David Scheiner

Experience With 100 Cases Treated With Botulinum-A Toxin Injections in the Detrusor Muscle for Idiopathic Overactive Bladder Syndrome Refractory to Anticholinergics

PURPOSE In this prospective, nonrandomized, ongoing study we evaluated the efficacy and safety of botulinum-A toxin injections in the detrusor muscle to treat patients with idiopathic overactive bladder resistant to conventional treatment, such as anticholinergic drugs. MATERIALS AND METHODS A total of 23 men and 77 women with a mean age of 63 years (range 24 to 89) with nonneurogenic overactive bladder, including urgency-frequency syndrome, and incontinence despite the administration of maximal doses of anticholinergics were consecutively treated with injections of 100 U botulinum-A toxin in the detrusor muscle at 30 sites under cystoscopic guidance. Micturition diary, full urodynamics, neurological status and urine probes were performed in all participants before treatment. Bladder biopsies were done only in cases of suspected bladder fibrosis or unclear findings. Special attention was given to reflex volume, maximal bladder capacity, detrusor compliance, post-void residual urine, urgency and frequency/nocturia. Clinical, urodynamic and quality of life assessments were performed at baseline, and 4, 12 and 36 weeks after botulinum-A toxin treatment. RESULTS Overall after 4 and 12 weeks 88% of our patients showed significant improvement in bladder function in regard to subjective symptoms, quality of life and urodynamic parameters (p <0.001). Urgency disappeared in 82% of the patients and incontinence resolved in 86% within 1 to 2 weeks after botulinum-A toxin injections. Mean frequency decreased from 14 to 7 micturitions daily (-50%) and nocturia decreased from 4 to 1.5 micturitions. Mean maximal bladder capacity increased 56% from 246 to 381 ml, mean detrusor compliance increased from 24 to 41 ml/cm H(2)O and pretreatment detrusor instability (mean reflex volume 169 ml) resolved in 74% of patients. Mean volume at first desire to void increased from 126 to 212 ml and mean urge volume increased from 214 to 309 ml. There were no severe side effects except temporary urine retention in 4 cases. Only in 8 patients was the clinical benefit poor and analysis revealed preoperative low detrusor compliance. Mean efficacy duration +/- SD was at least approximately 6 +/- 2 months and then symptoms began to increase. CONCLUSIONS Our results show that intradetrusor botulinum-A toxin injections may be an efficient and safe treatment option in patients with severe overactive bladder resistant to all conventional treatments.

Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial

BACKGROUND Escherichia coli infections are increasing worldwide in community and hospital settings. The E coli O-antigen is a promising vaccine target. We aimed to assess the safety and immunogenicity of a bioconjugate vaccine containing the O-antigens of four E coli serotypes (ExPEC4V). METHODS In this multicentre phase 1b, first-in-human, single-blind, placebo-controlled trial, we randomly assigned (1:1) healthy adult women with a history of recurrent urinary tract infection (UTI) to receive a single injection of either intramuscular ExPEC4V or placebo. The primary outcome was the incidence of adverse events among vaccine and placebo recipients throughout the study. Secondary outcomes included immunogenicity and antibody functionality, and the incidence of UTIs caused by E coli vaccine serotypes in each group. This study is registered with ClinicalTrials.gov, number NCT02289794. FINDINGS Between Jan 20, 2014, and Aug 27, 2014, 93 women received target-dose ExPEC4V and 95 received placebo. The vaccine was well tolerated: no vaccine-related serious adverse events occurred. Overall, 56 (60%) target-dose vaccines and 47 (49%) placebo recipients experienced at least one adverse event that was possibly, probably, or certainly related to injection. Vaccination induced significant IgG responses for all serotypes: at day 30 compared with baseline, O1A titres were 4·6 times higher, O2 titres were 9·4 times higher, O6A titres were 4·9 times higher, and O25B titres were 5·9 times higher (overall p<0·0001). Immune responses persisted at 270 days but were lower than those at 30 days. Opsonophagocytic killing activity showed antibody functionality. No reduction in the incidence of UTIs with 103 or more colony-forming units per mL of vaccine-serotype E coli was noted in the vaccine compared with the placebo group (0·149 mean episodes vs 0·146 mean episodes; p=0·522). In post-hoc exploratory analyses of UTIs with higher bacterial counts (≥105 colony-forming units per mL), the number of vaccine serotype UTIs did not differ significantly between groups (0·046 mean episodes in the vaccine group vs 0·110 mean episodes in the placebo group; p=0·074). However, significantly fewer UTIs caused by E coli of any serotype were noted in the vaccine group compared with the placebo group (0·207 mean episodes vs 0·463 mean episodes; p=0·002). INTERPRETATION This tetravalent E coli bioconjugate vaccine candidate was well tolerated and elicited functional antibody responses against all vaccine serotypes. Phase 2 studies have been initiated to confirm these findings. FUNDING GlycoVaxyn, Janssen Vaccines.

Randomized, double-blind placebo-controlled trial with Bryophyllum pinnatum versus placebo for the treatment of overactive bladder in postmenopausal women.

