A Comparative Study of Efficacy and Tolerability of Solifenacin and Mirabegron, for the Treatment of Overactive Bladder - A Randomized Prospective Control Study

BACKGROUND Overactive bladder (OAB) is a chronic, age-related disorder seen in 11 % of patients. Symptoms consist of urinary urgency, with or without urinary incontinence, usually with frequency or nocturia. The objective of the present study was to compare the efficacy and side effects of mirabegron and solifenacin as primary therapies in patients with overactive bladder. METHODS This was a prospective interventional study. 100 patients aged between 18 years and 50 years with overactive bladder were included and were assigned into two treatment groups of solifenacin 5 mg or mirabegron 50 mg. They were asked to record the number of micturitions in a day, urgency episodes, incontinence episodes and volume of each micturition. All patients went through a basic workup with blood sugar to rule out diabetes, USG KUB to rule out bladder stones, and urine culture and sensitivity to rule out urinary tract infection (UTI). RESULTS 100 patients with OAB were selected for the study and divided into equal groups, 50 receiving 5 mg solifenacin and 50 receiving 50 mg mirabegron. Both groups increased the mean micturition volume but mirabegron was more effective in increasing the mean micturition in patients with OAB. Both drugs were well tolerated. There was a significant increase in mean micturition volume in mirabegron 50 mg group (by 20.7 + / - 2.2 mL), P < 0.001 whereas in solifenacin group micturition volume was increased to 22.2 + / -0.97 ml). The most common side-effect in the mirabegron group was hypertension and the most common side effect in the solifenacin group was dry mouth. CONCLUSIONS Both mirabegron and solifenacin were effective in controlling the frequency of micturition, decreasing urgency and incontinence episodes and increasing the mean volume of micturition. Mirabegron was more effective than solifenacin in controlling urgency and incontinence episodes and increasing the mean volume of micturition. KEY WORDS Overactive Bladder (OAB), Micturition, Mirabegron, Solifenacin.

THE EFFICACY COMPARISON OF MIRABEGRON AS A MONOTHERAPY VERSUS ITS COMBINATION WITH SOLIFENACIN IN OVERACTIVE BLADDER: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Objective: This review aimed to evaluate the efficacy and safety of mirabegron as monotherapy and its combination with solifenacin for patients with overactive bladder (OAB). Material & Methods: A systematic search was conducted in PubMed, Google Scholar, and Science Direct using the keywords Overactive bladder or OAB and mirabegron or beta-3 agonist or β3 adrenoreceptor agonist and solifenacin or antimuscarinic based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline to include relevant randomized controlled trials (RCT)s. The included studies were assessed for their risks of bias using the Cochrane risk of bias tool for randomized controlled trials. Quantitative analysis using forest plot was performed in Review Manager 5.4. Results: A total of 4 RCTs were included from 227 studies. A fixed-effects model was chosen due to the low level of heterogeneity between the studies (I2 = 0%). The average micturition volume of patients in the combination group is higher compared to the monotherapy group (MD 17.13, 95% CI 12.78 - 21.48, p < 0.00001). The mean micturition frequency (MD - 0.54, 95% CI - 0.73 - -0.34, p < 0.00001) and incontinence incidence (MD -0.30, 95% CI -0.48 - -0.12, p = 0.001) in the combined group are significantly lower compared to the monotherapy group. Conclusion: The combination of mirabegron and solifenacin has better efficacy compared to mirabegron as monotherapy for OAB patients with a therapy duration of less than 12 weeks based on the micturition volume, micturition frequency, and incontinence incidence. The administration of combination therapy would not increase adverse event incidence compared to monotherapy.

Blueberry Prevents the Bladder Dysfunction in Bladder Outlet Obstruction Rats by Attenuating Oxidative Stress and Suppressing Bladder Remodeling

Various berries demonstrate antioxidant activity, and this effect is expected to prevent chronic diseases. We examined whether a diet containing blueberry powder could prevent the development of bladder dysfunction secondary to bladder outlet obstruction (BOO). Eighteen 8-week-old male Sprague-Dawley rats were randomly divided into three groups: Sham (sham operated + normal diet), N-BOO (BOO operated + normal diet) and B-BOO (BOO operated + blueberry diet). Four weeks after BOO surgery, the N-BOO group developed bladder dysfunction with detrusor overactivity. The B-BOO group showed significantly improved micturition volume and micturition interval. The urinary levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured as oxidative stress markers. In the N-BOO group, 8-OHdG increased 1.6-fold and MDA increased 1.3-fold at 4 weeks after surgery, whereas the increase in 8-OHdG was significantly reduced by 1.1-fold, despite a similar increase in MDA, in the B-BOO group. Bladder remodeling was confirmed due to bladder hypertrophy, fibrosis and increased connexin43 expression in the N-BOO group, but these histological changes were reduced in the B-BOO group. The intake of blueberries prevented the development of bladder dysfunction secondary to BOO. This effect seems to be related to antioxidation and the inhibition of bladder remodeling.

