Vasodilatory activity and antihypertensive profile mediated by inhibition of phosphodiesterase type 1 induced by a novel sulfonamide compound.

LASSBio-985 is a sulfonamide compound designed as a simplified structure of a nonselective phosphodiesterase type 4 (PDE-4) inhibitor that promotes vasodilatory activity in vitro. PDE are enzymes responsible for the hydrolysis of cyclic adenosine 3',5'- monophosphate and cyclic guanosine 3',5'-monophosphate. Five different isozymes of PDE are found in vascular smooth muscle (PDE1-PDE5). Aortic rings, with or without endothelium, from male normotensive and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. Blood pressure was measured in Wistar Kyoto (WKY) rats and SHR during intravenous infusion of LASSBio-985 (10 mg/kg/min) during 15 min. LASSBio-985 induced a concentration-dependent vasodilation in aortic rings from normotensive and SHR, which was almost completely inhibited in endothelium-denuded vessels. Vasodilatory activity was also reduced in endothelium-intact aortic rings that had been pretreated with N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide synthase inhibitor and 1H-[1,2,4]oxadiazolod[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. LASSBio-985-induced vasodilation was also inhibited by sildenafil (100 µm) and SQ 22536, a PDE5 inhibitor and adenylate cyclase inhibitor, respectively. To evaluate the involvement of some endothelial receptors, atropine, diphenhydramine, HOE 140, naloxone, propranolol, indomethacin, and wortmannin were tested, but none inhibited the effects of LASSBio-985. The residual effect observed on endothelium-denuded aortic rings was abolished by nicardipine, a voltage-sensitive-Ca(2+)-channel blocker. Intravenous infusion of LASSBio-985 (10 mg/kg/min) significantly reduced systolic and diastolic pressures in both WKY and SHR. LASSBio-985 is a compound with vasodilatory activity, which could be consequent to PDE1 inhibition and voltage-sensitive-Ca(2+)-channel blockade.

[Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption].

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% 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.

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.

[Theophylline, a new look to an old drug]. / Teofilina, una nueva mirada a un medicamento antiguo.

OBJECTIVES: To emphasize the safety and efficacy of theophylline in chronic inflammatory respiratory diseases. To mention its immunomodulatory effects. DATA SOURCES: PubMed search using the keywords: theophylline, histone deacetylase, antiinflammatory, asthma, chronic obstructive pulmonary disease (COPD), corticoresistance. RESULTS: Theophylline is a methylxantine, that inhibits phosphodiesterase (PDE), induces histone deacetylase and antagonizes adenosine. Its main effect is to relax airway smooth muscle. The immunomodulatory effects of theophylline are obtained at low plasma concentrations (less than 10 mg/L). The combination of inhaled corticoesteroids and theophylline exerts a synergistic antiinflammatory effect that improves asthma control and reduces COPD exacerbations. Histones are a group of transcriptional cofactors involved in chromatin remodeling. Histone deacetylases (HDACs) suppress inflammatory gene expression. In patients with COPD and severe asthma there is a reduction in HDAC-2 secondary to the increased oxidative and nitrative stress. HDAC-2 is required by corticosteroids to switch off activated inflammatory genes, then its reduction favors corticosteroid resistance. Theophylline via HDAC-2 induction and PDE inhibition, suppresses inflammatory gene expression, and inhibits free oxygen radicals production. CONCLUSIONS: Theophylline at low plasma concentrations exerts antiinflammatory effects, restoring corticosteroid sensitivity in COPD and severe asthma.

Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension.

OBJECTIVE: To evaluate the safety of intravenous (IV) sildenafil, an inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase, in treating near-term and term newborns with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: This was an open-label, dose-escalation trial in newborns with PPHN and an oxygenation index (OI) > 15. Sildenafil was delivered by continuous IV infusion for at least 48 hours and up to 7 days. RESULTS: Five centers enrolled a total of 36 neonates with PPHN at a mean of 34 +/- 17 hours of age; 29 of these neonates were already receiving inhaled nitric oxide (iNO). A significant improvement in OI (28.7 to 19.3; P = .0002) was observed after 4 hours of sildenafil infusion in the higher dose cohorts. Thirty-five neonates survived; 1 neonate required extracorporeal membrane oxygenation (ECMO) support. In 4 neonates, sildenafil was stopped due to adverse events. Seven neonates were enrolled before developing the need for iNO. In these neonates, OI improved significantly by 4 hours after initiation of sildenafil infusion (24.6 to 14.7; P = .009); 6 neonates completed treatment without the need for iNO or ECMO. CONCLUSIONS: IV sildenafil was well tolerated, and acute and sustained improvements in oxygenation were noted in those neonates who received the higher infusion doses.

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

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.

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