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The Efficacy and Safety of Liquid-Type Botulinum Toxin Type A for the Management of Moderate to Severe Glabellar Frown Lines
Abstract
Botulinum toxin type A has been widely used to correct unwanted hyperfunctional facial lines. Most forms of botulinum toxin type A currently used require reconstitution, which is very inconvenient for users. The authors compared the efficacy and safety of a newly developed liquid-type botulinum toxin type A (MT10109L) and onabotulinumtoxinA (Botox) for moderate to severe glabellar lines.
A double-blind, randomized, active drug-controlled, phase III study with 168 enrolled subjects was performed. The primary efficacy endpoint was the improvement rate at maximum frown at week 4 by the investigators' live assessment. The secondary efficacy endpoint included the improvement rate at maximum frown at week 16 and at rest at weeks 4 and 16 by live assessment, and the improvement rate at maximum frown and at rest based on photographic assessment at week 4. Self-assessment and self-satisfaction with glabellar line improvement were also evaluated.
The improvement rate at maximum frown by live assessment was not significantly different between the MT10109L and Botox groups. In addition, the improvement rate of glabellar lines at rest based on the investigators' live assessment and photographic assessment was similar in both treatment groups. However, the improvement rate at maximum frown by live assessment at week 16 was significantly higher in the MT10109L group compared with the Botox group. There were no severe adverse events.
The efficacy and safety of MT10109L were comparable to those of Botox for the management of glabellar frown lines. MT10109L provides greater convenience because it does not require dilution and has long-lasting effects.
Therapeutic, II.
... EB-001 tiene la particularidad de ser una TB de tipo E [3]. Por último, NT10109L es también una TB de tipo A, pero esta se presenta en forma líquida, por lo que no precisa reconstituirse [4]. ...
... Todas las toxinas comercializadas en España se presentan envasadas en polvo y deben ser reconstituidas antes de ser inyectadas. Kim et al (2015) publicaron un estudio para valorar la eficacia y seguridad de MT10109L, TB-A en presentación líquida, en el tratamiento de las líneas glabelares moderadas y severas [4]. Es un estudio de fase 3, doble ciego, randomizado, controlado por fármaco, que incluyó a 168 pacientes, divididos en dos grupos, uno recibió la 20 U de TB-A líquida y el otro 20 U de OnaBT-A (asumiendo una ratio de equivalencia de 1:1), inyectando 4 U en cada uno de los 5 puntos clásicos del tratamiento glabelar. ...
... Todas las toxinas comercializadas en España se presentan envasadas en polvo y deben ser reconstituidas antes de ser inyectadas. Kim et al (2015) publicaron un estudio para valorar la eficacia y seguridad de MT10109L, TB-A en presentación líquida, en el tratamiento de las líneas glabelares moderadas y severas [4]. Es un estudio de fase 3, doble ciego, randomizado, controlado por fármaco, que incluyó a 168 pacientes, divididos en dos grupos, uno recibió la 20 U de TB-A líquida y el otro 20 U de OnaBT-A (asumiendo una ratio de equivalencia de 1:1), inyectando 4 U en cada uno de los 5 puntos clásicos del tratamiento glabelar. ...
... Recently, a liquid-type BTX-A has been developed, which should simplify the procedure and enhance its efficacy. Liquid-type BTX-A has been approved in Korea for treatment of glabellar frown lines, 14 but there are no reports regarding the efficacy and safety of liquidtype BTX-A in the treatment of SD. Herein, we present a prospective pilot study to investigate the efficacy and safety of liquid-type BTX-A in the treatment of SD. ...
... Innotox consists of BTX-A-type macromolecular protein complexes with molecular weights of 900 kDa, which is similar to Allergan's Botox product. 14,20 Innotox was introduced to the domestic market in Korea in June 2013 and was approved by the Ministry of Food and Drug Safety (formerly Korea Food and Drug Administration) for treatment of glabellar lines in December 2013. We have been using Botox for treatment of SD at our voice and swallowing center, and Botox has been the best-known and most widely used brand of BTX-A across disciplines. ...
... It does not require reconstitution, and storage and reuse are more convenient than freeze-dried-type BTX-A. Liquid-type BTX-A maintains stability and is maximally usable for 22 months from the date of manufacture, 14 whereas Botox should be used within 4 hours to 6 weeks after reconstitution. 30,31 Liquid-type BTX-A is currently available for clinical use only in 0.625 mL vials (25 units/vial; 4 units/0.1 cc). ...
Objectives:
Botulinum toxin (BTX) has been widely used to treat adductor spasmodic dysphonia (ADSD). Most commercially available forms of BTX require reconstitution before use, which may increase the risk of contamination and requires careful titration. Recently, a liquid-type BTX type A (BTX-A) has been developed, which should simplify the procedure and enhance its efficacy. Herein, we present a prospective pilot study to investigate the efficacy and safety of liquid-type BTX-A in the treatment of ADSD.
Methods:
Twenty-six consecutive liquid-type BTX-A injections were performed in 12 patients with ADSD. We included as a control group 34 consecutive patients with ADSD who had previously undergone 52 vocal fold injection procedures with freeze-dried-type BTX-A.
Results:
All patients in both groups had improvement of symptoms related to ADSD and period of normal voice. Most patients experienced breathiness, and the onset time, the peak response time, and the duration of breathiness were similar in both groups. The duration of effect (days) was 96.96 ± 18.91 and 77.38 ± 18.97 in the freeze-dried-type and the liquid-type groups, and the duration of benefit (days) was 80.02 ± 18.24 and 62.69 ± 19.73 in the freeze-dried-type and the liquid-type groups. To compare the efficacy between the freeze-dried-type and the liquid-type BTX-A, the sessions of the unilateral vocal fold injection were included and were categorized as group A (1 ~ 2 units BTX-A) and group B (2 ~ 3 units BTX-A), according to the dose per vocal fold. There was no significant difference of effect time between freeze-dried-type and liquid-type BTX-A groups. No adverse events related to BTX or vocal fold injection were reported.
