pyrimidinones and Kidney-Failure--Chronic

This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CL(CR)), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CL(R)), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CL(R) and CL(CR). In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of approximately 45%, representing a approximately 23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.

Topics: Adolescent; Adult; Aged; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Uremic vascular calcification is a regulated cell-mediated process wherein cells in the arterial wall transdifferentiate to actively calcifying cells resulting in a process resembling bone formation. Wnt signalling is established as a major driver for vessel formation and maturation and for embryonic bone formation, and disturbed Wnt signalling might play a role in vascular calcification. ICG-001 is a small molecule Wnt inhibitor that specifically targets the coactivator CREB binding protein (CBP)/β-catenin-mediated signalling. In the present investigation we examined the effect of ICG-001 on vascular calcification in uremic rats. Uremic vascular calcification was induced in adult male rats by 5/6-nephrectomy, high phosphate diet and alfacalcidol. The presence of uremic vascular calcification in the aorta was associated with induction of gene expression of the Wnt target gene and marker of proliferation, cyclinD1; the mediator of canonical Wnt signalling, β-catenin and the matricellular proteins, fibronectin and periostin. Furthermore, genes from fibrosis-related pathways, TGF-β and activin A, as well as factors related to epithelial-mesenchymal transition, snail1 and vimentin were induced. ICG-001 treatment had significant effects on gene expression in kidney and aorta from healthy rats. These effects were however limited in uremic rats, and treatment with ICG-001 did not reduce the Ca-content of the uremic vasculature.

Topics: Animals; beta Catenin; Biomarkers; Bone and Bones; Bridged Bicyclo Compounds, Heterocyclic; CREB-Binding Protein; Disease Models, Animal; Gene Expression Regulation; Kidney Failure, Chronic; Male; Minerals; Organ Specificity; Pyrimidinones; Rats; Uremia; Vascular Calcification; Wnt Signaling Pathway; X-Ray Microtomography

The combination of dabrafenib and trametinib is a standard of care for the management of BRAF mutant metastatic melanoma. Clinical trials excluded patients with end-stage kidney disease (ESKD), and as such, no data are available regarding the safety, efficacy and pharmacokinetics of these drugs in such patients. Here, we present the case of a 78-yr-old male patient with ESKD managed with haemodialysis (HD), treated with dabrafenib and trametinib at reduced doses. The patient has had a partial response, and this response continues at 9 months since our last follow-up without any dose escalation. Treatment was complicated by the development of diarrhoea, attributed to trametinib, necessitating temporary cessation of trametinib. Pharmacokinetic profiling of dabrafenib was undertaken, and its metabolites were similar pre- and post-dialysis and comparable to those in patients with normal renal function. Moreover, HD did not lower the plasma concentration of dabrafenib or trametinib. It is feasible to administer dabrafenib, in combination with trametinib, to patients with ESKD undergoing HD.

Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Kidney Failure, Chronic; Male; Melanoma; Oximes; Pyridones; Pyrimidinones; Renal Dialysis; Tissue Distribution; Treatment Outcome

A 78-year-old man with chronic renal failure (CRF) on hemodialysis (HD) was diagnosed as having severe aortic regurgitation with left ventricular dysfunction. Aortic valve replacement with a 21 mm ATS mechanical bileaflet prosthesis was performed without intraoperative complications. Sustained ventricular tachycardia suddenly occurred 1 day after surgery, then intravenous administration of nifekalant hydrochloride (NIF) was started at a dose of 0.40 mg/kg/hr. Life-threating ventricular arrhythmia was controlled, hemodynamic compromise was improved dramatically. NIF was regulated with a low-dose of 0.24 mg/kg/hr to prevent malignant side effect such as torsa de pointes. Since QTc was elongated to 0.57 seconds 11 hours after administration, NIF was stopped. Low-dose intravenous administration of NIF in patients with CRF on HD could be useful to prevent ventricular tachyarrhythmias without any adverse effect after cardiac surgery.

Topics: Aged; Anti-Arrhythmia Agents; Aortic Valve; Heart Valve Prosthesis; Hemodialysis Solutions; Humans; Kidney Failure, Chronic; Male; Postoperative Complications; Pyrimidinones; Tachycardia, Ventricular

Topics: Aged; Fatal Outcome; Humans; Hypotension; Kidney Failure, Chronic; Male; Piperazines; Purines; Pyrimidinones; Sildenafil Citrate; Sulfones; Vasodilator Agents

To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis.. Prospective, observational study of HIV-infected hemodialysis patients receiving one 600 mg tablet daily of EFV (N = 13) or three 133.3/33.3 mg capsules twice daily of LPV/RTV (N = 13).. Twenty-four-hour EFV and 12-h LPV/RTV pharmacokinetics were assessed. Geometric mean ratios were calculated using historical controls with normal renal function. The effects of several candidate gene polymorphisms were also explored.. The geometric mean [95% confidence interval (CI); percentage of coefficient of variation (% CV)] Cmin, Cmax, and area under the curve (AUC) for the EFV group were 1.81 microg/ml (0.93, 3.53; 103%), 5.04 microg/ml (3.48, 7.29; 72%), and 71.5 microg h/ml (43.2, 118.3; 93%), respectively. These parameters were 2.76 microg/ml (1.86, 4.11; 53%), 8.45 microg/ml (6.41, 11.15; 52%), and 69.6 microg h/ml (55.6, 87.2; 37%) for LPV and 0.08 microg/ml (0.05, 0.14; 63%), 0.58 microg/ml (0.44, 0.76; 41%), and 3.74 microg h/ml (2.91, 4.80; 37%) for RTV. The AUC geometric mean ratios (90% CI) for EFV, LPV, and RTV were 132% (89, 197), 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group. Higher EFV concentrations were associated with the CYP2B6 516G>T polymorphism.. The pharmacokinetics of EFV and LPV/RTV in hemodialysis suggests that no dosing adjustments are necessary in treatment-naive patients. As HIV-infected hemodialysis patients are disproportionately black, the increased frequency of the CYP2B6 516G>T polymorphism may lead to higher EFV levels. The potentially lower LPV trough levels in this population suggest that LPV/RTV should be used with caution in protease-inhibitor-experienced patients.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Kidney Failure, Chronic; Lopinavir; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Pyrimidinones; Renal Dialysis; Reverse Transcriptase Inhibitors; Ritonavir