OnabotulinumtoxinA as a promising treatment for primary trochlear headache: A retrospective case series.

OBJECTIVES: To report the efficacy of onabotulinumtoxinA (BoNTA) injections in relieving pain in patients with primary trochlear headache (PRTH). METHODS: Examination of medical records for patients diagnosed with PRTH according to the International Classification of Headache Disorders, 3rd edition criteria and treated with BoNTA. Data were collected for variables related to pain relief, duration of effectiveness, and adverse effects. RESULTS: Six patients were included in the study. All had previously undergone standard care interventions, including infiltrations or oral treatments, yet experienced treatment failure or symptom recurrence. All patients received 20 units of BoNTA, administered in the corrugator and procerus muscles. Subsequent to the BoNTA injections, all six patients reported substantial pain relief, with five achieving complete remission of symptoms. The analgesic effect persisted for a duration of 3 months. No adverse events were reported in any of the cases. CONCLUSIONS: Our case series presents the first evidence of the potential of BoNTA as a safe and effective treatment option for PRTH. From a clinical standpoint, having a safer alternative is of paramount significance for patients with limited treatment options, such as those with PRTH. Further research is warranted to validate these findings and explore the long-term efficacy of BoNTA in PRTH management.

The Effect of Botulinum Toxin on Flap Viability of the Posterior Thigh Perforator Flap in Rats.

BACKGROUND: The use of perforator propeller flaps in lower limb reconstruction has increased recently. Many pharmacological agents are used to increase flap viability. Botulinum toxin has been used in various types of flaps in the literature. However, there is no study regarding the use of botulinum toxin in the lower limb propeller flaps. This study investigates the effect of botulinum toxin administration on flap survival for lower limb propeller flap in rats. MATERIALS AND METHODS: The study included 20 male Wistar albino rats, divided into two groups with a flap rotation of 90° in group 1 and 180° in group 2. In both groups, botulinum toxin was administered to the right thigh and a physiological saline solution was applied to the left thigh. Five days later, flaps were elevated over the posterior aspect of the right and left thighs and inset after 90° and 180° rotation was performed. Histopathological, immunohistochemical, and necrosis area analyses were performed. RESULTS: Necrosis area, edema, polymorphonuclear leukocyte infiltration, and necrosis were found to be higher on the left side of the groups, whereas epidermal thickness, collagen density, vascularization, and hair root density were found to be higher on the right side of the groups. No significant difference was found between the right posterior thighs in either group on any parameter other than vascularization. Histopathologically and immunochemically statistically significant differences were found between the two groups. CONCLUSIONS: The present study found that botulinum toxin increases flap viability in lower limb perforator-based propeller flaps.

A Multicenter Study to Evaluate Subject Satisfaction With Two Treatments of AbobotulinumtoxinA a Year in the Glabellar Lines.

BACKGROUND: Real-world re-treatment intervals for botulinum toxins vary, but most subjects receive treatment less frequently than the manufacturer-recommended minimum intervals. In subjects receiving treatment with AbobotulinumtoxinA (ABO) less frequently, high levels of satisfaction and psychosocial improvements in well-being, self-confidence, and quality of life are observed. OBJECTIVE: To evaluate subject satisfaction with a twice yearly re-treatment schedule. METHODS AND MATERIALS: This open-label, multicenter, interventional study evaluated subject satisfaction following injections of ABO 50 U in the glabellar lines at baseline and 6 months. The primary end point was subject satisfaction at 12 months. Secondary endpoints included subject satisfaction, FACE-Q scales, and glabellar line severity scale (GLSS). RESULTS: Ninety-five percent of the 120 subjects were "highly satisfied" or "satisfied" with their treatment outcomes at 12 months. FACE-Q total scores suggested that subjects were less bothered by glabellar lines and felt better about their facial appearance with each treatment versus baseline. Approximately half of subjects had ≥1-grade improvement from baseline in GLSS at 12 months. Median onset of effect was 2 days. CONCLUSION: The majority of subjects (95%) were satisfied with ABO treatment every 6 months; results were supported by high subject satisfaction, long duration, rapid onset, natural-looking results, and overall psychological wellness and safety.

An objective method to assess the improvements of skin texture roughness after botulinum toxin type a treatment of crow's feet.

BACKGROUND: Photo-numeric scales could lack precision and objectivity on evaluating the improvements on wrinkles after a treatment with botulinum toxin type A. The authors suggest a new digital evaluation method to analyze its effectiveness. OBJECTIVES: This study aims to investigate retrospectively the effect of intramuscular injection of botulinum toxin type A on skin texture in the lateral peri-orbital region with a new objective method. METHODS: Skin texture roughness (STR) in the lateral peri-orbital region is evaluated with a multi-directional light beam by light emitting diodes of different wavelengths (Antera 3D® ), before and after injections of 12 units of botulinum toxin type A. The wrinkles and lines deeper than 0.5 mm are filtered to measure accurately skin texture. RESULTS: We observed an improvement of STR in all cases treated with botulinum toxin type A. A significant decrease of STR was recorded as follows: 17.08% (P < .0001) at 4 weeks and 12.14% at 4 months (P = .001). CONCLUSION: Botulinum toxin type A treatment of crow's feet was able to improve STR. The Antera® device and software are a valuable, objective, easy and reproducible method to assess the effects of the toxin.

Influence of the neural microenvironment on prostate cancer.

BACKGROUND: Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. METHOD: We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. RESULT: Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non-neoplastic epithelial cells. CONCLUSION: Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer.

Activity-dependent vs. neurotrophic modulation of acetylcholine receptor expression: Evidence from rat soleus and extensor digitorum longus muscles confirms the exclusive role of activity.

Evoked electrical muscle activity suppresses the transcription of mRNAs for acetylcholine receptors in extrajunctional myonuclei. Muscle denervation or disuse releases such inhibition and extrajunctional receptors appear. However, in soleus muscles paralysed with nerve-applied tetrodotoxin, a restricted perijunctional region has been described where myonuclei remain inhibited, a finding attributed to nerve-derived trophic factor(s). Here, we reinvestigate extrajunctional acetylcholine receptor expression in soleus and extensor digitorum longus muscles up to 90 days after denervation or up to 20 days of disuse, to clarify the role of trophic factors, if any. The perijunctional region of soleus muscles strongly expressed acetylcholine receptors during the first 2-3 weeks of denervation. After 2-3 months, this expression had disappeared. No perijunctional expression was seen after paralysis by tetrodotoxin or botulinum toxin A. In contrast, the extensor digitorum longus never displayed suppressed perijunctional acetylcholine receptor expression after any treatment, suggesting that it is an intrinsic property of soleus muscles. Soleus denervation only transiently removed the suppression, and its presence in long-term denervated soleus muscles contradicts any contribution from nerve-derived trophic factor(s). In conclusion, our results confirm that evoked electrical activity is the physiological factor controlling the expression of acetylcholine receptors in the entire extrajunctional membrane of skeletal muscles.

Reversible Recruitment of a Homeostatic Reserve Pool of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity of Quantal Content.

Homeostatic regulation is essential for the maintenance of synaptic strength within the physiological range. The current study is the first to demonstrate that both induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds of blocking or unblocking acetylcholine receptors at the mouse neuromuscular junction. Our data suggest that the homeostatic upregulation of release is due to Ca(2+)-dependent increase in the size of the readily releasable pool (RRP). Blocking vesicle refilling prevented upregulation of quantal content (QC), while leaving baseline release relatively unaffected. This suggested that the upregulation of QC was due to mobilization of a distinct pool of vesicles that were rapidly recycled and thus were dependent on continued vesicle refilling. We term this pool the "homeostatic reserve pool." A detailed analysis of the time course of vesicle release triggered by a presynaptic action potential suggests that the homeostatic reserve pool of vesicles is normally released more slowly than other vesicles, but the rate of their release becomes similar to that of the major pool during homeostatic upregulation of QC. Remarkably, instead of finding a generalized increase in the recruitment of vesicles into RRP, we identified a distinct homeostatic reserve pool of vesicles that appear to only participate in synchronized release following homeostatic upregulation of QC. Once this small pool of vesicles is depleted by the block of vesicle refilling, homeostatic upregulation of QC is no longer observed. This is the first identification of the population of vesicles responsible for the blockade-induced upregulation of release previously described. Significance statement: The current study is the first to demonstrate that both the induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds. Our data suggest that homeostatic upregulation of release is due to Ca(2+)-dependent priming/docking of a small homeostatic reserve pool of vesicles that normally have slow-release kinetics. Following priming, the reserve pool of vesicles is released synchronously with the normal readily releasable pool of synaptic vesicles. This is the first description of this unique pool of synaptic vesicles.

