sildenafil-citrate and Liver-Diseases

To review special safety topics associated with sildenafil and to document the tolerability of 50- and 100-mg doses, overall and by age, in men with erectile dysfunction (ED).. Data were collated from 67 double-blind placebo-controlled (DBPC) trials (> 14,000 men) conducted by the manufacturer and from the manufacturer's postmarketing safety database (39,277 patients). The DBPC data were stratified by dose, starting dose and age (> or = 65 and > or = 75 years). Special safety topics included cardiovascular risk, priapism, non-arteritic anterior ischaemic optic neuropathy (NAION), impaired renal and hepatic function, drug interactions (i.e. nitrates, cytochrome P3A4 inhibitors, other ED therapies and alpha-blockers) and incorrect use.. Sildenafil was well tolerated at a dose of 50 or 100 mg in men with ED, overall, in those aged > or = 65 years, and in those aged > or = 75 years. Analyses of the databases did not reveal any causal link between sildenafil and cardiovascular events, or any new safety risks relating to cardiovascular events, priapism, NAION, hearing loss or drug interactions. In the small number of men with moderate impairment of renal function or hepatic function who were treated with sildenafil in DBPC trials, the safety profile was similar to that in men with no impairment of renal or hepatic function. Overdose with sildenafil was rare in the ED population. No new safety issues, emerging trends or adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse.. This collated review confirms generally the good tolerability and established safety profile of sildenafil 50 and 100 mg in men with ED and reveals no new safety issues.

Topics: Aged; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug Overdose; Erectile Dysfunction; Hearing Disorders; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Priapism; Product Surveillance, Postmarketing; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Treatment Outcome

To investigate the effects of age and renal and hepatic impairment on the pharmacokinetics, tolerability and safety of sildenafil (single 50-mg oral dose) and its major circulating N-desmethyl metabolite, UK-103,320.. Three open-label, parallel-group studies were conducted. The first study compared sildenafil pharmacokinetics, safety and toleration in 15 healthy young male subjects (mean age 30 years; range 19--45 years) to 15 healthy elderly male subjects (mean age 70 years; range 65--81 years). The second study included eight male volunteers with normal renal function and 16 male volunteers with varying degrees of renal impairment as assessed by measurement of creatinine clearance (CLcr). The third study included 12 male volunteers with normal hepatic function and 12 male volunteers with chronic stable hepatic cirrhosis (Child-Pugh A and B). For all three studies, blood and urine samples were collected predose and at specified intervals up to 48 h postdose for assays of sildenafil and UK-103,320, and measurements of protein binding.. Significant differences in Cmax and AUC were observed between the young and the elderly subjects for both the parent drug and the metabolite. In the elderly, AUC values were approximately twice as high and Cmax values 60--70% higher than those for young men, while t1/2 values were approximately 1 h longer for sildenafil and 2 h longer for UK-103,320. Due to a significantly smaller unbound fraction of drug in the elderly, free drug concentrations were only approximately 40% higher in the elderly group compared to the young group. In the renal impairment study, significant correlations with CLcr were demonstrated for sildenafil oral clearance (CL/F) and Cmax and UK-103,320 Cmax and AUC. Pairwise comparisons between subjects with normal renal function and those with severe renal impairment (CLcr<30 ml min-1) supported these findings, showing significant increases in Cmax and AUC for both the parent drug and the metabolite in the severely impaired subjects. The hepatic impairment study demonstrated that the pharmacokinetics of sildenafil were altered in subjects with chronic stable cirrhosis, as shown by a 46% reduction in CL/F and a 47% increase in Cmax compared with subjects with normal hepatic function, suggesting a reduction in first-pass metabolism as well as systemic clearance. The increase in systemic exposure for UK-103,320 was approximately twice that seen for the parent drug. In all three studies, sildenafil was well tolerated, most adverse events were mild and no subjects discontinued treatment.. Sildenafil pharmacokinetics were affected by age and by renal and hepatic impairment, suggesting that a lower starting dose of 25 mg should be considered for patients with severely compromised renal or hepatic function.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Area Under Curve; Humans; Kidney; Kidney Diseases; Liver; Liver Diseases; Male; Metabolic Clearance Rate; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidinones; Sildenafil Citrate; Sulfones

Physiologically based pharmacokinetic (PBPK) modeling permits clinical scientists to reduce practical constraints for clinical trials on patients with special diseases. In this study, simulations were carried out to validate the pharmacokinetic parameters of clozapine and sildenafil using Simcyp. A full PBPK model was built in the simulator for clozapine and sildenafil based on physicochemical properties and observed clinical results. The model used was Advanced, Dissolution, Absorption and Metabolism (ADAM) for both drugs.. The PBPK model adequately predicted the pharmacokinetic parameters of clozapine and sildenafil for the healthy adult population. In the simulation results, the bioavailability of both drugs was remarkably raised in both renal and hepatic impairment in young and elderly populations.. PBPK modeling could be helpful in the investigation and comparison of the pharmacokinetics in populations with specific disease conditions.

Topics: Adult; Clozapine; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Models, Biological; Sildenafil Citrate; Young Adult

We evaluated the role of sildenafil in a rat liver ischemia-reperfusion model. Forty male rats were randomly allocated in four groups. The sham group underwent midline laparotomy only. In the sildenafil group, sildenafil was administered intraperitoneally 60 minutes before sham laparotomy. In the ischemia-reperfusion (I/R) group, rats were subjected to 45 minutes of hepatic ischemia followed by 120 minutes of reperfusion, while in the sild+I/R group rats were subjected to a similar pattern of I/R after the administration of sildenafil, 60 minutes before ischemia. Two hours after reperfusion, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured and histopathological examination of the lobes subjected to ischemia as well as TUNEL staining for apoptotic bodies was performed. Additionally, myeloperoxidase (MPO) activity and the expression of intercellular adhesion molecule-1 (ICAM-1) were analyzed. Serum markers of hepatocellular injury were significantly lower in the sild+I/R group, which also exhibited lower severity of histopathological lesions and fewer apoptotic bodies, as compared to the I/R group. The I/R group showed significantly higher MPO activity and higher expression of ICAM-1, as compared to the sild+I/R group. Use of sildenafil as a preconditioning agent in a rat model of liver I/R exerted a protective effect.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Gene Expression Regulation; In Situ Nick-End Labeling; Intercellular Adhesion Molecule-1; Liver; Liver Diseases; Male; Peroxidase; Piperazines; Purines; Rats, Wistar; Reperfusion Injury; RNA, Messenger; Sildenafil Citrate; Staining and Labeling; Sulfones

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second(-1) cm(-5). The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences.

Topics: Adult; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Diseases; Liver Transplantation; Male; Piperazines; Pulmonary Artery; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents