Deyi Luo

Efficacy and Safety of Tramadol for Premature Ejaculation: A Systematic Review and Meta-analysis

OBJECTIVEnTo present a systematic review to assess efficacy and safety of tramadol for premature ejaculation.nnnMETHODSnA literature search was performed using the Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded. Literature reviewed included meta-analyses and randomized and nonrandomized prospective studies. End points included intravaginal ejaculation latency time (in minutes), adverse events, and patient-reported outcome assessments. We used mean difference to measure intravaginal ejaculation latency time and odds ratio to measure adverse events rates. These odds ratios were pooled using a random or fixed effects model and were tested for heterogeneity. We used the Cochrane Collaborations Review manager (RevMan) 5.1 software for statistical analysis.nnnRESULTSnWe identified 7 publications that strictly met our eligibility criteria. Meta-analysis of extractable data showed that tramadol was associated with a 3-minute intravaginal ejaculation latency time increasing (mean difference 2.77 minutes; 95% CI 1.12-4.47; P = .001) and significantly more patients with adverse events rates compared with placebo (odds ratio 2.89; 95% CI 1.88-4.43; P < .0001). There were no differences between the tramadol and the paroxetine of intravaginal ejaculation latency time (mean difference -0.44; 95% CI -5.07 to 4.18; P = .85). In addition, patients saw significantly greater improvement in patient-reported outcome.nnnCONCLUSIONnIn this diverse population, tramadol is an effective and safety pharmacologic therapy for premature ejaculation.

Integrin αv Mediates Contractility Whereas Integrin α4 Regulates Proliferation of Human Bladder Smooth Muscle Cells via FAK Pathway under Physiological Stretch

PURPOSEnThe requirement of integrins for mechanotransduction has been recognized for some time. We investigated the role of integrin subunits and their pathway in the physiological stretch induced contractility and proliferation of human bladder smooth muscle cells.nnnMATERIALS AND METHODSnHuman bladder smooth muscle cells were seeded on silicone membrane and subjected to stretch, simulating bladder cycles of various stretches and times, as controlled by customized software on a modified BioDynamic bioreactor. Cell proliferation, viability and cycle were determined by BrdU incorporation assay, the Cell Counting Kit-8 (Beyotime Institute of Biotechnology, Haimen, Peoples Republic of China) and flow cytometry, respectively. Cell contractility was determined using a collagen gel contraction assay.nnnRESULTSnPhysiological stretch increased cell contractility, proliferation and viability. Knockdown of integrin αv but not α4 in the cells disrupted the enhanced contractility induced by stretch. Under physiological stretch conditions, the integrin αv level and phospho-FAK/FAK ratio correlated positively with cell stretch induced enhanced contractility. Further examination revealed that contractile marker expression was associated with integrin αv activation through the FAK pathway. At the same time integrin α4 but not integrin αv mediated stretch induced cell proliferation and viability.nnnCONCLUSIONSnThese data revealed that different integrins have different roles in the contractility and proliferation of human bladder smooth muscle cells under physiological stretch. This suggests that different integrins may become specific therapeutic targets in patients with voiding dysfunction. They may also be used to design a specific microenvironment for optimal bladder tissue regeneration.

The safety and efficiency of onabotulinumtoxinA for the treatment of overactive bladder: a systematic review and meta-analysis.

PurposeTo assess the impact on safety and efficiency of onabotulinumtoxinA (BOTOX1, Allergan, Inc.) treatment in patients with an overactive bladder.Materials and MethodsWe searched the PubMed®, Embase®, and Cochrane Library Databases to identify all randomized controlled trials comparing the outcomes of onabotulinumtoxinA and placebo for overactive bladder. The outcomes included reductions in overactive bladder symptoms or improvements in the function of bladder and the side effects of two treatments. The Cochrane Collaboration Review Manager software (RevMan 5.1.4) was used for statistical analysis.ResultsThe study inclusion criteria were met by eight randomized controlled trials involving 1875 patients. The synthesized data from these randomized controlled trials indicated that onabotulinumtoxinA was better than placebo in decreasing most overactive bladder symptoms (pxa0<xa00.00001, pxa0<xa00.00001, pxa0<xa00.00001, pxa0<xa00.00001, pxa0=xa00.0003) in the micturition, urgency, urinary incontinence, urgency urinary incontinence (UUI), and nocturia per day change, respectively; however, the maximum cystometric capacity change from the baseline appeared not to be significantly different between two methods (pxa0=xa00.05). In addition, the side effects in the onabotulinumtoxinA group were more serious than the placebo group (pxa0<xa00.00001, pxa0=xa00.009, pxa0=xa00.07, pxa0<xa00.0001, pxa0=xa00.03 in the UTI, bacteriuria, dysuria, urinary retention, residual urine volume, respectively).ConclusionsCompared with the placebo, onabotulinumtoxinA had significantly and clinically relevant reductions in overactive bladder symptoms, but it also leaded to more side effects.

