Treatment of premature ejaculation: New drugs and treatment strategies

This review discusses treatment options for men with premature ejaculation (PE), a common sexual dysfunction characterized by short ejaculatory latency, decreased sexual satisfaction, and distress. For a number of reasons, including embarrassment and the belief that PE is a normal part of aging, that it has no effective treatment, or that it will resolve itself, few men with PE seek treatment. Although several treatment options exist (eg, behavioral, cognitive, and sex therapy methods; desensitizing drugs; off-label use of antidepressants, phosphodiesterase type 5 inhibitors, or à-blockers), the majority of men with PE are not satisfied with their results. New pharmacologic drugs develped specifically for the treatment of PE are undergoing evaluation in clinical trials. For example, recent clinical research studies have revealed on-demand administration of one such drug, dapoxetine, which achieved significant improvements in ejaculatory latency, control over ejaculation, and satisfaction with sexual intercourse. In addition, partners of men who received dapoxetine likewise reported improved satisfaction with sexual intercourse. Future studies may reveal that integration of pharmacologic drugs with psychologic and/or behavioral therapy techniques may be the optimal approach to the management of PE. PE is a treatable condition, and new drugs in development may provide benefits over those available.     

Preservation of Bile Ductules Mitigates Bile Duct Loss

The finer branches of the biliary tree (FBBT) contain a regenerative compartment. We hypothesized that preservation of the FBBT together with its microvasculature will lead to recovery of biliary damage and prolonged preservation of bile ductules during the development of chronic liver allograft rejection. The interlobular bile ducts, portal bile ductules and extraportal biliary cells with and without microvessels were studied in sequential biopsies in five patients who fulfilled the Banff criteria of early chronic rejection (CR) (imminence group). Biopsies of CR patients (n = 12) served as controls. Biopsies were double immunostained with CD34 (microvessels) and cytokeratin 7 (biliary structures). Proliferation and proangiogenic activity were assessed with Ki67 and VEGF-A immunostaining. Severe damage of bile ducts in the imminence group did not progress to significant bile duct loss. This was associated with a high proliferative activity in all biliary structures and preservation of the microvascular compartment. VEGF-A expression was increased in all but the reperfusion biopsies. In conclusion, both regenerative activity of the FBBT and an intact microvascular compartment are associated with less damage of the biliary tree and could therefore be prerequisites for biliary regeneration.     

A clinical approach to the management of a patient with suspected renovascular disease who presents with leg ischemia.

Atherosclerotic renal artery stenosis (ARAS) may cause hypertension, progressive renal failure, and recurrent pulmonary edema. It typically occurs in high risk patients with coexistent vascular disease elsewhere. Most patients with ARAS are likely to die from coronary heart disease or stroke before end-stage renal failure occurs. Recent controlled trials have shown that most patients undergoing angioplasty to treat renovascular hypertension still need antihypertensive agents 6 or 12 months after the procedure. Nevertheless, the number of antihypertensive agents required to control blood pressure adequately is lower following angioplasty than for medication alone. Trials assessing the value of revascularization for preserving renal function or preventing clinical events are only in the early recruitment phase. Revascularization should be undertaken in patients with ARAS and resistant hypertension or heart failure, and probably in those with rapidly deteriorating renal function or with an increase in plasma creatinine levels during angiotensin-converting enzyme inhibition. With or without revascularization, medical therapy using antihypertensive, hypolipidemic and antiplatelet agents is necessary in almost all cases.     

Is atrial fibrillation an inflammatory disorder?

I read with great interest the excellent review on the influenceof inflammation in the pathogenesis of atrial fibrillation (AF)by Boos      

IFN-alpha1,8 inhibits tumor-induced angiogenesis in murine angiosarcomas.

Interferon-alpha (IFN-alpha) has proved effective in the treatment of hemangiomas, hemangioblastomas, and Kaposi's sarcoma. To investigate the ability of IFNs to inhibit angiosarcoma, we used two transformed murine endothelial cell lines that form angiosarcomas in vivo. SVR and MS1-VEGF cell lines express oncogenic H-ras or vascular endothelial growth factor (VEGF), respectively. IFN-alpha1,8, which is active against murine and human cells, inhibited SVR and MS1-VEGF proliferation in vitro by 40% at 10(3) U/mL (p = 0.028). In vivo, IFN-alpha1,8 inhibited SVR tumor volume by 71% (p = 0.047) and MS1-VEGF volume by 79% (p = 0.003). Tumor-induced angiogenesis was decreased in SVR tumors by 52% (p = 0.005) and in MS1-VEGF tumors by 58% (p = 0.001). Sera from IFN-alpha1,8-treated mice bearing either SVR or MS1-VEGF tumors demonstrated a 5-fold increase in IP-10/CXCL10 (p = 0.001), an IFN-induced antiangiogenic protein. Both recombinant IP-10 and IFN-alpha1,8 inhibited human umbilical vein endothelial cell (HUVEC) vessel formation in the fibrin gel assay, a three-dimensional culture model of angiogenesis, by 56% at 25 ng/mL and 50% at 1.2 ng/mL, respectively (p < 0.001). An IP-10 blocking antibody restored vessel formation to 80% of untreated controls (p = 0.001). Given the magnitude of the in vivo response, these data suggested that the antitumor effects of IFN-alpha1,8 were likely mediated through angiogenesis inhibition rather than solely by direct inhibition of tumor cell proliferation.     

