Botulinum toxin type a blocks aquaporin 5 trafficking by decreasing synaptosomal-associated protein 23 in submandibular acinar cells.

The trafficking of aquaporin 5 (AQP5) is critical for salivary secretion. Synaptosomal-associated protein 23 (SNAP23) is an important regulator in the process of membrane fusion. However, the role of SNAP23 on AQP5 trafficking has not been explored. Botulinum toxin type A (BoNT/A) is a bacterial toxin that effectively treats sialorrhea. We previously reported that BoNT/A induced AQP5 redistribution in cultured acinar cells, but the mechanism remained unclear. In this study, SNAP23 was predominantly localized to the plasma membrane of acinar cells in the rat submandibular gland (SMG) and colocalized with AQP5 at the apical membrane of acinar cells. In stable GFP-AQP5-transfected SMG-C6 cells, the acetylcholine receptor agonist carbachol (CCh) induced trafficking of AQP5 from intracellular vesicles to the apical membrane. Furthermore, SNAP23 knockdown by siRNA significantly inhibited CCh-induced AQP5 trafficking, whereas this inhibitory effect was reversed by SNAP23 re-expression, indicating that SNAP23 was essential in AQP5 trafficking. More importantly, BoNT/A inhibited salivary secretion from SMGs, and the underlying mechanism involved that BoNT/A blocked CCh-triggered AQP5 trafficking by decreasing SNAP23 in acinar cells. Taken together, these results identified a crucial role for SNAP23 in AQP5 trafficking and provided new insights into the mechanism of BoNT/A in treating sialorrhea and thereby a theoretical basis for clinical applications.

Sustained benefits of onabotulinumtoxinA treatment in chronic migraine: An analysis of the pooled Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) randomized controlled trials.

OBJECTIVE: To characterize the long-term (56-week) benefits of continuous onabotulinumtoxinA treatment response in individuals with chronic migraine (CM) who achieved reduction to <15 headache days/month with treatment. BACKGROUND: There are limited data exploring reductions in monthly headache days to levels consistent with episodic migraine among those experiencing CM. Understanding the impact of sustained preventive treatment response in CM can provide important information about the impact of successful therapy. METHODS: The two Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy trials of onabotulinumtoxinA in adults included a 24-week, randomized, double-blind, placebo-controlled phase and a 32-week open-label phase. Data were pooled to determine proportions of individuals with <15 headache days/month while on treatment during several time periods in the double-blind phase (Weeks 21-24; any 12 consecutive weeks; Weeks 13-24) and the entire study (Weeks 53-56; any 12 consecutive weeks; any 4-week period). We assessed the long-term impact on mean monthly headache days and changes from baseline on the six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life questionnaire version 2.1 (MSQv2.1). RESULTS: We analyzed 1384 participants with chronic migraine (double-blind: onabotulinumtoxinA, n = 688; placebo, n = 696; open-label: n = 688 [onabotulinumtoxinA]). The discontinuation rates prior to the completion of the full 56-week treatment period for onabotulinumtoxinA and placebo were 25.4% (n = 175) and 29.3% (n = 204), respectively. During Weeks 13-24 of the double-blind phase, significantly more onabotulinumtoxinA-treated (386/688 [56.1%]) than placebo-treated (342/696 [49.1%]) individuals had <15 headache days/month (p = 0.010), with fewer monthly headache days for onabotulinumtoxinA versus placebo responders. The proportions of participants achieving <15 monthly headache days with onabotulinumtoxinA were 60.9% (419/688) at Weeks 25-56, 81.1% (558/688) at Weeks 53-56, and 79.4% (546/688) during any consecutive 12-week period. Mean changes from baseline on the HIT-6 and MSQv2.1 questionnaire surpassed within-group minimal important difference thresholds in all periods. At Week 24, onabotulinumtoxinA-treated participants who achieved <15 monthly headache days during Weeks 21-24 had a greater mean HIT-6 score reduction (-6.5 vs. -1.4) and greater mean MSQv2.1 Role-Function Restrictive score improvements (21.3 vs. 6.4) than those who did not achieve <15 monthly headache days during the same period. CONCLUSIONS: Participants who achieved <15 monthly headache days with onabotulinumtoxinA treatment achieved meaningful benefits in headache-related disability and migraine-specific quality of life compared with those who remained at or above the 15-monthly headache days threshold. Sustained benefits observed over 56 weeks support long-term onabotulinumtoxinA use for the prevention of CM.

