Repercussão cardiovascular, com e sem álcool, do carbonato de lodenafila, um novo inibidor da PDE5 / Repercusión cardiovascular, con y sin alcohol, del carbonato de lodenafila, un nuevo inhibidor de la PDE5 / Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption

FUNDAMENTO: A disfunção erétil afeta um grande número de homens no mundo e os inibidores de PDE 5 (iPDE5) estão entre os principais métodos de tratamento desses pacientes. O consumo social de álcool e o ato sexual apresentam uma relação considerável. Portanto, a associação entre álcool e iPDE5 pode ocorrer. O carbonato de lodenafila é um novo iPDE5 desenvolvido por uma empresa brasileira. OBJETIVO: Avaliar a repercussão cardiovascular do carbonato de lodenafila, associado ou não ao álcool, assim como as alterações na farmacocinética que esta associação possa determinar. MÉTODOS: Estudo realizado com 15 voluntários sadios que receberam em momentos diferentes o carbonato de lodenafila (CL) na dose de 160 mg em jejum, CL (160 mg) com álcool, ou somente placebo. Esses pacientes foram monitorados por 24 horas, sendo avaliado o quadro clínico, a pressão arterial (PA), a frequência cardíaca (FC), o intervalo QT e também os dados de farmacocinética. RESULTADOS: O carbonato de lodenafila, isoladamente ou associado com álcool, não determinou alterações clínicas significativas na PA ou FC, embora tenha ocorrido diminuição da PA estatisticamente significativa após 4 horas, nos voluntários que receberam medicamento e álcool, assim como um aumento da FC após 6 horas nos pacientes que receberam o CL. A análise do intervalo QT corrigido não mostrou alteração significativa. O álcool aumentou a biodisponibilidade do medicamento em 74 por cento. Houve somente 2 queixas de cefaleia leve, possivelmente associada ao medicamento. CONCLUSÃO: O carbonato de lodenafila, mesmo associado ao álcool, não determinou repercussões clínicas importantes na PA, FC, ou alterações no intervalo QTc; a ingestão com álcool, por sua vez, aumentou significativamente sua biodisponibilidade.

BACKGROUND: Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. OBJECTIVE: This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. METHODS: Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. RESULTS: Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74 percent when drug intake was associated with alcohol. CONCLUSION: These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

FUNDAMENTO: La disfunción eréctil afecta a un gran número de hombres en el mundo y los inhibidores de PDE5 (iPDE5) están entre los principales métodos de tratamiento de estos pacientes. El consumo social de alcohol y el acto sexual presentan una relación considerable. Por lo tanto, puede ocurrir una asociación entre alcohol e iPDE5. El carbonato de lodenafila es un nuevo iPDE5 desarrollado por una empresa brasileña. OBJETIVO: Evaluar la repercusión cardiovascular del carbonato de lodenafila, asociado o no al alcohol, así como las alteraciones en la farmacocinética que esta asociación pueda determinar. MÉTODOS: Estudio realizado con 15 voluntarios sanos que recibieron en momentos diferentes el carbonato de lodenafila (CL) en la dosis de 160mg en ayunas, CL (160 mg) con alcohol, o solamente placebo. Estos pacientes fueron monitoreados por 24 horas, siendo evaluado el cuadro clínico, la presión arterial (PA), la frecuencia cardíaca (FC), el intervalo QT y también los datos de farmacocinética. RESULTADOS: El carbonato de lodenafila, aisladamente o asociado con alcohol, no determinó alteraciones clínicas significativas en la PA o FC, aunque se haya registrado una disminución de la PA estadísticamente significativa después de 4 horas en los voluntarios que recibieron medicamento y alcohol, así como un aumento de la FC después de 6 horas en los pacientes que recibieron el CL. El análisis del intervalo QT corregido no mostró alteración significativa. El alcohol aumentó la biodisponibilidad del medicamento en un 74 por ciento. Se registraron sólo 2 quejas de cefalea leve, posiblemente asociada al medicamento. CONCLUSIÓN: El carbonato de lodenafila, aun asociado al alcohol, no determinó repercusiones clínicas importantes en la PA, FC, o alteraciones en el intervalo QTc; la ingestión con alcohol, a su vez, aumentó significativamente su biodisponibilidad.

effect of ciprofloxacin and clarithromycin on sildenafil oral bioavailability in human volunteers

Sildenafil is the first oral therapeutic agent for the management of male erectile dysfunction. Its oral bioavailability is only 40% due to extensive presystemic elimination, mainly by CYP3A4. This study examined the effect of coadministration of ciprofloxacin or clarithromycin which inhibit CYP3A4 on the bioavailability and pharmacokinetics of sildenafil. Twelve healthy male volunteers received sildenafil alone or after pretreatment with the inhibitors in a balanced three-way crossover design. The pharmacokinetic analysis showed that ciprofloxacin coadministration with sildenafil significantly increased the AUC from 1336 +/- 407 to 2751 +/- 968 micro g hr/L and the C max from 236 +/- 71 to 478 +/- 210 micro g/L. The CL tot/F was decreased from 40.1 +/- 9.9 to 20.9 +/- 8.6 L/hr and the Vd/F from 134.9 +/- 9.9 to 89.1 +/- 31.8 L, without affecting sildenafil elimination and absorption rate constants. Similarly, clarithromycin coadministration increased sildenafil AUC from 1336 +/- 407 to 2920 +/- 666 microg hr/L and C max from 236 +/- 71 to 520 +/- 176 microg/L. The CL tot/F significantly decreased from 40.1 +/- 9.9 to 18.1 +/- 5.0 L/hr and the Vd/F from 134.9 +/- 9.9 to 71.6 +/- 27.4 L, without affecting sildenafil elimination and absorption rate constants. These results indicate that coadministration of ciprofloxacin and clarithromycin significantly increased sildenafil bioavailability which can be inhibitory effect of ciprofloxacin and clarithromycin on CYP3A4. Dose adjustment of sidenafil is thus necessary when administered with such drugs

Intestinal absorption and presystemic disposition of sildenafil citrate in the rabbit: evidence for site-dependent absorptive clearance

Sildenafil citrate is the first oral treatment of erectile dysfunction. Its oral bioavailability is about 40%. This research characterized the intestinal transport parameters of sildenafil citrate in rabbit using in situ intestinal perfusion technique. This was studied in flint different anatomical sites, namely duodenum, jejunoileum, ascending-colon and rectum. The results revealed the highest absorptive clearance in the jejunoileum. The value of permeability area product normalized to segment length [ml/min cm] were 0.0101, 0.0063, 0.0059 and 0.0023 and those of percentage absorbed were 67.95, 32.27, 23 and 5.03 in jejunoileum, duodenum, ascending colon, and rectum respectively. The values of the length [cm] required for complete absorption were 87.58, l37.23, 153.27, and 384.09 for each segment in the some order. The absorptive clearance did not correlate with the net water flux in the four anatomical, regions studied, indicating mainly passive diffusion mechanism through transcellular pathway. The plasma sildenafil concentrations achieved dosing intestinal perfusion experiments and sildenafil total body clearance in rabbit were used to calculate the fraction of sildenafil that reached the systemic circulation relative to the amount disappeared from the intestinal segment. Only.34% of sildenafil disappeared from the intestinal segment appeared in the systemic circulation indicating that the presystemic elimination of slidenafil is 66%. These results confirm that the incomplete bioavailability of sildenafil is mainly due presystemic elimination

Involvement of alpha receptors and potassium channels in the mechanisn of action of sildenafil

Modulation of the adrenergic activity and interferring with channels such as potassium channels may affect relaxation and contraction of the corpus cavernosum. Sildenafil is a selective inhibitor of phosphodiesterase 5, proven effective in the treatment of erectile dysfunction. The objective of this study was to test the effect of sildenafil on alpha-receptors modulation and potassium channels. In the present study, it was found that the muscle relaxant effect of sildenafil [1 x 10 [-9] to 1 x 10 [-6] M] on phenylephrineprecontracted rabbit corpus cavernosum strips was not attenuated by NG-nitro-L-arginine [3 x 10 [-5] M]. Cumulative addition of sildenafil [1 x 10 [-9] - 1 x 10 [-6] M] and phentolamine [1 x 10 [-9] to 1 x 10 [-6] M] to the organ bath dose-dependently inhibited electrical field stimulation-induced contraction of rabbit corpus cavernosum and rat anococcygeus muscle with close ED50 values. Sildenafil [1 x 10 [-7] M] also inhibited phenylephrine-induced contraction of rat aortic rings by 39.83 +/- 3.01%. In addition. tetraethylammonium [1 x 10 [-3] M] significantly attenuated the muscle relaxant effect of sildenafil [1 x 10 [-9] - 1 x 10 [-6] M] on phenylephrine-precontracted strips of rabbit corpus cavernosum. sildenafil is capable of producing cavernosal smooth muscle relaxation by an additional mechanism involving alpha-receptors and potassium channel opening

Physiological basis and indications of treatment of erectile dysfunction with the phosphodiesterase inhibitor sildenafil citrate

The advent of the first effective oral agent in the management of erectile dysfunction, sildenafil, has had a revolutionary impact in the medical societal and economic aspects of this field. This review will examine the clinical research and field experience with respect to efficacy and safety as well as touch on the broader societal and economic issues related to sildenafil. The following topics are extensively presented and discussed in this article: molecular pharmacology, pharmacokinetics and pharmacokinetics in special populations (geriatrics, renal insufficiency, hepatic insufficiency). The indications, contraindications and precautions. Dosage and administration, efficacy in general and in diabetic patients, spinal cord injured patients, radical prostatectomy, and according to age and severity of erectile dysfunction. The safety and the side effects are also discussed

Pharmacology of sildenafil citrate.

Erectile dysfunction is a common and multi-factorial disease that strongly impairs the quality of life in men. During the past decade, many new therapeutic strategies have become available. But the need for oral treatment was strongly felt. This need appears to have been fulfilled with the introduction of sildenafil. The drug acts by enhancing smooth muscle relaxant effect of nitric oxide. A number of clinical studies have now proved its safety and efficacy. The drug has shaken social life all over the world and to accept this "magic pill" or not remains the question of individual choice.