Long-Term Treatment with OnabotulinumtoxinA Results in Consistent, Durable Improvements in Health Related Quality of Life in Patients with Overactive Bladder.

PURPOSE: We present the long-term effects of repeat onabotulinumtoxinA 100 U treatment on health related quality of life in patients with overactive bladder and urinary incontinence who had an inadequate response to and/or were intolerant of an anticholinergic. MATERIALS AND METHODS: Patients who completed either of 2, 24-week phase III trials could enter a 3-year extension study and request multiple onabotulinumtoxinA 100 U treatments as needed. Results of the I-QOL (Incontinence-Quality of Life) and KHQ (King's Health Questionnaire) are reported for up to 6 treatments. Consistency of the response to repeat onabotulinumtoxinA treatments was evaluated by classifying patients by the I-QOL response to the first treatment and analyzing responses to treatments 2 to 6. RESULTS: After onabotulinumtoxinA treatments 1 to 6, improvements in I-QOL scores were consistently 2 to 3 times the minimally important difference, and improvements in KHQ role limitations and social limitations domain scores were 5 to 6 and 3 to 4 times the minimally important difference, respectively. Most patients achieved or exceeded the minimally important difference for I-QOL and KHQ domain scores. Furthermore, 72.9% of patients who achieved or exceeded the minimally important difference for I-QOL after treatment 1 did so for all subsequent treatments. Of patients with a poor response after treatment 1, 38.3% achieved improvements greater than the minimally important difference for all subsequent treatments. CONCLUSIONS: In patients with overactive bladder and incontinence consistent and clinically meaningful improvements in health related quality of life were observed with repeat onabotulinumtoxinA 100 U treatments. A positive response after treatment 1 tended to predict similar responses to subsequent treatments, whereas a lack of response to treatment 1 did not preclude positive response(s) to later treatments.

Insights into the Functional Anatomy Behind the PREEMPT Injection Paradigm: Guidance on Achieving Optimal Outcomes.

OBJECTIVE: To provide clinically relevant insights on the identification of the muscles and techniques involved in the safe and effective use of onabotulinumtoxinA for chronic migraine prophylaxis. BACKGROUND: Although guidance on the use of onabotulinumtoxinA for chronic migraine is available, based on the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program, clinical experience has shown that insufficient understanding of the anatomy and function of the head and neck muscles may lead to undesirable outcomes and suboptimal efficacy. DESIGN/METHODS: Each muscle involved in the standardized PREEMPT injection paradigm is reviewed with a thorough description of each muscle's anatomy (ie, muscle description and location, innervation, vascular supply) and function. Key insights based on clinical experience are also provided to help improve outcomes. RESULTS: The identification of the muscles in the PREEMPT injection paradigm should be based on each patient's unique anatomy and injections should be administered using the advised techniques. A thorough examination of the patient prior to treatment is also critical to determine if any preexisting conditions may increase the risk for unwanted outcomes and appropriate expectations should be communicated. CONCLUSIONS: Thorough knowledge of the functional anatomy of the muscles involved in the standardized PREEMPT injection paradigm is critical to achieve the efficacy and safety observed in clinical trials. In addition, it is important to assess a patient's baseline condition to anticipate the risk for unwanted outcomes that may result from treatment.

Can botox improve night-time overactive bladder symptoms in women?