Increased proliferation of human bladder smooth muscle cells is mediated by physiological cyclic stretch via the PI3K‑SGK1‑Kv1.3 pathway

It is well known that specific mechanical stimuli induce positive changes in the physiological function and status of a number of cell types. However, an in‑depth understanding of the application of mechanical forces has yet to be developed. The aim of the present study was to explore the optimal elongation and frequency of stretch‑induced proliferation of human bladder smooth muscle cells (HBSMCs) and to investigate the mechanism involved in this process. HBSMCs were seeded in a silicone membrane and subjected to cyclic stretch of 2.5, 5, 10 and 15% equibiaxial elongation at frequencies of 0.05, 0.1, 0.2, 0.5 and 1xa0Hz, respectively. Bromodeoxyuridine (BrdU) assays were used to detect the proliferative activity of each group. To further determine the mechanism of the cell proliferation process triggered by physiological cyclic stretch, the expression of PI3K/SGK1/Akt/Kv1.3 was investigated at the transcriptional and translational levels by RT‑PCR and western blot analysis, respectively. Optimal physiological stretch was established as 5% elongation at a frequency of 0.1xa0Hz, whereby HBSMCs revealed a marked increase in proliferative activity compared with the other groups, including the non‑stretched group, which served as the control (P<0.05). The expression of PI3K/SGK1/Kv1.3; however, not Akt, were upregulated by cyclic stretch as compared with the control group. When separately treated with inhibitors of SGK1 and Kv1.3, increased stretch‑induced proliferation was largely eliminated. These results markedly indicate that cyclic stretch induces the proliferation of HBSMCs and the PI3K‑SGK1‑Kv1.3 pathway is involved in this process, either fully or at least partially, rather than its related pathway, PI3K‑Akt.

Expression and proliferation profiles of PKC, JNK and p38MAPK in physiologically stretched human bladder smooth muscle cells

OBJECTIVEnTo determine protein kinase C (PKC), c-Jun NH2-Terminal Kinase (JNK) and P38 mitogen-activated protein kinases (p38MAPK) expression levels and effects of their respective inhibitors on proliferation of human bladder smooth muscle cells (HBSMCs) when physiologically stretched in vitro.nnnMATERIALS AND METHODSnHBSMCs were grown on silicone membrane and stretch was applied under varying conditions; (equibiaxial elongation: 2.5%, 5%, 10%, 15%, 20%, 25%), (frequency: 0.05, 0.1, 0.2, 0.5, 1Hz). Optimal physiological stretch was established by assessing proliferation with 5-Bromo-2-deoxyuridine (BrdU) assay and flow cytometry. PKC, JNK and p38 expression levels were analyzed by Western blot. Specificity was maintained by employing specific inhibitors; (GF109203X for PKC, SP600125 for JNK and SB203580 for p38MAPK), in some experiments.nnnRESULTSnOptimum proliferation was observed at 5% equibiaxial stretch (BrdU: 0.837±0.026 (control) to 1.462±0.023)%, (P<0.05) and apoptotic cell death rate decreased from 16.4±0.21% (control) to 4.5±0.13% (P<0.05) applied at 0.1Hz. Expression of PKC was upregulated with slight increase in JNK and no change in p38MAPK after application of stretch. Inhibition had effects on proliferation (1.075±0.024, P<0.05 GF109203X); (1.418±0.021, P>0.05 SP600125) and (1.461±0.01, P>0.05 SB203580). These findings show that mechanical stretch can promote magnitude-dependent proliferative modulation through PKC and possibly JNK but not via p38MAPK in hBSMCs.

Efficacy of Phosphodiesterase-5 Inhibitor in Men With Premature Ejaculation: A New Systematic Review and Meta-analysis.

