Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/197875
Type: Artigo de periódico
Title: Pharmacological Characterization Of A Novel Phosphodiesterase Type 5 (pde5) Inhibitor Lodenafil Carbonate On Human And Rabbit Corpus Cavernosum.
Author: Toque, Haroldo A
Teixeira, Cleber E
Lorenzetti, Raquel
Okuyama, Cristina E
Antunes, Edson
De Nucci, Gilberto
Abstract: Nitrergic 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 microM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 microM) 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 PDE 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.
Subject: Administration, Oral
Adult
Animals
Carbonates
Chromatography, Liquid
Cyclic Gmp
Dogs
Dose-response Relationship, Drug
Drug Stability
Electric Stimulation
Erectile Dysfunction
Humans
Injections, Intravenous
Male
Penis
Phosphodiesterase Inhibitors
Piperazines
Prodrugs
Purines
Pyrimidines
Rabbits
Rats
Sulfones
Tandem Mass Spectrometry
Citation: European Journal Of Pharmacology. v. 591, n. 1-3, p. 189-95, 2008-Sep.
Rights: fechado
Identifier DOI: 10.1016/j.ejphar.2008.06.055
Address: http://www.ncbi.nlm.nih.gov/pubmed/18593576
Date Issue: 2008
Appears in Collections:Unicamp - Artigos e Outros Documentos

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