AIMS: Despite the efficacy of intravesical onabotulinumtoxinA (Botox) therapy for urgency, urgency incontinence, and daytime frequency, its value in treatment of nocturia remains unclear. The aim of the prospective observational study was to assess the effect of onabotulinumtoxinA on night-time symptoms in women with overactive bladder (OAB), including nocturia, night-time urgency incontinence, and nocturnal voided volume as end-points. METHODS: Women with idiopathic OAB (with at least one episode of urgency urinary incontinence (UUI) per day, ≥8 micturitions per 24 hr, and ≥2 nocturia episodes per night) were enrolled. Patients with nocturnal polyuria were excluded. Botox (100 U) was administered in 20 intra-detrusor injections. Post-void residual volumes (PVR) were checked at 2, 4, and 12 weeks. Participants completed a 3-day bladder diary and the King's Health Questionnaire (KHQ) before and 12 weeks after treatment, and reported the efficacy of the treatment on visual analog scale (VAS) at the final follow-up visit. RESULTS: Seventy-six women completed the study. Botox injections were effective in the reduction of nocturia episodes (mean -0.98; P < 0.001) and night-time UUI episodes (-0.37; P < 0.001) compared to the baseline. The increase of mean voided volume of the night-time micturitions was 92.6 ml (P < 0.001). Patients reported a mean 58 points of improvement on the VAS. Urinary retention, which required self-catheterization, was observed in three patients. CONCLUSIONS: Intravesical Botox injection provides significant benefit for night-time symptoms in OAB patients. Our results are applicable for women without nocturnal polyuria, and should prove useful when counseling patients about the risks and benefits of Botox. Neurourol. Urodynam. 36:648-652, 2017. © 2016 Wiley Periodicals, Inc.

The Practical Use of AbobotulinumtoxinA in Aesthetics.

Botulinum toxin (BoNT) has been approved for aesthetic use since 2002. Since then, clinical studies and expert use have informed our understanding of how BoNT exerts its clinical effect and the practical use of this product across a number of aesthetic applications. This review discusses the clinical properties and characteristics of abobotulinumtoxinA, which patients are suitable for its use, and how it can be utilized to treat facial rhytides.

Key Parameters for the Use of AbobotulinumtoxinA in Aesthetics: Onset and Duration.

Time to onset of response and duration of response are key measures of botulinum toxin efficacy that have a considerable influence on patient satisfaction with aesthetic treatment. However, there is no overall accepted definition of efficacy for aesthetic uses of botulinumtoxinA (BoNT-A). Mechanical methods of assessment do not lend themselves to clinical practice and clinicians rely instead on assessment scales such as the Frontalis Activity Measurement Standard, Frontalis Rating Scale, Wrinkle Severity Scale, and Subject Global Assessment Scale, but not all of these have been fully validated. Onset of activity is typically seen within 5 days of injection, but has also been recorded within 12 hours with abobotulinumtoxinA. Duration of effect is more variable, and is influenced by parameters such as muscle mass (including the effects of age and sex) and type of product used. Even when larger muscles are treated with higher doses of BoNT-A, the duration of effect is still shorter than that for smaller muscles. Muscle injection technique, including dilution of the toxin, the volume of solution injected, and the positioning of the injections, can also have an important influence on onset and duration of activity. Comparison of the efficacy of different forms of BoNT-A must be made with the full understanding that the dosing units are not equivalent. Range of equivalence studies for abobotulinumtoxinA (Azzalure; Ipsen Limited, Slough UK/Galderma, Lausanne CH/Dysport, Ipsen Biopharm Limited, Wrexham UK/Galderma LP, Fort Worth, TX) and onabotulinumtoxinA (Botox; Allergan, Parsippany, NJ) have been conducted, and results indicate that the number of units of abobotulinumtoxinA needs to be approximately twice as high as that of onabotulinumtoxinA to achieve the same effect. An appreciation of the potential influence of all of the parameters that influence onset and duration of activity of BoNT-A, along with a thorough understanding of the anatomy of the face and potency of doses, are essential to tailoring treatment to individual patient needs and expectations.

The impact of onabotulinumtoxinA on severe headache days: PREEMPT 56-week pooled analysis.

BACKGROUND: OnabotulinumtoxinA has been shown to reduce headache-days among patients with chronic migraine (CM). The objective of this analysis was to determine whether onabotulinumtoxinA has an impact on headache-day severity in patients with CM among those patients who were deemed non-responders based on reduction in the frequency of headache days alone. METHODS: Data from the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical trial program (a 24-week, 2-treatment cycle, double-blind, randomized, placebo-controlled, parallel-group phase, followed by a 32-week, 3-treatment cycle, open-label phase) were pooled for analysis. Patients kept a daily diary to record headache severity on a 4-point scale (from none to severe), and a 6-domain Headache Impact Test (HIT-6) was used to determine the clinical impact of headaches. Analysis was undertaken to assess whether the subset of patients that were headache-day frequency non-responders at week 24 (patients with <50% reduction in headache-day frequency) experienced a reduction in headache severity whilst receiving onabotulinumtoxinA. RESULTS: For headache-day frequency non-responders, significant reductions in the number of severe headache days, average daily headache severity, pooled percentage of severe headache days and headache severity score were observed at week 24 for patients who had received onabotulinumtoxinA compared with those who had received placebo. The between-group differences were reduced and non-significant at week 56. Similarly, headache-day frequency non-responders receiving onabotulinumtoxinA were found to have an improvement in the clinical impact of headaches using results from the HIT-6. CONCLUSIONS: These results suggest that even those patients with CM who are deemed non-responders based on analysis of headache frequency alone experience clinically meaningful relief from headache intensity following treatment with onabotulinumtoxinA.