Activation of soluble guanylyl cyclase by BAY 58-2667 improves bladder function in cyclophosphamide-induced cystitis in mice

Activators of soluble guanylyl cyclase (sGC) interact directly with its prosthetic heme group, enhancing the enzyme responsiveness in pathological conditions. This study aimed to evaluate the effects of the sGC activator BAY 58-2667 on voiding dysfunction, protein expressions of α1 and β1 sGC subunits and cGMP levels in the bladder tissues after cyclophosphamide (CYP) exposure. Female C57BL/6 mice (20–25 g) were injected with CYP (300 mg/kg ip) to induce cystitis. Mice were pretreated or not with BAY 58-2667 (1 mg/kg, gavage), given 1 h before CYP injection. The micturition patterns and in vitro bladder contractions were evaluated at 24 h. In freely moving mice, the CYP injection produced reduced the micturition volume and increased the number of urine spots. Cystometric recordings in CYP-injected mice revealed significant increases in basal pressure, voiding frequency, and nonvoiding contractions (NVCs), along with decreases in bladder capacity, intercontraction interval, and compliance. BAY 58-2667 significantly prevented the micturition alterations observed in both freely moving mice and cystometry and normalized the reduced in vitro carbachol-induced contractions in the CYP group. Reduced protein expressions of α1 and β1 sGC subunits and of cGMP levels were observed in the CYP group, all of which were prevented by BAY 58-2667. CYP exposure significantly increased reactive-oxygen species (ROS) generation in both detrusor and urothelium, and this was normalized by BAY 58-2667. The increased myeloperoxidase and cyclooxygenase-2 activities in the bladders of the CYP group remained unchanged by BAY 58-2667. Activators of sGC may constitute a novel and promising therapeutic approach for management of interstitial cystitis.

Inhibitory and excitatory perigenital-to-bladder spinal reflexes in the cat

This study revealed that in awake chronic spinal cord-injured (SCI) cats reflexes from perigenital skin area to the bladder can be either inhibitory or excitatory. Electrical perigenital stimulation at frequencies between 5 and 7 Hz significantly inhibited large-amplitude rhythmic reflex bladder activity, whereas frequencies between 20 and 40 Hz induced large-amplitude bladder contractions even at low bladder volumes when reflex bladder activity was absent. Both inhibitory and excitatory effects were enhanced as the stimulation intensity increased (5–30 V, 0.2-ms pulse width). During cystometrograms, the inhibitory stimulation (7 Hz) significantly increased the micturition volume threshold 35 ± 13% above the control volume, while the excitatory stimulation (30 Hz) significantly reduced the threshold 21 ± 3%. Mechanical perigenital stimulation applied by repeated light stroking of the perigenital skin with a cotton swab only induced an excitatory effect on the bladder. Both electrical and mechanical perigenital stimuli induced large-amplitude (>30 cmH2O) bladder contractions that were relatively consistent over a range of bladder volumes (10–90% of the capacity). However, the excitatory electrical stimulation only induced bladder contractions lasting on average 42.2 ± 3.9 s, but the mechanical stimulation induced bladder contractions that lasted as long as the stimulation continued (2–3 min). Excitatory electrical or mechanical perigenital stimulation also induced poststimulus voiding. The ability to either inhibit or excite the bladder by noninvasive methods could significantly transform the current clinical management of bladder function after SCI.