Conclusions:
Liquid-type BTX-A is safe and effective for the treatment of spasmodic dysphonia. With the advantages of simple preparation, storage, and reuse and animal protein-free constituents, liquid-type BTX-A may be a good option in the treatment of spasmodic dysphonia.
... A new formulation, called the liquid-type BoNT A, has been developed in Korea by Medytox under the name of Innotox that simplifies the procedure and avoids contamination. A similar liquid-type toxin named MT10109L is being developed in North America and is in its early stages of phase III clinical trials in Canada and USA [20]. It is being evaluated for safety and efficacy in treatment of moderate to severe glabellar and lateral canthal lines. ...
... MT10109L does not contain any animal-derived products or albumin. In a double-blind, randomized, phase III study of 168 patients, there was no significant difference in the improvement rate at maximum frown and at rest by both live and photographic assessment between the MT10109L and Botox groups at week 4 [20]. ...
Being the most popular non-surgical cosmetic procedure, botulinum neurotoxin (BoNT) injections are increasingly of interest to all cosmetic practitioners across the globe. This article serves to update readers on the new botulinum toxins that are currently in development or close to market in the USA and Canada, including daxibotulinumtoxin A, prabotulinumtoxin A, letibotulinumtoxin A, and botulinum toxin E. Despite having relatively similar characteristics and equivalent clinical efficacies, these neurotoxins manifest a multitude of unique potential advantages that will be explored in this review, including but not limited to a longer duration of action, the absence of animal-derived components or human albumin, and a rapid onset with short duration of action.
... 57 A ready-to-use sterile liquid formulation of a novel BoNT-A, MT10109L, developed by MedyTox, Inc. (Cheongju, South Korea), does not require dilution before use and contains no albumin or animal-derived proteins. 58 The molecular weight and diffusion capacity of MT10109L are reported to be similar to those of ONA. ...
... Similarly, rates of adverse events were similar in each group. 58 The differences in efficacy are readily explained by the fact that the potency units of botulinum products are specific to each product family and are not interchangeable. 1 Therefore, even at apparently "equal" doses, these differences may manifest as different clinical responses. ...
BotulinumtoxinA (BoNT-A) is now widely established for the main approved indication of reducing glabellar lines, and is also widely used off-label to improve the appearance of wrinkles and lines in other parts of the face. The number of aesthetic procedures continues to increase as the patient population becomes more diverse, in particular with increasing numbers of people of color and men. Further developments in treatment may continue to expand the audience for BoNT-A by making procedures more comfortable and by delivering a more natural, less static appearance. These may be achieved through use of combinations of BoNT-A with other aesthetic procedures, tailoring the dose of toxin to the patient’s muscle mass or by using novel injection and application techniques. Beyond amelioration of facial lines, encouraging results have been seen with the use of BoNT-A to improve the appearance of hypertrophic and keloid scars and even to prevent them. Studies have been conducted with scars in various parts of the body and further research is ongoing. Dermatological and other medical uses for BoNT-A are also active areas of research. Injections of BoNT-A have been shown to reduce signs and symptoms of acne, rosacea, and psoriasis, to reduce neuromuscular pain, and to bring about significant improvements in a number of rare diseases that are caused or exacerbated by hyperhidrosis. This paper reviews these new uses for BoNT-A, looking at the rationale for their use and discussing the results of published case studies and clinical trials. These areas have shown great promise to date, but more and larger clinical studies will be required before these treatments become a clinical reality. To this end details are also provided of clinical trials currently listed in the main clinical trials database to highlight research areas of particular interest.
... Recently, a liquid form of BT that can be used immediately without dilution or recombination (Innotox [Medytox Inc.]) was commercialized. The liquid product uses a medium with no animal-derived substances that contains L-methionine and polysorbate for stabilization and has been approved for safety by the U. S. FDA, instead of the traditional human serum albumin [18]. The toxin is directly transferred into the vial in a liquid state without freezing or vacuum drying. ...
The Korean Society of Laryngology, Phoniatrics and Logopedics set a task force to establish clinical practice guidelines for the use of botulinum toxin (BT) in the otolaryngology field. We selected ten disease categories: spasmodic dysphonia, essential vocal tremor, vocal fold granuloma, bilateral vocal fold paralysis, Frey's syndrome, sialocele, sialorrhea, cricopharyngeal dysfunction, chronic sialadenitis, and first bite syndrome. To retrieve all relevant papers, we searched the CORE databases with predefined search strategies, including Medline (PubMed), Embase, the Cochrane Library, and KoreaMed. The committee reported the final 13 recommendations with detailed evidence profiles. The guidelines primarily target all clinicians applying BT to the head and neck area. In addition, the guidelines aim to promote an improved understanding of the safe and effective use of BT by policymakers and counselors, as well as in patients scheduled to receive BT injections.
... Historically, commercial BoNT-A products have been formulated as a powder for reconstitution prior to injection. However, new products in a ready-to-use liquid formulation are coming to market, with products being approved in Korea [8] and in Europe (abobotulinumtoxinA (aboBoNT-A) in a novel liquid formulation (Alluzience ® )). Potency testing is a requirement for the registration of pharmaceuticals for human use [9]. ...
Botulinum neurotoxins (BoNTs) are important therapeutic agents. The in vivo median lethal dose (LD50) assay has been commonly used to measure the potency of BoNT commercial preparations. As an alternative, we developed cell-based assays for abobotulinumtoxinA in both powder (Dysport®, Azzalure®) and liquid (Alluzience®) formulations using the in vitro BoCell® system. The assays demonstrated linearity over 50–130% of the expected relative potency, with a correlation coefficient of 0.98. Mean recoveries of 90–108% of the stated potency were observed over this range. The coefficients of variation for powder and liquid formulations, respectively, were 3.6% and 4.0% for repeatability and 8.3% and 5.0% for intermediate precision. A statistically powered comparability assessment of the BoCell® and LD50 assays was performed. Equivalence was demonstrated between the assays for the liquid formulation at release and end of shelf life using a paired equivalence test with predefined equivalence margins. For the powder formulation, the assays were also shown to be equivalent for release samples and when determining loss of potency following thermal degradation. The BoCell® assay was approved for establishing the potency of abobotulinumtoxinA for both powder and liquid formulations in Europe and for the powder formulation only in the USA.
