From Waterloo to the Great Wall: A retrospective, multicenter study on the clinical practice and cultural attitudes in the management of premature ejaculation, in China.

Premature ejaculation (PE), despite its wide prevalence, is largely underdiagnosed and undertreated. Being a multifactorial dysfunction with strong cultural characteristics, PE requires skillful attitudes in the psychosexological support, necessary to manage the patient's and the couple's expectations, as well as in the medical treatment. Dapoxetine is a short-acting selective serotonin reuptake inhibitor approved for use in lifelong and acquired PE in a number of countries. Opinions, not always generated by the evidence-based medicine, impacted the attitudes of Western andrologists, as a nocebo effect which produced a drug's Waterloo, characterized by low prescription rates much more built on the patients' and doctors' expectations than on costs, side effects, and efficacy. In the present study, we retrospectively reviewed real-life data from eight Andrology and Sexual Medicine Public Centers in China to assess the prevalence of PE among attending patients, its association with erectile dysfunction, its subtype, and the proposed treatments. In 2019, among 156,486 patients coming to the centers, 32,667 visits having PE as the chief complaint were performed (20.9%). Almost all patients received treatment prescriptions (32,641 patients, 99.92%); 23,273 patients came back for a follow-up visit in the subsequent 12 months (71.2% of those who initially received treatment). Dapoxetine, either alone or in combination with another therapy, was the most prevalent treatment, prescribed to 22,767 patients (69.7% of treated patients), followed by traditional Chinese medicine (TCM) (39.4%). At follow-up, 8174 patients were unsatisfied with treatment, and a new treatment was proposed (35.12%). Dapoxetine was the best treatment, with an overall 27.1% switching rate when used either alone or in combination: Although the switching rate for Dapoxetine alone was 44.2%, the association of the same drug with psychotherapy resulted in much lower rates (19.5%) and reached a minimum of 12% when also combined with TCM demonstrating how cultural aspects and medical attitudes may dramatically impact on the therapy of a multifaceted, complex, and culture-grounded sexual symptom such as PE. In conclusion, taking switching rates as surrogate markers of treatment failure, this real-life study-the largest in the field-shows that in a more patient-oriented (as in Chinese medical culture), and less symptom-oriented (as in Western medical attitudes), Dapoxetine is a successful treatment for PE patients, with higher reliability when used alone or as part of combined and integrated therapies.

Topical clotrimazole cream for the treatment of tinea cruris: A retrospective study.

This retrospective study assessed the efficacy and safety of 1% topical clotrimazole cream for the treatment of patients with tinea cruris (TC).We included 86 patients with confirmed TC for the presence of fungal hyphae. Of those, 43 patients received 1% topical clotrimazole cream for a total of 4 consecutive weeks, and were assigned to an experimental group. The other 43 patients underwent 1% topical butenafine cream for a total of 2 consecutive weeks, and were allocated to a control group. The efficacy and safety were measured and analyzed after 4 weeks treatment.After treatment, patients in both groups achieved better improvements in erythema (P < .01), scaling (P < .01), itching (P < .01), and KOH-negative results (P < .01), compared with those in patients before the treatment. However, there were not significant differences in erythema (P = .61), scaling (P = .57), itching (P = .47), and KOH-negative results (P = .67) between 2 groups. In addition, no treatment-related adverse events were recorded in both groups.Both 1% topical clotrimazole and butenafine cream are found to be effective and safe for patients with TC. However, there is not significant difference in efficacy and safety between two groups.

Activation of the Liver X Receptor Pathway Inhibits HBV Replication in Primary Human Hepatocytes.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. APPROACH AND RESULTS: In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV-infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR-623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigen production following agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long-lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti-HBV effect was observed in HepG2-derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with small interfering RNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. CONCLUSIONS: We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti-HBV activity in PHHs, possibly through sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting the LXR pathway for the treatment of chronic HBV infection.

Ex vivo lung perfusion as a human platform for preclinical small molecule testing.