Efficacy and safety of an alternative onabotulinumtoxinA injection paradigm for refractory overactive bladder.

AIMS: In studies utilizing a 20-injection-site paradigm of onabotulinumtoxinA treatment for overactive bladder (OAB), some patients performed clean intermittent catheterization (CIC). An alternative injection paradigm of fewer injections targeting the lower bladder may reduce the need for CIC by maintaining upper bladder function. This study evaluated the efficacy and safety of an unapproved alternative 10-injection-site paradigm targeting the lower bladder. METHODS: In this phase 4, double-blind, parallel-group study, patients with OAB and urinary incontinence (UI) for ≥6 months with ≥3 episodes of urinary urgency incontinence (no more than 1 UI-free day) and ≥8 micturitions per day over 3 days during screening were randomized 2:1 to onabotulinumtoxinA 100 U or placebo injected at 10 sites in the lower bladder. RESULTS: Of 120 patients, 78 in the onabotulinumtoxinA group and 39 in the placebo group had efficacy assessments. In the double-blind phase, mean change from baseline at week 12 in daily frequency of UI episodes was greater with onabotulinumtoxinA (-2.9) versus placebo (-0.3) (least squares mean difference [LSMD]: -2.99, p < 0.0001). Achievement of 100% (odds ratio [OR]: 6.15 [95% confidence interval, CI: 0.75-50.37]), ≥75% (OR: 7.25 [2.00-26.29]), and ≥50% improvement (OR: 4.79 [1.87-12.28]) from baseline in UI episodes was greater with onabotulinumtoxinA versus placebo. Reductions from baseline in the daily average number of micturitions (LSMD: -2.24, p < 0.0001), nocturia (LSMD: -0.71, p = 0.0004), and urgency (LSMD: -2.56, p < 0.0001) were greater with onabotulinumtoxinA than with placebo. Treatment benefit was improved or greatly improved in the onabotulinumtoxinA group (74.0% of patients) versus placebo (17.6%) (OR: 13.03 [95% CI: 3.23-52.57]). Mean change from baseline in Incontinence Quality of Life score was greater with onabotulinumtoxinA versus placebo (LSMD: 24.2, p = 0.0012). Two of 78 (2.6%) patients in the onabotulinumtoxinA group used CIC during the double-blind period; no females used CIC during the double-blind period. Commonly reported adverse events (≥5%) were urinary tract infection (UTI), dysuria, and productive cough for both groups; rate of UTI was higher with onabotulinumtoxinA versus placebo. CONCLUSION: In patients treated with onabotulinumtoxinA for OAB with UI, an unapproved alternative injection paradigm targeting the lower bladder demonstrated efficacy over placebo, with a low incidence of CIC.

Efficacy and safety of onabotulinumtoxinA for the treatment of overactive bladder in men and women: A pooled analysis.

BACKGROUND: This pooled analysis of randomized controlled studies investigated the safety and efficacy of onabotulinumtoxinA in male and female patients with overactive bladder (OAB). METHODS: Data were pooled from four similarly designed trials in North America and Europe. Adults with idiopathic OAB for ≥6 months inadequately managed by at least one anticholinergic were randomized 1:1 or 2:1 to receive onabotulinumtoxinA 100 U or matched placebo in Cycle 1 and could request open-label retreatment with onabotulinumtoxinA 100 U at ≥12 weeks. Efficacy outcomes at Week 12 included the primary endpoint of mean urinary incontinence (UI) episodes per day and other variables, such as the proportion of patients with ≥50% reduction in daily UI episodes. Safety was assessed by monitoring treatment-emergent adverse events (TEAEs). Analyses by sex were descriptive. Males were further analyzed by benign prostatic hyperplasia (BPH) diagnosis status. RESULTS: In the pooled population (N = 1564), there were 194 males (12.4%) and 1370 females (87.6%). Mean number of baseline UI episodes per day was 4.9 in males and 5.5 in females. At Week 12, numerically greater mean reductions from baseline in number of daily UI episodes were observed with the onabotulinumtoxinA 100 U group (females: -3.0; males: -2.2) versus placebo (females: -1.1; males: -1.3). Achievement of ≥50% reduction in daily UI episodes was numerically greater with onabotulinumtoxinA 100 U (females: 64.8%; males: 61.2%) versus placebo (females: 30.6%; males: 44.8%), and numerically higher in males without BPH (onabotulinumtoxinA: 65.1%; placebo: 50.9%) versus with BPH (onabotulinumtoxinA: 54.3%; placebo: 36.6%). A total of 34.7% of males and 39.4% of females experienced at least one TEAE in the first 12 weeks during treatment Cycle 1. Urinary tract infection rate was 13.1% in females and 4.2% in males; incidence of hematuria was 6.8% in males and 1.1% in females. Incidence of urinary retention (defined as incomplete emptying, requiring catheterization) was 2.7% in females and 4.7% in males. CONCLUSION: OnabotulinumtoxinA 100 U was efficacious and well tolerated in men and women with OAB, including in males with and without BPH. No new safety findings were identified when data were analyzed by sex.