Impact of state of arousal and stress neuropeptides on urodynamic function in freely moving rats

Corticotropin-releasing factor (CRF) is a neurotransmitter in Barrington’s nucleus neurons. These neurons can coregulate parasympathetic tone to the bladder (to modulate micturition) and brain noradrenergic activity (to affect arousal). To identify the role of CRF in the regulation of micturition, the effects of CRF agonists and antagonists on urodynamics in the unanesthetized rat were characterized. Rats were implanted with bladder and intrathecal or intraperitoneal catheters under isoflurane anesthesia. Cystometry was performed in the unanesthetized, unrestrained state at least 24 h later. In some cases, cortical electroencephalographic activity (EEG) was recorded simultaneously to assess arousal state. During cystometry, the state of arousal often shifted between waking and sleeping and urodynamic function changed depending on the state. Micturition threshold, bladder capacity, and micturition volume were all increased during sleep. The CRF1/CRF2 receptor agonists CRF and urocortin 2 increased bladder capacity and micturition volume in awake but not in sleeping rats. Conversely, the CRF1 receptor antagonists antalarmin and NBI-30775 increased urinary frequency and decreased bladder capacity in awake rats. The present results demonstrate a profound effect of the state of arousal on urodynamic function and suggest that simultaneous monitoring of EEG and cystometry may provide a useful model for studying nocturnal enuresis and other urinary disorders. In addition, the results provide evidence for an inhibitory influence of CRF in the spinal pathway on micturition. Targeting the CRF system in the spinal cord may provide a novel approach for treating urinary disorders.

Effects of Goshajinkigan (Niu-Che-Sen-Qi-Wan) for Resiniferatoxin-Sensitive Afferents on Detrusor Overactivity Induced by Acetic Acid in Conscious Rats

This study was performed to investigate the effects of goshajinkigan, a traditional Chinese herbal mixture, in conscious rats undergoing continuous cystometry. Systemic resiniferatoxin (RTX) pretreatment can block resiniferatoxin-sensitive (C-fiber) nerve-mediated bladder overactivity, such as that induced by intravesical administration of acetic acid. The effects of pretreatment with goshajinkigan and RTX alone or in combination on acetic acid-induced bladder overactivity in conscious rats were also compared. Female SD rats were divided into four groups. Groups 1 and 3 received normal food for 4 weeks, while groups 2 and 4 received goshajinkigan (0.09 g/kg/day) during the same period. Two days after bladder catheterization, groups 3 and 4 received RTX (0.3 mg/kg) injection, while groups 1 and 2 received vehicle alone. Cystometric investigations were performed on all animals 24 hours after RTX or vehicle injection. The effects of intravesical instillation of acetic acid ( pH = 4.0) were compared with those of intravesical saline. Goshajinkigan significantly increased threshold pressure, voiding interval, micturition volume, and bladder capacity. Intravesical instillation of acetic acid induced bladder overactivity in both normal rats and in those pretreated with goshajinkigan. However, the effects of acetic acid on voiding interval and micturition volume were significantly different between rats given normal diet and those pretreated with goshajinkigan. The effect of acetic acid was not different between goshajinkigan- and RTX-pretreated rats. The results of the present study indicated that goshajinkigan increases voiding interval, micturition volume, and bladder capacity, and pretreatment with goshajinkigan partially blocks the bladder overactivity induced by intravesical administration of acetic acid in rats.

Effects of capsaicin on micturition and associated reflexes in rats

The effect of capsaicin on micturition and associated reflexes was studied in urethan-anesthetized female rats. Capsaicin or vehicle solution were administered 4 days before the experiment in a dose of 125 mg/kg sc or during the experiment in a dose of 50-100 mg/kg sc. Activity of the urinary bladder was recorded by measuring intravesical pressure via a urethral catheter while slowly filling (0.052 ml/min) the bladder or when the bladder was distended beyond the micturition threshold and maintained at a constant volume. Pretreatment with capsaicin did not significantly change various parameters of urinary bladder function including micturition volume threshold or the amplitude, duration, and interval between reflex bladder contractions. However, capsaicin pretreatment significantly reduced (80% decrease) the arterial pressor responses accompanying reflex bladder contractions and reduced by approximately one-half the percentage of animals in which bladder activity was inhibited by stimulation of the uterine cervix. A large dose of capsaicin (50 mg/kg sc) elicited an acute block of bladder activity that persisted for 8-15 h. This effect is attributable to an action on myelinated afferent or efferent components of the micturition reflex pathway. It is concluded that capsaicin-sensitive afferents are not essential for the performance of micturition in the rat. However, these afferents are involved in cervicovesical reflex mechanisms that modulate bladder activity and in vascular reflexes triggered by isometric bladder contractions.