The acute respiratory distress syndrome (ARDS) causes an estimated 70,000 US deaths annually. Multiple pharmacologic interventions for ARDS have been tested and failed. An unmet need is a suitable laboratory human model to predictively assess emerging therapeutics on organ function in ARDS. We previously demonstrated that the small molecule BC1215 blocks actions of a proinflammatory E3 ligase-associated protein, FBXO3, to suppress NF-κB signaling in animal models of lung injury. Ex vivo lung perfusion (EVLP) is a clinical technique that maintains lung function for possible transplant after organ donation. We used human lungs unacceptable for transplant to model endotoxemic injury with EVLP for 6 hours. LPS infusion induced inflammatory injury with impaired oxygenation of pulmonary venous circulation. BC1215 treatment after LPS rescued oxygenation and decreased inflammatory cytokines in bronchoalveolar lavage. RNA sequencing transcriptomics from biopsies taken during EVLP revealed robust inflammatory gene induction by LPS with a strong signal for NF-κB-associated transcripts. BC1215 treatment reduced the LPS induction of genes associated with inflammatory and host defense gene responses by Gene Ontology (GOterm) and pathways analysis. BC1215 also significantly antagonized LPS-mediated NF-κB activity. EVLP may provide a unique human platform for preclinical study of chemical entities such as FBXO3 inhibitors on tissue physiology.

Comprehensive Examination of Therapies for Pain in Parkinson's Disease: A Systematic Review and Meta-Analysis.

Pain in Parkinson's disease (PD) is a debilitating symptom with a prevalence of 68%, yet is untreated 50% of the time. What is unclear, however, is which treatment is optimal for minimizing pain severity in PD. Thus, the objective of this systematic review and meta-analysis was to investigate the efficacy of a variety of novel, complimentary, and conventional treatments for pain in PD and elucidate which therapy is the most effective. A systematic search was performed using MEDLINE, PsycINFO, Embase, CINAHL, and CENTRAL databases. To identify additional articles, manual searches of reference lists of included trials were also searched. Major neurology conference proceedings occurring between January 2014 and February 2018 were also searched to identify unpublished studies that may be potentially eligible. Twenty-five randomized controlled trials that encompassed medical, surgical, and complementary therapies met our inclusion criteria and exhibited moderate quality evidence. Two reviewers conducted assessments for study eligibility, risk of bias, data extraction, and quality of evidence rating. A conservative random-effects model was used to pool effect estimates of pain severity. The greatest reductions in pain were found with safinamide (Standardized mean difference = -4.83, 95% CI [-5.07 to -4.59], p < 0.0001), followed by cannabinoids and opioids, multidisciplinary team care, catechol-O-methyltransferase inhibitors, and electrical and Chinese therapies. Moderate effects in reducing pain were in pardoprunox and surgery, while the weakest effects were in dopaminergic agonists and miscellaneous therapies. Safinamide is an important adjunct to standard parkinsonian medication for alleviating pain in PD.

Effects of different anticoagulant drugs on the prevention of complications in patients after arthroplasty: A network meta-analysis.

BACKGROUND: After arthroplasty treatment, some complications commonly occur, such as early revision, infection/dislocation, and venous thromboembolism (VTE). This study aims to use a network meta-analysis to compare effects of 9 anticoagulant drugs (edoxaban, dabigatan, apixaban, rivaroxaban, warfarin, heparin, bemiparin, ximelagatran, and enoxaparin) in preventing postoperative complications in arthroplasty patients. METHODS: After retrieving PubMed, Embase, and Cochrane Library database from the inception to November 2016, randomized controlled trials were enrolled. The integration of direct and indirect evidences was performed to calculate odd ratios and the surface under the cumulative ranking curves. Nineteen eligible randomized controlled trials were included. RESULTS: The network meta-analysis results showed that compared with warfarin, edoxaban, apixaban, and rivaroxaban had a lower incidence rate in asymptomatic deep venous thrombosis, which indicated that edoxaban, apixaban, and rivaroxaban had better effects on prevention. Similarly, in comparison to enoxaparin, edoxaban and rivaroxaban had better effect; rivaroxaban was better than ximelagatran in preventive effects. Compared with apixaban, edoxaban, dabigatan, rivaroxaban, and enoxaparin had a higher incidence rate in clinically relevant non-major bleeding, which showed that preventive effects were relatively poor. In addition, the results of the surface under the cumulative ranking curves showed that rivaroxaban and bemiparin worked best on symptomatic deep venous thrombosis and pulmonary embolism. In terms of bleeding, apixaban and warfarin had better preventive effects. CONCLUSION: Our findings suggested that rivaroxaban may work better in terms of symptomatic deep venous thrombosis and pulmonary embolism, whereas apixaban had better preventive effects in bleeding.

Pharmacokinetic drug evaluation of safinamide mesylate for the treatment of mid-to-late stage Parkinson's disease.

INTRODUCTION: Patients with Parkinson's disease suffer from a heterogeneous expression of neurotransmitter deficits. They cause an individual variable expression of motor and non-motor symptoms. Thus, drugs with various mechanisms of actions are suitable to counteract these disease related neurotransmitter alterations. Areas covered: This invited review suggests safinamide as an ideal compound for therapy of Parkinson's disease, as its pharmacological profile includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and abnormal glutamate release. Safinamide may provide benefits effects on non-motor symptoms in addition to the demonstrated amelioration of motor impairment in levodopa treated patients with Parkinson's disease. Safinamide was well tolerated and safe when administered in dose of 50 or 100 mg daily in pivotal trials. Expert opinion: Clinical handling, safety and tolerability of Safinamide are better than of dopamine agonists or levodopa. Safinamide supplements the existing armamentarium of drugs for Parkinson's disease. Safinamide will help to reduce dosing of levodopa but also of dopamine agonists during long term treatment in patients with Parkinson's disease.

A Prospective Randomized Controlled Study to Compare Acupuncture and Dapoxetine for the Treatment of Premature Ejaculation.

PURPOSE: To compare the safety and efficacy of dapoxetine and acupuncture for the treatment of premature ejaculation (PE) with other treatment methods. METHODS: One hundred twenty patients with PE in an outpatient urology clinic were randomized to receive dapoxetine 30 mg and 60 mg, acupuncture or sham acupuncture. The intravaginal ejaculatory latency time (IELT), the PE diagnostic tool (PEDT) score, and adverse events were compared. RESULTS: There were no differences between the groups in terms of age, body mass index, baseline IELT and PEDT scores (p > 0.05). After 4 weeks, IELT was significantly longer compared to baseline values in all groups (p < 0.001 for all comparisons). Comparisons between the groups showed that changes in IELT and PEDT observed after 4 weeks with dapoxetine 60 mg was significantly higher than those achieved in all other groups (p < 0.001 for all comparisons), changes observed with dapoxetine 30 mg was significantly higher than those achieved with acupuncture and sham acupuncture groups (p < 0.001 for both comparisons) and changes observed with acupuncture was significantly higher than those observed with sham acupuncture (p < 0.001). CONCLUSION: Our results confirm previous reports on the efficacy and safety of dapoxetine. Although less effective than dapoxetine, acupuncture had a significant ejaculation-delaying effect.

Adjuvant therapies for Parkinson's disease: critical evaluation of safinamide.

Safinamide (SAF) is a new drug developed for the treatment of Parkinson's disease (PD). It is a benzylamino derivative with multiple mechanisms of action and antiparkinsonian, anticonvulsant, and neuroprotective properties. SAF inhibits monoamine oxidase B and dopamine reuptake and glutamate release, blocks voltage-dependent sodium channels, and modulates calcium channels. Although the antiparkinsonian effect can be ascribed in part to the inhibition of the monoamine oxidase B, which is complete at 50 mg, the enhanced benefit seen at the 100 mg dose is probably due to nondopaminergic mechanisms. SAF will represent an important option for patients with both early and advanced PD. In early PD patients, the addition of SAF to dopamine agonists may be an effective treatment strategy to improve motor function, prolong the use of dopamine agonists, and/or delay the introduction of levodopa. In advanced parkinsonian patients, SAF has been demonstrated to significantly increase on time with no, or nontroublesome dyskinesias. All studies performed have demonstrated its efficacy in benefiting both short-term and long-term quality-of-life outcomes in both early and advanced PD patients. SAF has been investigated in long-term (24 months), double-blind, placebo-controlled studies, where it showed a very good safety profile. SAF has not been studied in de novo PD patients, and its potential positive effect on dyskinesia deserves further dedicated studies.

[Efficacy and safety of Yimusake Tablets plus dapoxetine hydrochloride in the treatment of premature ejaculation].

