Efficacy and Safety of LetibotulinumtoxinA in the Treatment of Moderate and Severe Glabellar Lines in Females 35 to 50 Years of Age: Post Hoc Analyses of the Phase 3 Clinical Study Data.

Background: Botulinum toxin type A (BoNT-A) injections continue to be widely used as a common treatment for both males and females. According to a recent survey conducted by the International Society of Plastic Aesthetic Surgeons, the majority of patients receiving these injections are females between the ages 35 and 50. Objectives: A post hoc analysis was conducted to examine whether there were variances in the effectiveness and safety of letibotulinumtoxinA for treating vertical glabellar lines between the broader female study population and a particularly defined group of female participants aged 35 to 50. Methods: For this post hoc analysis, data from females aged 35 to 50 were extracted and analyzed from the BLESS III study. In this Phase 3 clinical trial, 355 participants with moderate-to-severe glabella frown lines received either 20 U of letibotulinumtoxinA or a placebo. The study evaluated Glabella Line Severity (GLS) score, treatment onset, duration of effects, time to retreatment, and adverse events. A positive response was determined by achieving a GLS score of 0 or 1, as assessed by both patients and investigators, along with at least a 2-point improvement in GLS score relative to baseline at Week 4 after the injections. Results: Composite responder rates for patients aged 35 to 50 receiving active treatment were significantly higher than for the remaining female population receiving active treatment at Weeks 1, 2, and 4. Females aged 35 to 50 showed higher rates of GLS improvement of ≥1 at Weeks 1, 2, 4, 8, 12, 16, and 20 compared with the remaining female population receiving active treatment. At Week 4, a higher percentage of females aged 35 to 50 achieved a GLS score of 0 upon maximum frowning compared with the remaining females. Females aged 35 to 50 had a shorter median time to onset of GLS improvement compared with the remaining female population. Safety assessments showed a low incidence of treatment-related adverse events in females aged 35 to 50. Conclusions: LetibotulinumtoxinA showed significantly higher response rates in females aged 35 to 50 compared with other female patients at Weeks 1, 2, and 4. Response rates remained higher up to Week 16. The treatment demonstrated efficacy and safety in treating vertical glabellar lines in this patient group.

Validated 5 - Point photonumeric scales for the assessment of hand atrophy.

OBJECTIVE: Quantifying the degree of dorsal hand atrophy is a challenging endeavor, but often necessary, in both the clinical and the research setting. The aim of this investigation was to create and consecutively validate a 5-point photonumeric scale for assessment of dorsal hand atrophy. MATERIAL AND METHODS: A medical team created a novel 5-point photonumeric scale. Twelve international raters were involved in the digital validation, while five raters performed a live validation. RESULTS: For the digital validation of the Croma Hand Atrophy Assessment Scale, a total of 72 subjects (58 females, 14 males) with a mean age of 43.0 ± 14.4 years [18-73 years] were assessed. For the live validation, 88 subjects (73 females, 15 males) with a mean age of 45.0 ± 14.1 years [20-73 years] were rated. The results revealed almost perfect intra-rater (ICC: 0.90 [95% CI: 0.88-0.92]) and inter-rater agreements (ICC: 0.85 [95% CI: 0.81-0.89] and 0.86 [95% CI:0.82-0.89]) in the digital validation and substantial intra-rater (ICC: 0.79 [95% CI: 0.75-0.82]) and inter-rater agreements (ICC: 0.75 [95% CI: 0.68-0.81] and ICC: 0.67 [95% CI: 0.54-0.77]) in the live validation. CONCLUSION: The created scale to assess dorsal hand atrophy has been shown to provide substantial-to-almost perfect agreement in the digital and live validation cycles and reached comparable intra-rater and inter-rater agreement to already published and validated scales. It is expected that the created scale will help physicians and researchers in the assessment of hand atrophy in the clinical and research setting in the future.

Efficacy and Safety of Letibotulinumtoxin A in the Treatment of Glabellar Lines: A Randomized, Double-Blind, Multicenter, Placebo-Controlled Phase 3 Study.

