Tamoxifen Pharmacokinetics Beyond the Genotyping Era

__Abstract__ Breast cancer is the most commonly diagnosed malignancy in women in almost all countries worldwide and is the primary cause of cancer death among women. Approximately 1.7 million new cases of breast cancer an

Компьютерная оценка формы графита в высокопрочном чугуне

Разработана методика индивидуальной и групповой оценки фактора формы графита в высокопрочном чугуне на основе некоммерческой программы ImageJ. Установлены графические и аналитические зависимости для перехода от значений фактора формы графита к соответствующим эталонным структурам, и наоборот, – от эталонных структур к фактору формы.Розроблена методика індивідуальної та групової оцінки фактора форми графіту у високоміцному чавуні на основі некомерційної програми ImageJ. Встановлено графічні та аналітичні залежності для переходу від значень фактора форми графіту до відповідних еталонних структур, і навпаки, – від еталонних структур до фактора форми.The technique of individual and group assessment form factor of graphite in ductile iron, based on a non-profit program ImageJ. Established graphic and analytic expressions for the transition from the values of the form factor of graphite to the corresponding reference structures and vice versa - from the reference structures to the form factor

Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch

Background and Objective: The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochr

The Risk of QTc-Interval Prolongation in Breast Cancer Patients Treated with Tamoxifen in Combination with Serotonin Reuptake Inhibitors

Purpose: Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval. Methods: Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI. Results: The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8–23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4–33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4–20.6 ms; P 500 ms. Conclusions: Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred

Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients

The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen Cmax and area under the curve (AUC)0–8 h were 20 % higher (P max was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0–24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen

Glycosylation defects underlying fetal alcohol spectrum disorder: a novel pathogenetic model: “When the wine goes in, strange things come out” – S.T. Coleridge, The Piccolomini

Fetal alcohol spectrum disorder (FASD) is an umbrella term used to describe the craniofacial dysmorphic features, malformations, and disturbances in growth, neurodevelopment and behavior occurring in individuals prenatally exposed to alcohol. Fetal alcohol syndrome (FAS) represents the severe end of this spectrum. Many pathophysiological mechanisms have hitherto been proposed to account for the disrupted growth and morphogenesis seen in FAS. These include impaired cholesterol-modification of the Sonic hedgehog morphogen, retinoic acid deficiency, lipoperoxidative damage due to alcohol-induced reactive oxygen species combined with reduced antioxidant defences, and malfunctioning cell adhesion molecules. In this report, we propose a completely novel concept regarding the pathogenesis of FAS. Based on our observation that transferrin isoelectric focusing (TIEF) – the most widely used screening tool for congenital disorders of glycosylation (CDG) – was transiently abnormal in a newborn with FAS and a confirmed maternal history of gestational alcohol abuse, we came to believe that FAS exemplifies a congenital disorder of glycosylation secondary to alcohol-inflicted disruption of (N-linked) protein glycosylation. Various pieces of evidence were found in the literature to substantiate this hypothesis. This observation implies, among others, that one might need to consider the possibility of maternal alcohol consumption in newborns with transient glycosylation abnormalities. We also present an integrated pathophysiological model of FAS, which incorporates all existing theories mentioned above as well as our novel concept. This model highlights the pivotal role of disrupted isoprenoid metabolism in the origination of FAS

‘Placing’ Space: exploring the socio-spatial impacts of cosmopolitan place-marketing approaches on British migrants in Spain

This article explores the sociospatial underpinnings of cosmopolitan place-marketing narratives and their impacts on British migrants living in Sitges, an affluent tourist town in Spain. Sitges’ place-marketing suggests that moving there automatically fosters a cosmopolitan identity. For British migrants in Sitges, this was understood to be exemplified through integration into the local community. Yet the vast majority found such integration impossible, not least because this conceptualization of cosmopolitanism overlooked the subjectivity of locals themselves, by whom they were most often rejected. It is argued that this mismatch between British migrants’ experiences and Sitges’ cosmopolitan place-marketing occurs because it relies on an understanding of subjective identity as generated locationally, enacted via movement to a specific “type” of place that incorporates particular understandings of space, place, and culture in relation to that identity. This overrides the necessity of relationality, undermining the ideal of reflexive identity-making on which cosmopolitan place-marketing narratives rely

Relationship Between Sunitinib Pharmacokinetics and Administration Time: Preclinical and Clinical Evidence

Background and Objective: Circadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are subject to circadian variation. Methods: We performed studies in male FVB-mice aged 8–12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration–time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times. Results: Sunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (p ≤ 0.04). The combined AUC from time zero to 10 h (AUC10) was 14–27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (Ctrough) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (Ctrough-1 p.m. 66.0 ng/mL; Ctrough-6 p.m. 58.9 ng/mL; Ctrough-8 a.m. 50.7 ng/mL; p = 0.006). The AUC was not significantly different between dosing times. Conclusions: Our results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower Ctrough values, probably resulting from differences in elimination. This can have implications fo