Efficacy and safety of abobotulinumtoxinA liquid formulation in cervical dystonia: A randomized-controlled trial.

BACKGROUND: Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA. OBJECTIVES: The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia. METHODS: This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N = 369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores. RESULTS: At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P < .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events. CONCLUSIONS: Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. © 2016 International Parkinson and Movement Disorder Society.

The Botulinum Toxin as a Therapeutic Agent: Molecular Structure and Mechanism of Action in Motor and Sensory Systems.

Botulinum neurotoxin (BoNT) produced by Clostridium botulinum is the most potent molecule known to mankind. Higher potency of BoNT is attributed to several factors, including structural and functional uniqueness, target specificity, and longevity. Although BoNT is an extremely toxic molecule, it is now increasingly used for the treatment of disorders related to muscle hyperactivity and glandular hyperactivity. Weakening of muscles due to peripheral action of BoNT produces a therapeutic effect. Depending on the target tissue, BoNT can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. In recent observations of the analgesic properties of BoNT, the toxin modifies the sensory feedback loop to the central nervous system. Differential effects of BoNT in excitatory and inhibitory neurons provide a unique therapeutic tool. In this review the authors briefly summarize the structure and mechanism of actions of BoNT on motor and sensory neurons to explain its therapeutic effects and future potential.

When EMG contamination does not necessarily hide high-frequency EEG: scalp electrical recordings before and after Dysport injections.

The main aim of the present study was to investigate effects of partial reductions of electromyogram (EMG) on high-frequency scalp electroencephalogram (EEG) at rest and during performance of certain cognitive tasks. Nineteen healthy women performed the same cognitive tasks before and after cosmetic injections of Dysport in certain sites of facial muscles. Scalp EEG and EMG were recorded. Impact of Dysport injections on changes of spectral power in ß2 and low γ frequency ranges (18-40 Hz) in EEG and EMG derivations was investigated. Also changes of spectral power in EEG and EMG derivations during comparisons of different cognitive states were calculated before and after Dysport injections separately. Dysport injections led to EMG decreases in facial muscles around the injection zones and also led to reductions of power of electric processes in scalp derivations. Along with it results of EEG power comparisons between the pairs of the cognitive states were qualitatively similar before and after Dysport injections. These facts to all appearance demonstrate that though scalp EEGs in the range above 15-40 Hz are contaminated by EMG, in certain experimental situations EMG contamination does not preclude qualitative detections of electroencephalographic correlates of mental activities in ß2 and low γ frequency ranges. Parallel EEG and EMG registrations can help not to overestimate EMG contamination in psychophysiological EEG studies.

Effects of onabotulinumtoxinA treatment on efficacy, depression, anxiety, and disability in Turkish patients with chronic migraine.

Chronic migraine causes a serious labour loss and disability in the society and increases the risk of depression and anxiety by negatively affecting the quality of life. The purpose of this study was to investigate the effects of onabotulinumtoxinA (BoNT-A) treatment on efficacy before and after treatment in our cases with chronic migraine as well as on depression, anxiety and disability caused by migraine. According to the International Headache Classification (ICHD-III beta version), 60 adult patients who were diagnosed with chronic migraine were included in the study. A total of 155 IU BoNT-A treatment from 31 regions was administered in accordance with the protocol of PREEMPT study. Information about the characteristics of patients' headaches, background and family history, drugs they used was recorded. At the baseline and in the first and third month after the BoNT-A injection, VAS scores, the number of both headache days and attacks, the headache duration, the frequency of application to emergency services and the intake of both analgesics and triptans during attacks were evaluated. MIDAS, BDI and BAI were evaluated at the baseline and in the third month after the BoNT-A injection. BoNT-A injection provided a significant decrease in the number of days and severity of headaches, MIDAS disability scores and psychiatric complaints in cases with chronic migraine who did not respond to prophylactic treatments in the third month of the treatment.

