Onset of efficacy of tadalafil once daily in men with erectile dysfunction: a randomized, double-blind, placebo controlled trial.

PURPOSE: We evaluated the efficacy onset and safety of tadalafil 2.5 and 5 mg once daily for 14 days compared with placebo in men with erectile dysfunction. MATERIALS AND METHODS: In this randomized, double-blind, placebo controlled, parallel group study we randomized 372 men after a 4-week run-in period to receive placebo, or tadalafil 2.5 or 5 mg once daily for 14 days, followed by a 14-day open label extension period of tadalafil 5 mg once daily. Primary analysis focused on the cumulative percent of men with a successful intercourse attempt during the first 4 days of treatment. On secondary analysis we evaluated the percent of successful attempts during the study. The Sexual Encounter Profile diary question 3 was used to assess efficacy. Safety was assessed by monitoring adverse events and vital signs. RESULTS: Significantly more men in the tadalafil 5 mg group achieved successful intercourse, as indicated by a yes response to diary question 3, than those on placebo by day 2 (48.6% vs 36.6%, p < 0.025). The tadalafil 2.5 mg group did not separate from the placebo group on primary analysis. Secondary analysis showed that men on tadalafil 2.5 mg achieved a significantly higher percent of successful intercourse attempts than those on placebo by day 3 (35.5% vs 27.2%, p < 0.025). All groups further improved during the open label extension period. Tadalafil was well tolerated. CONCLUSIONS: This prospective trial shows the onset of efficacy of tadalafil 2.5 and 5 mg once daily within a few days of initiating therapy.

Durability of response following cessation of tadalafil taken once daily as treatment for erectile dysfunction.

INTRODUCTION: Research has focused on improvement of erectile function during treatment with phosphodiesterase type 5 (PDE5) inhibitors, but less is known about what occurs after treatment cessation. AIM: The aim of this retrospective analysis was to examine durability of response, defined as sustainability of erectogenic benefits following treatment cessation, in men with erectile dysfunction (ED) following long-term treatment with daily tadalafil. METHODS: The subjects (N=160) had participated in a 12-week double-blind trial followed by a one-year, open-label extension of tadalafil 5mg once daily. The extension was followed by a 4-week, treatment-free follow-up period. A total of 158 subjects completed International Index of Erectile Function-Erectile Function (IIEF-EF) domain score and were included in this analysis. MAIN OUTCOME MEASURES: The primary measures for this analysis were changes in ED severity category as captured by the IIEF-EF domain score. RESULTS: At the end of the 1-year open-label treatment period, a majority (86.1%, n=136) of subjects had either improved by at least one ED severity category (e.g., Severe to Moderate) (n=128), or maintained Normal erectile function (EF domain score ≥26) (n=8), compared to baseline. Following the 4-week, treatment-free period, 63 of those subjects (46.3% of the 136 subjects) had continued improvement of at least one ED severity category (n=61) or maintained scores in the Normal category (n=2) compared with baseline. Subjects who showed a sustained benefit of treatment were considered to have demonstrated a "durable response." Seventy-three subjects (53.7%) did not have a durable response following treatment cessation. A few patient characteristics were associated with durability of response. CONCLUSIONS: Of those men who demonstrated improved erectile function while taking tadalafil 5mg once daily for 1 year, 46.3% continued to show improvement compared with baseline following a 4-week treatment free period. Durability of response should be a focus of future research.

Impact on erectile function and sexual quality of life of couples: a double-blind, randomized, placebo-controlled trial of tadalafil taken once daily.

INTRODUCTION: Clinical research on erectile dysfunction (ED) has focused primarily on the male and the impact of treatment on their erectile function (EF) and sexual quality of life. However, ED affects the quality of life of both the male and the female partner. The literature examining the impact on the female partner resulting from treating the male's ED is somewhat limited. AIMS: To determine the efficacy of tadalafil 5 mg taken once daily compared with placebo on men's EF and sexual quality of life, and to determine the impact of this treatment on the female partner's sexual quality of life. MAIN OUTCOME MEASURES: The co-primary outcome measures for this study were changes from baseline to end point in the EF domain of the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) question 2 (SEP-2) and question 3 (SEP-3), and the Sexual Quality of Life (SQoL) domain of the Sexual Life Quality Questionnaire (SLQQ) (subject and partner). Methods. Following a 4-week treatment-free run-in phase, 342 subjects and their partners were randomly assigned to either placebo (N = 78) or tadalafil 5 mg (N = 264) for 12 weeks. The subjects' and partners' responses to study measures were collected throughout the study. RESULTS: Compared with placebo, tadalafil-treated subjects showed a significant improvement on efficacy measures (P < 0.001) including changes in the IIEF-EF, SEP-2 and SEP-3. In addition, the sexual quality of life of men and their female partners, as measured by the SQoL domain, was significantly improved with tadalafil 5 mg taken once daily (P < 0.001) compared with placebo. CONCLUSIONS: Tadalafil 5 mg once daily significantly improved EF and sexual quality of life for men with ED. In addition, the sexual quality of life of the female partners of the men treated with tadalafil was significantly improved.

Phase II study of gemcitabine and bevacizumab as first-line treatment in taxane-pretreated, HER2-negative, locally recurrent or metastatic breast cancer.

BACKGROUND: In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine. PATIENTS: Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval. METHODS: This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%). CONCLUSION: Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.

Impact of tadalafil once daily in men with erectile dysfunction--including a report of the partners' evaluation.

OBJECTIVES: To evaluate the effect of tadalafil 5 mg taken once daily on efficacy (erection achievement and penetration) and overall sexual satisfaction in men with erectile dysfunction (ED) and their female partners. METHODS: This retrospective analysis included data pooled from 2 multicenter, randomized, double-blind, placebo-controlled trials that included 505 couples (tadalafil, n=373; placebo, n=132) in which the men received tadalafil 5 mg once daily or placebo for 12 weeks. Individual Sexual Encounter Profile (SEP) diaries were completed independently by the male subject and his female partner after each sexual intercourse attempt. The mean per-subject/per-partner percentage of "yes" responses to SEP diary questions were assessed, as was agreement between subjects' and partners' responses. RESULTS: Subjects and partners in the tadalafil-treated group reported significantly greater improvements in the man's ability to achieve some erection, vaginal penetration, and overall sexual satisfaction compared with the placebo-treated group (P<.001). For all intercourse attempts, the mean per-couple percentage of agreement for those in the tadalafil and placebo groups, respectively, was high for erection achievement (99.0% and 96.6%), vaginal penetration (98.6% and 97.4%), and overall satisfaction (84.3% and 82.8%). CONCLUSIONS: Tadalafil 5 mg taken once daily as treatment for ED improved overall satisfaction for men and their female partners. This analysis demonstrates the high concordance among couples in their responses to the man's treatment for ED.

A Phase II trial of Denileukin Diftitox in patients with previously treated advanced non-small cell lung cancer.

INTRODUCTION: Denileukin diftitox, a chimeric protein, uses the cytocidal properties of diphtheria toxin to cells expressing interleukin-2 receptors. The aim of this study was to evaluate the efficacy and safety of denileukin diftitox in the treatment of advanced relapsed nonsmall cell lung cancer (NSCLC). PATIENTS AND METHODS: Multicenter phase II trial in patients with NSCLC with Eastern Cooperative Oncology Group PS 0-2, stage IIIB/IV at diagnosis, who had failed at least 1 previous chemotherapy regimen. Denileukin diftitox was infused at 18 microg/kg/d x 5 days, every 21 days for 6 cycles. RESULTS: For the 41 patients enrolled, the median age was 56 years (range, 21-80), 25 were men, and the median number of previous chemotherapy regimens was 2 (range, 1-5). The median number of treatment cycles was 2 (range, 1-6). By RECIST criteria, 18 (44%) had stable disease, 10 (24%) progressive disease, and 13 (32%) were not evaluable for response as they received less than 2 treatment cycles. The median time to disease progression was 1.8 months [range, 0.3-11.3; 95% confidence interval (CI) 1.3-2.6]. Median survival was 5.8 months (range, 0.3-33.6; 95% CI 3.4-11.4). The median follow-up time was 16.1 month. One death from myocarditis verified at autopsy was attributed to treatment. One grade 4 toxicity (vascular leak syndrome) was encountered, and 18 grade 3 toxicities, primarily gastro-intestinal, vascular leak syndrome, and constitutional symptoms. CONCLUSION: Denileukin diftitox at current dose schedule has limited activity in patients with previously treated NSCLC, manifested by disease control without impact on survival.

Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure.

OBJECTIVES: The purpose of this study was to determine whether central sleep apnea (CSA) contributes to mortality in patients with heart failure (HF). BACKGROUND: Cheyne-Stokes breathing with CSA commonly occurs in patients with systolic HF. Consequences of CSA, including altered blood gases and neurohormonal activation, could result in further left ventricular dysfunction. Therefore, we hypothesized that CSA might contribute to mortality of patients with HF. METHODS: We followed 88 patients with systolic HF (left ventricular ejection fraction < or =45%) with (n = 56) or without (n = 32) CSA. The median follow-up was 51 months. RESULTS: The mean (+/-SD) of apnea-hypopnea index was significantly higher in patients with CSA (34 +/- 25/h) than those without CSA (2 +/- 1/h). Most of these events were central apneas. In Cox multiple regression analysis, 3 of 24 confounding variables independently correlated with survival. The median survival of patients with CSA was 45 months compared with 90 months of those without CSA (hazard ratio = 2.14, p = 0.02). The other 2 variables that correlated with poor survival were severity of right ventricular systolic dysfunction and low diastolic blood pressure. CONCLUSIONS: In patients with systolic HF, CSA, severe right ventricular systolic dysfunction, and low diastolic blood pressure might have an adverse effect on survival.

Respiratory protection provided by N95 filtering facepiece respirators against airborne dust and microorganisms in agricultural farms.

A new system was used to determine the workplace protection factors (WPF) for dust and bioaerosols in agricultural environments. The field study was performed with a subject wearing an N95 filtering facepiece respirator while performing animal feeding, grain harvesting and unloading, and routine investigation of facilities. As expected, the geometric means (GM) of the WPFs increased with increasing particle size ranging from 21 for 0.7-1 microm particles to 270 for 5-10 microm particles (p < 0.001). The WPF for total culturable fungi (GM = 35) was significantly greater than for total culturable bacteria (GM = 9) (p = 0.01). Among the different microorganism groups, the WPFs of Cladosporium, culturable fungi, and total fungi were significantly correlated with the WPFs of particles of the same sizes. As compared with the WPFs for dust particles, the WPFs for bioaerosols were found more frequently below 10, which is a recommended assigned protection factor (APF) for N95 filtering facepiece respirators. More than 50% of the WPFs for microorganisms (mean aerodynamic diameter < 5 microm) were less than the proposed APF of 10. Even lower WPFs were calculated after correcting for dead space and lung deposition. Thus, the APF of 10 for N95 filtering facepiece respirators seems inadequate against microorganisms (mean aerodynamic size < 5 microm). These results provide useful pilot data to establish guidelines for respiratory protection against airborne dust and microorganisms on agricultural farms. The method is a promising tool for further epidemiological and intervention studies in agricultural and other similar occupational and nonoccupational environments.