... Many commercially available BoNT/A products have been used, and many novel BoNT/A products have been developed [11,12]. OBoNT, Abo-BoNT/A and Neu- BoNT/A consist of a complex of BoNT/A and complexing proteins, although the exact molecular composition of each product is undisclosed. ...
Background:
Botulinum toxin type A is widely used to treat primary axillary hyperhidrosis and has proven to be an effective and safe approach. Onabotulinumtoxin A was approved by the FDA as a treatment for primary axillary hyperhidrosis. This study aimed to evaluate the efficacy and safety of Neu-BoNT/A in subjects diagnosed with primary axillary hyperhidrosis.
Methods:
The Hyperhidrosis Disease Severity Scale, gravimetric measurement of sweat, and Global Assessment Scale were analyzed at weeks 4, 8, 12, and 16 to determine the effect of treatment. Adverse events, physical examination, and vital signs were monitored.
Results:
Subjects treated with Neu-BoNT/A showed statistically significant improvement by all 3 methods at weeks 4, 8, 12, and 16 (P value = 0.00). There were no severe adverse events or significant changes in vital signs, physical examination, or laboratory tests.
Conclusion:
Neu-BoNT/A can be effectively and safely used for primary axillary hyperhidrosis.
Level of evidence ii:
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
... NivobotulinumtoxinA (NIVO; Innotox®, Medytox, Inc., Seoul, South Korea, and MT10109L, Allergan, Inc., Irvine, California, USA) is non-inferior to ONA for the treatment of frown lines, and is undergoing studies to determine clinical efficacy for glabellar lines. 67,68 QM-1114 (Galderma Laboratories, L.P., Lausanne, Switzerland) is superior for the treatment of glabellar lines compared to placebo, and is currently being studied for the reduction of lateral canthal lines. [69][70][71] In addition to new formulations of BoNT-A, liquid BoNT-E (ED-001, Bonti, Inc., Newport Beach, California, USA) is being pursued due to its purported faster onset of action (24 hours post-injection) and decreased duration of clinical results (14-30 days). ...
Background: Botulinum toxin (BoNT), a bacterially produced neurotoxin, is a mainstay in the dermatologic armamentarium. Although BoNT is commonly used to treated rhytides associated with ageing, it can be employed for a variety of other cosmetic purposes and medical disorders. Objective: In this review, the authors aim to describe the multitude of uses for BoNT in the dermatologic field. Materials and Methods: This manuscript was designed as a retrospective review of the on- and off-label applications of BoNT in dermatology.Results: In addition to treatment of rhytides, BoNT has been shown to decrease rosacea, menopause-associated flushing, and facial sebum production, while improving patient confidence in their appearance. Furthermore, BoNT has been successfully used to treat primary hyperhidrosis, hair loss, aberrant scarring, Raynaud’s phenomenon-associated vasospasm, as well as a variety of skin diseases. Side effects of BoNT include pain or discomfort associated with injections during treatment, bruising, asymmetry, and swelling. Patients are generally satisfied with clinical results after BoNT treatment. Conclusion: Dermatologists should be aware of all on- and off-label applications of BoNT to provide patients with timely and appropriate medical care. Further research must be completed to fully characterise the safety and use of BoNT for off-label purposes.
... Unlike other BoNT/A products that contain HSA, Prosigne contains bovine gelatin, which is potentially allergenic. 76 Clinical data on the safety and efficacy of Botulax, Nabota/Jeuveau, Meditoxin/Neuronox, and Coretox in medical esthetics are limited [77][78][79][80] (Table 2). To our knowledge, 2 esthetic trials with Botulax have been completed, the results of which have not yet been disclosed or published (ClinicalTrials.gov ...
Recently launched esthetic botulinum toxin serotype A (BoNT/A) products include Nabota/Jeuveau, Meditoxin/Neuronox, and Botulax, which contain nontoxic accessory proteins and excipients. Clinical evidence supporting these formulations, including their purity and potential immunogenicity or their link to treatment failures, is limited. Any nonhuman protein, including nontoxin accessory proteins, can initiate immune reactions, especially if administered repeatedly, yet the issue of BoNT/A-induced immunogenicity is widely contested. However, there have been multiple reports of treatment failures and observations of BoNT/A-induced neutralizing antibodies. Compared with the purified formulation in Xeomin, these recently launched toxins contain higher total neurotoxin quantities, much of which is inactive and exposes patients to potentially immunogenic nontoxin proteins or inactive neurotoxins that increase their risk of developing treatment failure. Well-established products [especially abobotulinumtoxinA (Dysport), onabotulinumtoxinA (Botox) and Xeomin] are accompanied by comprehensive and long-ranging clinical evidence on safety and efficacy in esthetic facial indications, which still remains undisclosed for many of the recently introduced toxins. Clinicians need this information as patients will require repeated BoNT treatments and may be unnecessarily but cumulatively exposed to potential immunogens. To underscore the need for caution and further evidence, we review some of the issues surrounding BoNT/A-induced immunogenicity and antibody-induced treatment failures and argue that using highly purified toxins that do not negatively impact patient outcomes is a prudent clinical decision.
... 13 Finally, freeze-dried BoNT-A products contain human serum albumin and other animal-derived materials for stabilization, thereby increasing the risk of disease transmission and immune reactions. 5 In summary, the development of a liquid formulation of BoNT-A may represent a significant advancement over existing commercial products. ...