BACKGROUND: Letibotulinumtoxin A (Hugel, Inc., Chuncheon, Republic of Korea and CROMA Pharma, Leobendorf, Austria) is a newly manufactured neurotoxin derived from Clostridium botulinum strain CBFC26. OBJECTIVES: The aim of this study was to assess the efficacy and safety of letibotulinumtoxin A in reducing glabellar line severity (GLS) and to evaluate long-term safety and efficacy following repeated injections. METHODS: In this prospective, randomized, parallel-group, double-blind, multicentre, placebo-controlled Phase III clinical trial, 355 subjects with moderate to severe glabella frown lines received injections of 20 U of letibotulinumtoxin A or placebo. GLS, onset and duration of effect, time to retreatment, and adverse events were evaluated. Response to treatment was defined as a GLS score of 0 or 1 (assessed by the subject and the investigator) and an improvement at Week 4 of ≥2 points in GLS score relative to baseline. RESULTS: At 4 weeks, 78.6% of the active treatment subjects were responders based on the investigator's assessment and 68.8% based on the subject's assessment, resulting in a composite responder rate of 64.7% for the active treatment group, whereas the corresponding rate was 0.0% in the placebo group (P < 0.001). Subjects noted a substantial improvement in GL severity as early as Day 2, with the median time to onset of effect being 3 days. The mean [standard deviation] time until first retreatment for the letibotulinumtoxin A group was 127.26 [65.6] days. Letibotulinumtoxin A was well tolerated. CONCLUSIONS: Letibotulinumtoxin A demonstrates high efficacy and a convincing safety profile in the treatment of glabellar lines.

Validated 5-point photonumeric scales for the assessment of the periorbital region.

OBJECTIVE: The objective of this investigation was to create and validate 5-point photonumeric scales for the assessment of dynamic crow's feet, static crow's feet, and infraorbital hollows. MATERIAL AND METHODS: Three novel 5-point photonumeric scales were created by a medical team. A total of 12 raters from all over the world performed a digital validation, and a total of 5 raters a live validation of the created scale. RESULTS: The statistical analysis revealed almost perfect intra-rater and inter-rater reliability in the digital validation of the scales for the assessment of static and dynamic crow's feet as well as infraorbital hollows. In the live validation, both crow's feet scales showed almost perfect intra-rater reliability, while the Croma Infraorbital Hollow Assessment Scale showed substantial intra-rater reliability. Inter-rater reliability was substantial for all three scales in the live validation. All three scales, the Croma Dynamic Crow's Feet Assessment Scale, Croma Static Crow's Feet Assessment Scale, and Croma Infraorbital Hollow Assessment Scale, were validated digitally and in a live setting. CONCLUSION: The created scales to assess infraorbital hollowing, dynamic and static crow's feet have been shown to provide substantial to almost perfect agreement in the digital and live validation and can thus be considered as helpful tools in the clinical and research setting. While technical methods and appliances to assess the degrees of severity of age-dependent features are advancing, validated scales are of great importance due to their ease of use and, as shown by the validations, reliability, and reproducibility.

Validated 5-point photonumeric scales for the assessment of the jowls and chin.

