Injection Of Botulinum Neurotoxin Type Research Articles

Association analysis of ADRB3:rs4994 with urodynamic outcome, six months after a single intra-detrusor injection of botulinum toxin, in women with overactive bladder.

Intra-detrusor injection of botulinum neurotoxin type A (BoNT/A) is recommended as a possible treatment for patients with overactive bladder (OAB) in whom first-line therapies have failed. The c.190T > C (rs4994) polymorphism in the gene encoding the beta-3 adrenergic receptor (ADRB3) has been suggested to be associated with predisposition to OAB or with response to OAB treatment via a cholinergic muscarinic receptor antagonist. This prospective study aimed to use a urodynamic parameter-based assessment of response, six months after a single intra-detrusor injection of BoNT/A in female OAB patients, to elucidate possible association with the ADRB3 polymorphism. The study group consisted of 138 consecutive, Polish, adult, female OAB patients. Urodynamic parameters were recorded before injection of BoNT/A and at six months after administration. ADRB3:rs4994 variants were identified by the sequencing of genomic DNA extracted from buccal swabs. Apart from baseline, and relative, increase in Maximum Cystometric Capacity (MCC) six months after BoNT/A injection, no significant differences were found in urodynamic parameters between reference TT homozygotes and women with at least one C allele. Our results do not exclude that ADRB3:rs4994 variants are associated with a positive urodynamic test-based response to intra-detrusor injection of BoNT/A in females with OAB.

Exploring the Interplay between the Clinical and Presumed Effect of Botulinum Injections for Cervical Dystonia: A Pilot Study.

Repetitive intramuscular injections of botulinum neurotoxin type A (BoNT/A) are the treatment of choice in patients with cervical dystonia (CD). As soon as BoNT therapy is initiated, the natural course of CD cannot be observed anymore. Nevertheless, the present study focuses on the "presumed" course of disease severity under the assumption that no BoNT therapy had been performed. The "experienced" benefit is compared with the "presumed" worsening. Twenty-seven BoNT/A long-term-treated CD patients were recruited. They had to assess the remaining severity of CD in percent of its severity at the start of BoNT therapy (RS-%). Then, they had to draw the course of severity from the onset of symptoms to the start of BoNT/A therapy (CoDB graph), as well as the course of severity from the start of BoNT/A therapy until the day of recruitment (CoDA graph). Then, they were instructed to presume the development of CD severity from the day of the start of BoNT/A therapy until the day of recruitment under the assumption that no BoNT/A therapy had been performed, and to assess the maximal severity they could presume in percent of the severity at the start of BoNT therapy (IS-%). Then, they had to draw the "presumed" development of CD severity (CoDI graph). The "experienced" change in disease severity and the "presumed" change since the start of BoNT/A therapy were compared and correlated with a variety of demographical and treatment-related data, including the actual severity of CD at the day of recruitment, which was assessed using the TSUI score and the actual dose per session (ADOSE). No CD patients expected an improvement without BoNT therapy. "Presumed" worsening ((IS-%)-100) was about 50% in the mean and did not correlate with the "experienced" benefit (100-(RS-%)). However, IS-% was significantly correlated with ATSUI and ADOSE. Obviously, CD patients have the opinion that their CD would have further progressed and worsened if no BoNT/A therapy had been performed. Thus, the total benefit of BoNT/A therapy for a patient with CD is a combination of the "experienced" benefit under BoNT/A therapy and the prevented worsening of CD that the patient expects to occur without BoNT/A therapy.

Morphological Evidence for the Presence of Nerve Sprouting and Stable Poly-Innervation in Human Orbicularis oculi Muscles Treated With Repeated Injections of Botulinum Neurotoxin Type A

Morphological Evidence for the Presence of Nerve Sprouting and Stable Poly-Innervation in Human Orbicularis oculi Muscles Treated With Repeated Injections of Botulinum Neurotoxin Type A

Cortical Rewiring Following Peripheral Injection of Botulinum Neurotoxin Type A

Cortical Rewiring Following Peripheral Injection of Botulinum Neurotoxin Type A

Botulinum Neurotoxin Therapy for Depression: Therapeutic Mechanisms and Future Perspective.

