pyrimidinones 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

MEK- and BRAF-inhibitors trametinib and dabrafenib are successfully used for BRAF-mutated, metastasizing melanoma, but these compounds may induce side effects. We report a 50 years old female with BRAF-mutated metastasizing melanoma who received trametinib (2 mg/d) and dabrafenib (200 mg/d) after using interferon without benefit. Shortly after starting trametinib/dabrafenib, she experienced an inability to abduct the left eye. Eight days after starting this therapy the patient experienced loss of appetite, vomiting, diarrhea, vertigo, and fever of 40°C. Two days later she experienced visual loss, requiring permanent support for her daily activities. Two further days later myoglobinuria appeared in the absence of myalgias or muscle weakness but accompanied by marked tiredness and inactivity. She could not eat or drink during four days prior to admission. The patient suspected an adverse effect of trametinib/dabrafenib and discontinued it 2 days prior to admission. Thereafter, she experienced an almost complete remission of the deficits except for ocular muscle weakness and visual impairment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Renal Insufficiency; Rhabdomyolysis; Skin Neoplasms; Vision Disorders

To evaluate and compare the pharmacokinetics and tolerability of a single oral dose of mirodenafil in volunteer patients with severe renal impairment and healthy volunteers.. This open-label, single-dose, parallel group clinical study enrolled a total 12 volunteers (6 healthy volunteers and 6 volunteer patients with severe renal impairment). Each volunteer was orally administered 50 mg mirodenafil and serial blood samples were obtained after drug administration to determine the plasma concentration of mirodenafil using LC-MS/MS. The measured individual plasma concentrations were used to calculate the pharmacokinetic parameters using noncompartmental methods. Tolerability was also assessed using measurements of vital signs, clinical chemistry tests, and interviews.. All of the volunteers completed the study with no serious adverse events (AEs). A total of 4 AEs were reported, but all were of mild or moderate intensity and not considered to be related to the study drug. The geometric mean (95% CI) of the terminal half-life (t1/2β) and the apparent clearance (CL/F) values of mirodenafil were 2.2 (1.4 - 3.4) h and 127.2 (95.1 - 170.2) l/h in the volunteer patients, and 3.0 (2.1 - 4.4) h and 136.1 (74.4 - 249.2) l/h in the healthy volunteers, respectively. The geometric mean of the AUC0-t of the volunteer patients was 8% higher and the geometric mean for clearance was 7% lower compared with the healthy volunteers. However, the geometric mean of the Cmax of the volunteer patients was 38% higher than that of the healthy volunteers.. A single oral 50-mg dose of mirodenafil was well tolerated. Exposure (AUC0-t) to mirodenafil was similar in both healthy volunteers and volunteer patients with severe renal impairment and healthy volunteers.

Topics: Adult; Chromatography, Liquid; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pyrimidinones; Renal Insufficiency; Sulfonamides; Tandem Mass Spectrometry

The authors describe an HIV-infected patient with moderate renal failure receiving combination antiretroviral therapy. Because of dyslipidaemia he was initially treated with pravastatin but developed rhabdomyolysis after a switch to rosuvastatin. With this case we illustrate that statins as well as antiretroviral therapy are susceptible to clinical relevant drug-drug or drug-disease interactions. Knowledge of these interactions is important to provide patients with the best possible care.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Dyslipidemias; Fluorobenzenes; HIV Infections; HIV-1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lopinavir; Male; Middle Aged; Pyrimidines; Pyrimidinones; Renal Insufficiency; Rhabdomyolysis; Ritonavir; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome

Excretion in the urine is an important pathway for the elimination of nifekalant hydrochloride (NIF), a novel class III antiarrhythmic agent. Three patients with renal failure were undergoing hemodialysis and receiving NIF for the prevention of ischemia-induced ventricular tachyarrhythmia. Because NIF is not dialyzed, dose adjustment at relatively low concentrations was required, with monitoring of the QT interval.

Topics: Aged; Anti-Arrhythmia Agents; Diabetic Nephropathies; Drug Monitoring; Electrocardiography; Humans; Injections, Intravenous; Male; Myocardial Ischemia; Pyrimidinones; Renal Dialysis; Renal Insufficiency; Tachycardia, Ventricular

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antiprotozoal Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Leishmaniasis; Lopinavir; Male; Pyrimidinones; Renal Dialysis; Renal Insufficiency; Ritonavir