sildenafil-citrate and Renal-Insufficiency

The development of the ASTED (automated sequential trace enrichment of dialysates) system to prepare plasma samples prior to high-performance liquid chromatography (HPLC) of sildenafil and its demethylated metabolite (UK-103,320) is described. Investigations to elucidate potential pitfalls of the ASTED on-line sample preparation system prior to separation of the analytes by HPLC are presented. The procedure is shown to be selective for sildenafil and UK-103,320, and linear over the range 1.00-250 ng/ml. The intra-batch imprecision (C.V.) of the method at plasma analyte concentrations of 1.00, 5.00, 50.0 and 200 ng/ml was 11.2, 3.10, 1.50, and 1.30%, respectively, and the corresponding inter-batch imprecision was estimated to be 13.5, 7.09, 3.69, and 5.43%. At these plasma analyte concentrations the overall inaccuracy (% bias) of the procedure ranged from 3.6 to 8.4%. The method showed similar assay performance for the estimation of the metabolite, UK-103,320. The application of the assay to a pharmacokinetic investigation during a clinical study is presented.

Topics: Chromatography, High Pressure Liquid; Cross-Over Studies; Dialysis; Drug Stability; Humans; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidinones; Renal Insufficiency; Reproducibility of Results; Sensitivity and Specificity; Sildenafil Citrate; Sulfones

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKA

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiomegaly; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Desoxycorticosterone; Female; Hyperglycemia; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mineralocorticoids; Phosphodiesterase 5 Inhibitors; Renal Insufficiency; Sildenafil Citrate; Sodium Chloride; Tyramine

Methylmalonic acidemia or aciduria (MMA) is an inborn error of metabolism that results in the accumulation of methylmalonic acid in blood with an increased excretion in urine. MMA usually presents in early infancy and its effects vary from mild to life-threatening. The clinical symptoms mainly include vomiting, dehydration, hypotonia, developmental delay, and failure to thrive. An association between pulmonary arterial hypertension (PAH) and MMA has been rarely reported. In the present work, the authors report a 16-month boy, who was admitted to the Pediatric Department for cyanosis and fever. He had a family history of primary pulmonary hypertension in a sister. The echocardiography showed a mild pericardial effusion and PAH. The metabolic screening led to the diagnosis of MMA. The condition of the baby worsened rapidly- and he died a few days later. Physicians should be aware about this atypical presentation of the disease, which can be fatal if not diagnosed and managed promptly.

Topics: Amino Acid Metabolism, Inborn Errors; Cyanosis; Familial Primary Pulmonary Hypertension; Fatal Outcome; Fever; Humans; Infant; Male; Methylmalonic Acid; Renal Insufficiency; Sildenafil Citrate; Tachycardia; Vasodilator Agents

The goal of this study was to investigate the effect of different phosphodiesterase inhibitors (PDEIs), on renal oxidant/antioxidant balance in diabetic rats. Our study was conducted on 125 rats, diabetes was induced in 100 rats by a single administration of streptozocin (STZ). Diabetic rats were divided into four equal groups. The first group was assigned as diabetic control, the remaining three groups were treated with pentoxifylline, sildenafil and milrinone via drinking water for 15 successive days, another group of 25 normal rats was assigned as non-diabetic control. Significant increase in plasma levels of glucose, urea, creatinine, malondialdehyde (MDA), and nitric oxide (NO) with a concomitant decrease in the levels of insulin, reduced glutathione (GSH), glutathione peroxidase (Gpx), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC) were observed in diabetic rats. These alterations were reverted back to near normal level after treatment with PDEIs. Our data seem to suggest a potential role of PDEIs in maintaining health in diabetes by reducing the progression of diabetic nephropathy.

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Kidney; Lipid Peroxidation; Male; Milrinone; Oxidative Stress; Oxidoreductases; Pentoxifylline; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Random Allocation; Rats, Sprague-Dawley; Renal Insufficiency; Sildenafil Citrate

Cisplatin-induced nephrotoxicity in large proportion of patients. The aim of this work is to clarify the effect of combination of sildenafil and gemfibrozil on cisplatin-induced nephrotoxicity either before or after cisplatin treatment and determination of nephrotoxicity predictors among the measured tissue markers.. Thirty two adult male albino rats were divided into four equal groups (G) GI control, GII received cisplatin, GIII received sildenafil and gemfibrozil before cisplatin, GIV received sildenafil and gemfibrozil after cisplatin. Creatinine and urea were measured and animals were sacrificed and kidney was taken for histopathology. The following tissue markers were measured, heme oxygenase-1 (HO-1) activity, reduced glutathione, quantitative (real-time polymerase chain reaction) RT-PCR for gene expression of tumor necrosis factor alpha (TNF-α) and endothelial nitric oxide synthase (ENOS) level.. GII developed AKI demonstrated by significantly high urea and creatinine and severe diffuse (80-90%) tubular necrosis. TNF-α was highly and significantly elevated while the rest of tissue markers were significantly reduced in GI1 compared to other groups. GIV showed better results compared to GIII. There was a significant positive correlation between creatinine and TNF-α when combining GI and GII while there were significant negative correlation between creatinine and other tissue markers in same groups. Linear regression analysis demonstrated that HO-1 was the independent predictor of AKI demonstrated by elevated creatinine among GI and GII.. Combination of sildenafil and gemfibrozil can be used in treatment of cisplatin-induced nephrotoxicity. HO-1 is a promising target for prevention and/or treatment of cisplatin-induced nephrotoxicity.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Cisplatin; Creatinine; Disease Models, Animal; Drug Therapy, Combination; Gemfibrozil; Glutathione; Heme Oxygenase-1; Humans; Kidney; Male; Neoplasms; Oxidative Stress; Rats; Renal Insufficiency; Sildenafil Citrate; Treatment Outcome; Urea