INTRODUCTION Overactive bladder syndrome (OAB) is a chronic disorder that often requires long-term treatment. There is a growing interest in new substances. In vitro experiments of Bryophyllum pinnatum (BP) on porcine bladder muscle have shown a muscle-relaxing effect. In this clinical trial we evaluated BP versus placebo regarding efficacy and safety. MATERIALS AND METHODS Prospective, double-blind randomized, placebo-controlled study with 20 patients (10 BP, 10 placebo); medication over 8 weeks; dosage 3×2 capsules BP 50% (350 mg)/day or placebo (lactose). Primary aim: reduction of the micturition frequency/24h. Secondary aim: change in quality of life, alterations of parameters in the bladder diary and adverse events (AE). Statistical analysis was performed with IBM SPSS Statistics 20. The groups were compared using Fishers exact test and the Mann-Whitney test; the visits using the Wilcoxon signed ranks test. RESULTS Both groups did not differ significantly in demographical data. For the primary endpoint, a trend in the reduction of the micturition frequency/24h in the BP group was found: 9.5±2.2 before and 7.8±1.2 after BP versus 9.3±1.8 before and 9.1±1.6 after placebo, p=0.064. From visit 2 to visit 4, micturition frequency/24h improved in 8/10 patients in the BP group (p=0.037). In the placebo group, micturition frequency/24h improved in 5/9 patients (p=0.89). Improvement of the QoL did not differ between the two groups. The incidence of AE was similar in both groups, no SAE occurred. CONCLUSION The successful safety outcome and positive trend for efficacy permits BP to be further evaluated as a favorable treatment option for OAB.

Prospects and limitations of treatment with botulinum neurotoxin type A for patients with refractory idiopathic detrusor overactivity.

In this review we summarize the recent innovation of botulinum‐A neurotoxin (BoNT‐A) injections in the bladder as a potential new treatment option for idiopathic detrusor overactivity, refractory to conventional anticholinergic medication. BoNT‐A is produced by Clostridium botulinum and consists of a 150‐kDa neurotoxic protein that has the ability to cleave proteins within the nerve terminal. BoNT‐A is thereby able to prevent acetylcholine release at the presynaptic membrane, resulting in a chemodenervation of the detrusor muscle after intravesical injection; this can reduce symptoms in patients with refractory idiopathic detrusor overactivity. BoNT‐A intradetrusor injections might be an alternative to invasive surgery for patients in whom conservative measures and anticholinergic treatment have failed. Clinical studies with different dosages and injection protocols show success rates of 60–96% for neurogenic and non‐neurogenic detrusor overactivity, with wide variations in the duration of response. The drug is still under development for the indication of idiopathic detrusor overactivity, and is under ongoing investigation for long‐term efficacy and safety.

Pelvic floor muscle training for urinary incontinence: a comparison of outcomes in premenopausal versus postmenopausal women.

Objectives Previous studies examining the effectiveness of pelvic floor muscle training (PFMT) for urinary incontinence in premenopausal and postmenopausal women have shown ambiguous results. The aim of this study was to compare subjective PFMT outcome in premenopausal versus postmenopausal women. Methods This is a retrospective study including premenopausal and postmenopausal women after PFMT for urodynamically proven stress urinary incontinence, mixed urinary incontinence, or urgency urinary incontinence from January 2003 to December 2008, with assessment of the need of an incontinence surgery in a follow-up time of least 24 months. Patients evaluated the change of their urinary incontinence on a 4-point Likert scale (1, no improvement; 2, slightly better; 3, no relevant incontinence; 4, excellent outcome; no incontinence at all) and their goal attainment on a 3-point Likert scale (1, less than expected; 2, as expected; and 3, more than expected). Results Successful outcome was reported by 59% of the premenopausal patients and 70% of the postmenopausal patients (P = 0.16), the attainment of the subjective goal by 68% and 81% (P = 0.09), and the need of an incontinence operation in a follow-up of 30 to 102 months by 15% and 14% (P = 1.0), respectively. None of the outcome parameters reached significance. Conclusions In comparing premenopausal to postmenopausal women, we could not detect any statistically significant difference with regard to patients’ satisfaction for the outcome of PFMT.

Wenn die Blase brennt: interstitielle Zystitis/Bladder Pain Syndrome (IC/BPS)

Interstitial cystitis/bladder pain syndrome (BPS) is still an etiologically poorly understood chronic pain syndrome. BPS is a clinical diagnosis. The current treatment modalities are aimed at symptom relief because no cure is possible. Analgesics may be used at any point in treatment but preferably for short-term relief for flares or bladder pain. AUA has issued clinical practice guidelines with a stepwise approach. The first-line therapy begins with self-care and behavior modification. Physical therapy and oral medications such as amitriptyline, PPS, or antihistamines belong to the second-line therapy. Third-line therapy requires cystoscopy and hydrodistension, treatment of Hunner lesions, or intravesical use of e.g. DMSO. Neuromodulation is considered a fourth-line therapy in patients who have failed third-line treatments. Fifth-line therapies consist of intravesical injection of BoNT or oral cyclosporin A. Cystectomy is the sixth-line therapy and the treatment of last resort.

