Vardenafil: a review of its use in erectile dysfunction.

Vardenafil (Levitra) is a potent and highly selective oral phosphodiesterase type 5 (PDE5) inhibitor. Vardenafil ( Levitra ) improved erectile function in men with mild to severe erectile dysfunction (ED) of varying aetiology in two randomised, double-blind, multicentre, fixed-dose studies of 12 or 26 weeks' duration. Men receiving Vardenafil ( Levitra ) 10 or 20 mg had significantly greater improvements in International Index of Erectile Function (IIEF) questionnaire erectile function domain scores than placebo recipients. Moreover, improvements in penetration and maintenance of erection (assessed using IIEF or Sexual Encounter Profile [SEP] questions) were significantly greater with Vardenafil ( Levitra ) 5-20 mg than with placebo. Improvements in IIEF intercourse satisfaction and orgasmic function domain scores were significantly greater with Vardenafil ( Levitra ) 10 or 20 mg than with placebo and the proportion of patients with a positive response to a Global Assessment Question (GAQ) concerning improvement in erections after 12 or 26 weeks' therapy was significantly higher with Vardenafil ( Levitra ) 5-20 mg than with placebo. Vardenafil ( Levitra ) improved erectile function in men with ED associated with diabetes mellitus or ED following unilateral or bilateral nerve-sparing radical retropubic prostatectomy in two randomised, double-blind, multicentre, fixed-dose, 3-month studies. In both studies, improvements from baseline in the erectile function domain score of the IIEF and in positive responses to SEP questions were significantly greater with Vardenafil ( Levitra ) 10 or 20 mg than with placebo. In addition, a significantly higher proportion of Vardenafil ( Levitra ) 10 or 20 mg recipients than placebo recipients had positive GAQ responses. Vardenafil ( Levitra ) was generally well tolerated in men with ED; treatment-emergent adverse events were of mild to moderate intensity and transient in nature. The most commonly reported adverse events (typical of those seen with PDE5 inhibitors) in Vardenafil ( Levitra ) 5-20 mg recipients included headache, flushing, rhinitis, dyspepsia and sinusitis. There were no reports of abnormal colour vision in men with ED taking Vardenafil ( Levitra ) at clinically recommended doses (5-20 mg). CONCLUSION: Vardenafil ( Levitra ) is a potent and highly selective oral PDE5 inhibitor. It is effective and generally well tolerated in men with mild to severe ED of varying aetiology, as well as in men with ED associated with diabetes mellitus or ED after radical prostatectomy. Vardenafil ( Levitra ) should be considered a first-line treatment option in men with ED who are suitable candidates for oral PDE5 inhibitor therapy.

Vardenafil preclinical trial data: potency, pharmacodynamics, pharmacokinetics, and adverse events.

Vardenafil potently inhibits human phosphodiesterase 5 (PDE5) with an IC50 of 0.7 nM. Enhancement of nitric oxide (NO)-induced erections in rabbits by 0.1 mg/kg Vardenafil ( Levitra ) is limited by its pharmacokinetic properties (Tmax=1 h; T1/2=1.2 h), although erectile effects have been observed after 7 h. In humans, Vardenafil ( Levitra ) is rapidly absorbed (Tmax approximately 40 min) and more slowly metabolized (T1/2 approximately 4 h), with an absolute bioavailability of 14.5% (vs 40% for sildenafil). Although the consumption of high-fat meals does not affect the drug's relative bioavailability, it retards intestinal absorption. Coadministration of CYP3A4 inhibitors such as ritonavir can affect hepatic metabolism. M1, an active metabolite of Vardenafil ( Levitra ), is a four-fold-less potent inhibitor of PDE5 than its parent compound, contributing approximately 7% to Vardenafil ( Levitra )'s overall efficacy. The side effects of all selective PDE5 inhibitors commonly include vasodilation, small reductions in blood pressure, headache, and nasal congestion.

Gateways to clinical trials. March 2003.

Gateways to clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and devlopment protal, http://integrity.prous.com. This issue focuses on the following selection of drugs: AAV-CF, adalimumab, ademetionine, afeletecan hydrochloride, agomelatine, alemtuzumab, almotriptan, amdoxovir, aplidine, aranose, arsenic sulfide, atazanavir, atlizumab; Bimatoprost, BMS-181176, BMS-188667, bortezomib, bryostatin 1; Combretastatin A-4 phosphate; Darbepoetin alfa, darusentan, deferasirox, desloratadine, DTaP-HBV-IPV/Hib-vaccine, DTI-0009; Eculizumab, edodekin alfa, emtricitabine, enfuvirtide, epoetin, esomeprazole magnesium etoricoxib; Fampridine, fenretinide, FR-146687; Galiximab, gamma-Hydroxybutyrate sodium, ganirelix acetate, gefitinib, Gemtuzumab ozogamicin, gimatecan; HEA125xOKT3, hIL-13-PE38QQR, HSV-2 theracine, Hu14.18-IL-2, human gammaglobulin; Idraparinux sodium, imatinib mesylate, IMiD3, insulin detemir, interleukin-4, irofulven, ISAtx-247; JT-1001; Levetiracetam, levosimendan, liposomal doxorubicin, liposomal vincristine sulfate, lixivaptan, lopinavir, lumiracoxib; Maxacalcitol, melatonin, midostaurin, MLN-518; Neridronic acid, nesiritide, nitronaproxen; Oblimersen sodium, oregovomab; PEG-filgrastim polyglutamate paclitaxel, prasterone, pregabalin; Rosuvastatin calcium, rotigotine hydrochloride; SGN-30; T-1249, tenofovir disoproxil fumarate, teriparatide, tiotropium bromide, tipranavir, TMC-114, trabectedin, transdermal selegiline; UK-427857; Valdecoxib, valganciclovir hydrochloride, Vardenafil ( Levitra ), vatalanib succinate, vincristine sulfate TCS; Zofenopril calcium.

Radiolabeled Ligand Binding to the Catalytic or Allosteric Sites of PDE5 and PDE11.

Cyclic nucleotide phosphodiesterases (PDEs) have been investigated for years as targets for therapeutic intervention in a number of pathophysiological processes. Phosphodiesterase-5 (PDE5), which is highly specific for guanosine 3'-5'-cyclic-monophosphate (cGMP) at both its catalytic site and its allosteric sites, has generated particular interest because it is potently and specifically inhibited by three drugs: Sildenafil Citrate ( Viagra ) (Viagratrade mark, Pfizer), Tadalafil ( Cialis ) (Cialistrade mark, Lilly-ICOS), and Vardenafil ( Levitra ) (Levitratrade mark, Bayer GSK). Previously, we have used [3H]cGMP to directly study the interaction of cGMP with the allosteric sites of PDE5, but because cGMP binds with relatively low affinity to the catalytic site, it has been difficult to devise a binding assay for this particular binding reaction. This approach using measurement of radiolabeled ligand binding continues to allow us to more precisely define functional features of the enzyme. We now use a similar approach to study the characteristics of high-affinity [3H]inhibitor binding to the PDE5 catalytic domain. For these studies, we have prepared [3H]sildenafil and [3H]tadalafil, two structurally different competitive inhibitors of PDE5. The results demonstrate that radiolabeled ligands can be used as probes for both catalytic site and allosteric site functions of PDE5. We describe herein the methods that we have established for studying the binding of radiolabeled ligands to both types of sites on PDE5. These techniques have also been successfully applied to the study of binding of radiolabeled PDE5 inhibitors to PDE11, suggesting that these methods are applicable to the study of other PDEs, and perhaps other enzyme families.