... The results of the present study were comparable to those of a recent study that confirmed the safety and efficacy of MT10109L (Neuronox Aqua, Medy Tox, Inc.), a liquid formulation of BoNT-A for use in the management of glabellar frown lines. 16 Approximately one third of subjects in each group had at least one TEAE. The incidence and type of TEAEs were similar across the active treatment groups. ...
Background:
In most countries, approved botulinum toxin type A formulations require reconstitution before injection.
Objectives:
To evaluate the efficacy and safety of a ready-to-use liquid formulation of abobotulinumtoxinA (abobotulinumtoxinA solution for injection, ASI) in subjects with moderate to severe glabellar lines (GL).
Methods:
In this Phase II, double-blind, placebo-controlled, randomized study, 176 female subjects (aged 30 to 60 years) were randomized into five treatment groups: ASI 20, 50, or 75 U, reconstituted abobotulinumtoxinA (aboBoNT-A) 50 U, and placebo. GL severity was assessed at maximum frown using a 4-point grading scale. Responders were subjects with severity grade of moderate [2] or severe [3] at baseline improving to none [0] or mild [1], evaluated at each time-point by Investigator's Live Assessment (ILA) or Subject's Self-Assessment (SSA). Safety profiles were also determined.
Results:
Baseline characteristics were similar across groups. Responder rates on Day 29 by ILA were significantly greater for ASI 20, 50, and 75 U versus placebo (88.9%, 91.4%, and 87.9% vs. 0%, respectively; P < 0.0001). Similar results were observed by SSA. A greater proportion of responders was observed in ASI groups vs placebo from Day 8 to 113 for ILA and SSA (P < 0.001). AboBoNT-A responder rate on Day 29 for ILA was 77.1% (P < 0.1006 vs ASI 50 U); with comparable results by SSA. The ASI safety profile was comparable to that of aboBoNT-A.
Conclusions:
Ready-to-use liquid formulation of abobotulinumtoxinA was shown to be efficacious, with comparable results to reconstituted abobotulinumtoxinA, and to have a favorable safety profile in subjects with severe to moderate GL.
Level of evidence 1:
Objective
This article provides a comprehensive overview of recent advancements in cosmetic dermatology and aesthetics. It covers topics including dermal fillers, botulinum toxin (BTX anti‐aging cosmeceuticals, artificial intelligence (AI) applications, and energy‐based devices.
Methods
The review summarizes the current literature on dermal fillers, BTX, cosmeceuticals, AI applications, and energy‐based devices. It explores emerging technologies, new treatment methods, and ongoing research in these areas. The sources of data include peer‐reviewed journals, clinical trials, and expert opinions to provide a thorough understanding of recent developments and future trends.
Results
Dermal fillers, particularly hyaluronic acid (HA), are popular in cosmetic treatments, with innovations like Bioorthogonal strategies and thiomer‐based technology emerging. Biostimulators such as poly‐ l ‐lactic acid and calcium hydroxyapatite promote neo‐collagenesis. BTX remains a cosmetic standard, with new recombinant toxins, hybrid BTXs, and delivery methods enhancing safety and efficacy. Anti‐aging trends include cellular senescence‐targeting treatments like exosomes, NMN, and PDRN, which need further validation. AI improves diagnosis, personalized treatments, and patient consultations but faces data privacy and bias challenges. Advanced energy‐based devices (RF, HIFU, lasers) and treatments like cryolipolysis and MFU‐V enhance skin rejuvenation and body contouring.
Conclusion
Recent advancements in cosmetic dermatology and aesthetics, including innovative dermal fillers, BTX developments, anti‐aging cosmeceuticals, AI applications, and energy‐based devices, are transforming the field. These innovations provide enhanced treatment options and improved patient outcomes, although further research is necessary to validate efficacy and address emerging challenges. The future of cosmetic dermatology is promising, with ongoing technological advancements driving continuous improvements in aesthetic medicine.
Background
Skin of color (SOC) individuals represent a growing market for cosmetic injectables and can have different aesthetic goals and responses to treatment.
Objective
A review of the uses, safety, and effectiveness of injectable neuromodulators and dermal fillers in SOC individuals.
Methods and Materials
A search of the PubMed/MEDLINE database was conducted from August 1960 to December 2020. Studies that were included either had a focus on SOC (>20% SOC study participants) or dedicated article content commenting on the safety and/or efficacy of injectables in SOC participants.
Results
Of the 503 publications identified, a total of 88 articles were selected for this review. Differences in aging and cultural factors can influence aesthetic goals amongst SOC populations. Available data suggests that botulinum toxin (BTX) and dermal fillers are safe and effective in SOC populations, with the largest amount of data existing for Asian populations. There remains a paucity of research on Black and Latinx populations.
Conclusion
BTX and dermal fillers are generally effective and well tolerated in SOC populations, particularly Asian populations for which the greatest amount of data exists. More high quality, randomized controlled trials in Black and Latinx populations are warranted.
Botulinum toxins are produced by the Gram‐positive, spore‐forming anaerobe Clostridium botulinum , and cause chemical denervation by suppressing the release of the neurotransmitter acetylcholine from the axon terminals of peripheral nerves. The process of chemical denervation requires that the neurotoxin heavy chain bind the synaptic vesicle glycoprotein 2 on the presynaptic nerve terminal. The neurotoxin–protein complex size of Botox is approximately 900 kDa and the most common vial size used is 100 units, though it is available in 50 units as well. The frontalis muscle is contiguous with the galea aponeurotica of the scalp superiorly, and inserts inferiorly into the skin of the brow. Botox is the only botulinum neurotoxin type A (BoNTA) approved for the treatment of periorbital rhytides. Immunogenicity to BoNTA has been reported in the literature but is very rare in patients treated with the newer formulation of Botox.
Background:
Botulinum toxin type A (BontA) is the most frequent treatment for facial wrinkles, but its effectiveness and safety have not previously been assessed in a Cochrane Review.
Objectives:
To assess the effects of all commercially available botulinum toxin type A products for the treatment of any type of facial wrinkles.
Search methods:
We searched the following databases up to May 2020: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs).
Selection criteria:
We included RCTs with over 50 participants, comparing BontA versus placebo, other types of BontA, or fillers (hyaluronic acid), for treating facial wrinkles in adults.
Data collection and analysis:
We used standard methodological procedures expected by Cochrane. Primary outcomes were participant assessment of success and major adverse events (AEs) (eyelid ptosis, eyelid sensory disorder, strabismus). Secondary outcomes included physician assessment of success; proportion of participants with at least one AE and duration of treatment effect. We used GRADE to assess the certainty of the evidence for each outcome.
Main results:
We included 65 RCTs, involving 14,919 randomised participants. Most participants were female, aged 18 to 65 years. All participants were outpatients (private office or day clinic). Study duration was between one week and one year. No studies were assessed as low risk of bias in all domains; the overall risk of bias was unclear for most studies. The most common comparator was placebo (36 studies). An active control was used in 19 studies. There were eight dose-ranging studies of onabotulinumtoxinA, and a small number of studies compared against fillers. Treatment was given in one cycle (54 studies), two cycles (three studies), or three or more cycles (eight studies). The treated regions were glabella (43 studies), crow's feet (seven studies), forehead (two studies), perioral (two studies), full face (one study), or more than two regions (nine studies). Most studies analysed moderate to severe wrinkles; mean duration of treatment was 20 weeks. The following results summarise the main comparisons, based on studies of one treatment cycle for the glabella. AEs were collected over the duration of these studies (over four to 24 weeks). Compared to placebo, onabotulinumtoxinA-20 U probably has a higher success rate when assessed by participants (risk ratio (RR) 19.45, 95% confidence interval (CI) 8.60 to 43.99; 575 participants; 4 studies; moderate-certainty evidence) or physicians (RR 17.10, 95% CI 10.07 to 29.05; 1339 participants; 7 studies; moderate-certainty evidence) at week four. Major AEs are probably higher with onabotulinumtoxinA-20 U (Peto OR 3.62, 95% CI 1.50 to 8.74; 1390 participants; 8 studies; moderate-certainty evidence), but there may be no difference in any AEs (RR 1.14, 95% CI 0.89 to 1.45; 1388 participants; 8 studies; low-certainty evidence). Compared to placebo, abobotulinumtoxinA-50 U has a higher participant-assessed success rate at week four (RR 21.22, 95% CI 7.40 to 60.56; 915 participants; 6 studies; high-certainty evidence); and probably has a higher physician-assessed success rate (RR 14.93, 95% CI 8.09 to 27.55; 1059 participants; 7 studies; moderate-certainty evidence). There are probably more major AEs with abobotulinumtoxinA-50 U (Peto OR 3.36, 95% CI 0.88 to 12.87; 1294 participants; 7 studies; moderate-certainty evidence). Any AE may be more common with abobotulinumtoxinA-50 U (RR 1.25, 95% CI 1.05 to 1.49; 1471 participants; 8 studies; low-certainty evidence). Compared to placebo, incobotulinumtoxinA-20 U probably has a higher participant-assessed success rate at week four (RR 66.57, 95% CI 13.50 to 328.28; 547 participants; 2 studies; moderate-certainty evidence), and physician-assessed success rate (RR 134.62, 95% CI 19.05 to 951.45; 547 participants; 2 studies; moderate-certainty evidence). Major AEs were not observed (547 participants; 2 studies; moderate-certainty evidence). There may be no difference between groups in any AEs (RR 1.17, 95% CI 0.90 to 1.53; 547 participants; 2 studies; low-certainty evidence). AbobotulinumtoxinA-50 U is no different to onabotulinumtoxinA-20 U in participant-assessed success rate (RR 1.00, 95% CI 0.92 to 1.08, 388 participants, 1 study, high-certainty evidence) and physician-assessed success rate (RR 1.01, 95% CI 0.95 to 1.06; 388 participants; 1 study; high-certainty evidence) at week four. Major AEs are probably more likely in the abobotulinumtoxinA-50 U group than the onabotulinumtoxinA-20 U group (Peto OR 2.65, 95% CI 0.77 to 9.09; 433 participants; 1 study; moderate-certainty evidence). There is probably no difference in any AE (RR 1.02, 95% CI 0.67 to 1.54; 492 participants; 2 studies; moderate-certainty evidence). IncobotulinumtoxinA-24 U may be no different to onabotulinumtoxinA-24 U in physician-assessed success rate at week four (RR 1.01, 95% CI 0.96 to 1.05; 381 participants; 1 study; low-certainty evidence) (participant assessment was not measured). One participant reported ptosis with onabotulinumtoxinA, but we are uncertain of the risk of AEs (Peto OR 0.02, 95% CI 0.00 to 1.77; 381 participants; 1 study; very low-certainty evidence). Compared to placebo, daxibotulinumtoxinA-40 U probably has a higher participant-assessed success rate (RR 21.10, 95% CI 11.31 to 39.34; 683 participants; 2 studies; moderate-certainty evidence) and physician-assessed success rate (RR 23.40, 95% CI 12.56 to 43.61; 683 participants; 2 studies; moderate-certainty evidence) at week four. Major AEs were not observed (716 participants; 2 studies; moderate-certainty evidence). There may be an increase in any AE with daxibotulinumtoxinA compared to placebo (RR 2.23, 95% CI 1.46 to 3.40; 716 participants; 2 studies; moderate-certainty evidence). Major AEs reported were mainly ptosis; BontA is also known to carry a risk of strabismus or eyelid sensory disorders.
Authors' conclusions:
BontA treatment reduces wrinkles within four weeks of treatment, but probably increases risk of ptosis. We found several heterogeneous studies (different types or doses of BontA, number of cycles, and different facial regions) hindering meta-analyses. The certainty of the evidence for effectiveness outcomes was high, low or moderate; for AEs, very low to moderate. Future RCTs should compare the most common BontA (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, daxibotulinumtoxinA, prabotulinumtoxinA) and evaluate long-term outcomes. There is a lack of evidence about the effects of multiple cycles of BontA, frequency of major AEs, duration of effect, efficacy of recently-approved BontA and comparisons with other treatments.
Facial rejuvenation is gaining immense popularity among patients and clinicians. Botulinum toxins derived from bacteria are well-tolerated options as minimally invasive interventions for facial rejuvenation or other aesthetic procedures. These products have revolutionized aesthetic treatments. Several types of botulinum toxins (BoNT) are available. Currently type A and B are clinically used and only BoNT‑A products are approved for use for cosmetic indications in the Germany and the United States. Each product is unique in terms of its composition. Understanding the various BoNT‑A products is essential in choosing the optimal treatment for our patients. In this article we discuss different BoNT‑A products used for aesthetic intervention.
Botulinum neurotoxins (BoNTs), produced by Clostridia and other bacteria, are the most potent toxins known. Their cleavage of the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins in neurons prevents the release of neurotransmitters, thus resulting in the muscle paralysis that is characteristic of botulism. This mechanism of action has been exploited for a variety of therapeutic and cosmetic applications of BoNTs. This chapter provides an overview of the native BoNTs, including the classical serotypes and their clinical use, mosaic BoNTs, and novel BoNTs that have been recently identified in clostridial and non-clostridial strains. In addition, the modular structure of native BoNTs, which are composed of a light chain and a heavy chain, is amenable to a multitude of novel fusions and mutations using molecular biology techniques. These novel recombinant BoNTs have been used or are being developed to further characterize the biology of toxins, to assist in vaccine production, to serve as delivery vehicles to neurons, and to be utilized as novel therapeutics for both neuronal and non-neuronal cells.
Introduction:
The pursuit of youth and beauty has undergone a resurgence of interest which is evidenced by increasing cosmetic procedures. Botulinum Toxin Type A (Botox) is one among the many procedures invented for facial rejuvenation which denervates certain muscles of facial expression responsible for facial wrinkles. It has been applied in the forehead, glabella, lateral canthal area and neck. In maxillofacial area hyperactive forehead wrinkles show sagging.
Aim:
This study was aimed to clinically evaluate the efficacy of Botox injection in the elimination of hyperdynamic forehead wrinkles and the objectives were to compare pre-operative and post-operative improvement in the number of wrinkles, photographic grading and patient satisfaction responses after 1(st) week, 4(th) week and 16(th) week.
Materials and methods:
A total of 10 patients were randomly included in the present study who were cooperative, motivated and aesthetically conscious with moderate to severe forehead wrinkles. Assessment was performed clinically, photographically (using standardized photographs) and patient satisfaction responses were recorded at 1(st) week, 4(th) week and 16(th) week.
Results:
The study showed a significant difference in the elimination of wrinkles at rest and in action when assessed at 1(st) week and 4(th) week and it was consistent at 16(th) week. The patient showed positive satisfaction response without ptosis of the upper eyelid.
Conclusion:
Treatment with Botox is simple, safe and an effective modality for reduction of forehead wrinkles. It offers an alternative management in a cost-effective way when compared to surgical procedures.
Botulinum toxin (BoNT) has been in use since the late 1970s, and over the last 20 years, its use has been extended to new indications in various areas of medicine. During these years of clinical use, some of the initial ideas have changed, and others have remained stable along with increasing experience with and knowledge about BoNTs.
To review the literature and prescribing information on all of the available products and to update the concept of handling toxins (preparations, reconstitution, storage, sterility, and dilution).
A review (not Cochrane type analysis) of the medical literature based on relevant databases (MEDLINE, PubMed, Cochrane Library, specialist textbooks, and manufacturer information) was performed.
Many of the precautions around BoNT use, often recommended by the manufacturers, are described in the clinical literature as too restrictive. The literature suggests that toxins may be sturdier and more-resistant to degradation than previously understood.
It is recommended that botulinum toxin be used immediately or within 2 weeks after its reconstitution because its efficacy might be compromised by prolonged storage.
To evaluate the efficacy of botulinum toxin type A (BTX-A) reconstituted over 6 consecutive weeks for the treatment of glabellar frown lines.
Four vials of BTX-A were reconstituted each of 7 days over a period of 6 weeks, totaling 28 vials, corresponding to seven reconstitution dates. During this period, the BTX-A was stored according to the manufacturer's instructions. On the day after the last reconstitution, all of the reconstituted vials were injected in patients from four dermatologic centers taking part in this study. A total of 88 patients were treated on the same day and were followed every 2 weeks for 4 months. All patients were photographed at all stages. A number of professionals assessed the efficacy of reconstituted BTX-A based on the reduction of the maximum frowning capacity of the treated muscles.
Of the 88 patients who were selected, 3 were excluded. Three forms of evaluation were applied, and no statistically significant differences were found in the results presented.
BTX-A may be applied up to 6 weeks after reconstitution without losing its effectiveness. Other factors, which are probably individual, may influence the response to BTX-A injections.
Botulinum toxin (Botox) is a neurotoxin produced by Clostridium botulinum and has been used for medical treatment since 1978. The treatment of expression lines with Botox described in 1992 is effective and widely used, but needs good training to avoid the few possible complications. Our experience (2 years, 130 patients treated) has shown that it is a safe and very reproducible procedure with no complications if the technique is good. We can predict the movement of the brows in relation to the site of injection. Botox is one of the best treatments for expression lines of the glabella, forehead and periorbital area.
Background:
Duration of effect of aesthetic treatments with botulinum toxin potentially influences subject satisfaction, treatment frequency, and annual costs, but quantitative outcomes for measuring duration of effect and correlations with subject satisfaction have yet to be fully elucidated.