Temporalis Muscle Changes Following Botulinum Toxin A Injections in Masseter Hypertrophy Patients: A Randomized Triple-Blinded Trial.

BACKGROUND: This study aimed to elucidate the effects of botulinum toxin A (BoNT-A) treatment for patients diagnosed with masseter hypertrophy on the temporalis muscle, with a particular focus on assessing alterations in muscle thickness, electromyographic (EMG) activity, and the development of muscle pain. METHODS: The present randomized triple-blinded clinical trial enrolled 26 female participants aged between 25 and 50 years complaining about masseter hypertrophy. Participants received 75U of BoNT-A (abobotulinumtoxinA) in both masseter muscles and after three months were randomized to receive a second treatment session of saline solution (S-BoNT-A) or BoNT-A (M-BoNT-A). Longitudinal assessments included temporalis muscle thickness through ultrasound, EMG activity, subjective pain, and masseter prominence severity after one, three, and six months of the first injection session. Muscle thickness, EMG, and subjective pain were analysed using two-way ANOVA with repeated measures and post hoc Sidak test, and for masseter prominence severity, Friedman and Mann-Whitney tests were used. RESULTS: Regarding inter-group comparisons, a higher muscle thickness (p < 0.02) and a higher EMG activity (p < 0.01) were found in the M-BoNT-A group at the 6-month follow-up. For subjective pain assessments, inter-group comparisons showed a higher prevalence of painful regions in M-BoNT-A group at the 6-month follow-up (p < 0.02). No significant differences were found in masseter prominence severity at the 6 months assessment between groups. CONCLUSION: BoNT-A treatment for masseter hypertrophy lead to structural and functional changes in the temporalis muscle, presenting higher changes after multiple injections of this treatment. LEVEL OF EVIDENCE I: 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 .

Nerve Distribution Method is Superior to the Conventional Method in BoNT-A Treatment of Trapezius Hypertrophy: A Randomized Controlled Trial.

The contour of the neck and shoulder is defined by the trapezius muscle (TM). Beyond facial procedures, botulinum toxin A (BoNT-A) injections has been increasingly adopted to create a smooth shoulder line. Several studies described the intramuscular nerve branching and the pattern of perforating branch of the accessory nerve in the trapezius muscle, providing essential information for botulinum neurotoxin injection. To this date, research groups seldom perform clinical investigations, especially randomized controlled trials, that demonstrates whether BoNT-A injections using the nerve distribution method for aesthetic purposes is more effective. Patients met the criteria for inclusion were randomized to either the Nerve Distribution group (ND group) or control group. Control group patients received injection using the conventional method while ND group patients received the nerve distribution method. Photographic and ultrasonographic evaluations were carried out at baseline, one month, three months, and six months after the procedure. Patients were also required to complete a questionnaire to evaluate their feedbacks to the injection. After screening, 30 healthy young Chinese women were included. At one-month follow-up, no statistically significant difference was observed between the two methods. At the three-month follow-up, the reduction of the TM thickness for the ND group (0.21 ± 0.09 cm) was more than that for the control group (0.27 ± 0.08 cm), with p = 0.047*. Similar differences were observed for the reduction of the shoulder area proportion (p = 0.031*) and the shoulder angle (p = 0.035*). At the six-month follow-up, the reduction in TM thickness in the ND group (0.2 ± 0.09 cm) was more than that of the control group (0.28 ± 0.06 cm), with p = 0.041*. The global aesthetic improvement scale feedbacks of the two methods showed no significant difference (3.4 ± 0.71 vs 3.8 ± 0.91, p = 0.207). The patients did not experience severe side effects. Compared to the conventional injection method, the nerve distribution method is more effective in reducing the trapezius muscle thickness, shoulder area proportion, and shoulder angle at three months, and shows longer lasting effects. The results of this study introduce unique insights into the design and tailoring of treatment protocols for shoulder-line contouring using BoNT-A.Level of Evidence I 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 .