Depression is one of the most common mental disorders, which causes global burden. Antidepressants and psychotherapies are the mainstay of treatment for depression, which have limited efficacy. Thus, alternative approaches for preventing and treating depression are urgently required. Recent clinical trials and preclinical researches have clarified that peripheral facial injection of botulinum neurotoxin type A (BoNT/A) is a rapid, effective and relative safe therapy for improving some symptoms of depression. Despite its safety and efficacy, the underlying therapeutic mechanisms of BoNT/A for depression remains largely unclear. In the present review, we updated and summarized the clinical and preclinical evidence supporting BoNT/A therapy for the treatment of depression. We further discussed the potential mechanisms underlying therapeutic effects of BoNT/A on depression. Notably, we recently identified that the anti-depressant effects of BoNT/A associated with up-regulation of 5-HT levels and brain-derived neurotrophic factor (BDNF) expression in the hippocampus in a preclinical mouse model. In summary, these studies suggest that BoNT/A therapy is a potential effective and safe intervention for the management of depression. However, fundamental questions remain regarding the future prospects of BoNT/A therapy, including safety, efficacy, dose-response relationships, identification of potential predictors of response, and the precise mechanisms underlying BoNT/A therapy.

Botulinum Toxin Type-A for Lip Augmentation: "Lip Flip".

Over the last 10 years there has been an explosion in the number of minimally invasive procedures that patients undertake with increasing uses of botulinum neurotoxin type A for off label indications. One area of expansion over the past several years is the "Lip Flip" which involves injection of botulinum neurotoxin type A along the vermillion border to improve lip contour, eversion and fullness. While techniques and results for "gummy smile" and perioral vertical rhytids have been previously reported, minimal literature exists on this new trend, including whether such increased interest truly exists. Therefore, the authors aim to explore whether there is a rising trend regarding "lip flip" and report on clinical results from patients treated in our practice.

The impact of the initial severity on later outcome: retrospective analysis of a large cohort of botulinum toxin na\xefve patients with idiopathic cervical dystonia

BackgroundThe aim of study was to demonstrate that the first three injections of botulinum neurotoxin type A (BoNT/A) appear to be less effective in botulinum toxin naïve patients with idiopathic cervical dystonia (CD) with mild symptoms and low severity scores (TSUI-scores) at onset of BoNT/A-therapy compared to patients with full-blown CD and high initial TSUI-scores.MethodsIn 337 patients with CD who started BoNT/A-therapy in the BoNT-outpatient clinic of the university hospital in Düsseldorf during the last 12 years, demographical and treatment-related data as well as outcome measures (TSUI-scores) of the first four visits were extracted from the treatment ACCESS data bank.ResultsDistribution of the severity of CD scored using the TSUI-score significantly changed with the first three injections. In patients with a high baseline severity (TSUI-score > 10), mean TSUI-score continuously decreased (p < 0.001), whereas in patients with a low initial severity (TSUI-score < 6), mean TSUI-score increased (p < 0.001) during the first three injection cycles. Individual responses varied between 100% improvement, no response at all, and even worsening. Improvement of CD at the end of an injection cycle was observed in less than 25% in the mildly affected patients, but in more than 80% in the more severely affected patients.ConclusionClinical response to the first three BoNT/A-injections in severely affected de novo CD-patients is different from the response to BoNT/A in mildly affected de novo CD-patients. This has implications for further scientific studies and the patient management of mildly affected de novo patients with cervical dystonia.

Cumulative effects of long-term treatment with abobotulinumtoxinA in cervical dystonia: Findings from a prospective, observational study

ObjectivePatients with cervical dystonia (CD) require regular injections of botulinum neurotoxin type A (BoNT-A) to maintain treatment effectiveness. In this secondary analysis of a large routine-practice study, we assessed the response to abobotulinumtoxinA over repeated cycles and compared the responses of patients previously naïve to BoNT treatment to those already treated with BoNT-A. MethodsINTEREST IN CD2 was a prospective, 3-year, observational study following CD patients treated with BoNT-A. Patients were assessed at each injection visit using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Tsui scale; patient satisfaction with symptom control (previous cycle) was recorded. ResultsThis analysis included 466 patients treated with abobotulinumtoxinA over 3 years. TWSTRS-Total scores continually decreased; the mean ± SD reduction from baseline to 36 months was −7.4 ± 11.9. BoNT-naïve patients tended to show greater reductions in TWSTRS scores than already treated patients, particularly in the first 6 months. Incremental improvements were also seen in Tsui-tremor scores. Overall levels of patient satisfaction at peak effect (84.1–91.2%) were consistently higher than at the end of cycle (47.2–53.2%). The most frequently reported adverse events were dysphagia (6.8%) and muscular weakness (3.7%). ConclusionsThese data support the long-term effectiveness and safety of abobotulinumtoxinA in a real-world setting.

