PSD502 improves ejaculatory latency,control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III,multicentre, double‐blind,placebo‐controlled study

OBJECTIVES

To determine the effect of PSD502 applied topically 5 min before intercourse on the Index of Premature Ejaculation (IPE) and intravaginal ejaculatory latency time (IELT) of men with lifelong premature ejaculation (PE) defined according to the International Society of Sexual Medicine (ISSM) definition; secondary objectives were to evaluate the safety and tolerability of PSD502 in patients with PE, and their sexual partners.

PATIENTS AND METHODS

Men aged >18 years, in stable heterosexual, monogamous relationships, and with lifelong PE diagnosed according to both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) criteria and the ISSM definition, consented (together with their partners) to enter the baseline period of the study. Patients who documented an IELT of ≤1 min with two or more of the first three sexual encounters during the 4‐week baseline period were randomized, in a 2:1 ratio, to receive double‐blind treatment with PSD502 (three actuations of spray each containing 7.5 mg lidocaine and 2.5 mg prilocaine applied 5 min before intercourse) or placebo for 3 months. Patients completed IPE and Premature Ejaculation Profile (PEP) questionnaires at entry and at monthly clinic visits, and recorded stopwatch‐timed IELT during each sexual encounter. Patients rated the quality of their orgasms on a 5‐point scale at baseline and at the end of the treatment period, and rated the study medication on a 4‐point scale. Safety was assessed by collecting adverse event data.

RESULTS

In all, 300 men with PE were randomized from 31 centres in Europe. The geometric mean (range) IELT over the 3‐month treatment period increased from a baseline of 0.6 min in both groups to 3.8 (0.3–57.8) and 1.1 (0–15.0) min in the PSD502 and placebo groups, respectively. Adjusting for treatment‐group imbalances, this represents a 6.3‐fold and 1.7‐fold increase in adjusted geometric means. There were significantly greater increases in the scores for the IPE domains of ejaculatory control and sexual satisfaction in the PSD502 group than in the placebo group, with a mean (sem ) 7.0 (0.59)‐point difference between treatments in change from baseline in the IPE domain for ejaculatory control and a 5.9 (0.57)‐ point difference in change from baseline in the IPE domain for sexual satisfaction (both P < 0.001). This was supported by improvements in all secondary endpoints. At the end of the treatment period 66% of patients rated PSD502 as ‘good’ or ‘excellent’. PSD502 was well tolerated and no systemic adverse events were reported. Localized treatment‐related adverse events were reported by 2.6% and 3.1% of patients and partners, respectively.

CONCLUSION

PSD502 applied topically 5 min before intercourse improved ejaculatory latency and significantly improved ejaculatory control and sexual satisfaction, factors relevant for acceptance of a PE treatment by both patient/physician and regulatory authorities. PSD502 was well tolerated by both patients and partners, with no systemic side‐effects and a low incidence of localized effects, and was rated favourably by most users. PSD502 therefore appears to offer significant advantages over other therapies in development for the treatment of PE.     

Spatiotemporal expression of PSD‐95 in Fmr1 knockout mice brain

To investigate and compare the spatial and temporal expression of post‐synaptic density‐95 (PSD‐95) in Fmr1 knockout mice (the animal model of fragile X syndrome, FXS) and wild‐type mice brain, on postnatal day 7 (P7), P14, P21, P28 and P90, mice from each group were decapitated, and three principal brain regions (cerebral cortex, hippocampus and cerebellum) were obtained and stored for later experiments. PSD‐95 mRNA in the three brain areas was analyzed with quantitative RT‐PCR. PSD‐95 protein was measured by immunohistochemical staining and Western blot. In the three principal brain areas of Fmr1 knockout mice and wild‐type mice, the expression of PSD‐95 mRNA and protein were detected at the lowest levels on P7, and then significantly increased on P14, reaching the peak levels in adolescents or adults. Moreover, it was found that PSD‐95 mRNA and protein in the hippocampus were significantly decreased in Fmr1 knockout mice during the developmental period (P7, P14, P21 and P28) as well as at adulthood (P90) (P < 0.05, and P < 0.01, respectively). However, there was no significant difference of expression of PSD‐95 in the cortex and cerebellum between Fmr1 knockout and wild mice. The expression of PSD‐95 in the hippocampus might be regulated by fragile X mental retardation protein (FMRP) during mice early developmental and adult periods. It is suggested that impairment of PSD‐95 is possibly involved in hippocampal‐dependent learning defects, which are common in people with FXS.     