A Phase III Clinical Study of the Efficacy and Safety of Botulinum Toxin Type A (MASPORT) with DYSPORT for the Treatment of Glabellar Lines.

BACKGROUND: Botulinum toxin type A is a widely used treatment of facial wrinkles. The objective of this study was to compare the efficacy and safety of a new botulinum toxin type A (Masport [abobotulinum toxin A], MasoonDarou Co) with DYSPORT® for the treatment of glabellar lines. METHODS: 262 subjects with moderate-to-severe glabellar lines received either a fixed dose of 50 units of MASPORT® or DYSPORT® (Ipsen Company, England). Subjects were followed up at 14, 30, 60, 90 and 120 days after injection. Efficacy was assessed by investigator at maximum frown and rest and also by Subject Global Assessment of Change (SGA). The responders were defined as persons with +2 grade improvement from baseline for both investigator and patient assessment. The occurrence and duration of adverse effects were recorded up throughout the study. RESULTS: According to the investigator evaluations, the responder rate at maximum frown were 94.5% for MASPORT and 95.6% for DYSPORT group on day 30 and at rest were 85.45% and 85.68% for MASPORT and DYSPORT group, respectively. According to the subject self-assessment, the proportion of responders in MASPORT group at day 30 was 95.28% versus 97.04% for DYSPORT group. No serious drug related adverse effect was recorded in either study groups, and the rates of adverse effects were similar for both groups. CONCLUSION: Abobotulinum toxin A [MASPORT] is equally safe and effective as commercial product [DYSPORT] for the treatment of glabellar lines with the dose of 50 units, up to 120 days. LEVEL OF EVIDENCE I: 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 .

Temporary Delayed Hypersensitivity Reaction to Botulinum Toxin-A After COVID-19 Vaccination: A Case Series.

PURPOSE: The occurrence of a hypersensitivity reaction with the injection of botulinum toxin type A (BTX-A) in cosmetic use is a rare complication. We report the largest case series of temporary delayed hypersensitivity reaction (DHR) with BTX-A following COVID-19 vaccination and the first cases to incobotulinum toxin A (incoBTX-A). METHODS: A retrospective multicentric case series of patients who developed a DHR to BTX-A after COVID-19 vaccination. RESULTS: Twelve patients were treated with BTX-A injections for the management of facial rhytids. The age range was between 29 and 45 years. Ten (83.3%) were female. Ten (83.3%) patients received incoBTX-A, and two received onabotulinum toxin A (onaBTX-A). All patients had COVID-19 vaccination (mRNA vaccine) between 1 and 7 months before. Within an average time of 24 h after BTX-A injection, all patients developed progressive facial swelling and erythema that were more prominent at the injection points. Intradermal allergic tests to BTX-A were performed in six (50%) patients, and the results were all negative. Adequate clinical control was achieved with systemic corticosteroids and antihistamines. After 1 year with no further vaccination, a new BTX-A treatment (provocation test) was performed in all patients with no secondary effects. CONCLUSION: Previous COVID-19 vaccination and the absence of new adverse events with further BTX-A injections suggest a temporary DHR. Clinicians should be aware of the importance of immunization history and its potential post-vaccine immunogenic effects with BTX-A. LEVEL OF EVIDENCE IV: 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 .

Three-Dimensional Photography for Evaluating the Effectiveness of Botulinum Toxin Injection for Masseter Hypertrophy.

BACKGROUND: Masseter hypertrophy is a common condition that causes a undesirable square face, and often treated with botulinum toxin type A (BoNTA). Subjective assessments of BoNTA effectiveness vary from physician to patient, necessitating an objective approach for evaluation. This study introduces three-dimensional photography (3DP) for the first time in clinical assessment to evaluate BoNTA treatment for masseter hypertrophy. METHODS: Ten patients received 36U of BoNTA at three injection points on each side masseter muscle. 3DP scanner using Artec Eva® was taken at the first, third, and sixth postoperative months for objective evaluation. Patient's self-perceived prominence, patients self-rated satisfaction, and physicians provided 5-grade scores were the subjective indicators. RESULTS: A significant decrease in left masseter volume at the sixth month (P = 0.002, P = 0.004 at rest and clenching, respectively) was observed. Patient's self-perceived prominence decreased at the first (P = 0.021) and third (P = 0.039) months. Physicians' scores significantly decreased at all postoperative months. No significant changes were noted in the right masseter volume and patients self-rated satisfaction. Patient self-rated satisfaction did not consistently correlate with objective measures, except for left masseter with clenching at the sixth month. CONCLUSION: Three-dimensional photography accurately quantifies facial changes post-BoNTA treatment. Despite objective improvements, patient satisfaction may not align consistently. Reliable assessment tools are crucial in cosmetic surgery to manage expectations and prevent disputes. LEVEL OF EVIDENCE IV: 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 .