Methods and materials:
Phase III clinical trials with similar designs were identified and their data pooled to ascertain duration of clinical effect of onabotulinumtoxinA in glabellar muscles. Duration was calculated using the Kaplan-Meier method for investigator-rated Facial Wrinkle scale (FWS) scores and subject global assessment (SGA) of glabellar lines. Responders were determined according to FWS score at maximum contraction and at repose 30 days after injection.
Results:
Data from four trials with 621 onabotulinumtoxinA-treated (20 U) subjects were analyzed, 523 of these (84.2%) were identified as day-30 responders on the FWS at maximum contraction. Pooled median duration of effect for day-30 responders was 120 days for FWS at maximum contraction and 131 days for FWS at repose. Higher day 30 SGA scores were correlated with a greater duration of effect on dynamic, but not static lines.
Conclusion:
Treatment of glabellar lines with 20 U of onabotulinumtoxinA resulted in sustained clinical benefit for 4 months in more than 50% of responders; subject satisfaction increased with duration of effect.
Botulinum neurotoxin treatment is the most common aesthetic procedure in the United States. A number of serotypes and formulations are available worldwide. Similarities and differences among these toxins were evaluated by reviewing the existing literature.
Reports of botulinum neurotoxin for aesthetic use, published in peer-reviewed literature or presented at recent professional congresses, were reviewed to summarize key features of different toxins. Data from therapeutic uses in comparable anatomical areas were included in the review when aesthetic literature was limited.
Serotypes of neurotoxins share molecular structures and mechanisms of action but exhibit important differences between serotypes and between different formulations within the same serotype, including differences in distribution/diffusion patterns and risk/benefit profiles. The differences attributable to dissimilarities in bacterial strains, manufacturing techniques, and assays are likely to influence clinical performance.
Injection patterns, techniques, dilutions diffusion, and injection volumes established for a specific formulation of botulinum neurotoxin are not likely to be applicable to other formulations, and formulations are not interchangeable by any single conversion ratio. A large proportion of the clinical literature documents the aesthetic uses of the Allergan formulation of botulinum toxin type A. Additional studies are needed to establish optimal procedures for the Ipsen formulation and botulinum neurotoxin, and for diverse aesthetic uses.
Eighteen patients with glabellar frown lines were treated with C. botulinum-A exotoxin. Sixteen of the 17 patients followed showed improvement for periods ranging from 3 months to 11 months. Side-effects were minimal and transient. Because C. botulinum-A exotoxin therapy of glabellar frown lines treats the underlying cause of these lines, it is more effective than soft tissue augmentation although this improvement is temporary. Treatment with C. botulinum-A exotoxin is a simple, safe procedure.
A clinical trial was undertaken to evaluate the effects of commercially available botulinum toxin on 14 hyperactive corrugator muscles, 14 procerus muscles, one case of congenital aplasia of the depressor labii inferioris muscle, and one case of iatrogenic injury to the ramus mandibularis branch of the facial nerve with paralysis of the depressor labii and mentalis muscles. Of the 31 muscles injected, 28 were appropriately paralyzed with the initial injection. The desired results were obtained in the 3 remaining muscles following a second injection. The ability to frown was nullified in all subjects, resulting in the elimination of glabellar lines. Facial symmetry was achieved in both patients with muscle imbalance. The average duration of the paralysis was 8 weeks, with a range of 2 to 16 weeks. However, this period was prolonged in the latter part of the study with an adjustment of the toxin dose. Our results demonstrate that botulinum toxin injected into overactive facial muscles does produce a predictable and reversible paralysis and eliminates or ameliorates deep frown lines. We also illustrate its use in achieving facial symmetry in one patient with congenitally absent depressor labii inferioris and platysma muscles and in another with postrhytidectomy facial nerve paralysis.
Botulinum toxin has a well-defined role among dermatologists for the treatment of facial wrinkling, brow position, and palmar and axillary hyperhidrosis.
The purpose of this study is to educate dermatologists on the pharmacology of botulinum toxin.
A retrospective review of the literature on botulinum toxin from 1962 to the present was conducted. We examined the clinical applications of botulinum toxin, cholinergic neuromuscular transmission, the toxin's structure and molecular actions, drug and disease interactions at the neuromuscular junction, toxin assays, determinants of clinical response, and adverse side effects.
Botulinum toxin blocks the release of acetylcholine from the presynaptic terminal of the neuromuscular junction. Several drugs and diseases interfere with the neuromuscular junction and the effects of botulinum toxin. The mouse bioassay, the most sensitive and specific measurement of toxin activity, is the gold standard for botulinum toxin detection and standardization. The major determinants of clinical response to treatment are the toxin preparation, individual patient's anatomy, dose and response relationships, length of toxin storage after reconstitution, and immunogenicity. To minimize potential antibody resistance, one should use the smallest effective dose, utilize treatment intervals of more than 3 months, and avoid booster injections. Uncommon adverse effects include ptosis, ectropion, diplopia, bruising, eyelid drooping, hematoma formation, and temporary headaches.
Botulinum toxin is a safe and effective treatment. Knowledge of the pharmacologic basis of therapy will be useful for standardizing techniques and achieving consistent therapeutic results in the future.
The use of Botox for the treatment of hyperkinetic facial lines and furrows is another effective primary, adjunctive, or prophylactic therapy to offer cosmetic patients in the spectrum of treatment options for full facial rejuvenation. Unwanted side effects can be minimized, and beneficial effects can be maximized with a thorough understanding of the facial soft-tissue anatomy, proper patient selection, and administration of the lowest effective doses with minimal volume of delivery. Most often, Botox injection does not replace surgery, skin resurfacing, soft-tissue augmentation, or skin care; however, it is useful when used alone or with the various treatment options to give selected patients the most effective and comprehensive solutions for a more youthful appearance.
