group experienced higher rates of complications due to neurotoxin overdose.16 In concordance with previous observations, this suggests that although the comparative potencies of both products have not been investigated; unit-to-unit, onabotulinumtoxinA may have a higher potency than CBTX-A.19 With injectable neurotoxins, the anatomic proximity and functional complexity of facial muscles demand accuracy and precision. Therefore, it is imperative to understand the diffusion properties of the injected toxin and be able to predict its action in order to avoid untoward effects in patients. A study conducted by Jiang et al sought to compare the diffusion properties of CBTXA and onabotulinumtoxinA.17 In the double-blinded, randomized, controlled study, CBTX-A and onabotulinumtoxinA were injected intradermally and subcutaneously into the foreheads of the study subjects. The Minor’s starch iodine test was then performed on the subjects’ foreheads in order to assess the area of anhidrosis created by the toxin, as an indirect measurement of its diffusion area. The study concluded that with both intradermal and subcutaneous injections, CBTX-A consistently demonstrated a greater area of diffusion when compared with onabotulinumtoxinA.17 Larger and longer-term studies are needed to characterize the inherent properties, potency, efficacy, and side-effect profile of CBTX-A. In time, CBTX-A may eventually provide patients with yet another alternative product with similar results as other neurotoxins, and at a much lower cost.19 NABOTA (DWP450)
NABOTA (DWP450, Daewoong, Co Ltd, Seoul, Korea) is a type A botulinum toxin that is almost identical to onabotulinumtoxinA. Similar to onabotulinumtoxinA, this complexed toxin weighs 900 kDa, is packaged in a 100-U vial, and each vial’s excipients are human serum Vol. 33, December 2014, Seminars in Cutaneous Medicine and Surgery 153
n n n Update on botulinum neurotoxin use in aesthetic dermatology
n TablE 1 Summary of recent botulinum toxin formulations Agent
Company
City
Country
Approval
IncobotulinumtoxinA (Xeomin)
Merz Pharmaceuticals
Frankfurt
Germany
United States, Europe, South Korea, Argentina for glabellar lines
Neuronox
Medytox Inc.
Cheonwon-gun
Korea
South Korea for blepharospasm
Chinese botulinum toxin A
Lanzhou Biological Products Institute
Lanzhou
China
China for glabellar lines
NABOTA (DWP450)
Daewoong, Co. Ltd.
Seoul
Korea
Pending
Botulinum toxin A gel (RT001)
Revance Therapeutics Inc.
Newark, California
US
Pending
albumin and sodium chloride.20 In a comparative trial by Kim and colleagues, onabotulinumtoxinA and DWP450 were injected into rats in a split-body fashion, and compound muscle action potentials were measured postinjection. The trial showed that there were no differences in paralytic effects between the 2 formulations.20 Another trial by Ko and colleagues compared the diffusion behaviors of 3 toxins: onabotulinumtoxinA, DWP450, and abobotulinumtoxinA.21 AbobotulinumtoxinA (Dysport, Medicis Aesthetics, Inc, Scottsdale, Arizona) is another type A botulinum neurotoxin that was FDA approved in the United States in 2009 for the treatment of glabellar lines.1 The results of this comparative trial demonstrated that 3.3 U of DWP450 and 3.3 U of onabotulinumtoxinA injected into the forehead exhibited almost identical anhidrotic halos on Minor’s starch iodine test 2 weeks posttreatment, suggesting that these 2 formulations may have similar diffusion properties. The anhidrotic halo of a bioequivalent 8.3 U of abobotulinumtoxinA was almost 3 times as large as those of the other 2 toxins, suggesting a greater diffusion capacity in comparison to onabotulinumtoxinA and DWP450.21 No other descriptive or comparative clinical trials exist that explore DWP450 further; however this product may soon expand in the literature and in the international market. Botulinum toxin type A topical gel (RT001)
Although the cosmetic use of botulinum toxin injections provides patients with desired results with an acceptable safety profile, adverse events still do occur. The lateral canthal area (LCA) is of particular concern due to the anatomic proximity of the orbicularis oris muscle to the globe of the eye, as well as to the zygomaticus major, contributing to the elevation of the lateral upper cutaneous lip.22 Misplaced injections in the LCA targeting lateral canthal lines (LCLs) can lead to partial lip ptosis or uncomfortably dry eyes.23-25 Complications have been reported involving light sensitivity and pupillary reflexes when injected at the LCA.26,27 In addition to expected injection-related pain, erythema, and swelling, bruising in the LCA is of particular concern due to thin skin and superficial blood vessels in the area.22 In attempts to minimize the risk of these complications, a novel botulinum toxin type A gel (RT001, Revance Therapeutics, Inc, Newark, CA) has been developed. The product contains an albumin-free 150-kDa toxin and a novel peptide that facilitates transcutaneous flux of the toxin.22 This product was specifically created to treat moderate-to-severe LCLs. In one of the first reported clinical 154 Seminars in Cutaneous Medicine and Surgery, Vol. 33, December 2014