Effects of botulinum toxin type A in the prevention and treatment of facial hypertrophic scars: A meta-analysis.

A meta-analysis was conducted to comprehensively evaluate the prophylactic and therapeutic efficacy of botulinum toxin type A (BTX-A) in the treatment of facial hypertrophic scars. Computerised searches were performed in databases, from their inception to November 2023, including Embase, Google Scholar, Cochrane Library, Wanfang, PubMed and China National Knowledge Infrastructure databases, focusing on randomised controlled trials (RCTs) that investigated the use of BTX-A for treating facial hypertrophic scars. Two researchers independently screened the literature, extracted data and conducted quality assessments. Stata 17.0 software was employed for data analysis. Seventeen RCTs were ultimately included, involving 1605 patients who underwent facial cosmetic surgery. The analysis revealed that compared with conventional treatments, BTX-A significantly reduced visual analogue scale (VAS) scores (standardized mean difference [SMD]: -3.50, 95% confidence interval [CI]: -5.16 to -1.84, p < 0.001) and Vancouver scar scale (VSS) scores (SMD: -2.86, 95% CI: -4.03 to -1.68, p < 0.001), and narrowed scar width (SMD: -1.80, 95% CI: -2.48 to -1.13, p < 0.001), while also enhancing the overall effectiveness of the treatment. This study indicates that BTX-A is an effective modality in the prophylaxis and treatment of facial hypertrophic scars, significantly alleviating scar-related pain and preventing scar widening, and is thus worthy of broader clinical application.

Vestibulodynia: Clinical characteristics, first-line treatments, and factors associated with escalation of treatment with EMG-guided injections of botulinum toxin in a retrospective french cohort study.

BACKGROUND: Vestibulodynia is a highly prevalent chronic pain disorder affecting the vulva having a major impact on women's physical, psychological, and sexual well-being. It remains an underrecognized disease that responds insufficiently to therapies such as physiotherapy and medication. AIM: To assess the global efficacy of first-line therapies and factors associated with treatment escalation in women with vestibulodynia. PATIENTS AND METHODS: This retrospective cohort study was conducted at the dermatology outpatient clinic of the University Hospital in Besancon (France) between 2013 and 2017 and follow-up until 2021. RESULTS: Among 132 patients, the mean [standard deviation] age at diagnosis was 27.2 [±9.45] years, with an average duration of symptoms of 42.3 [±37.92] months. Most cases comprised provoked (75.0%) or secondary (72.7%) vestibulodynia. At least one comorbid pain or psychologic condition was identified respectively in 63 (47.7%) and 23 patients (54.5%). Vulvar hyperesthesia associated with pelvic floor muscle dysfunction was present in 121 patients (91.6%) and vulvar erethism was noted in 94 patients (71.2%). First-line treatments consisted of pelvic floor physiotherapy with biofeedback in 85% of patients, associated with amitriptyline in 36% of cases, and of additional lidocaine cream in 17%. Fifty-two patients (39%) presented at least a good response to first-line treatment, with only 21 (15%) being in complete remission, irrespective of therapeutic strategy (p = 0.25). Botulinum toxin injections were performed in 54 patients. Patients with either primary vestibulodynia (p = 0.04) or spontaneous vestibulodynia (p = 0.03) were more likely to receive this treatment. CONCLUSION: Our study highlights the current lack of efficacy of first-line treatments in vestibulodynia. Considering the high prevalence of muscular dysfunction, botulinum toxin injections are of particular interest despite a lack of randomized controlled trials in this indication.

Clinical benefit of botulinum toxin for treatment of persistent TMD-related myofascial pain: A randomized, placebo-controlled, cross-over trial.