Physical therapy, intra-articular dextrose prolotherapy, botulinum neurotoxin, and hyaluronic acid for knee osteoarthritis: randomized clinical trial.

This study aimed to compare the efficacy of four treatments in the management of knee osteoarthritis. We carried out a randomized clinical trial with four study arms in an outpatient Department of Physical Medicine and Rehabilitation at a University Hospital. In total, 120 patients with knee osteoarthritis ≥50 years of age were randomly allocated to four groups. The primary outcome was knee pain in visual analog scale and the secondary outcome was the Knee Injury and Osteoarthritis Outcome Score. The exercise was prescribed daily for all participants throughout the study. For physical therapy (group 1), participants received superficial heat, transcutaneous electrical nerve stimulation and pulsed ultrasound. We administered a single intra-articular injection of botulinum neurotoxin type A (group 2) and three injections of hyaluronic acid (group 3) or 20% dextrose (group 4) to patients in the corresponding groups. Mixed analysis of variance showed that there was statistically significant difference between the groups in pain (P < 0.001), and Knee Injury and Osteoarthritis Outcome Score (P < 0.001). Pairwise between- and within-group comparisons showed that botulinum neurotoxin and dextrose prolotherapy were the most, and hyaluronic acid was the least efficient treatments for controlling pain and recovering function in patients. An intra-articular injection of botulinum toxin type A or dextrose prolotherapy is effective first-line treatments. In the next place stands physical therapy particularly if the patient is not willing to continue regular exercise programs. Our study was not very supportive of intra-articular injection of hyaluronic acid as an effective treatment of knee osteoarthritis.

Exploring the effects of extracranial injections of botulinum toxin type A on prolonged intracranial meningeal nociceptors responses to cortical spreading depression in female rats.

BackgroundBotulinum neurotoxin type A, an FDA-approved prophylactic drug for chronic migraine, is thought to achieve its therapeutic effect through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with myelinated nociceptors and potentially the vasculature and immune cells. Prior investigations to determine botulinum neurotoxin type A effects on meningeal nociceptors were carried out in male rats and tested with stimuli that act outside the blood brain barrier. Here, we sought to explore the effects of extracranial injections of botulinum neurotoxin type A on activation of meningeal nociceptors by cortical spreading depression, an event which occurs inside the blood brain barrier, in female rats.Material and methodsUsing single-unit recording, we studied myelinated C- and unmyelinated Aδ-meningeal nociceptors' responses to cortical spreading depression 7–14 days after injection of botulinum neurotoxin type A or saline along calvarial sutures.ResultsIn female rats, responses to cortical spreading depression were typically more prolonged and, in some cases, began at relatively longer latencies post-cortical spreading depression, than had been observed in previous studies in male rats. Extracranial administration of botulinum neurotoxin type A reduced significantly the prolonged firing of the meningeal nociceptors, in the combined sample of Aδ- and C-fiber, but not their response probability.DiscussionThe findings suggest that the mechanism of action by which botulinum neurotoxin type A prevents migraine differ from the one by which calcitonin gene-related peptide monoclonal antibodies prevent migraine and that even when the origin of migraine is central (i.e. in the cortex), a peripherally acting drug can intercept/prevent the headache.