耳穴贴压法治疗中风后抑郁随机对照研究

目的:评价耳穴贴压法治疗中风后抑郁(PSD)的疗效。方法:将114例符合试验要求的PSD病人按随机号随机进入试验组及对照组,各57例。试验组采用耳穴贴压法,对照组口服百忧解。两组均治疗8周,以汉密顿抑郁量表-21项(HAMD)、中国脑卒中临床神经功能缺损程度评分量表(神经功能缺损)和日常生活活动能力量表(BI)为观察指标,在治疗前、第2周末、第4周末、第8周末各检测1次,共4次。结果:试验组与对照组共有107例完成试验(分别为55例、52例)。试验组与对照组治疗后HAMD评分均有下降,试验组与对照组治疗后分值的下降均有统计学意义,但两组治疗后HAMD评分下降的差异无统计学意义。试验组与对照组治疗后神经功能缺损均有下降,试验组与对照组治疗后分值的下降均无统计学意义。同样,两组治疗后神经功能缺损下降的差异无统计学意义。两组治疗后BI评分均有提高,两组治疗后分值的提高均有统计学意义,同样,两组治疗后BI评分下降的差异无统计学意义。结论:耳穴贴压法治疗PSD可获得与百郁解相似的疗效。     

解郁合剂配合认知行为疗法治疗卒中后抑郁疗效分析

[目的]探讨解郁合剂配合认知行为疗法治疗卒中后抑郁的临床疗效.[方法]将128例卒中后抑郁患者依照随机数字表法分为治疗组(解郁合剂配合认知行为疗法组)和对照组(西酞普兰组),其中治疗组68例,对照组60例,所有患者均于治疗前、治疗4周及治疗8周分别进行汉密尔顿抑郁量表(HAMD)、副反应量表(TESS)评分比较.[结果]采用解郁合剂配合认知行为疗法可明显减少患者HAMD评分,改善患者抑郁状态,其效果优于单纯西药治疗(P＜0.05),且副反应小.[结论]解郁合剂配合认知行为疗法治疗卒中后抑郁症安全有效,适合临床推广.     

益气开郁汤合西药治疗中风后抑郁症32例临床观察

目的：观察益气开郁汤合西药治疗中风后抑郁症的疗效。方法：将64例患者随机分为治疗组32例,对照组32例。两组患者均口服西药氟西汀治疗,治疗组在此基础上加用自拟益气开郁汤治疗。结果：治疗组的总有效率优于对照组（P〈0．05）,具有可比性。结论：益气开郁汤加减合西药可以明显提高中风后抑郁症的治疗效果,同时也无明显不良反应,值得在临床应用。     

In vitro and in vivo effects of a novel dimeric inhibitor of PSD‐95 on excitotoxicity and functional recovery after experimental traumatic brain injury

PSD‐95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD‐95, UCCB01‐147, on histopathology and long‐term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01‐147 and related compounds on NMDA‐induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01‐147 (10 mg/kg), the non‐competitive NMDAR‐receptor antagonist MK‐801 (1 mg/kg) or saline immediately after injury. At 2 and 4 weeks post‐trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01‐147 nor MK‐801 resulted in significant improvements of cognition and histopathology after CCI. Although MK‐801 provided robust neuroprotection against NMDA‐induced toxicity in cultured cortical neurons, UCCB01‐147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects of PSD‐95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration.     

