Neurotoxins and Combination Therapies.

BACKGROUND: Facial aging involves multilevel changes, extending from the skin to deep support structures. A comprehensive treatment approach targeting the many aspects of facial dynamics and architecture is often necessary to achieve optimal correction, prevent changes before they occur, and/or help highlight inherited features. OBJECTIVE: To explore the integration of botulinum toxin type A (BoNT-A) into multimodal aesthetic treatment plans. MATERIALS AND METHODS: This article reviews evidence supporting the combination of BoNT-A with other minimally invasive cosmetic therapies, including dermal fillers, lasers, and energy-based devices as well as with plastic and reconstructive surgeries for more controlled healing and improved scar cosmesis. RESULTS: Combination treatment protocols including BoNT-A demonstrate higher patient satisfaction and retention rates compared to monotherapy or sequential treatments. Some guidelines for sequencing of treatments exist, but evidence is scant with certain combinations. CONCLUSION: Integrating BoNT-A into a larger aesthetic treatment plan is crucial for achieving natural and satisfying results in facial rejuvenation. Evidence supports better outcomes when incorporating with both surgical and nonsurgical modalities. Understanding how to address anatomy over time through different aesthetic therapies together allows for individually tailored, more deeply impactful treatment plans.

Botulinum Toxin-A Injection in Chronic Pelvic Pain Syndrome Treatment: A Systematic Review and Pooled Meta-Analysis.

INTRODUCTION: Pain management of patients with chronic pelvic pain syndrome (CPPS) is challenging, because pain is often refractory to conventional treatments. Botulinum toxin A (BTX-A) may represent a promising therapeutic strategy for these patients. The aim of this systematic review was to investigate the role of BTX-A in CPPS treatment. METHODS: We reviewed the literature for prospective studies evaluating the use of BTX-A in the treatment of CPPS. A comprehensive search in the PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed from English language articles published between January 2000 and October 2021. The primary outcome was to evaluate pain improvement in CPPS after BTX-A treatment. Pooled meta-analysis of the included studies, considering the effect of BTX-A on pain evaluated at last available follow-up compared to baseline values, was performed together with meta-regression analysis. RESULTS: After screening 1001 records, 18 full-text manuscripts were selected, comprising 13 randomized clinical trials and five comparative studies. They covered overall 896 patients of both sexes and several subtype of CPPS (interstitial cystitis/bladder pain syndrome, chronic prostatitis/prostate pain syndrome, chronic scrotal pain, gynecological pelvic pain, myofascial pelvic pain). The clinical and methodological heterogeneity of studies included makes it difficult to do an overall estimation of the real effect of BTX-A on pain and other functional outcomes of various CPPS subtypes. However, considering pooled meta-analysis results, a benefit in pain relief was showed for BTX-A-treated patients both in the overall studies populations and in the overall cohorts of patients with CPP due to bladder, prostate, and gynecological origin. CONCLUSIONS: BTX-A could be an efficacious treatment for some specific CPPS subtypes. Higher level studies are needed to assess the efficacy and safety of BTX-A and provide objective indications for its use in CPPS management.

Botulinum Toxin Injection Plus Topical Diltiazem for Chronic Anal Fissure: A Randomized Double-Blind Clinical Trial and Long-term Outcome.

BACKGROUND: Chemical sphincterotomy avoids the risk of permanent incontinence in the treatment of chronic anal fissure, but it does not reach the efficacy of surgery and recurrence is high. Drug combination has been proposed to overcome these drawbacks. OBJECTIVE: This study aimed to compare the clinical, morphological, and functional effects of combined therapy with botulinum toxin injection and topical diltiazem in chronic anal fissure and to assess the long-term outcome after healing. DESIGN: This is a randomized, controlled, double-blind, 2-arm, parallel-group trial with a long-term follow-up. SETTINGS: This study was conducted at a tertiary care center. PATIENTS: A total of 70 consecutive patients were referred to the gastroenterology department of a hospital in Valencia, Spain. INTERVENTION: After botulinum toxin injection (20 IU), patients were randomly assigned to local diltiazem (diltiazem group) or placebo gel (placebo group) for 12 weeks. MAIN OUTCOME MEASURES: The primary outcome was fissure healing (evaluated by video register by 3 independent physicians). Secondary outcomes included symptomatic relief (30-day diary), effect on anal sphincters (manometry), safety, and long-term recurrence (24 months and 10 years). RESULTS: Healing was achieved per protocol in 13 of 25 (52%) patients of the diltiazem group and 11 of 30 (36.7%) patients of the placebo group (p = 0.25); on an intention-to-treat basis in 37.1% and 31.4% (p = 0.61). Both groups displayed significant reduction of anal pressures. Thirty percent reported minor and transitory incontinence, without differences between groups. Nine (69.2%) of the diltiazem group and 6 (54.5%) of the placebo group experienced a relapse at 24 months (p = 0.67). The overall recurrence rate at 10 years was 83.3% (20/24 patients). LIMITATIONS: This study was limited by the loss of patients during the trial. The low healing rate led to a small cohort to assess recurrence. CONCLUSIONS: Combined botulinum toxin injection and topical diltiazem is not superior to botulinum toxin injection in the treatment of chronic anal fissure. Both options offer suboptimal healing rates. Long-term recurrence is high (>80% at 10 years) and might appear at any time after healing. See Video Abstract at http://links.lww.com/DCR/B527. INYECCIN DE TOXINA BOTULNICA MS DILTIAZEM TPICO EN FISURA ANAL CRNICA UN ENSAYO CLNICO ALEATORIZADO DOBLE CIEGO Y RESULTADOS A LARGO PLAZO: ANTECEDENTES:La esfinterotomía química evita el riesgo de incontinencia permanente en el tratamiento de la fisura anal crónica, pero no alcanza la eficacia de la cirugía y la recurrencia es alta. Se ha propuesto la combinación de fármacos para superar estos inconvenientes.OBJETIVO:Comparar los efectos clínicos, morfológicos y funcionales de la terapia combinada con inyección de toxina botulínica y diltiazem tópico en fisura anal crónica y evaluar el resultado a largo plazo después de la cicatrización.DISEÑO:Ensayo aleatorizado, controlado, doble ciego, de dos brazos, de grupos paralelos con un seguimiento a largo plazo.ESCENARIO:Estudio realizado en un centro de atención terciaria.PACIENTES:Un total de 70 pacientes consecutivos referidos al servicio de gastroenterología de un hospital de Valencia, España.INTERVENCIÓN:Después de la inyección de toxina botulínica (20UI), los pacientes fueron asignados al azar a diltiazem local (grupo de diltiazem) o gel de placebo (grupo de placebo) durante 12 semanas.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la cicatrización de la fisura (evaluado por registro de video por tres médicos independientes). Los resultados secundarios incluyeron alivio sintomático (diario de 30 días), efecto sobre los esfínteres anales (manometría), seguridad y recurrencia a largo plazo (24 meses y 10 años).RESULTADOS:La curación se logró por protocolo en 13/25 (52%) en el grupo de Diltiazem y 11/30 (36,7%) en el grupo de Placebo (p = 0.25); por intención de tratar en el 37.1% y el 31.4%, respectivamente (p = 0.61). Ambos grupos mostraron una reducción significativa de las presiones anales. El 30% refirió incontinencia leve y transitoria, sin diferencias entre grupos. 9 (69.2%) del grupo de Diltiazem y 6 (54.5%) del grupo de placebo recurrieron a los 24 meses (p = 0.67). La tasa global de recurrencia a los 10 años fue del 83.3% (20/24 pacientes).LIMITACIONES:La pérdida de pacientes a lo largo del ensayo. La baja tasa de curación llevó a una pequeña cohorte para evaluar la recurrencia.CONCLUSIONES:La inyección combinada de toxina botulínica y diltiazem tópico no es superior a la inyección de TB en el tratamiento de la fisura anal crónica. Ambas opciones ofrecen tasas de curación subóptimas. La recurrencia a largo plazo es alta (> 80% a los 10 años) y puede aparecer en cualquier momento después de la curación. Consulte Video Resumen en http://links.lww.com/DCR/B527.

Long-term antibody response and protective effect induced by attenuated scorpion toxins: Involvement of memory plasma cells.

In Algeria, Androctonus australis hector scorpion envenomation remains a major problem of public health because of non-efficient therapy. The development of safe vaccine against scorpion venom could be one key strategy for the envenomation prevention. The irradiation of venom by γ-rays develops suitable immunogens which produced effective antivenom and safe vaccine. In this study, we investigated the ability of the irradiated toxic fraction (γ-FtoxG50) to induce long-term memory humoral response in immunized animals (mice and rabbits), by involving the long-lived plasma cells to prevent efficiently the lethality of scorpion envenomation. For this purpose, an appropriate immunization schedule was established in mice and rabbits using three (3) similar doses of γ-FtoxG50 associated with Alum adjuvant. Obtained results indicate that the long-term immunogenicity of γ-FtoxG50 is able to induce the long-term memory humoral response with a high level of specific antibodies. The long-term persistence of antibody levels could depend on bone marrow memory plasma cells. These cells produce continuously antibodies without antigen stimulus. Furthermore, an enhanced memory response was obtained post-repeated envenomation with toxic native venom that leads to improved protection of animals. Together, pre-existing protective antibodies and the activation of memory B-cells could induce a rapid neutralization of scorpion toxins and long-term protection against scorpion envenomation.

Review of the Current Medical and Surgical Treatment Options for Microstomia in Patients With Scleroderma.

BACKGROUND: Most patients with scleroderma suffer from microstomia, which can have debilitating consequences on their quality of life. Unfortunately, treatment options remain limited. No specific guidelines exist; hence, microstomia remains a challenge to treat in this patient population. OBJECTIVE: This review aims to evaluate the different medical and surgical treatment modalities currently available for microstomia in patients with scleroderma and make recommendations for future research. MATERIALS AND METHODS: A search of PubMed, Ovid MEDLINE, and Ovid Embase was conducted to identify articles discussing the treatment of microstomia in scleroderma. Twenty articles discussing surgical therapy and one article discussing medical therapy were reviewed. RESULTS: Mostly because of a scarcity of high-level evidence, no individual therapy has documented long-term efficacy. Some treatments demonstrate positive results and warrant further research. CONCLUSION: Given the variability of results, specific recommendations for the treatment of microstomia in patients with scleroderma are difficult to establish. A multifaceted approach that includes surgical and medical therapy is likely the best option to improve oral aperture in this patient population. Surgical treatments such as neurotoxins, autologous fat grafting, and ultraviolet A1 phototherapy may hold the most potential for improvement.

Midlevel Injectable Practice Patterns in Dermatology and Plastic Surgery Offices.

BACKGROUND: There is limited knowledge on the extent physicians delegate cosmetic procedures to midlevel providers. OBJECTIVE: To assess dermatology and plastic surgery practice patterns for the injections of neurotoxins and dermal fillers. MATERIALS AND METHODS: Four hundred ninety-two dermatology and plastic surgery practices were identified from 10 major US metropolitan areas. These practices were contacted, and staff were asked a series of questions to best characterize the practice patterns in regard to who performs the injectables in the office. RESULTS: Although most dermatology and plastic surgery practices had physicians as the only provider who gives injectables, 18.35% of dermatology and 25.4% of plastic surgery practices had nurse practioners and physician assistants giving injectables both with and without oversight of the supervising physician onsite. CONCLUSION: In a large majority of both plastic surgery and dermatology practices, physicians exclusively perform injections of neurotoxins and fillers. For practices that allow midlevel providers to perform injectables, the level of physician supervision is variable. In a small percentage of plastic surgery practices, surveyed midlevel providers exclusively performed injectables.

Pituitary adenylate cyclase-activating polypeptide promotes cutaneous dendritic cell functions in contact hypersensitivity.

BACKGROUND: Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. OBJECTIVE: This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. METHODS: We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. RESULTS: CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro. CONCLUSION: These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.

Characterizing the effects of in utero valproic acid exposure on NF-κB signaling in CD-1 mouse embryos during neural tube closure.

Nuclear factor kappa B (NF-κB) is a heterodimer of protein subunits p65 and p50, that regulates the expression of a large number of genes related to cell growth and proliferation. The p65 subunit is activated after phosphorylation by Pim-1, while the p50 subunit is the cleaved product of its precursor molecule p105. Valproic acid (VPA), an antiepileptic drug, is a known teratogen and its exposure during pregnancy is associated with 1-2% of neural tube defects in the offspring. The current study aimed at investigating the effects of in utero VPA exposure on the key components of the NF-κB signaling pathway including p65, p50, and Pim-1 in CD-1 mouse embryos during the critical period of neural tube closure. Here we report that p65, Pim-1 and p105/p50 mRNA were significantly (p < 0.05) downregulated at 1 and 3 h following in utero exposure to a teratogenic dose (400 mg/kg) of VPA in gestational day (GD)9 exposed embryos. At GD13 heads of control, non-exencephalic and exencephalic embryos were used for analysis and we found significant upregulation of p65 protein expression in non-exencephalic GD13 heads while p50 protein levels were significantly downregulated in both non-exencephalic and exencephalic groups. On the other hand, p65 and p50 protein levels remained unchanged in the nuclear extracts of the VPA-exposed non-exencephalic and exencephalic GD13 embryo heads. The reported results suggest that VPA exposure perturbates p65, p105/p50, Pim-1 transcript and p65/p50 protein levels in mouse embryos.

Dual effects of S-adenosyl-methyonine on PC12 cells exposed to the dopaminergic neurotoxin MPP.

OBJECTIVES: To investigate S-adenosyl-methyonine (SAM) effects on PC12 cells viability and neuritogenesis treated with MPP+ (1-methyl-4-phenylpyridinium). METHODS: PC12 cell viability test (MTT assay) in DMEM medium with SAM and/or MPP+; PC12 cell neuritogenesis test in F-12K medium with nerve growth factor (NGF); DNMT activity in PC12 cells (DNMT Activity Assay Kit) with SAM and/or MPP+. KEY FINDINGS: (1) MPP+ decreased cell viability; (2) SAM did not affect cell viability per se, but it increased MPP+ neurotoxicity when co-incubated with the neurotoxin, an effect abolished by DNA methyltransferases (DNMT) inhibitors; (3) pretreatment with SAM for 30 min or 24 h before MPP+ addition had no effect on cell viability. Neuritogenesis: Treatment with SAM for 30 min or 24 h (1) increased cell differentiation per se, (2) increased NGF differentiating effects (additive effect) and (3) blocked the neuritogenesis impairment induced by MPP+. SAM with MPP+ increased the DNMT activity, whereas SAM alone or MPP+ alone did not. CONCLUSIONS: (1) SAM might induce neurotoxic or neuroprotective effects on PC12 cells, depending on the exposure conditions; (2) DNMT inhibitors might attenuate the MPP+ exacerbation toxicity induced by SAM; (3) DNA methylation might be involved in the observed effects of SAM (needs further investigation).

Improving the Appearance of Surgical Facial Scars With IncobotulinumtoxinA and Microneedling.

BACKGROUND: The appearance of post-surgical scars on the face is a major concern for surgeons and a source of anxiety for patients after Mohs surgery due to nonmelanoma skin cancer (NMSC). The objective of this retrospective study was to assess the effectiveness of combining incobotulinumtoxinA and microneedling to improve the appearance of post-operative facial scars. Enrolled subjects underwent surgical removal of facial NMSCs followed by flap reconstruction by the same surgeon during 2014 (n=35) and 2015 (n=35). Sutures were removed 7 days after the procedure. Subjects treated during 2014 received no additional treatment and served as a control group. Subjects treated during 2015 also received micro-doses of incobotulinumtoxinA along the scar border and microneedling of the surgical area. Microneedling was repeated after 15 days. Scar severity was determined by the surgeon and an independent dermatologist using the modified Vancouver Scar Scale (VSS) scores on day 7 and day 30 following suture removal. Patient Satisfaction Scale scores were also determined using a 5-point scale on day 30. Mean (SD) VSS scores were 10.4 (1.14) on day 7 among treated subjects vs. 9.5 (1.88) among control subjects (P<0.05). On day 30, mean VSS scores had decreased to 1.1 (0.89) for treated subjects vs. 7.6 (1.72) for control subjects (P<0.05). Patient Satisfaction Scores were significantly higher among treated patients vs control subjects (4.45 vs 3.14; P<0.001). The use of incobotulinumtoxinA is a promising therapeutic option for improving scar appearance. Combined with microneedling, it significantly reduced VSS scores and improved overall satisfaction of treated subjects following surgery for NMSCs. J Drugs Dermatol. 2020;19(6): doi:10.36849/JDD.2020.4772.

Memory deterioration based on the tobacco smoke exposure and methylazoxymethanol acetate administration vs. aripiprazole, olanzapine and enrichment environment conditions.

Enrichment environment conditions, as well as tobacco smoke exposure, may affect cognitive function (e.g. spatial memory) in an animal model of schizophrenia and schizophrenic patients. The aim of this study was to find whether spatial memory function impairment is found in methylazoxymethanol acetate treated rats (an animal model of schizophrenia) and whether aripiprazole (1.5 mg/kg) and olanzapine (0.5 mg/kg) modify these functions. We also were able to determine whether tobacco smoke exposure and enrichment environment conditions have an impact on drug efficacy. The effect of methylazoxymethanol acetate, tobacco smoke exposure, enrichment environment and the use of drugs were studied in the Morris Water Maze test (spatial memory). The results of our study clearly show that enriched environment may have a procognitive effect while tobacco smoke and methylazoxymethanol acetate have a contradictory effect. This paper also confirmed that the use of neuroleptics, namely ARI and OLA, reduced the process of spatial memory deterioration tested in the Morris water maze both in terms of the number of escape latencies and crossed quadrants.

Symptomatic Brain Hemorrhages from Cavernous Angioma After Botulinum Toxin Injections, a Role of TLR/MEKK3 Mechanism? Case Report and Review of the Literature.

BACKGROUND: Cavernous angiomas (CAs) are vascular malformations that may result in stroke. CASE DESCRIPTION: Herein, we evaluate a CA patient with chronic migraine who experienced 2 documented symptomatic hemorrhages after receiving respective high doses of botulinum toxin (Btx). CONCLUSIONS: Recently, bacterial lipopolysaccharide has been reported to contribute to CA development through Toll-like receptor signaling, causing hemorrhagic angiogenic proliferation. Lipopolysaccharide and Btx share a common intracellular signaling pathway driving CA development and hemorrhage. Significance of these observations is demonstrated by previous works on plasma molecules showing prognostic associations with symptomatic hemorrhages in human CA, related to the same canonical pathways. Authors suggest careful tracking of the association of Btx and hemorrhage in CA patients.

Sonographically guided botulinum toxin injections in patients with neurogenic thoracic outlet syndrome: correlation with surgical outcomes.

OBJECTIVE: We examined the role of botulinum toxin (BTX) injections of anterior scalene (AS) and pectoralis minor (PM) muscles in patients undergoing surgery for neurogenic thoracic outlet syndrome (NTOS). We hypothesized that symptomatic improvement from BTX injections correlates with favorable long-term response to surgery for NTOS. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act compliant study was approved by the institutional review board and prior informed consent requirement was waived. We retrospectively analyzed prospectively acquired data in NTOS patients who underwent sonographically guided chemodenervation of AS and PM using BTX type A followed by scalenectomy and first rib resection. Overall responses to BTX injections and surgery were recorded after each procedure. Statistical analyses were performed to determine correlation between responses to BTX injections and surgery. RESULTS: In 157 patients, 178 BTX injections followed by surgery were identified (114 females; mean age 38 ± 13 years). Responders and non-responders to BTX injections and surgery had similar preoperative symptom duration and age (P > 0.14). Better response to BTX injections correlated positively with better response to surgery (P = 0.003), persisting after adjustment for age, gender, and symptom duration (P = 0.03). A high proportion of responders to BTX injections also responded to surgery (positive predictive value of 99%), and BTX injections showed high specificity (90%). BTX injections were moderately sensitive (66%) and accurate (67%) to determine surgical response and had low negative predictive value (14%). CONCLUSION: Response to BTX injections correlates positively with long-term surgical outcome in subjects with NTOS, potentially playing an important role in patient management.

Surgical Cosmetic Procedures of the Face.

Surgical techniques for cosmetic facial rejuvenation, antiaging concerns, and the optimization of facial beauty can be nuanced and complex. Generally speaking, surgical interventions, including facelift, necklift, blepharoplasty, and rhinoplasty, are the gold standard approaches for the enhancement of facial features. A detailed understanding of facial anatomy, aesthetics, and techniques is necessary to master these approaches.

Flexible two-layer dissolving and safing microneedle transdermal of neurotoxin: A biocomfortable attempt to treat Rheumatoid Arthritis.

This study is directed towards the gentle transdermal delivery of Neurotoxin (NT) and study of the treatment of Rheumatoid Arthritis (RA) in rats by NT loaded dissolving Microneedles (DMNs-NT). The DMNs-NT fabrication involved a two-step centrifugation method. The quadrangular pyramid shape needles had great mechanical strength. The upper part of the needle contained 15.4 ±â€¯0.5 µg of drug per patch. Blank DMNs showed favorable biocompatibility and low toxicity on the chondrocyte cells. Both NT and DMNs-NT displayed anti-inflammatory capabilities ex-vitro. The results of ex-vitro evaluation of DMNs the skin penetration depth of DMNs-NT rats was higher than 70 µm and the cumulative penetration of NT in DMNs could reach 95.8% in 4 h, whereas, the NT solution could barely penetrate the skin, thereby proving the favorable facilitation of NT transdermal delivery. The needle structure dissolved completely after 10 min in vivo and the channel on the Stratum Corneum (SC) was closed after 6 h. There was no significant adverse reaction on the skin after 15 days of administration. The pharmacodynamic study showed that DMNs-NT significantly reduced the toe swelling of RA rats and reduced the levels of TNF-α and IL-1ß in serum to alleviate the injury of the ankle joints. DMNs-NT held favorable stability in 3 months. All these results established that DMNs-NT could penetrate the skin of rats in a biocompatible manner, and have a strong therapeutic effect on rat RA by transdermal delivery.