OBJECTIVEnTo clarify the efficacy of phosphodiesterase-5 inhibitor (PDE5i) in men with premature ejaculation (PE).nnnMETHODSnWe searched the PubMed, Embase, and Cochrane Library databases to identify all randomized controlled trials and compared results, including intravaginal ejaculation latency time, satisfaction, side effects, and others, after treatment with PDE5i vs placebo, PDE5i vs selective serotonin reuptake inhibitor (SSRI), or combined use of PDE5i with SSRI vs SSRI alone for treating PE.nnnRESULTSnThe study inclusion criteria were met by 10 studies (10 randomized controlled trials with 3 crossover studies) involving 775 patients. The data synthesized from these studies indicated that the efficacy of PDE5i was better than that of placebo; however, more patients had side effects while taking PDE5i. The efficacy of PDE5i was better than that of SSRIs, and no significant difference was observed in the frequency of side effects. The efficacy of the combined treatment was significantly better than that of SSRI alone; however, more patients had side effects from the combined treatment. The major limitations of this meta-analysis were that there is no universally agreed definition of PE, and the types of medications differed among the studies evaluated.nnnCONCLUSIONnPDE5i was significantly more effective than a placebo or SSRI for treating PE; however, it had more side effects than placebo. The combined treatment of PDE5i and SSRI had better efficacy but more side effects than the use of SSRI alone.

The treatment of anterior vaginal wall prolapsed by repair with mesh versus colporrhaphy

PurposeTo compare patient outcomes of mesh repair and colporrhaphy for the treatment of anterior vaginal wall prolapse (AVP).Materials and methodsWe searched PubMed®, Embase®, and Cochrane Library databases to identify the included studies. The outcome measures included anatomical success, patient satisfaction, patient sexual function, perioperative data, and complications. Statistical analyses were performed using Cochrane Collaboration Review Manager software (RevMan 5.1.4).ResultsThe study inclusion criteria were met by 11 articles involving 1455 patients. Synthesized data indicated that mesh surgery was more complex than colporrhaphy with regard to perioperative condition [mean difference (MD) 0.28, 95xa0% confidence interval (CI) 0.07–0.49, pxa0=xa00.010]. There were no significant differences for the following complications: urinary retention [relative risk (RR) 1.12, 95xa0% CI 0.65–1.94, pxa0=xa00.68], urinary incontinence (RR 1.01, 95xa0% CI 0.63–1.63, pxa0=xa00.96), voiding difficulty (RR 1.11, 95xa0% CI 0.69–1.80, pxa0=xa00.66), dyspareunia (RR 1.21, 95xa0% CI 0.87–1.67, pxa0=xa00.26), urinary tract infection (RR 1.15, 95xa0% CI 0.74–1.78, pxa0=xa00.53), and vaginal bulge (RR 1.08, 95xa0% CI 0.93–1.25, pxa0=xa00.32). There were instances of more serious complications in group 1, i.e., the mesh group. However, AVP cure rate was significantly higher in the mesh group (RR 1.44, 95xa0% CI 1.34–1.55, pxa0<xa00.00001). The cure rate was not significantly dependent on patient satisfaction (RR 1.10, 95xa0% CI 0.96–1.26, pxa0=xa00.16) or postoperative sexual function (RR 1.03, 95xa0% CI 0.90–1.11, pxa0=xa00.71).ConclusionsSurgical repair with the mesh procedure appears to be a better choice for the treatment of anterior vaginal wall prolapse.

The purinergic component of human bladder smooth muscle cells' proliferation and contraction under physiological stretch

