vardenafil, Levitra
Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.

Sung BJ, Hwang KY, Jeon YH, Lee JI, Heo YS, Kim JH, Moon J, Yoon JM, Hyun YL, Kim E, Eum SJ, Park SY, Lee JO, Lee TG, Ro S, Cho JM.

Division of Drug Discovery, CrystalGenomics, Inc., Daedeok Biocommunity, Jeonmin-dong, Yuseong-gu, Daejeon, 305-390, South Korea.

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12955149&dopt=Abstract vardenafil Levitra



vardenafil, Levitra
Pro-erectile effect of vardenafil: in vitro experiments in rabbits and in vivo comparison with sildenafil in rats.

Giuliano F, Bernabe J, Alexandre L, Niewoehner U, Haning H, Bischoff E.

Pelvipharm Laboratories, CNRS Bat 5, 1 avenue de la Terrasse, 91140 Gif-sur-Yvette, France. giuliano cyber-sante.org

OBJECTIVES: To assess pro-erectile responses to vardenafil, a new selective PDE5 inhibitor, in vitro in isolated rabbit corpora cavernosa, and in vivo in anaesthetized rats. METHODS: Rabbit cavernosal strips were precontracted with 10 microM phenylephrine. Dose-response relaxation curves to cumulative dosings of vardenafil (1 nM-10 microM) were constructed alone and in the presence of 10 mM L-NAME. Relaxation responses to electrical field stimulation (EFS) (2 Hz, 2 ms, 10 V) were compared in control preparations and in the presence of vardenafil (1-10 nM). Male Sprague-Dawley rats were anaesthetized with urethane and prepared for measurement of blood pressure and intracavernous pressure. Erectile responses (ICPmax/dBP x 100) to cavernous nerve submaximal stimulation (10 Hz, 1 ms, 0.45-1.6 V) were determined before, and 3, 10 and 23 min after i.v. administration of saline, vardenafil or sildenafil (0.1, 1 mg/kg). RESULTS: Vardenafil was effective in relaxing precontracted rabbit cavernosal strips (IC50 54 +/- 18 nM). This relaxing activity was partially antagonized with 10 mM L-NAME, increasing the IC50 to 620 +/- 81 nM. Vardenafil significantly increased (more than 4 times) relaxation of precontracted rabbit cavernosal strips to EFS at 10 nM. In anaesthetized rats, erectile responses were significantly facilitated 3 and 13 min after 0.1 and 1 mg/kg vardenafil was administered. In contrast, 1 mg/kg sildenafil only significantly increased erectile responses at 3 min post-injection. CONCLUSIONS: Vardenafil relaxes rabbit corpus cavernosum in vitro and is effective at a lower dose than sildenafil in facilitating erectile responses to cavernous nerve stimulation in anaesthetized rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14644128&dopt=Abstract vardenafil Levitra



vardenafil, Levitra
Drug Interactions Among the Antiretrovirals.

McNicholl IR.

University of California at San Francisco Positive Health Program, Building 80, Ward 86, San Francisco General Hospital, 995 Potrero Avenue, San Francisco, CA 94110, USA. imcnicholl php.ucsf.edu

There are 20 antiretroviral agents approved by the US Food and Drug Administration (FDA), four of which were approved in 2003. With 20 antiretrovirals FDA-approved, interactions occur when the medications alter the toxicity profile or efficacy of the other medication. In order to maintain clinical relevance, only the most significant interactions published within the past 12 months are highlighted in this article. Interactions discussed involve atazanavir, fosamprenavir, lopinavir/ritonavir, tenofovir, proton pump inhibitors, H(2)-blockers, clarithromycin, and vardenafil. Important interaction-management strategies also are discussed. The field of HIV pharmacology is constantly advancing, as are the drug interaction data. To screen, manage, dose adjust, and counsel, the physician and other health care professionals are highly advised and encouraged to consult with an infectious disease clinical pharmacist when managing patients receiving highly active antiretroviral therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15023279&dopt=Abstract vardenafil Levitra



vardenafil, Levitra
Sexual pharmacology in the 21st century.

Rosen RC.

Department of Psychiatry, Center for Sexual and Marital Health, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.

Sexual dysfunction is highly prevalent in both sexes. Considerable progress has been made in the development of new pharmacologic treatments since the approval of sildenafil in 1998. A variety of oral erectogenic agents are available or are in late-phase development, including centrally active dopamine agonists (e.g., sublingual apomorphine), peripheral nonselective alpha-blockers (e.g., oral phentolamine), and other phosphodiesterase type-5 inhibitors (e.g., vardenafil). These drugs have recently been evaluated for the treatment of female sexual arousal disorder, although results to date have been inconclusive. Pharmacologic therapies have also been proposed for the treatment of premature ejaculation and hypoactive sexual desire disorder. Strong evidence exists for the value of serotonergic drugs (e.g., selective serotonin reuptake inhibitors) in the treatment of premature ejaculation. Further research is needed, particularly on the effects of these drugs on female sexual dysfunction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11253255&dopt=Abstract vardenafil Levitra



vardenafil, Levitra
Inhibition of cyclic GMP hydrolysis in human corpus cavernosum smooth muscle cells by vardenafil, a novel, selective phosphodiesterase type 5 inhibitor.

Kim NN, Huang YH, Goldstein I, Bischoff E, Traish AM.

Department of Urology, Boston University School of Medicine, Massachusetts 02118, USA. nnkim bu.edu

One of the key mediators of penile erectile function is nitric oxide (NO), which activates soluble guanylyl cyclase within the smooth muscle of erectile tissue and stimulates the production of cGMP. In addition to synthesis by cyclases, intracellular cGMP concentrations are tightly regulated by phosphodiesterases, which hydrolyze and inactivate cyclic nucleotides. In this study, we compared the inhibition of cGMP hydrolysis by vardenafil and sildenafil; two inhibitors selective for phosphodiesterase type 5 (PDE5). Vardenafil is a novel, high affinity PDE5 inhibitor currently under clinical development. In soluble extracts of human corpus cavernosum smooth muscle cells, vardenafil and sildenafil effectively inhibited cGMP hydrolysis at substrate concentrations of 1, 5 and 10 microM cGMP. The IC50 values for vardenafil were approximately 5-fold lower than for sildenafil at the substrate concentrations tested. Dixon plot analyses of the inhibition data demonstrated that vardenafil had a smaller inhibition constant (Ki = 4.5 nM) than sildenafil (Ki = 14.7 nM) in the same cellular extracts. In intact cells, 10 microM of the nitric oxide donor sodium nitroprusside resulted in a minimal (17%) increase in cGMP, relative to basal levels (321 +/- 65 fmol/mg prot). Treatment of cells with 10, 50 or 100 nM vardenafil, in the presence of 10 microM sodium nitroprusside, elevated cGMP levels in a dose dependent fashion, from 63% to 137% of basal levels. Equimolar concentrations of sildenafil also caused dose dependent increases in intracellular cGMP, but to a lesser extent (27-60%). These observations suggest that vardenafil is a more potent PDE5 inhibitor, than sildenafil in vitro. The more pronounced increase of cGMP in the presence of NO in intact cells suggests that vardenafil will be effective at lower doses than sildenafil under clinical conditions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11669467&dopt=Abstract vardenafil Levitra