Combination of Doxazosin and Sildenafil Exerts an Additive Relaxing Effect Compared with Each Compound Alone on Human Cavernosal and Prostatic Tissue

IntroductionPhosphodiesterase 5 inhibitors (PDE5) such as sildenafil are first-line treatment for erectile dysfunction (ED). Alpha1 (α1)-adrenoceptor antagonists such as doxazosin are indicated for the treatment of patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). ED and LUTS/BPH are conditions that are often associated. Accordingly, α1-adrenoceptor antagonists and PDE5 inhibitors will be often prescribed in real life setting together.AimTo evaluate the effects of the combination of sildenafil and doxazosin on human cavernosal and prostatic tissue.MethodsProstatic and erectile tissues were obtained from nine to 12 patients, respectively. Patients underwent cystoprostatectomy for infiltrating bladder cancer or penile surgery for penile implant, congenital curvature or Peyronie's disease.Main Outcome MeasuresIn organ baths, prostatic and cavernosal strips were submitted to either concentration-response curves (CRC) to phenylephrine (Phe) or norepinephrine (NE), respectively, in presence of vehicle, sildenafil (10^?6 M, 10^?5 M), doxazosin (10^?8 M, 3.10^?8 M, or 10^?7 M), or a combination of both. Continuous electrical field stimulation (EFS; 32 Hz, 5 ms, 5 seconds, 300 mA) was performed on prostatic strips which were incubated with sildenafil 10^?6 M or vehicle before the successive addition of doxazosin (10^?7 M, 10^?6 M) or vehicle. Cavernosal strips were pre-incubated with doxazosin (10^?9 M, 10^?8 M) or vehicle, then CRC to sildenafil were constructed on NE (3.10^?6 M) precontracted cavernosal strips.ResultsCombination of sildenafil and doxazosin exerted a greater relaxing effect on CRC to Phe or NE compared with each compound alone in both tissues. Sildenafil significantly enhanced the relaxing effect of doxazosin on EFS-induced contractions in prostatic strips. Doxazosin significantly increased the ability of sildenafil to inhibit NE-induced contractions in cavernosal strips.ConclusionsSildenafil and doxazosin reduced adrenergic tone of prostatic and cavernosal smooth muscle and their combination provided a significant benefit when targeting relaxation of both tissues. These experiments provide support for further clinical evaluation of the sildenafil and doxazosin combination in ED patients with LUTS/BPH. Oger S, Behr-Roussel D, Gorny D, Lecoz O, Lebret T, Denoux Y, Faix A, Leriche A, Wayman C, Alexandre L, and Giuliano F. Combination of doxazosin and sildenafil exerts an additive relaxing effect compared with each compound alone on human cavernosal and prostatic tissue. J Sex Med 2009;6:836–847.     

Diagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure.

Chronic obstructive pulmonary disease (COPD) and heart failure (CHF) are common conditions. The prevalence of COPD ranges from 20% to 30% in patients with CHF. The diagnosis of CHF can remain unsuspected in patients with COPD, because shortness of breath is attributed to COPD. Measurement of plasma B-type natriuretic peptide (BNP) levels helps to uncover unsuspected CHF in patients with COPD and clinical deterioration. Noninvasive assessment of cardiac function may be preferable to BNP to uncover unsuspected left ventricular (LV) systolic dysfunction in patients with stable COPD. Patients with COPD or CHF develop skeletal muscle alterations that are strikingly similar. Functional intolerance correlates with severity of skeletal muscle alterations but not with severity of pulmonary or cardiac impairment in COPD and CHF, respectively. Improvement of pulmonary or cardiac function does not translate into relief of functional intolerance in patients with COPD or CHF unless skeletal muscle alterations concomitantly regress. The mechanisms responsible for skeletal muscle alterations are incompletely understood in COPD and in CHF. Disuse and low-level systemic inflammation leading to protein synthesis/degradation imbalance are likely to contribute. The presence of COPD impacts on the treatment of CHF, as COPD is still viewed as a contraindication to beta-blockade. Therefore, COPD often deprives patients with CHF due to LV systolic dysfunction of the most beneficial pharmacologic intervention. A large body of data indicates that patients with COPD tolerate well selective beta-blockade that should not be denied to CHF patients with concomitant COPD.     

Diagnostic criteria in predicting a biliary origin of acute pancreatitis in the era of endoscopic ultrasound: multicentre prospective evaluation of 213 patients.

BACKGROUND: No study on bioclinical criteria predicting a biliary origin for acute pancreatitis has included endosonography as a reference examination. Re-examination of bioclinical parameters deserves consideration in the era where other causes are known (e.g. hereditary, autoimmune). AIM AND METHODS: To determine the performance of bioclinical markers in predicting a biliary origin of acute pancreatitis where the diagnosis of biliary lithiasis was established or ruled out using endosonography. Only patients with a first acute episode of pancreatitis were included. RESULTS: 213 patients (male: 55%; median age: 56 years) were prospectively included in 14 centres. Causes of acute pancreatitis were: biliary (62%), alcoholic (25%), other (13%). Delay between symptom-onset and admission was <48 h in 80%. Endosonography was the sole method establishing the diagnosis of biliary pancreatitis in 15% of patients. At univariate analysis, age, female sex, declared alcohol consumption, elevated aspartate and alanine transaminases on admission, gammaglutamyl transferase, alkaline phosphatase, total bilirubin, lipase, mean corpuscular volume were predictive of a biliary origin. Only age (p < 0.0001), sex (p < 0.0008) and alanine transaminase (p < 0.0004) remained significant at multivariate analysis. At age 50, the respective sensitivity and specificity were 73 and 65%. With an elevated alanine transaminase at 2 times the upper limit of normal range, the respective sensitivity and specificity were 74 and 84%. The probability of a biliary origin of acute pancreatitis could be estimated by the following formula: = 1/1 + exp(4.6967 - 0.0656 x age + 1.1208 x sex - 0.6909 x alanine transaminase). CONCLUSION: When endosonography is performed to confirm or exclude a biliary origin of acute pancreatitis, age, sex and alanine transaminase at admission are the only factors predictive of a biliary cause.     

The MPO Study: just a European HEMO Study or something very different?

Although results from observational and epidemiological studies suggested a survival benefit associated with high-flux hemodialysis, conclusive evidence from prospective randomized clinical trials has been lacking. Both the HEMO Study in the USA and the Membrane Permeability Outcome Study (MPO Study) in Europe are randomized studies investigating the effect of high- and low-flux hemodialysis on patient outcomes, even though there were some significant differences in the design of the two studies. An earlier randomized clinical trial could not show differences on patient survival between patient groups being treated with membranes of different material and permeability, but this trial was not designed specifically to examine this particular endpoint. Based on these previous experiences, the MPO Study addressed a hemodialysis patient population which was considered to be more susceptible to the intervention with high-flux dialysis. To identify these patients with an elevated risk, low serum albumin levels were chosen as an indicator; low serum albumin is associated with malnutrition, inflammation, atherosclerosis, and with increased risk of morbidity and mortality. Together with low serum albumin, patients had to be new to dialysis to be selected for the MPO Study. These particular considerations on patient selection, together with additional methodological refinements in the study design allow the conclusion that the MPO Study is valid on its own rather than being a European version of the HEMO Study.     

New and Recurrent Colorectal Cancers After Resection: a Systematic Review and Meta-analysis of Endoscopic Surveillance Studies

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