Author index for volume 286

Susceptibility to renal injury varies among individuals. Previously, we found that individual endothelial function of healthy renal arteries in vitro predicted severity of renal damage after 5/6 nephrectomy. Here we hypothesized that individual differences in endothelial function in vitro and renal perfusion in vivo predict the severity of renal damage in a model of adriamycin-induced nephropathy. In three separate studies, the following baseline parameters were measured in healthy male Wistar rats: (1) acetylcholine (ACh)-induced relaxation in small renal arteries in vitro (n = 16) and the contribution of prostaglandins, nitric oxide (NO) and endothelium-dependent hyperpolarizing factor (EDHF) to the relaxation; (2) glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in spontaneously voiding rats in vivo (n = 16) and (3) the acute effect of the NO-synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME, n = 12) on renal blood flow (RBF) as compared to vehicle infusion (n = 9). Following these measurements, adriamycin (1.75 mg/kg i.v.) was injected and subsequent renal damage after 6 weeks was related to the baseline parameters. Total ACh-induced (r = 0.51, P <0.05) and EDHF-mediated relaxation (r = 0.68, P <0.05), as well as ERPF (r = 0.66, P <0.01), positively correlated with the severity of proteinuria 6 weeks after injection. In contrast, pronounced baseline NO-mediated dilation was associated with lower proteinuria (r = 0.71, P <0.01). Nevertheless, an acute L-NAME infusion, strongly reducing RBF by 22 +/- 8%, during adriamycin administration provided protection against the development of proteinuria. Individual animals with pronounced baseline endothelial dilatory ability measured in vitro and high ERPF in vivo are vulnerable to renal damage after the adriamycin injection. Acute inhibition of NO during adriamycin administration, resulting in a decrease of RBF, protects against renal injury, probably by limiting the delivery of the drug to the kidney. Therefore, interindividual variability in renal haemodynamics might be crucially involved in susceptibility to nephrotoxic renal damag

Population pharmacokinetic model and limited sampling strategy for clozapine using plasma and dried blood spot samples

BACKGROUND: To improve efficacy, therapeutic drug monitoring is often used in clozapine therapy. Trough level monitoring is regular, but trough levels provide limited information about the pharmacokinetics of clozapine and exposure in time. The area under the concentration time curve (AUC) is generally valued as better marker of drug exposure in time but calculating AUC needs multiple sampling. An alternative approach is a limited sampling scheme in combination with a population pharmacokinetic model meant for Bayesian forecasting. Furthermore, multiple venepunctions can be a burden for the patient, whereas collecting samples by means of dried blood spot (DBS) sampling can facilitate AUC-monitoring, making it more patient friendly. OBJECTIVE: Development of a population pharmacokinetic model and limited sampling strategy for estimating AUC(0-12h) (a twice-daily dosage regimen) and AUC(0-24h) (a once-daily dosage regimen) of clozapine, using a combination of results from venepunctions and DBS sampling. METHOD: From 15 schizophrenia patients, plasma and DBS samples were obtained before administration and 2, 4, 6, and 8 h after clozapine intake. MwPharm(®) pharmacokinetic software was used to parameterize a population pharmacokinetic model and calculate limited sampling schemes. RESULTS: A three-point sampling strategy with samples at 2, 6, and 8 h after clozapine intake gave the best estimation of the clozapine AUC(0-12h) and at 4, 10, and 11 h for the AUC(0-24h). For clinical practice, however, a two-point sampling strategy with sampling points at 2 and 6 h was sufficient to estimate AUC(0-12h) and at 4 and 11 h for AUC(0-24h). CONCLUSION: A pharmacokinetic model with a two–time point limited sampling strategy meant for Bayesian forecasting using DBS sampling gives a better prediction of the clozapine exposure in time, expressed as AUC, compared to trough level monitoring. This limited sampling strategy might therefore provide a more accurate prediction of effectiveness and occurrence of side effects compared to trough level monitoring. The use of DBS samples also makes the collection of clozapine samples easier and wider applicable

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce