Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel

It has been hypothesized that the paclitaxel vehicle Cremophor EL (CrEL) is responsible for nonlinear drug disposition by micellar entrapment. To gain further insight into the role of CrEL in taxane pharmacology, we studied the pharmacokinetics of paclitaxel in the presence and absence of CrEL after i.p. and i.v. dosing. Patients received an i.p. tracer dose of [G-(3)H]paclitaxel in ethanol without CrEL (100 microCi diluted further in isotonic saline) on day 1, i.p. paclitaxel formulated in CrEL (Taxol; 125 mg/m(2)) on day 4, an i.v. tracer of [G-(3)H]paclitaxel on day 22, and i.v. Taxol (175 mg/m(2)) on day 24. Four patients (age range, 54-74 years) were studied, and serial plasma samples up to 72 h were obtained and analyzed for total radioactivity, paclitaxel, and CrEL. In the presence of CrEL, i.v. paclitaxel clearance was 10.2 +/- 3.76 liters/h/m(2) (mean +/- SD), consistent with previous findings. The terminal disposition half-life was substantially prolonged after i.p. dosing (17.0 +/- 11.3 versus 28.7 +/- 8.72 h), as was the mean residence time (7.28 +/- 2.76 versus 40.7 +/- 13.8 h). The bioavailability of paclitaxel was 31.4 +/- 5.18%, indicating insignificant systemic concentrations after i.p. treatment. CrEL levels were undetectable after i.p. dosing (<0.05 microl/ml), whereas after i.v. dosing, the mean clearance was 159 +/- 58.4 ml/h/m(2), in line with earlier observations. In the absence of CrEL, the bioavailability and systemic concentrations of i.p. paclitaxel were significantly increased. This finding is consistent with the postulated concept that CrEL is largely responsible for the pharmacokinetic advantage for peritoneal cavity exposure to total paclitaxel compared with systemic delivery

Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion

Dropout bij klinisch psychotherapeutische behandeling van persoonlijkheidsproblematiek

achtergrond Drop-out is een belangrijk probleem bij psychotherapie. Factoren die in eerdere studies samenhingen met drop-out zijn onder meer te verdelen in cliëntkenmerken zoals jonge leeftijd en lage sociaaleconomische status en kenmerken van stoornissen zoals ernst van de problematiek en problematisch middelengebruik. doel Onderzoeken van kenmerken van de cliënt en van de stoornis die samenhangen met drop-out en voorspellen van drop-out bij cliënten met overwegend persoonlijkheidsproblematiek. methode Kenmerken van cliënt en stoornis werden in een retrospectieve studie onder 372 cliënten vastgesteld aan de hand van vier databronnen: intakebrieven, Gestructureerd Klinisch Interview dsm-iv (scid)-ii-persoonlijkheidsvragenlijst, (scid-i- en -ii-interviews) en ontslagbrieven. De samenhang van deze kenmerken met drop-out werd bi- en multivariaat getoetst. resultaten Het drop-outpercentage was 33,3. De factoren die significant bijdroegen aan de voorspelling van drop-out waren een jonge leeftijd, een lage Global Assessment of Functioning(gaf)-score en de aanwezigheid van middelenproblematiek bij ontslag. De mate en de ernst van de as i-problematiek en de aard van de persoonlijkheidsproblematiek droegen nauwelijks bij aan de voorspelling van drop-out. conclusie Deze bevindingen impliceren dat er voor aanvang van de behandeling meer aandacht moet zijn voor de aanwezigheid van middelenproblematiek. Drop-out blijft een moeilijk te voorspellen en daarmee lastig te beïnvloeden fenomeen.