BACKGROUND: Injections of botulinum toxin type A (BoNT-A) have been proposed as an additional treatment modality for patients suffering chronic temporomandibular disorder (TMD)-related myofascial pain (MFP). BoNT-A impairs muscle function, along with its analgesic effect, and a minimal effective dose should be used. The objective of this randomized placebo-controlled crossover study was to evaluate the clinical benefit of a moderate dose (50 U) of BoNT-A. METHODS: Sixty-six subjects were randomized into two groups, one which received BoNT-A first and a second which received a saline solution (SS) first. Follow-ups were performed 2, 11, and 16 weeks after the injections. Diagnostic criteria for temporomandibular disorders (DC/TMD) diagnostic algorithms were used to evaluate characteristic pain intensity (CPI) and pain-related disability based on the Graded Chronic Pain Scale (GCPS). Electromyographic and bite force were also evaluated. RESULTS: The within-group analysis showed a significant improvement in pain intensity and pain-related disability after BoNT-A (p < 0.001, p = 0.005, p = 0.011) and SS (p = 0.003, p = 0.005, p = 0.046) injections up to week 16. The between-group analysis of pain-related variables revealed no differences between groups at any time. Nonetheless, BoNT-A, but not SS, caused a significant decline in muscle performance. The number needed to treat (NNT) regarding a clinically significant pain reduction (≥30%) was 6.3, 57.0, and 19.0 at 2, 11, and 16-week follow-ups favoring BoNT-A. CONCLUSIONS: Injections of 50 U of BoNT-A might improve MFP symptoms, but the specific effect of the drug on pain compared to the placebo is not obvious.

Mechanical loading and autophagy: A study on the BoNT-A injection-induced condylar cartilage degeneration.

Botulinum toxin A (BoNT-A) has emerged as a treatment option for temporomandibular disorder (TMD). By injecting BoNT-A into the masseter muscle, it is possible to reduce mechanical loading on the temporomandibular joint (TMJ). However, numerous prior studies have indicated excessive reduction in mechanical loading can have detrimental effects on TMJ cartilage. This study proposes that autophagy, a process influenced by mechanical loading, could play a role in BoNT-A-induced mandibular condyle cartilage degeneration. To explore this hypothesis, we employed both BoNT-A injection and an excessive biting model to induce variations in mechanical loading on the condyle cartilage of C57BL/6 mice, thereby simulating an increase and decrease in mechanical loading, respectively. Results showed a significant reduction in cartilage thickness and downregulation of Runt-related transcription factor 2 (Runx2) expression in chondrocytes following BoNT-A injection. In vitro experiments demonstrated that the reduction of Runx2 expression in chondrocytes is associated with autophagy, possibly dependent on decreased YAP expression induced by low mechanical loading. This study reveals the potential involvement of the YAP/LC3/Runx2 signaling pathway in BoNT-A mediated mandibular condylar cartilage degeneration.

Intrathecal Injection of Botulinum Toxin Type A has an Analgesic Effect in Male Rats CCI Model by Inhibiting the Activation of Spinal P2X4R.

Purinergic receptor P2X4 (P2X4R) plays an essential role in neuropathic pain. However, the specific mechanism needs to be clarified. Botulinum toxin type A is a neurotoxin produced by Clostridium botulinum type A. This study found that intrathecal injection of botulinum toxin type A produced an excellent analgesic effect in a rat model of chronic constriction sciatic nerve injury and inhibited the activation of P2X4R, microglia, and astrocytes. The administration of a P2X4R activator can up-regulate the expression of P2X4R and eliminate the analgesic effect of intrathecal injection of botulinum toxin type A. In addition, we found that microglia and astrocytes in the spinal cord of rats injected with botulinum toxin type A were reactivated after administration of the P2X4R activator. Our results suggest that intrathecal injection of botulinum toxin type A has an analgesic effect in a rat model of chronic constriction sciatic nerve injury by inhibiting the activation of P2X4R in the spinal cord.

Onabotulinum toxin A block of the sphenopalatine ganglion in patients with persistent idiopathic facial pain: a randomized, triple-blind, placebo-controlled, exploratory, cross-over study.

OBJECTIVE: To investigate the efficacy and safety of injecting onabotulinum toxin A (BTA) towards the sphenopalatine ganglion (SPG) using the MultiGuide® in patients with persistent idiopathic facial pain (PIFP). METHODS: This cross-over, exploratory study compared the injection of 25 units BTA versus placebo in patients who met modified ICDH-3 criteria for PIFP. Daily pain diaries were registered for a 4-week baseline, a 12-week follow-up after each injection, and an 8-week conceptual washout period in between. The primary efficacy endpoint was the change from baseline to weeks 5-8 in average pain intensity using a numeric rating scale. Adverse events were recorded. RESULTS: Of 30 patients who were randomized to treatment, 29 were evaluable. In weeks 5-8, there was no statistically significant difference in average pain intensity between BTA versus placebo (0.00; 95% CI = -0.57 to 0.57) (P = 0.996). Following both BTA and placebo injections, five participants reported at least a 30% reduction in average pain during weeks 5-8 (P = 1.000). No serious adverse events were reported. Post-hoc analyses indicated a possible carry-over effect. CONCLUSIONS: Injection of BTA toward the SPG with the MultiGuide® did not appear to provide a reduction in pain reduction at 5-8 weeks, although this finding may be influenced by a carry-over effect. The injection appears to otherwise be safe and well-tolerated in patients with PIFP.Trial Registration: The study protocol is registered in ClinicalTrial.gov (NCT03462290) and EUDRACT (number: 2017-002518-30).

Injection technique of the upper face with onabotulinumtoxinA in chronic migraine.

BACKGROUND: The objective is to review the technique of onabotulinumtoxinA injection treatment in the glabellar and frontal regions using the PREEMPT (Phase III REsearch Evaluating Migraine Prophylaxis Therapy) paradigm, with review of the aesthetic issues related to the procedure. OnabotulinumtoxinA is an effective medication for the prevention of chronic migraine. The PREEMPT injection paradigm has been validated in randomized clinical trials and real-world settings. This treatment includes injections in the forehead and glabella area. In addition, for aesthetic uses, glabella onabotulinumtoxinA injections are done in similar muscles specifically the procerus, corrugator supercilii, and frontalis muscles. Often patients who have been injected with onabotulinumtoxinA for chronic migraine have concerns about their appearance and will ask if they can see an aesthetic injector to improve this. This is a difficult issue as onabotulinumtoxinA should be injected with an interval of 10-12 weeks to avoid development of antibodies against onabotulinumtoxinA, so all injections (migraine and aesthetic) should ideally be done close together; however, if an aesthetic injection is done on the same day as a PREEMPT injection, the effect of the PREEMPT injection will not yet be visible as it takes time for onabotulinumtoxinA effects to be seen. Thus, there is a risk of a potential overdose in a particular area if aesthetic injections are done without input from the PREEMPT injector. METHODS: This is a narrative review supported by photographic documentation showing the technique of onabotulinumtoxinA injection of the upper face, considering anatomical differences between patients, and combining the needs in neurology and aesthetic medicine fields. RESULTS: Practitioners treating chronic migraine often modify some of the principles of the PREEMPT paradigm. Many practitioners are unsure about injections in the glabellar and frontal areas. The authors present a technique for using the PREEMPT protocol and adapting this to the individual patient's anatomy to prevent an unsightly appearance or ptosis. In addition, sites are provided where an aesthetic injector could inject to improve the patient's appearance without overlapping with the PREEMPT injection sites. CONCLUSION: Adherence to the PREEMPT injection protocol provides an evidence-based approach to achieving clinical benefit for patients with chronic migraine. Aesthetic elements of the treatment of the glabella and forehead require additional attention. The authors provide practical considerations and recommendations regarding this.

Alteration of tight junctions during botulinum toxin type A-inhibited salivary secretion.

OBJECTIVES: Tight junctions (TJs) are involved in the regulation of salivary secretion via paracellular pathway. Botulinum toxin type A (BTXA) is widely used for the treatment of hypersecretion diseases such as sialorrhea. This study aimed to investigate the role of TJs in BTXA-inhibited secretion of the submandibular gland (SMG). MATERIALS AND METHODS: BTXA was injected into the SMGs of rats, and the same amount of saline was injected as a control. Western blot, real-time PCR, and immunofluorescence staining were used to detect the expression and distribution of TJ proteins. Paracellular permeability was evaluated using the transepithelial electrical resistance (TER) measurements and fluorescent tracer detection in BTXA-stimulated SMG-C6 cells. RESULTS: BTXA injection into the SMGs of rats led to increased expression of claudin (Cldn) -1 and Cldn3. Immunofluorescence staining showed no significant changes in the distribution of TJ proteins. In vitro, BTXA increased the TER values and significantly reduced the permeability of fluorescent tracer, suggesting that BTXA decreased the paracellular permeability. The expression levels of Cldn1, Cldn3, and Cldn4 were upregulated after BTXA treatment. CONCLUSION: The expression of TJ proteins changed in both animal models and SMG-C6 cells after BTXA treatment, which may contribute to the inhibition of salivary secretion.

Alteration of myoepithelial cells during botulinum toxin type A-inhibited salivary secretion.