experiments evaluating the product, investigators set out to determine the efficacy and safety of 2 sequential applications of RT001 in treating moderate-to-severe LCLs.22 Thirty-six subjects were randomized to receive either RT001 or placebo to bilateral LCAs at baseline and again at 4 weeks. Outcomes were measured using the Investigator’s Global Assessment of Lateral Canthal Line at Rest (IGA-LCL) Severity Scale. At 8 weeks, 50% of LCAs treated with RT001 demonstrated a 2-point or more improvement in baseline IGA-LCL versus none of the placebo subjects, and 94.7% of LCAs treated with RT001 demonstrated a 1-point or greater improvement in baseline IGA-LCL severity at 8 weeks posttreatment. Subjects reported significant improvements in LCLs after treatment with RT001. Of note, there were no treatment-related adverse events.22 In a similar study by Glogau et al, the investigators sought to assess the efficacy and safety of a single application of RT001 in the treatment LCLs. Subjects were randomized to receive either one treatment of RT001 or placebo. At 4 weeks posttreatment, 44.4% of the RT001 study group demonstrated a 2-point or greater improvement in baseline IGA-LCL versus 0% of the placebo. Furthermore, 88.9% of the RT001 study group achieved clinically relevant improvement by investigator assessment.28 In both studies combined, one subject exhibited mild, transient posttreatment erythema. None of the RT001 treated subjects experienced stinging, burning, scaling, ocular symptoms, or unwanted diffusion beyond the treated areas.22,28 In the near future, RT001 may come to the forefront as a viable noninvasive treatment of LCLs. Injection-associated pain, erythema, edema, and swelling would most likely be evaded, and most importantly, precision in treatment could be achieved. In recent years, the goal of neurotoxin injections has shifted towards a softer, more natural look, focusing more on eliminating wrinkles at rest while preserving normal facial movement. Aggressive treatment of LCLs can result in elimination of LCLs during active smiling, resulting in what patients deem as an unnatural, insincere, and undesirable smile.28 With further comparative and analytical studies, RT001 may soon become a staple in the gentler treatment of LCLs. Table 1 summarizes in detail the newer and upcoming botulinum toxin formulations. Novel uses of injectable neurotoxins Botulinum toxin and keloids
Keloids can be aesthetically displeasing and, depending on size and location, can have profound psychological and social conse-
O. Ibrahim, E. C. Keller, and K. A. Arndt quences on the patient. More than just cosmetically disfiguring, keloids can also be tender, sensitive, or pruritic. Many treatment modalities including intralesional corticosteroids or 5-fluorouracil, silicone sheets and gels, lasers, and cryotherapy have been attempted with varying degrees of success.29 Injection of botulinum toxin A (BTA) has been implemented in attempts to prevent keloid formation after surgery, and more recently, to treat keloids after trauma or surgery.30 In one study, injection of 15 U of onabotulinumtoxinA per 2 cm into the musculature adjacent to a surgical wound within 24 hours resulted in less noticeable scar formation compared with placebo.31 Another study showed similar results when BTA was injected 4-7 days prior to surgery. These investigations suggest that reduction of tension during the wound healing process may result in less noticeable scars.30 Recently, a prospective, uncontrolled study suggested the therapeutic use of BTA in the treatment of established keloids.32 Twelve subjects’ keloids (varying from 1 to 3 per subject) were injected at 3-month intervals for 3 total injections, and dosages ranged from 70 to 140 U per session. At 1-year follow-up, 3 subjects reported excellent results, 5 subjects reported good results, and 4 subjects reported fair results. Overall, some degree of improvement was noted in all subjects and there were no signs of recurrence within the follow-up period.32 The suggested mechanism of action of BTA was the toxin-induced decrease in fibroblast proliferation and reduction in fibrogenic factors like transforming growth factor b-1.33 Nevertheless, subsequent in vitro observations have contradicted this theory.30 The theory of reducing wound tension peri-operatively to prophylactically improve the cosmetic appearance of scars makes sense; however, the clinical efficacy and mechanism by which BTA acts on established keloids still merits further exploration. Preliminary findings suggest its efficacy in treating these lesions, but further in-depth, controlled studies are needed to characterize the effects of BTA on keloids. Botulinum toxin and skin texture
