Klotz, T. et al. Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J. Urol. 19, 32-39
University of Cologne, Köln, North Rhine-Westphalia, Germany World Journal of Urology
(Impact Factor: 2.67).
02/2001; 19(1):32-9. DOI: 10.1007/s003450000168
The pharmacodynamic effect on penile rigidity and tumescence and the pharmacokinetic properties of single oral doses of 10 and 20 mg vardenafil, a new PDE5-inhibitor, were investigated in 21 erectile dysfunction patients. Patients were evaluated with RigiScan on three occasions in a randomized, placebo-controlled, double-blind crossover fashion, while receiving visual sexual stimulation. Relative to placebo, a single dose of 10 mg vardenafil led to a mean increase in the duration of >60% penile rigidity of 24.4 min (95% CI: 7.4 to 41.3) at the base and of 24.8 min (8.5 to 41.1) at the tip. For the 20-mg dose, the increase in duration of > 60% penile rigidity relative to placebo was 37.2 min (20.2 to 54.1) at the base and 28.7 min (12.7 to 44.7) at the tip. Single doses of 10 and 20 mg vardenafil led to a rapid rise in the plasma concentrations of vardenafil, with a median tmax of 0.9 h and 0.7 h and a geometric mean Cmax of 9.1 microg/l (geometric SD = 1.63) and 20.9 microg/l (geometric SD = 1.83), respectively. In the post-absorptive phase, the concentrations declined with an average terminal t 1/2 of 4.2 h (geometric SD = 1.27) and 3.9 h (geometric SD = 1.31). The systemic exposure of vardenafil expressed as AUC normalized for dose and body weight was dose-proportional (associated 90% CI: -4 to 30%) as well as Cmax (associated 90% CI: -12 to 33%). The treatments were well tolerated. There was a small, clinically irrelevant reduction in blood pressure with a small compensatory rise in heart rate. There were no electrocardiographic effects or relevant changes of the safety laboratory screens. The observed pro-erectile properties, pharmacokinetic characteristics and safety profile make vardenafil a suitable candidate for further evaluation in the treatment of erectile dysfunction.
Available from: PubMed Central
- "The Tmax and t1/2 values for mirodenafil are 1.25 and 2.5 hours, respectively . As summarized in Table 1 [14,15,16,17,18,19], the Tmax value is similar to that of sildenafil, and the t1/2 value is shorter than that of any other drug listed in Table 1. However, no head-to-head comparative study has been conducted. "
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ABSTRACT: Phosphodiesterase type 5 (PDE5) inhibitors are the most commonly used treatment for erectile dysfunction (ED). Since the launch of sildenafil, several drugs-including mirodenafil, sildenafil citrate (sildenafil), tadalafil, vardenafil HCL (vardenafil), udenafil, and avanafil-have become available. Mirodenafil is a newly developed pyrrolopyrimidinone compound, which is a potent, reversible, and selective oral PDE5 inhibitor. Mirodenafil was launched in Korea in 2007, and an orally disintegrating film of mirodenafil was developed in 2011 for benefitting patients having difficulty in swallowing tablets. This study aimed to review the pharmacokinetic characteristic profile of mirodenafil and report evidence on its efficacy in the case of ED. In addition, we reviewed randomized controlled studies of mirodenafil's daily administration and efficacy for lower urinary tract symptoms.