Conjugates of cytochrome c and antennapedia peptide activate apoptosis and inhibit proliferation of HeLa cancer cells

Polycationic cell-penetrating peptides (CPPs) deliver macromolecules into cells without losing the functional properties of the cargoed macromolecule. The aim of this study was to determine whether exogenous cytochrome c is delivered to HeLa cervical carcinoma cells by the CPP antennapedia (Antp) and activates apoptosis. HeLa cervical carcinoma cells were treated with conjugated Antp-SMCC-cytochrome c (cytochrome c chemically conjugated to Antp) or with non-conjugated Antp and cytochrome c. Sensitivity to the treatments was determined by the clonogenic assay (proliferation) and by immunoblot analysis (apoptosis activation). We report that conjugated Antp-SMCC-cytochrome c activated apoptosis in HeLa cells as demonstrated by poly (ADP-ribose) polymerase 1 (PARP-1) cleavage and inhibited their proliferation. The Antp-SMCC-cytochrome c-induced apoptosis was inhibited by z-VAD-fmk, a pan-caspase inhibitor peptide. Unconjugated Antp or cytochrome c demonstrated no inhibitory effect on survival and proliferation. Our results suggest that chemical coupling of cytochrome c to CPPs may present a possible strategy for delivering cytochrome c into cells and for activating apoptosis.

Measuring tissue displacement of the anterior vaginal wall using the novel aspiration technique in vivo

Little is known about the mechanical properties of pelvic floor structures and their role in the course and treatment of pelvic organ prolapse (POP). We hypothesize that in vivo mechanical properties of the vaginal wall are related to the appearance of POP and pre-and post-operative states. We used a suction device for intravaginal application, the aspiration device, to evaluate two in vivo mechanical parameters of the anterior vaginal wall, the load dependent tissue displacement and the initial displacement, by image analysis in pre- and post-menopausal women with (POP) and without (control) cystocele (POP: pre-menopausal: N = 6, post-menopausal: N = 19, control: pre-menopausal: N = 17, post-menopausal: N = 6). Mechanical parameters in women with and without cystocele and pre- and post-operative parameters were compared. Statistically significant differences were observed between the two mechanical parameters in pre- and post-operative states (P = 0.04, P = 0.03), but not between the parameters for women with and without cystocele (P = 0.92, P = 0.75). The mechanical behavior of pelvic floor structures is influenced by factors such as POP, age or estrogenization that are apparent at different length scales, which cannot be separated by the aspiration based biomechanical measurements. When comparing pre- and post-operative states of the same patient, a firmer tissue response was observed after intervention.

Überaktive Blase: Möglichkeiten und Grenzen der Botoxtherapie

Das Botulinumneurotoxin ist das potenteste bekannte Gift. Das vom Erreger Clostridium botulinum gebildete Neurotoxin besteht aus einer schweren Kette, die für die Internalisierung des Toxins ins Zytosol an der Nervenendigung verantwortlich ist, und aus einer leichten Kette, die die Fusion der acetylcholinhaltigen Vesikel mit der Zellmembran und somit dessen Ausschüttung in den synaptischen Spalt verhindert. Die daraus resultierende Chemodenervation nach zystoskopischer Botulinumneurotoxin-Injektion in den Musculus detrusor vesicae führt zu einer eindrücklichen Reduktion der Beschwerden der überaktiven Blase. Klinische Studien zeigen Erfolgsraten zwischen 60 und 96% bei der neurogenen und nicht neurogenen überaktiven Blase. Mit dem Botulinumneurotoxin steht somit in der Urogynäkologie zur Behandlung der überaktiven Blase ein effizientes, nebenwirkungsarmes Medikament zur Verfügung, das durch einen minimal invasiven Eingriff appliziert werden kann.

Überaktive Blase bei Frauen: Schritt für Schritt zum Ziel

Zusammenfassung. OAB (overactive bladder syndrome) ist zwar ein haufiges Leiden, doch wird es oft nicht diagnostiziert und deshalb nicht behandelt. Die Behandlung erfolgt symptomatisch. Im Praxisalltag muss vorgangig eine Basis-(Ausschluss)-Diagnostik durchgefuhrt werden. Das Fuhren eines Blasentagebuchs ist sowohl fur die Diagnostik als auch fur den Verlauf wichtig. Eine urogynakologische Abklarung mit Urodynamik empfiehlt sich in unklaren Situationen und beim Vorliegen einer gemischten Symptomatik mit Symptomen einer Belastungsinkontinenz oder bei gleichzeitigem Vorliegen einer Blasenentleerungsstorung. Die Therapie erfolgt Schritt fur Schritt. Schon einfache Verhaltensanderungen und ein Blasen- und Beckenbodentraining konnen die Symptomatik deutlich verbessern. Viele Patientinnen profitieren aber zusatzlich von der medikamentosen Therapie. Jahrzehntelang standen dazu alleinig Anticholinergika zur Verfugung. Doch die Langzeitcompliance ist unter diesen Medikamenten gering. Neu erweitern β3-Adrenorezepto...