Treatment of dysfunctional uterine bleeding in the perimenopause: the effects of adding combined estradiol/norethisterone acetate therapy to goserelin acetate treatment--a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To assess the effects of adding combined estradiol/norethisterone acetate therapy (CENT) to goserelin acetate treatment (GA) of dysfunctional uterine bleeding (DUB) in perimenopausal women. METHODS: In a randomized, placebo-controlled, double-blind trial followed by an open follow-up study, 31 perimenopausal women with DUB were recruited from gynecological outpatient departments of two Dutch hospitals and randomized for treatment with either GA/placebo or GA/CENT for 6 months followed by 18 months of GA/CENT for all. The main outcome measures were abdominal pain, number of bleeding days, double-layer endometrial thickness (DET), Greene climacteric score (GCS), visual analog scale for well-being, bone mineral density (BMD) and mammographic density (BI-RAD score). RESULTS: Abdominal pain, number of bleeding days and DET decreased in both groups, the between-group difference in decrease not being statistically significant. GCS initially showed significant improvement in the GA/CENT group. BMD decreased significantly in the GA/placebo group (-4.1%) compared with the GA/CENT group (-0.3%). Another 18 months of GA/CENT did not result in a lasting difference in BMD between groups. BI-RAD scores did not differ significantly between or within the two groups. CONCLUSIONS: Adding CENT to GA treatment for DUB in perimenopausal women initially prevented BMD loss and improved climacteric complaints, while having no negative impact on vaginal bleeding, abdominal pain or BI-RAD scores. However, prolonged treatment did not result in a lasting prevention of bone loss.     

Matrix metalloproteinases-2 and -9 in cervical cancer: different roles in tumor progression

The incidence of uterine cervical cancer has increased slightly in Western countries, with an increase in relatively young women. Overexpression of matrix metalloproteinases (MMPs)-2 and -9 has turned out as a prognostic factor in many cancers. We compared the expression of the proteins MMP-2 and MMP-9 in cervical primary tumors with clinical outcome and risk factors of cervical cancer. One hundred sixty-one patients with cervical cancer treated in Ume? University Hospital or Sahlgrenska University Hospital, Sweden, between 1991 and 1995 were included in the study. Paraffin-embedded tissue samples obtained prior to treatment were examined immunohistochemically by specific antibodies for MMP-2 and MMP-9. Forty-two percent of the tumors were intensively positive for MMP-2 and 31% for MMP-9. Nineteen percent of the samples were intensively positive for both proteinases and 47% negative or weak for both. Overexpression of MMP-2 seemed to predict unfavorable survival under Kaplan-Meier analysis and in the multivariate analysis. Early sexual activity and low parity seemed to correlate to overexpression of MMP-2. MMP-9 was not associated with survival or sexual behavior. Intensive MMP-9 was noted in grade 1 tumors. We conclude that MMP-2 and MMP-9 have different roles in uterine cervical cancer. MMP-2 could be associated with aggressive behavior, but MMP-9 expression diminishes in high-grade tumors.     

Statistical analysis of pathologic risk factors for intramyometrial lymphvascular space involvement in myoinvasive endometrial carcinoma

In a retrospective study using univariate analysis, we identified tumor type (nonendometrioid vs endometrioid), depth of myoinvasion (MI), mode of MI (infiltrative vs cohesive), and direct anatomic invasion of the cervical wall from the isthmus as significant positive risk factors for intramyometrial lymphvascular space involvement (LVSI). On multivariate analysis, tumor grade, depth of MI, and mode of MI retained their significance. We created a grid for the relative risks of LVSI with respect to these variables individually or in combination. We suggest that our indirect estimate of the risk of LVSI can help in assessing prognosis and determining the need for adjuvant therapy whenever LVSI is important in clinical decision making, but its pathologic diagnosis is uncertain.