OBJECTIVE: To evaluate the effect and safety of Yimusake Tablets combined with dapoxetine hydrochloride and either of them used alone in the treatment of premature ejaculation (PE). METHODS: We randomly assigned 180 PE patients to oral medication of Yimusake Tablets at 1.5 g per night (group A), dapoxetine hydrochloride at 30 mg at 1－3 hours before anticipated sexual activity (group B), the Yimusake Tablets plus dapoxetine hydrochloride simultaneously (group C), all for 8 weeks. After 4 and 8 weeks of medication, we recorded and compared the changes in the intravaginal ejaculation latency time (IELT), measures of the PE profile (PEP), and adverse events among the three groups of patients. RESULTS: The treatment was accomplished and complete data obtained from 154 of the patients, 56 in group A, 52 in group B, and 46 in group C. After 4 and 8 weeks of medication, the mean IELT was dramatically prolonged in all the three groups as compared with the baseline (P<0.01), most significantly at 8 weeks in group C (ï¼»2.08±0.68ï¼½ min), followed by B (ï¼»1.76±0.52ï¼½ min) and A (ï¼»1.47±0.44ï¼½ min), with statistically significant differences among the three groups (P<0.01). The PEP measures were remarkably improved in group A at 8 weeks (P<0.05), and both in B and C at 4 and 8 weeks (P<0.05), most significantly at 8 weeks in group C (P<0.05), in which the patients scored 1.96±0.77 in perception of control over ejaculation, 2.62±0.98 in satisfaction with sexual intercourse, 3.04±0.62 in PE-related distress, and 3.57±0.80 in PE-induced difficult relationship with their partners, all markedly improved as compared with groups A and B (P<0.05). Adverse reactions were observed in 2 cases (3.6%) in group A, 6 cases (9.6%) in B, and 5 cases (10.9%) in C. No severe adverse events occurred in any of the patients during the study. CONCLUSIONS: Combined medication of Yimusake Tablets and dapoxetine hydrochloride, with its advantages of effectiveness and safety, deserves to be recommended for the treatment of PE.

Comparative efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation: A network meta-analysis with the adjustment for the possible bias from open label studies.

BACKGROUND: This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date. METHOD: We performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002-2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed. RESULTS: A systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150mg 0.77; edoxaban 60mg 0.87; rivaroxaban 0.86] except for dabigatran 110mg and edoxaban 30mg. Apixaban and edoxaban 30mg and 60mg had significantly fewer major bleeding events than dabigatran 150mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110mg and 150mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60mg, and rivaroxaban. CONCLUSIONS: Our indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.

Inflammation, immunity, and hypertensive end-organ damage.

For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.

Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor-induced hypercoagulability in vitro and in vivo.

BACKGROUND: Increased hypercoagulability has been reported with low doses of direct thrombin inhibitors but not with direct factor Xa inhibitors. OBJECTIVES: To compare the effects of rivaroxaban with those of melagatran and dabigatran on thrombin generation (TG) and tissue factor-induced hypercoagulability and to explore the possible involvement of the thrombin-thrombomodulin/activated protein C system. METHODS: In normal human plasma and in protein C-deficient plasma, TG was investigated in vitro in the presence and absence of recombinant human soluble thrombomodulin (rhs-TM). TG was determined by calibrated automated thrombography and an ELISA for prothrombin fragments 1+2 (F1+2 ). In an in vivo rat model, hypercoagulability was induced by tissue factor; levels of thrombin-antithrombin (TAT) and fibrinogen and the platelet count were determined. RESULTS: Rivaroxaban inhibited TG in a concentration-dependent manner. In the absence of rhs-TM, melagatran and dabigatran also inhibited TG concentration dependently. However, in the presence of rhs-TM, lower concentrations of melagatran (119-474 nmol L(-1) ) and dabigatran (68-545 nmol L(-1) ) enhanced endogenous thrombin potential, peak TG, and F1+2 formation in normal plasma but not in protein C-deficient plasma. In vivo, rivaroxaban dose-dependently inhibited TAT generation, whereas melagatran showed a paradoxical effect, with an increase in TAT and a small decrease in fibrinogen and platelet count at lower doses. CONCLUSION: Low concentrations of the direct thrombin inhibitors melagatran and dabigatran enhanced TG and hypercoagulability, possibly via inhibition of the protein C system. In contrast, rivaroxaban reduced TG and hypercoagulability under all conditions studied, suggesting that it does not suppress this negative-feedback system.

Novel oral anticoagulants in acute coronary syndrome: re-evaluating the thrombin hypothesis.