NSCs promote hippocampal neurogenesis,metabolic changes and synaptogenesis in APP/PS1 transgenic mice

Adult neurogenesis and synaptic remodeling persist as a unique form of structural and functional plasticity in the hippocampal dentate gyrus (DG) and subventricular zone (SVZ) of the lateral ventricles due to the existence of neural stem cells (NSCs). Transplantation of NSCs may represent a promising approach for the recovery of neural circuits. Here, we aimed to examine effects of highly neuronal differentiation of NSCs transplantation on hippocampal neurogenesis, metabolic changes and synaptic formation in APP/PS1 mice. 12‐month‐old APP/PS1 mice were used for behavioral tests, immunohistochemistry, western blot, transmission electron microscopy and proton magnetic resonance spectroscopy (1H‐MRS). The results showed that N‐acetylaspartate (NAA) and Glutamate (Glu) levels were increased in the Tg‐NSC mice compared with the Tg‐PBS and Tg‐AD mice 10 weeks after NSCs transplantation. NSC‐induced an increase in expression of synaptophysin and postsynaptic protein‐95, and the number of neurons with normal synapses was significantly increased in Tg‐NSC mice. More doublecortin‐, BrdU/NeuN‐ and Nestin‐positive neurons were observed in the hippocampal DG and SVZ of the Tg‐NSC mice. This is the first demonstration that engrafted NSCs with a high differentiation rate to neurons can enhance neurogenesis in a mouse model of AD and can be detected by 1H‐MRS in vivo. It is suggested that engraft of NSCs can restore memory and promote endogenous neurogenesis and synaptic remodeling, moreover, 1H‐MRS can detect metabolite changes in AD mice in vivo. The observed changes in NAA/creatine (Cr) and glutamate (Glu)/Cr may be correlated with newborn neurons and new synapse formation.     

Visuospatial perception and navigation in Parkinson’s disease

A shifted field of view, an altered perception of optic flow speed, and gait asymmetries may influence heading direction in Parkinson’s disease (PD). PD participants (left body-side onset, LPD, n = 14; right body-side onset, RPD, n = 9) and Healthy Control participants (n = 17) walked a virtual hallway in which the optic flow speeds of the walls varied. Three-dimensional kinematics showed participants veered away from the faster moving wall. Although veering normally occurs toward the side with smaller step length, in both LPD and RPD this bias was overridden by a shifted field of view, which caused veering in the opposite direction, toward the side of the brain with more basal ganglia damage.     

PSD95 Gene Specific siRNAs Attenuate Neuropathic Pain through Modulating Neuron Sensibility and Postsynaptic CaMKIIα Phosphorylation

Objective To observe the effects of PSD95 gene specific siRNAs on neuropathic pain relief, neuron viability, and postsynaptic calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) phosphorylation in vitro and in vivo. Methods Gene-specific siRNAs of rat PSD95 were synthesized chemically for transfection. Adult male Sprague-Dawley (SD) rats were randomly divided into 3 groups: nave group (n=6), sham group (n=6), and sciatic nerve chronic constriction injury (CCI) group (n=24). The CCI group was further divided into 4 groups (n=6 in each group), which were pretreated with normal saline, transfection vehicle, negative control siRNAs, and PSD95 gene specific siRNAs respectively. All the subgroups received corresponding agents intrathecally for 3 days, started one day before the CCI of sciatic nerve. Both mechanical allodynia and thermal hyperalgesia were measured on post-operative day 3 and 7. PSD95 gene silenced NG108-15 cells were further stimulated by glutamate, with the cell viability and the expression/phosphorylation of CaMKIIα measured by MTT cell proliferation assay and Western blot, respectively. Results The siRNAs decreased PSD95 mRNA level significantly both in vivo and in vitro. Neuropathic pain rats pretreated with PSD95 gene specific siRNAs exhibited significant elevation in the mechanical withdrawal threshold and paw withdrawal thermal latency, without affecting the baseline nociception. PSD95 gene silencing enhanced neuronal tolerance against the glutamate excitotoxicity, meanwhile the phosphorylation of CaMKIIα Thr286 was attenuated. Conclusion Pre-emptive administration of PSD95 gene specific siRNAs may attenuate the central sensitization CaMKIIα-related signaling cascades, leading to the relief of neuropathic pain.