OBJECTIVE: The objective of this investigation was to create and to examine the reproducibility and validity of 5-point photonumeric assessment scales that allow objective assessment of chin retrusion and jawline sagging using a digital and a live validation. MATERIAL AND METHODS: Two new 5-point photonumeric scales created to assess chin projection and jawline sagging were validated by 12 experts in a digital validation and by 5 experts in a live validation setting. Intra-rater agreement and inter-rater agreement were assessed. RESULTS: For the digital validation, an almost perfect intra-rater (Kappa: 0.89 [95% CI: 0.86-0.91]) and almost perfect inter-rater agreement in both sessions (Kappa: 0.80 [95% CI: 0.74-0.86] and 0.80 [95% CI: 0.74-0.86]) was achieved for the Croma Chin Projection Assessment Scale, while intra-rater agreement (Kappa: 0.88 [95% CI: 0.85-0.91]) was almost perfect for the Croma Jawline Sagging Assessment Scale and inter-rater agreement being substantial in the first session (Kappa: 0.76 [95% CI: 0.71-0.81]) and almost perfect in the second session (Kappa: 0.81 [95%CI: 0.76-0.85]). For the live validation, intra-rater agreement was almost perfect for the Croma Chin Projection Assessment Scale (Kappa: 0.82 [95%CI: 0.74-0.90]) and the Croma Jawline Sagging Assessment Scale (Kappa: 0.83 [95%CI: 0.77-0.89]), while inter-rater agreement was substantial in both sessions for both scales. CONCLUSION: The created chin and jawline photonumeric grading scales are valid and reliable tools for assessing chin projection and jawline sagging. The scales will be of value for standardized chin evaluation and quantifying outcomes in clinical research and daily practice.

Copper-mediated synthesis of N-alkenyl-α,ß-unsaturated nitrones and their conversion to tri- and tetrasubstituted pyridines.

A Chan-Lam reaction has been used to prepare N-alkenyl-α,ß-unsaturated nitrones, which undergo a subsequent thermal rearrangement to the corresponding tri- and tetrasubstituted pyridines. The optimization and scope of these transformations is discussed. Initial mechanistic experiments suggest a reaction pathway involving oxygen transfer followed by cyclization.

Preparation of α-imino aldehydes by [1,3]-rearrangements of O-alkenyl oximes.

The synthesis of α-imino aldehydes has been achieved through the thermal [1,3]-rearrangement of O-alkenyl benzophenone oximes. A copper-mediated C-O bond coupling between benzophenone oxime and alkenyl boronic acids provides facile access to the required O-alkenyl oximes and a Horner-Wadsworth-Emmons olefination can be applied to the α-imino aldehyde products to give γ-imino-α,ß-unsaturated esters. The scope of the method is described and mechanistic experiments are discussed.

Preparation of α-oxygenated ketones by the dioxygenation of alkenyl boronic acids.

Two in two: Dioxygenation of alkenyl boronic acids has been achieved with N-hydroxyphthalimide. The two-step process involves etherification of an alkenyl boronic acid with N-hydroxyphthalimide followed by a [3,3] rearrangement. The dioxygenated product can then be hydrolyzed to form either the corresponding α-hydroxy ketone or the α-benzoyloxy ketone.

Regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles via [3,3] or [1,3] rearrangements of O-vinyl oximes.

The regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles has been achieved via [3,3] and [1,3] sigmatropic rearrangements of O-vinyl oximes, respectively. Iridium-catalyzed isomerization of easily prepared O-allyl oximes enables rapid access to O-vinyl oximes. The regioselectivity of pyrrole formation can be controlled by either the identity of the α-substituent or through the addition of an amine base. When enolization is favored, a [3,3] rearrangement followed by a Paal-Knorr cyclization provides a 2,3,4-trisubstituted pyrrole; when enolization is disfavored, a [1,3] rearrangement occurs prior to enolization to produce a 2,3,5-trisubstituted pyrrole after cyclization. Optimization and scope of the O-allyl oxime isomerization and subsequent pyrrole formation are discussed and mechanistic pathways are proposed. Conditions are provided for selecting either the [3,3] rearrangement or the [1,3] rearrangement product with ß-ester O-allyl oxime substrates.

Carbon-carbon bond formation and pyrrole synthesis via the [3,3] sigmatropic rearrangement of O-vinyl oxime ethers.

A new method for the synthesis of 2,4- and 2,3,4-substituted pyrroles in two or three steps from commercially available ketones and allyl hydroxylamine is described. An iridium-catalyzed isomerization reaction has been developed to convert O-allyl oximes to O-vinyl oximes, which undergo a facile [3,3] rearrangement to form 1,4-imino aldehyde Paal-Knorr intermediates that cyclize to afford the corresponding pyrroles. Optimization and examples of the isomerization and pyrrole formation are discussed.