Saliva changes in Parkinson\u2019s disease patients after injection of Botulinum neurotoxin type A

Patients with Parkinson’s disease (PD) are compromised by poor oral condition due to oropharyngeal bradykinesia, dysphagia, and the side effects of treatment. Intrasalivary gland injections of Botulinum neurotoxin type A (BNT-A) have been known to treat sialorrhea effectively in these patients. However, the decreased amount of saliva reduces self-cleaning ability that deteriorates oral hygiene and increases dental caries. The aim of this study was to determine the changes in the oral microflora and saliva in patients with PD treated for sialorrhea by means of sonography-controlled BNT-A injections into the bilateral parotid and submandibular glands. Altogether, 38 persons participated in the study: 12 PD patients who were injected with BNT-A for treatment of sialorrhea and passed salivary tests before and 1 month after the injections; and 13 PD patients and 13 healthy subjects who were not injected with BNT-A and passed salivary tests once. The condition of oral health was measured by the amount of saliva, salivary flow rate, and salivary composition. A good outcome with a significant decrease in salivary flow rate occurred at 1-month follow-up in the BNT-A-treated group while no significant change was found in salivary composition. BNT-A treatment did not change the Streptococcus mutans levels in saliva but there was statistically significant increase in levels of Lactobacilli. BNT-A injections can effectively treat sialorrhea while considering the change of oral microflora, and the patients should be under dentists’ care more frequently. EudraCT clinical trial number: 2015-000682-30.

The Use of Botulinum Neurotoxin Type A in Aesthetics: Key Clinical Postulates.

The most common aesthetic procedure performed worldwide is the injection of botulinum neurotoxin Type A (BoNT-A). Aesthetic providers must fully comprehend the objective scientific data, theoretical mechanisms of action, and differences between brands of BoNT-A. To determine and review the relevant clinical postulates for the use of botulinum toxin in aesthetics. The BoNT-A clinical postulates presented here discuss how each brand of BoNT-A acts identically, how the molecular potency may vary between the different products, how patient age, gender, genetics, and muscle mass cause variation in toxin receptor number and density, and how both practitioner and patient can affect toxin distribution. A total of 8 clinical postulates have been identified that are key to understanding the use of botulinum toxin in aesthetics and to obtaining the best clinical results. All of these factors affect the potential efficacy of the injected toxin and hence the aesthetic results obtained.

Direct central nervous system effects of botulinum neurotoxin

Local intramuscular injections of botulinum neurotoxin type A (BoNT/A) are effective in the treatment of focal dystonias, muscle spasms, and spasticity. However, not all clinical effects of BoNT/A may be explained by its action at peripheral nerve terminals. For example, the therapeutic benefit may exceed the duration of the peripheral neuroparalysis induced by the neurotoxin. In cellular and animal models, evidence demonstrates retrograde transport of catalytically active BoNT/A in projection neurons. This process of long-range trafficking is followed by transcytosis and action at second-order synapses. In humans, several physiological changes have been described following intramuscular delivery of BoNT/A. In particular, clinical studies have documented a decrease in Renshaw cell-mediated inhibition (i.e., recurrent inhibition), which may be important therapeutically for normalizing uncoordinated movements and overflow of muscle activity. In this review, we present data obtained in animal and experimental models that support direct central actions of BoNT/A mediated via retrograde axonal trafficking. We also discuss the reorganization of central circuitry induced by BoNT/A in patients, and the potential contribution of these effects to the therapeutic efficacy of the neurotoxin.

Impact of Dysphagia Therapy in Parkinson's Disease

Background: Dysphagia is a common symptom in Parkinson's disease (PD) which indicates a difficulty in swallowing. It has been accompanied with poor quality of life (QoL), anxiety and depression. Aim of the Study: to assess the effects of dysphagia treatment in Parkinson’s disease. Materials and methods: Studies published up to July 2017 were found via a systematic comprehensive electronic database search using PubMed, Embase, and The Cochrane Library.Two reviewers independently assessed the studies using strict inclusion criteria. Results: Thirteen studies were enrolled in the present study and qualitatively analyzed using critical appraisal items. The review includes rehabilitative (exercises, electrical stimulation, bolus modification etc.) and pharmacologic treatment. Some well-designed controlled trials were included. However, none of the included studies fulfilled all criteria for external and internal validity. Thus, a meta-analysis was not carried out as most of the studies were not of sufficient quality. Conclusion: Rehabilitative treatment including Expiratory Muscle Strength Training (EMST) may be effective for dysphagia treatment solely coupled with dopaminergic therapy for PD. Recently developed other treatment methods such as implant-prosthodontic treatment and percutaneous injection of botulinum neurotoxin type A in the cricopharyngeal muscle on dysphagia is rather promising. Nevertheless, these preliminary results warrant further investigation concerning their clinical applicability, and further research should be conducted.

Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors' responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle?

BackgroundAdministration of onabotulinumtoxinA (BoNT-A) to peripheral tissues outside the calvaria reduces the number of days chronic migraine patients experience headache. Because the headache phase of a migraine attack, especially those preceded by aura, is thought to involve activation of meningeal nociceptors by endogenous stimuli such as changes in intracranial pressure (i.e. mechanical) or chemical irritants that appear in the meninges as a result of a yet-to-be-discovered sequence of molecular/cellular events triggered by the aura, we sought to determine whether extracranial injections of BoNT-A alter the chemosensitivity of meningeal nociceptors to stimulation of their intracranial receptive fields.Material and methodsUsing electrophysiological techniques, we identified 161 C- and 135 Aδ-meningeal nociceptors in rats and determined their mechanical response threshold and responsiveness to chemical stimulation of their dural receptive fields with TRPV1 and TRPA1 agonists seven days after BoNT-A administration to different extracranial sites. Two paradigms were compared: distribution of 5 U BoNT-A to the lambdoid and sagittal sutures alone, and 1.25 U to the sutures and 3.75 U to the temporalis and trapezius muscles.ResultsSeven days after it was administered to tissues outside the calvaria, BoNT-A inhibited responses of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. BoNT-A inhibition of responses to capsaicin was more effective when the entire dose was injected along the suture lines than when it was injected into muscles and sutures. As in our previous study, BoNT-A had no effect on non-noxious mechanosensitivity of C-fibers or on responsiveness of Aδ-fibers to mechanical and chemical stimulation.DiscussionThis study demonstrates that extracranial administration of BoNT-A suppresses meningeal nociceptors’ responses to stimulation of their intracranial dural receptive fields with capsaicin and mustard oil. The findings suggest that surface expression of TRPV1 and TRPA1 channels in dural nerve endings of meningeal nociceptors is reduced seven days after extracranial administration of BoNT-A. In the context of chronic migraine, reduced sensitivity to molecules that activate meningeal nociceptors through the TRPV1 and TRPA1 channels can be important for BoNT-A’s ability to act as a prophylactic.

1079 A randomized clinical trial comparing prostatic injection of botulinum neurotoxin type A (Botox®) to optimized medical therapy in patients with BPH-related LUTS: End-of-study results of the PROTOX trial

1079 A randomized clinical trial comparing prostatic injection of botulinum neurotoxin type A (Botox®) to optimized medical therapy in patients with BPH-related LUTS: End-of-study results of the PROTOX trial

Characterizing the Lateral Border of the Frontalis for Safe and Effective Injection of Botulinum Toxin.

The forehead is a common site for injection of botulinum neurotoxin type A (BoNT-A) to treat hyperactive facial muscles. Unexpected side effects of BoNT-A injection may occur because the anatomy of the forehead musculature is not fully characterized. The authors described the lateral border of the frontalis in terms of facial landmarks and reference lines to determine the safest and most effective forehead injection sites for BoNT-A. The hemifaces of 49 embalmed adult Korean cadavers were dissected in a morphometric analysis of the frontalis. L2 was defined in terms of FT (the most protruding point of the frontotemporal region), L0 (the line connecting the infraorbital margin with the tragus), and L1 (the line parallel to L0 and passing through FT) such that L2 was positioned 45° from L1 and passed through FT. The distance from FT to the superior margin of the orbicularis oculi was 12.3 ± 3.3 mm. The frontalis extended more than 5 cm along L2 in 49 of 49 cases (100%), more than 6 cm in 47 cases (95.9%), more than 7 cm in 34 cases (69.4%), more than 8 cm in 11 cases (22.4%), and more than 9 cm in 3 cases (6.1%). The lateral border of the frontalis ran parallel to and within 1 cm of the medial side of L2. Surface anatomy mapping can assist with predicting the lateral border of the frontalis to minimize the side effects and maximize the efficiency of BoNT-A injections into the forehead.