Subjective reports and observations have described improvement in skin texture, appearance of pores, and oiliness after treatment with botulinum toxin for rhytids.34 Patients have noted smoother, tighter skin with smaller pores and less oil. Oily skin not only gives the skin a shiny, greasy appearance, but is related to the activity of acne.34 Rose and Goldberg sought to prospectively investigate the efficacy and safety of intradermal injections of abobotulinumtoxinA in the treatment of oily skin.34 Twenty-three subjects with mild-to-moderate oiliness of their forehead were treated with 30-
45 U of intradermal abobotulinumtoxinA. Sebum levels before and after treatment were measured with a sebometer. Sebum production decreased by 75%, 80%, 73%, and 59% at 1 week, 1 month, 2 months, and 3 months posttreatment, respectively. Subjective improvement in pore size was also noted. Twenty-one patients reported 50%-75% improvement in skin oiliness, one patient reported >75% improvement, and one patient reported 25%-50% improvement. Two subjects exhibited decreased tone of the frontalis muscle after treatment; otherwise no other side effects were noted.34 The mechanism by which botulinum toxin improves oiliness and texture is not completely understood; however, a recent study by Li and colleagues helped elucidate the pathophysiology.35 Using immunohistochemistry and immunocytofluorescence, the investigators showed that sebaceous glands and sebocytes express acetylcholine receptors, and that stimulating these receptors leads to increased lipid synthesis. Further, when sebocytes were incubated with a-bungarotoxin, an acetylcholine receptor antagonist, lipid synthesis was inhibited.35 The findings of these studies suggest that botulinum toxin may aid in the treatment of sebum-induced conditions like acne vulgaris, as well as the improvement in skin texture and clarity. Botulinum toxin and menopausal hot flashes
Menopausal women commonly exhibit uncomfortable and sometimes debilitating hot flashes characterized by intense heat and diaphoresis. These episodes can also be accompanied by sleep disturbances, irritability, and depressed mood.36 In a randomized, controlled trial, investigators showed that intradermal injections of abobotulinumtoxinA into the glabella, mid- and lateral-forehead, tip of the nose, chin, scalp, chest, and neck, objectively decreased perspiration using the Minor’s starch iodine test. The authors suggest that decreased sweating reduces the intensity of hot flashes and reduces the perceived number of hot flashes possibly by making them less noticeable to patients. With decreased numbers of perceived hot flashes and less intense breakthrough episodes, subjects exhibited improvements in mood disturbances, night sweats, and irritability.36 Botulinum toxin and Raynaud phenomenon
Raynaud phenomenon is a potentially debilitating condition in which patients exhibit marked arterial constriction in response to cold, leading to pale or blue fingers, numbness, and even digital ulceration. Raynaud phenomenon affects nearly 3% of the US population and is more common in women.37 This condition,
n TablE 2 Experimental therapeutic uses of botulinum toxin Agent
Therapeutic Indication
Level of Evidence
References
OnabotulinumtoxinA
Pre- and intra-operative keloid prevention
Level 2c
31
OnabotulinumtoxinA
Keloid treatment
Level 2c
32
AbobotulinumtoxinA
Oily skin
Level 2c
34
AbobotulinumtoxinA
Menopausal hot flashes
Level 2b
36
OnabotulinumtoxinA
Raynaud phenomenon
Level 2b
38
Vol. 33, December 2014, Seminars in Cutaneous Medicine and Surgery 155
n n n Update on botulinum neurotoxin use in aesthetic dermatology whether primary or secondary to autoimmune disease, is notoriously difficult to treat. In recent years, investigators and clinicians have implemented botulinum toxin injections in the treatment of Raynaud phenomenon. In the pilot study, around 10 U of onabotulinumtoxinA were injected into each of 4 sites on the palmar aspect of the hand, subadjacent to the palmar fascia, targeting the superficial palmar arch. At 6 weeks posttreatment, toxin-treated hands demonstrated increased digital pulp temperatures when compared to saline-treated hands.38 Other reports and reviews also demonstrated that treatments with botulinum toxin led to reduction in pain, improvement in digital oxygenation, and dramatic healing of chronic ulcers.37 With further investigation and larger studies, botulinum toxin may prove to be a leading contender in the treatment of Raynaud phenomenon.Table 2 summarizes some of the more recent therapeutic applications of botulinum toxin injections. Conclusion Botulinum toxin has proved over the last 2 decades to be one of the most versatile and widely applicable medications in modern medicine. Knowledge of the new formulations, as well as some of the novel uses, is essential in order to offer patients a variety of treatments options in an innovative and safe manner founded in evidence-based medicine. Although much evolution and advancement has already occurred with these toxins, there is much more research that has yet to transpire. The future applications and indications of neurotoxins in aesthetic cutaneous medicine remains bright. References
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9.
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