In aesthetic medicine, many different methods of skin rejuvenation are available. At the end of the 1980s, the neurotoxin Botulinum toxin A (BT-A) led to a revolution in aesthetic-corrective dermatology for the treatment of mimic facial wrinkles. The toxin is produced by Clostridium botulinum and causes a reversible, selective muscle relaxation that leads to a temporary flattening of the mechanical part of wrinkling without the stigmata of invasive surgery. After two decades of experience in different medical disciplines, there has been remarkable clinical development and progress in research, the identification of new botulinum toxin serotypes, and also innovation in indications and combined modalities. These lead to new and interesting questions. BT-A offers the experienced, critical dermatologist a time-saving, effective, cosmetically satisfactory, non-invasive treatment for mimic facial wrinkles and neck and decollete lines, with only minor side effects. Dermatologists should have a profound anatomical knowledge and should be able to perform all injection techniques to meet the needs of ever more demanding patients and to ensure optimization of patient satisfaction. The following review summarizes the historical development and the mechanism of action of both frequently and rarely used injection techniques with BT-A for the treatment of wrinkles and lines of the upper face, neck and décolleté, and gives an update of different experiences encountered.
Botulinum toxin type A (BTX-A) is widely used for facial esthetics but is incompletely studied.
This study was conducted to evaluate the efficacy and safety of BTX-A treatment of glabellar lines.
Patients with moderate to severe glabellar lines at maximum frown received intramuscular injections of 20 U BTX-A (BOTOX, Allergan, Inc, Irvine, Calif) or placebo into 5 glabellar sites. Patients were followed up for 120 days after injection. Outcome measures were physician rating of glabellar line severity at maximum frown and rest, patient assessment of improvement, and vital sign and adverse event monitoring.
Two hundred sixty-four patients were enrolled (BTX-A: 203, placebo: 61). There was a significantly greater reduction in glabellar line severity with BTX-A than with placebo (all measures, every follow-up visit; P <.022). The effect was maintained for many patients through day 120. There was a low occurrence (5.4%) of mostly mild blepharoptosis in the BTX-A group.
BTX-A injections are safe and effective in reducing the severity of glabellar lines.
THE TREATMENT of hyperfunctional facial lines with botulinum A exotoxin injection is safe, usually effective, and without serious adverse effects. Millions of individual clinical doses have been delivered without major complications. The average lethal dose, at 40 U/kg (eg, 2800 U for a 70-kg person), is orders of magnitude greater than the average dose delivered for glabellar frown lines (15-50 U).1 Indeed, cosmetic use of botulinum A exotoxin has become routine within dermatology. Initiated by pioneering dermatologists, ophthalmologists, and otolaryngologists during the 1980s, and honed by leaders in dermatologic surgery during the past decade,2- 6 techniques for botulinum injection are now commonly taught in residency and postgraduate education programs. Overall safety and efficacy, however, do not imply that bothersome adverse effects seldom occur. There is understandable reluctance to document these, which are usually mild and time limited.7- 12
Yet adherence to a few simple guidelines can reduce the likelihood that the patient will be dissatisfied and the physician embarrassed. Injecting botulinum toxin without subsequent undesired effects is largely a function of knowing where not to inject.
The objective of this study was to evaluate the efficacy and safety of botulinum toxin type A for the treatment of glabellar lines. Patients with moderate or severe glabellar lines at maximal frown received intramuscular injections of placebo or 20 U of botulinum toxin type A (Botox; Allergan, Inc., Irvine, Calif.) distributed among five injection sites (one in the procerus muscle and two in each corrugator supercilii). Follow-up assessments were performed at 7, 30, 60, 90, and 120 days after injections. Efficacy measures were the physician's rating of glabellar line severity at maximal frown and at rest (none, mild, moderate, or severe) and the patient's global assessment of changes in glabellar lines, from +4 (100 percent better) to -4 (100 percent worse). A total of 273 patients were enrolled (botulinum toxin, 202 patients; placebo, 71 patients). All except five patients (botulinum toxin, two patients; placebo, three patients) completed the study. For the physician's rating at maximal frown, the responder rate (percentage of patients with severity ratings of none or mild in follow-up evaluations) for the botulinum toxin group peaked at 77 percent at day 30 and was significantly greater than that for the placebo group at every follow-up visit (p < 0.001). For the patient's assessment, the responder rate (percentage of patients with scores of +2 or more) for the botulinum toxin group peaked at 89 percent at day 30 and was significantly greater than that for the placebo group at every follow-up visit (p < 0.001). Rates of adverse events were similar for the two groups. The only adverse event with an incidence of >/=5 percent was headache (botulinum toxin, 11 percent; placebo, 20 percent). The incidence of blepharoptosis was 1 percent for the botulinum toxin group. Botulinum toxin type A was remarkably safe and effective in reducing glabellar lines.
The use of botulinum toxin type A for facial enhancement is the most common cosmetic procedure currently undertaken in the United States. Overall clinical and study experience with botulinum toxin type A treatment for facial enhancement has confirmed that it is effective and safe in both the short and long term. Nevertheless, consistent guidelines representing the consensus of experts for aesthetic treatments of areas other than glabellar lines have not been published. Therefore, a panel of experts on the aesthetic uses of Botox Cosmetic (botulinum toxin type A; Allergan, Inc., Irvine, Calif.) was convened to develop consensus guidelines. This publication comprises the recommendations of this panel and provides guidelines on general issues, such as the importance of the aesthetic evaluation and individualization of treatment, reconstitution and handling of the botulinum toxin type A, procedural considerations, dosing and injection-site variables, and patient selection and counseling. In addition, specific considerations and recommendations are provided by treatment area, including glabellar lines, horizontal forehead lines, "crow's feet," "bunny lines" (downward radiating lines on the sides of nose), the perioral area, the dimpled chin, and platysmal bands. The review of each area encompasses the relevant anatomy, specifics on injection locations and techniques, starting doses (total and per injection point), the influence of other variables, such as gender, and assessment and retreatment issues. Factors unique to each area are presented, and the discussion of each treatment area concludes with a review of key elements that can increase the likelihood of a successful outcome. Summary tables are provided throughout.