Multimodal Physiotherapy as an Add-On Treatment to Botulinum Neurotoxin A-Therapy in Patients with Cervical Dystonia

<b>Background:</b> The treatment of choice for cervical dystonia comprises a local injection of botulinum neurotoxin type A (BoNT-A). Whether additional physiotherapy can achieve better results is not clearly documented in the literature. The present study aims to show possible effects of physiotherapy as an add-on treatment to therapy with botulinum neurotoxin type A in terms of pain, severity of dystonia, statics and function of the cervical spine as well as the quality of life in order to optimize the treatment of cervical dystonia. <b>Design/Methods:</b> This is a prospective, single-center, interventional study of a target patient population comprising 20 participants. The study is divided into 2 phases, with each phase lasting for 3 months. During the first phase, the usual BoNT-A will be applied. In addition, the baseline values will be collected and these assessments will be repeated at an interval of 6 weeks. In the second phase, participants will undergo a physiotherapy program consisting of two 45 min sessions per week in addition to the BoNT-A treatment. The assessments will be undertaken at the same intervals as in the first phase. <b>Analysis:</b> In order to determine the effect of the add-on physiotherapy program, the following parameters will be measured for each assessment: quality of life using the SF- 36 score and the range of motion determined by the ZEBRIS measurement system which will comprise the primary endpoints. Furthermore, for each assessment the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and electrical activity from the trapezius and the sternocleidomastoid muscles measured by a surface electromyography will be recorded. Descriptive statistical analysis will be performed for all of the collected data. Possible changes in the measured values will be compared to the baseline values over the 2 periods by means of the Wilcoxon-test at a significance level of p<0.05. For the statistical analysis the software SPSS 22.0 will be used. <b>Trial registration:</b> Deutsches Register Klinischer Studien: DRKS00006562

Transurethral intraprostatic injection of botulinum neurotoxin type A for the treatment of chronic prostatitis/chronic pelvic pain syndrome: results of a prospective pilot double-blind and randomized placebo-controlled study.

To evaluate the effect of botulinum neurotoxin type-A (BoNT-A) on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) refractory to medical therapy. Between November 2011 and January 2013, 60 men aged ≥18 years with CP/CPPS, and with National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores ≥10 and pain subscale scores ≥8, who were refractory to 4-6 weeks' medical therapy, underwent transurethral intraprostatic injection of BoNT-A or normal saline in a prospective pilot double-blind randomized study. The patients' NIH-CPSI total and subscale scores, American Urological Association (AUA)-symptom score (SS), visual analogue scale (VAS) and quality of life (QoL) scores and frequencies of diurnal and nocturnal urination were evaluated and compared at baseline and at 1, 3 and 6 months after injection and also were compared between the two groups. A total of 60 consecutive patients were randomized to a BoNT-A (treatment) or normal saline (placebo) group. In the treatment group at the 1-, 3- and 6-month evaluation the NIH-CPSI total and subscale scores, and the AUA-SS, VAS and QoL scores, along with frequencies of diurnal and nocturnal urinations, had significantly improved compared with baseline values (P < 0.05). By contrast, in the placebo group, none of these values showed improvement and the values were significantly different from those in the treatment group. Although the differences between the two groups in AUA-SS and frequencies of nocturnal urination were not significant at 1-month follow-up, repeated-measure analysis showed significant improvement in each of these values over the entire follow-up period in the treatment group. The most prominent improvement was related to the pain subscale score, which decreased by 64.76, 75.63 and 79.97% at 1, 3 and 6 months after treatment compared with baseline, followed by the VAS score, which decreased by 62.3, 72.4 and 82.1% at each follow-up, respectively. Only two patients developed mild transient gross haematuria, which was managed conservatively. Transurethral intraprostatic BoNT-A injection maybe an effective therapeutic option in patients with CP/CPPS as it reduces pain and improves QoL.

685 A randomised clinical trial comparing prostatic injection of botulinum neurotoxin type A (Botox®) to optimized medical therapy in the treatment of LUTS related to BPH: The PROTOX study

685 A randomised clinical trial comparing prostatic injection of botulinum neurotoxin type A (Botox®) to optimized medical therapy in the treatment of LUTS related to BPH: The PROTOX study