Chronic sildenafil improves erectile function and endothelium-dependent cavernosal relaxations in rats: lack of tachyphylaxis

OBJECTIVES: Sildenafil is a widely-prescribed effective on-demand treatment of erectile dysfunction (ED). Chronic treatment with sildenafil could help patients with ED. METHODS: The effects of an 8-week long treatment with sildenafil (60 mg/kg/d sc) in male Sprague Dawley rats were evaluated on electrically-elicited erectile responses in vivo before and after an acute injection of sildenafil (0.3mg/kg iv). In addition, endothelium-dependent and -independent relaxations of strips of corpus cavernosum in vitro were examined. All experiments were performed 36 hours after the last injection of sildenafil. RESULTS: Endothelium-dependent relaxations of cavernosal strips to acetylcholine were enhanced after chronic treatment with sildenafil while relaxations to A23187 or sodium nitroprusside were unchanged. Frequency-dependent erectile responses elicited by cavernous nerve stimulation were significantly improved. Moreover, the erectile responses to acute sildenafil were greater in chronically-treated rats with sildenafil. CONCLUSIONS: This is the first report providing experimental support for chronic dosing with sildenafil which could be of use for patients that are poor responders to on-demand treatment. Chronic sildenafil may regulate the transduction pathway leading to the activation of eNOS but has no effect on NO bioavailability or on the cGMP pathway, thereby eliminating a possible concern for tachyphylaxis.     

The weight-reduction index: Suitable for cross-study comparisons?

The past 10 yr have witnessed a remarkable proliferation of behavioral strategies for weight reduction. Treatment studies have reported on the effectiveness of these strategies, however, using a variety of outcome measures, thereby making cross-study comparisons difficult at best. The Weight-Reduction Index (RI), an algebraic combination of weight lost, initial weight, surplus weight, and target weight, has been proposed as a more widely applicable dependent measure and has been used in several studies. The RI, however, appears to be inordinately influenced by initial degree of obesity and duration of treatment. This and other drawbacks regarding its feasibility as a cross-study index are discussed, along with suggestions for more suitable indices.     

Health economic evaluation in idiopathic pulmonary fibrosis in France

Background: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause. To date, there is no specific cure for IPF, and only two treatments (pirfenidone and nintedanib) have marketing authorizations and recommendations in international and French guidelines.

Objectives: A cost-utility analysis (CUA) has been conducted to evaluate the efficiency of nintedanib, in comparison to all available alternatives, in a French setting using the official methodological guidelines.

Methods: A previously developed lifetime Markov model was adapted to the French setting by simulating the progression of IPF patients in terms of lung function decline, incidence of acute exacerbations, and death. Considering the effect of IPF on patients’ quality-of-life, a CUA integrating quality adjusted life years (QALY) was chosen as the primary outcome measure in the main analysis. One-way, probabilistic, and scenario sensitivity analyses were performed to evaluate the robustness of the model.

Results: Treatment with nintedanib resulted in an estimated total cost of €76,414 (vs €82,665 for pirfenidone). In comparison with all other available options, nintedanib was predicted to provide the most QALY gained (3.34 vs 3.29). This analysis suggests that nintedanib has a 59.0% chance of being more effective than pirfenidone and s 77.3% chance of being cheaper than pirfenidone. Sensitivity analyses showed the results of the CUA to be robust.

Conclusions: In conclusion, this CUA has found that nintedanib appears to be a more cost-effective therapeutic option than pirfenidone in a French setting, due to fewer acute exacerbations and a better tolerability profile.