Despite widespread adoption of acetylsalicylic acid and P2Y12 receptor inhibitor therapy as the standard of care for secondary event prevention in patients with acute coronary syndrome (ACS), the rate of cardiovascular death or myocardial infarction following discharge is approximately 24-31% over five years, indicating an important unmet need to reduce further the risk of recurrent ACS events. Because thrombin has a role in arterial thrombus generation, a mechanistic rationale exists for adding an anticoagulant to dual antiplatelet therapy to reduce cardiovascular event rates and mortality. The direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitors rivaroxaban and apixaban have been investigated for this application, with only rivaroxaban successfully completing a phase III trial. These results suggest that dose selection is of paramount importance in this indication, with lower anticoagulant doses (relative to those used in other indications, such as stroke prevention in atrial fibrillation) plus low-dose acetylsalicylic acid potentially improving cardiovascular outcomes. This article reviews clinical trial data of anticoagulants for secondary event prevention in patients with ACS; it also discusses the mechanistic reasons that may underlie these observations and looks towards the potential impact of findings from the ATLAS ACS 2 TIMI 51 trial on clinical practice.

Inhibition of inducible nitric oxide synthase prevents shock wave therapy induced renal injury.

OBJECTIVES: Shock wave lithotripsy treatment (SWT) is not completely free from side effects; one of the accused mechanisms for renal injury during SWT is oxygen- and nitrogen-derived free radical productions. Therefore, we aimed to evaluate the effect of inhibition of nitric oxide (NO) production by N-[3(aminomethyl) benzyl) acetamidine] (1400W), highly selective inducible nitric oxide synthase (iNOS) inhibitor, at SWT-induced kidney damage. MATERIALS AND METHODS: Twenty-four rats those underwent right nephrectomy procedure were divided equally into three groups as control, SWT, and SWT + 1400W. 1400W was administered at a dose of 10 mg/kg at 2 h prior to SWT procedure and at the beginning of SWT procedure via intraperitoneal route and continued daily for consecutive 3 days. At the end of the fourth day, animals were killed via decapitation and trunk blood and the left kidneys were taken for biochemical and histopathologic evaluation. RESULTS: SWT caused renal tubular damage and increased lipid peroxidation and antioxidant enzyme activities and SWT also significantly increased nitro-oxidative products. Inhibition of iNOS via administration of 1400W ameliorated renal injury and decreased tissue lipid peroxidation (malondialdehyde), superoxide dismutase, glutathione peroxidase and nitrite/nitrate levels (NOx). In addition, it was seen that histolopathological changes were attenuated in the SWT + 1400W group when compared to SWT group. CONCLUSION: SWT-induced renal injury might be due to excessive production of oxygen free radicals and NO production. Inhibition of iNOS attenuates renal injury following SWT treatment. It can be concluded that iNOS inhibitors or peroxynitrite scavengers might be used to protect the kidneys against SWT-induced morphological and functional injuries.

Results from a prospective observational study of men with premature ejaculation treated with dapoxetine or alternative care: the PAUSE study.

BACKGROUND: Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the first drug approved for the on-demand treatment of premature ejaculation (PE). Its safety was established in a thorough clinical development program. OBJECTIVE: To characterize the safety profile of dapoxetine in PE treatment and to report the incidence, severity, and type of adverse events. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 12-wk, open-label, observational study with a 4-wk, postobservational contact. A total of 10,028 patients were enrolled, with 6712 patients (67.6%) treated with dapoxetine 30-60 mg (group A) and 3316 (32.4%) treated with alternative care/nondapoxetine (group B). INTERVENTIONS: Treatment with dapoxetine or alternative care/nondapoxetine. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Treatment-emergent adverse events (TEAEs) and concomitant therapy use during the 12-wk observational and the postobservational period were reported. RESULTS AND LIMITATIONS: The mean age for all patients was 40.5 yr. In group A, 93.0% of the patients were initially prescribed dapoxetine 30 mg. Treatment options for group B patients included clomipramine, paroxetine, fluoxetine, sertraline, topical drugs, condoms, and behavioral counseling. Both treatment regimens were well tolerated. TEAEs were reported by 12.0% and 8.9% of group A and group B, respectively, with the highest incidence observed in patients aged >65 yr for group A (21.4%) and 30-39 yr (9.8%) for group B. The most commonly reported TEAEs were nausea, headache, and vertigo, with a higher incidence in group A (3.1%, 2.6%, and 1.0%, respectively) than in group B (oral drugs: 2.3%, 1.3%, and 0.9%, respectively). There were no cases of syncope in group A and one case in group B. A major limitation is that this was a nonrandomized, open-label, short-term study lacking efficacy data. CONCLUSIONS: The results of this postmarketing observational study demonstrated that dapoxetine for treatment of PE has a good safety profile and low prevalence of TEAEs. Syncope and major cardiovascular adverse events were not reported. The high level of adherence by healthcare providers to the contraindications, special warnings, and precautions for dapoxetine minimizes the risk for its use in routine clinical practice. The current risk minimization measures for its identified and potential risks are effective.