Healing of rotator cuff tendons using botulinum toxin A and immobilization in a rat model.

BACKGROUND: We evaluated effects of botulinum toxin A (Botox) and cast immobilization on tendon healing in a rat model. Injection of Botox into rat supraspinatus was hypothesized to reduce muscle active force and improved healing. METHODS: Eighty-four supraspinatus tendons were surgically transected and repaired in 42 Sprague-Dawley rats (transosseous technique). After repair, supraspinatus muscle was injected with saline or Botox (3 or 6 U/kg). Half the shoulders were cast-immobilized for the entire postoperative period; half were allowed free cage activity. Histology was examined at 2, 4, 8, and 12 weeks. A healing zone cross-sectional area was measured, and biomechanical testing of repair strength and tendon viscoelastic properties was conducted at 4 and 12 weeks. RESULTS: Botox alone and cast immobilization alone exhibited increased ultimate load compared with controls (saline injection, no immobilization) at 4 weeks. No difference in ultimate load occurred between Botox-only and cast-only groups. At 12 weeks, the Botox (6 U/kg) plus cast immobilization group was significantly weakest (p < 0.05). A trend was shown toward decreased healing zone cross-sectional areas in casted groups. CONCLUSIONS: Supraspinatus Botox injection after rotator cuff repair might help protect the repair. However, cast immobilization plus Botox administration is harmful to rotator cuff healing in a rat tendon model.

Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium.

AIMS: Botulinum neurotoxin serotype A (BoNT/A) has emerged as an effective treatment of urinary bladder overactivity. Intravesical lipotoxin (BoNT/A delivery using liposomes), which may target the urothelium, is effective in blocking acetic acid induced hyperactivity in animals. The objective of this study was to assess the possible site of toxin action within the urothelium. METHODS: We examined expression of the toxin receptor (SV2) and its cleavage targets (SNAP-25 and SNAP-23) within urothelium as well as effects of the toxin on mechanically evoked release of ATP from cultured rat urothelial cells. ATP release was measured using the luciferin-luciferase assay; we examined expression of SNAP-23 and -25 in urothelial cells and mucosa of rat and human bladders. RESULTS: BoNT/A (1.5 U; 1-3 hr) blocked hypotonic evoked release of urothelial ATP, without affecting morphology. The expression of protein targets for BoNT/A binding (SV2) was detected in human and rat bladder mucosa and catalytic action (SNAP-23, -25) in urothelial cells and mucosa (differed in intensity) from rat and human bladder. Incubation of cultured (rat) urothelial cells with BoNT/A decreased expression levels of both SNAP-23 (44%) and SNAP-25 (80%). CONCLUSIONS: Our findings reveal that the bladder urothelium expresses the intracellular targets and the binding protein for cellular uptake of BoNT/A; and that the toxin is able to suppress the levels of these targets as well as hypotonic-evoked ATP release. These data raise the possibility that intravesical treatment with BoNT/A suppresses bladder reflex and sensory mechanisms by affecting a number of urothelial functions including release of transmitters.

Rationale for use of onabotulinum toxin A (BOTOX) in chronic migraine.

Chronic migraine is a severely disabling headache evolving from episodic migraine as a result of different transforming factors and characterized by atypical pain modulation and peripheral and central sensitization. Discovered by serendipity, onabotulinum toxin A (BoNT-A) represents the only drug specifically approved for CM prophylaxis. According to the dominant opinion, BoNT-A acts peripherally, impairing the exocytosis of neuropeptide and neurotransmitter and the delivery of receptors and ion channels on the cell surface of peripheral trigeminal endings, thereby indirectly reducing central sensitization. However, it is not excluded that BoNT-A has also a central antinociceptive action, probably associated with an enhanced opioidergic and GABA-ergic transmission. This review discusses the rationale for use of BoNT-A in CM including its mechanisms of action and molecular targets and provides suggestions for a more tailored BoNT-A prophylaxis in patients with CM.