Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum

dc.creatorToque, HA
dc.creatorTeixeira, CE
dc.creatorLorenzetti, R
dc.creatorOkuyama, CE
dc.creatorAntunes, E
dc.creatorDe Nucci, G
dc.date2008
dc.dateSEP 4
dc.date2014-11-16T10:14:55Z
dc.date2015-11-26T16:21:52Z
dc.date2014-11-16T10:14:55Z
dc.date2015-11-26T16:21:52Z
dc.date.accessioned2018-03-28T23:03:41Z
dc.date.available2018-03-28T23:03:41Z
dc.identifierEuropean Journal Of Pharmacology. Elsevier Science Bv, v. 591, n. 41699, n. 189, n. 195, 2008.
dc.identifier0014-2999
dc.identifierWOS:000259162300030
dc.identifier10.1016/j.ejphar.2008.06.055
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/59406
dc.identifierhttp://www.repositorio.unicamp.br/handle/REPOSIP/59406
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/59406
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1268012
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionNitrergic nerves and endothelial cells release nitric oxide (NO) in the corpus cavernosum, a key mediator that stimulates soluble guanylyl cyclase to increase cGMP levels causing penile erection. Phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, prolong the NO effects by inhibiting cGMP breakdown. Here, we report a novel PDE5 inhibitor, lodenafil carbonate, (Bis-(2-(4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl)-ethyl)carbonate) that is a dimer of lodenafil. We therefore aimed to compare the effects of sildenafil, lodenafil and lodenafil carbonate on in vitro human and rabbit cavernosal relaxations, activity of crude PDE extracts from human platelets, as well as stability and metabolic studies in rat, dog and human plasma. Pharmacokinetic evaluations after intravenous and oral administration were performed in male beagles. Functional experiments were conducted using organ bath techniques. Pharmacokinetics was studied in beagles by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), following oral or intravascular administration. All PDE5 inhibitors tested concentration-dependently relaxed (0.001-100 mu M) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 mu M) or electrical field stimulation (EFS, 1-20 Hz) were markedly potentiated by sildenafil, lodenafil and lodenafil carbonate. Lodenafil carbonate was more potent to inhibit the cGMP hydrolysis in POE extracts compared with lodenafil and sildenafil. Following intravascular and single oral administration of lodenafil carbonate, only lodenafil and norlodenafil were detected in vivo. These results indicate that lodenafil carbonate works as a prodrug, being lodenafil the active moiety of lodenafil carbonate. (C) 2008 Elsevier B.V. All rights reserved.
dc.description591
dc.description41699
dc.description189
dc.description195
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.languageen
dc.publisherElsevier Science Bv
dc.publisherAmsterdam
dc.publisherHolanda
dc.relationEuropean Journal Of Pharmacology
dc.relationEur. J. Pharmacol.
dc.rightsfechado
dc.rightshttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.sourceWeb of Science
dc.subjecterectile dysfunction
dc.subjectsildenafil
dc.subjectnitric oxide
dc.subjectcyclic GMP
dc.subjectpro-drug
dc.subjectdimerization
dc.subjectCyclic-nucleotide Phosphodiesterase
dc.subjectTissue In-vitro
dc.subjectErectile-dysfunction
dc.subjectSmooth-muscle
dc.subjectSildenafil Citrate
dc.subjectPenile Erection
dc.subjectGmp
dc.subjectRelaxation
dc.subjectRat
dc.subjectAmp
dc.titlePharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum
dc.typeArtículos de revistas


Este ítem pertenece a la siguiente institución