OBJECTIVE: Intraglandular injection of botulinum toxin type A (BoNT/A) effectively treats sialorrhea. Myoepithelial cells (MECs) are essential for salivary secretion. The role of MECs in BoNT/A-inhibited salivary secretion, and its underlying mechanisms remain unknown. MATERIALS AND METHODS: BoNT/A was injected into rat submandibular glands (SMGs). At 1, 2, 4, 8, and 12 weeks postinjection, salivary flow rate of SMGs was measured. Electron microscopy, immunohistochemistry, immunofluorescence, and Western blot analysis were used to detect morphological and functional changes in MECs and chemical denervation in SMGs. RESULTS: BoNT/A temporarily decreased salivary secretion in rat SMGs and this inhibitory effect lasted 4 weeks. During the inhibitory period, MECs atrophied and expressed reduced α-smooth muscle actin (α-SMA), vimentin, and phosphorylated myosin light chain 2 (p-MLC2), suggesting that BoNT/A attenuated MEC contractility. Furthermore, BoNT/A cleaved synaptosome-associated protein 25 (SNAP-25) and decreased the expression and activity of acetylcholinesterase (AChE), indicating that BoNT/A-induced chemical parasympathetic denervation of SMGs by cleaving SNAP-25. CONCLUSIONS: BoNT/A temporarily caused MEC atrophy and decreased MEC contractility in rat SMGs, which contributed to reversible inhibition of salivary secretion. The underlying mechanisms involved temporary parasympathetic denervation caused by SNAP-25 cleavage. These findings provide new insights into the mechanisms of BoNT/A-inhibited salivary secretion.

Unparallel improvement patterns of dynamic wrinkles and skin quality after botulinum toxin type A treatment on the upper face.

BACKGROUND: Botulinum toxin type A (BoNT-A) can not only reduce the dynamic wrinkles but also improve the skin quality. This study aims to quantitaively and comprehensively assess the improvement of dynamic wrinkles and skin quality following BoNT-A treatment on the upper face. METHODS: Patients were recruited to receive BoNT-A treatment of the glabellar, frontal, and lateral periorbital wrinkles. Antera 3D camera was used to evaluate the skin quality and dynamic wrinkle severity. Follow-up visits were at 1 week, 1 month, 3 months, and 6 months after treatment. Different filters were utilized to quantitatively detect the severity of fine wrinkles (FWS), the volume of pores (PV), the roughness of skin texture (STR), and the severity of dynamic wrinkles (DWS). RESULTS: Twenty-four participants (average 30.5 ± 7.2 years) were recruited. The significant improvement of PV, FWS, and STR in different areas usually maintained from 1 to 6 months after injections but of DWS only existed within 3 months. For each area, the improvement rates of FWS, PV, and STR peaked at 3 months or 6 months after treatment while the maximal improvement of DWS was observed at 1 month posttreatment. CONCLUSION: After BoNT-A treatment for dynamic wrinkles on the upper face, the skin quality of target regions can also be ameliorated. The improvement of skin quality and dynamic wrinkles presented unparallel patterns. The former is with a slower onset but longer duration while the latter exhibits a more rapid onset but shorter duration.

Therapeutic Effectiveness of Needle Injection Versus Needle-Free Jet Injector System for Botulinum Toxin Type A in Palmar Hyperhidrosis.

BACKGROUND: The most important problem with local injections of botulinum toxin type A (BTX-A) in palmar hyperhidrosis is pain during the injections. OBJECTIVES: We evaluated therapeutic effectiveness and pain of local injections of BTX-A using needle-free direct administration system. METHODS: We performed BTX-A local injection therapy using a conventional injection needle in the left hand and a needle-free direct administration system in the right hand. RESULTS: A reduction in the quantity of perspiration was observed 4 weeks after administration of both Needle and Needle-free BTX-A, and reduction was maintained throughout 28 weeks observation period. Both hyperhidrosis Disease Severity Scale scores and Dermatology Life Quality Index for hands treated with Needle BTX-A and hands treated with Needle-free BTX-A had decreased significantly by 4 weeks after treatment. Pain visual analog scale scores and the degree of pain were significantly lower in hands treated with Needle-free BTX-A than in hands treated with Needle BTX-A. CONCLUSIONS: When the trigger of the pressurized needle-free injector device is activated, the gas powered driving pressure propels BTX-A through an orifice (0.13 mm) about four times narrower than a 30 G needle at very high speed. As most pain occurs during the needle prick itself, the advantage of a small orifice coupled with high-speed penetration of BTX-A through the pressurized device results in reduced pain during administration. The needle-free direct administration system administers the injectate under the skin without a visible needle.