OBJECTIVEnTo investigate whether cyclic stretch induces proliferation and contraction of human smooth muscle cells (HBSMCs), mediated by P2X purinoceptor 1 and 2 and the signal transduction mechanisms of this process.nnnMETHODSnHBSMCs were seeded on silicone membrane and stretched under varying parameters; (equibiaxial elongation: 2.5%, 5%, 10%, 15%, 20%, 25%), (Frequency: 0.05Hz, 0.1Hz, 0.2Hz, 0.5Hz, 1Hz). 5-Bromo-2-deoxyuridine assay was employed for proliferative studies. Contractility of the cells was determined using collagen gel contraction assay. After optimal physiological stretch was established; P2X1 and P2X2 were analyzed by real time polymerase chain reaction and Western Blot. Specificity of purinoceptors was maintained by employing specific inhibitors; (NF023 for P2X1, and A317491for P2X2), in some experiments.nnnRESULTSnOptimum proliferation and contractility were observed at 5% and 10% equibiaxial stretching respectively, applied at a frequency of 0.1Hz; At 5% stretch, proliferation increased from 0.837±0.026 (control) to 1.462±0.023%, p<0.05. Mean contraction at 10% stretching increased from 31.7±2.3%, (control) to 78.28 ±1.45%, p< 0.05. Expression of P2X1 and P2X2 was upregulated after application of stretch. Inhibition had effects on proliferation (1.232±0.051, p<0.05 NF023) and (1.302±0.021, p<0.05 A314791) while contractility was markedly reduced (68.24±2.31, p<0.05 NF023) and (73.2±2.87, p<0.05 A314791). These findings shows that mechanical stretch can promote magnitude-dependent proliferative and contractile modulation of HBSMCs in vitro, and P2X1 and 2 are at least partially responsible in this process.

The Antimuscarinic Agent Tolterodine Regulates Bladder Extracellular Matrix in Partial Bladder Outlet Obstruction in Rats

Background/Aims: Antimuscarinic agents can delay the progression of bladder dysfunction caused by bladder outlet obstruction (BOO). To date, the relationship between muscarinic receptor activity and the bladder extracellular matrix (ECM) remains unclear. Thus, an animal model of partial BOO (PBOO) in female rats was established to explore the variation in bladder wall ECM proteins under PBOO conditions with antimuscarinic agent administration. Methods: Rats were randomly divided into three groups: sham, PBOO, and PBOO plus tolterodine. Picrosirius red staining was used to examine the smooth muscle and collagen content of bladder samples. Gene microarray and RT-PCR were performed to survey the expression of ECM proteins, receptors, and metabolism regulators in the rat bladder. Positive results were further evaluated by immunohistochemistry. Results: Picrosirius red staining showed that smooth muscle volume significantly increased in the PBOO and PBOO plus tolterodine groups (p < 0.05), while collagen significantly increased in the PBOO group (p < 0.05) but not in the PBOO plus tolterodine group. Gene microarray and RT-PCR revealed that none of the collagen subtypes exhibited significant changes after PBOO establishment and tolterodine administration. However, matrix metalloproteinases (MMPs) increased significantly in the PBOO plus tolterodine group (p < 0.05). Additionally, PBOO inhibited the expression of non-collagen ECM proteins in the rat bladder wall, while tolterodine induced the expression of non-collagen ECM proteins and ECM receptors. Conclusions: Tolterodine decreased the volume of collagen in PBOO rat bladder wall, possibly via MMPs, and regulated the expression of ECM proteins and receptors.

Protective Effects of Antimuscarinics on the Bladder Remodeling After Bladder Outlet Obstruction

Background/Aims: Overactive bladder associated with bladder outlet obstruction (BOO) is a highly prevalent condition, which is usually treated with antimuscarinics. However, the potential effects of antimuscarinics on the structure and function of bladder have not been investigated thus far. Methods: Sprague-Dawley(R) rats accepted bladder neck obstruction surgery or sham surgery, and then received treatment of three different antimuscarinics (Solifenacin, Darifenacin, and Tolterodine) or vehicle. After 3, 6 and 12 weeks, the bladder function and structure were measured. The effect of antimuscarinics on cellular alteration in vitro was observed under mechanical stimulation. Bladder morphology were examined by immunohistochemistry, and the bladder function were investigated by cystometry and strip contractility test. The expression of muscarinic receptors and inflammatory cytokines were measured by PCR and Western blotting. Results: Here we demonstrate, both in vitro and in vivo, that antimuscarinics are protective regulators for the bladder structure and function. Antimuscarinics decrease the weight of bladders with BOO. Antimuscarinics improve the voiding parameter and enhance the contraction of bladder smooth muscle. The results also show that antimuscarinics inhibit the proliferation of bladder smooth muscle cells both in vivo and in vitro, it can reduce the collagen deposition and inflammatory cytokines in bladders with BOO. During this process, the expression of M2 and M3 receptors was altered by antimuscarinics. Conclusion: Antimuscarinics could reverse the structural and functional changes of BOO bladder wall at cellular and tissue level, and the alteration of M2 and M3 receptors may be involved in this biological process.