[Drugs for sexual medicine]. / Les médicaments de la médecine sexuelle.

AIM: To describe drugs used in sexual medicine. METHOD: Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies web sites (HAS and ANSM). RESULTS: 5PDIs and intracavernous injection of alprostadil are first- and second-line therapies of erectile dysfunction. Dapoxetine is the first specific and approved treatment of premature ejaculation. Androgene supplementation improves sexual desire among patient with hypogonadism as much as initial serum testosterone levels are low. Female sexual dysfunctions pharmacology is to date less developed, although candidate drugs reach phase III clinical studies. CONCLUSION: Pharmacology is one but not the only therapeutic avenue in sexual medicine. Despite real breakthrough such as 5PDIs for erectile dysfunction, incomplete knowledge and understanding of physiology, pathophysiology and pharmacology of human sexual function reduces its development particularly for women.

Which is first? The controversial issue of precedence in the treatment of male sexual dysfunctions.

INTRODUCTION: In male sexual dysfunction (MSD), the presence of sexual comorbidities is relatively frequent. However, what is still a matter of controversy is what the first-line therapy in these patients should be. METHODS: Three scientists and the editor of the Controversies section, all experts in the medical treatment of MSD, present different perspectives on the use of phosphodiesterase type 5 inhibitors (PDE5), testosterone and dapoxetine in erectile dysfunction (ED), hypogonadism, and premature ejaculation (PE). The psychological aspects are discussed by an outstanding expert in psychosexology. MAIN OUTCOME MEASURE: Expert opinion supported by the critical review of the currently available literature. RESULTS: Testosterone should be used before PDE5s in hypogonadal men with comorbid ED; PDE5s should be used before dapoxetine in PE patients with comorbid ED, and counseling should be offered to all subjects with MSD. CONCLUSIONS: Although the answer to the question "which should be first?" is controversial in almost all MSDs, intuition, experience, and evidence should guide the choice of which treatment should be used first. This decision is highly critical in influencing the therapeutic outcome as well the patient's and couple's adherence to treatment.

Inhibition of calcium(2+)/calmodulin-dependent protein kinase type IV ameliorates experimental nephrotic syndrome.

OBJECTIVE: Evidence has demonstrated that Ca(2+)/calmodulin-dependent protein kinase type IV (CaMKIV) contributes to altered cytokine production by promoting the production of inflammatory cytokines. This study aimed to explore the protective role and underlying mechanisms of CaMKIV inhibition in experimental nephrotic syndrome. METHODS: BALB/c mice received single intravenous injections of adriamycin (10 mg/kg) then were sacrificed at two, four and six weeks. In the second study, treatment with KN-93, a CaMKIV inhibitor, or vehicle administered via intraperitoneal injection was started five days after adriamycin injection. Functional and pathologic parameters, the presence of inflammatory infiltration and the expressions of pro-inflammatory cytokines were assessed. RESULTS: The CaMKIV protein expression levels were upregulated in the mice with adriamycin nephropathy, which was significantly inhibited by KN-93 (p<0.01). As compared with the vehicle-treated controls, KN-93 treatment resulted in marked suppression of proteinuria and serum creatinine at week 6 (p<0.01), but not at two weeks after induction of the disease. KN-93 inhibited glomerulosclerosis and the development of tubulointerstitial lesions. The renal alpha-smooth muscle actin (α-SMA) expression was also significantly suppressed by KN-93 treatment at week 6 (p<0.01). Moreover, KN-93 inhibited the renal monocyte chemoattractant protein-1 (MCP-1) expression, paralleled by a reduction in the interstitial infiltration of macrophages and T-cells (p<0.01). CONCLUSION: Our findings suggest that activation of CaMKIV signaling is involved in the progression of glomerular diseases with a proteinuric state. Our data therefore justify the development of small molecule CaMKIV inhibitors for the treatment of clinical nephrotic syndrome.