Available from: Barbara Dhooghe
- "Heart, lung, liver, kidney, oocytes, adipocytes, T lymphocytes, platelets, inflammatory cells Cilostamide, Cilostazol, Enoxamone, Milrinone, Siguazodan b,d Palmer and Maurice (2000), Vandecasteele et al. (2001), Shin et al. (2007), Nohria et al. (2003), Carev et al. (2010) 4 cAMP 1.5–10 – Kidney, brain, liver, lung, smooth muscle, cardiovascular tissues, Sertoli cells inflammatory cells Rolipram, Roflumilast, Cilomilast, Drotaverine, ibudilast b,d,e Tenor et al. (1995a,b,c), Essayan (2001), Scott et al. (1991), O'Byrne and Gauvreau (2009) 5 cGMP 290 2.9–6.2 Lung, platelets, vascular, smooth muscle Sildenafil, Vardenafil, Tadalafil, Zaprinast b,d,e Hamet and Coquil (1978), Coquil et al. (1980), Francis et al. (1980), Francis and Corbin (1988), Moncada and Martin (1993), Sebkhi et al. (2003), Ghofrani et al. (2006), Milligan et al. (2002), Nichols et al. (2002), Muirhead et al. (2002), Burgess et al. (2008), Klotz et al. (2001), Gresser and Gleiter (2002), Stark et al. (2001), Ormrod et al. (2002), Eardley and Cartledge (2002), Bella and Brock (2003), Staab et al. (2004), Brock (2003), Porst et al. (2003), Curran and Keating (2003), Corbin et al. (2005), Wharton et al. (2005), Prickaerts et al. (2002), Baratti and Boccia (1999) 6 cGMP 610–700 15–17 Photoreceptor Dipyridamole Zhang et al. (2005), Estrade et al. (1998) 7 cAMP 0.03–0.2 – Skeletal muscle, heart, kidney, brain, pancreas, T lymphocytes, eosinophils, neutrophils BRL-50481, BC30 b Gardner et al. (2000), Sasaki et al. (2000), Hetman et al. (2000a), Smith et al. (2003), Pitts et al. (2004), Vergne et al. (2004), Zhang et al. (2008) 8 cAMP 0.06 – Testis, eye, liver, skeletal muscle, heart, kidney, ovary, brain, T lymphocytes PF-04957325 f Perez-Torres et al. (2003), Wang et al. (2001), Hayashi et al. (2007), Kobayashi et al. (2003), Glavas et al. (2001), Dong et al. (2006), Vasta et al. (2006), Vang et al. (2010), Tsai et al. (2011), Dov et al. (2008) 9 cGMP 230 0.2–0.7 Kidney, liver, lung, brain, spleen, small intestine BAY 73-6691 Soderling et al. (1998a,b), van der Staay et al. (2008) 10 cAMP < cGMP 0.2–1.0 "
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ABSTRACT: Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil, or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.
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- "Vardenafil and sildenafil are potent and selective inhibitors of cyclic GMP-specific phosphodiesterase type 5 (PDE5) in the smooth muscle cells lining blood vessels, particularly in the corpus cavernosum of the penis. These properties make these drugs effective in the treatment of erectile dysfunction (Klotz et al. 2001; Rajagopalan et al. 2003). "
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ABSTRACT: In the present study, we examined the roles of specific multidrug resistance proteins (MRPs) in the efflux transport of the phosphodiesterase type 5 inhibitors, vardenafil and sildenafil. Using MDCKII cells overexpressing MRP1, MRP2, and MRP3 (MDCKII-MRP1, -MRP2, and MRP3, respectively) as model systems, we measured the basal to apical and apical to basal transport of vardenafil and sildenafil at concentrations ranging from 1 to 100 μM. Vardenafil had a much greater basal to apical than apical to basal transport rate in MDCKII-MRP1, -MRP2, and MRP3 cells, suggesting that vardenafil is a substrate for MRP1, MRP2, and MRP3. In contrast, the basal to apical and apical to basal transport rate were similar to each other in each of the MRPs-overexpressing MDCKII cells, indicating that sildenafil was not pumped out via MRP1, MRP2, and MRP3. Vardenafil efflux from MDCKII-MRP1, MRP2, and MRP3 cells was concentration dependent and occurred with K
m values of 48.2 ± 15.5, 12.8 ± 4.18, and 14.1 ± 7.4 μM, respectively. In conclusion, MRP1, MRP2, and MRP3 may influence the absorption, disposition, and cellular accumulation of vardenafil, but not sildenafil.
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