In-utero ethanol exposure may result in fetal alcohol spectrum disorder (FASD). Studies have suggested that women who drink ethanol are more likely to consume illicit drugs. Detection of such exposures has been done via meconium and hair testing and can serve to direct needed prevention methods and appropriate management and intervention for the neonate and the mother. This study examined maternal diabetes as a possible confounder for in-utero ethanol exposure testing and determined the trends in drug use associated with heavy in-utero ethanol exposure in a high-risk obstetric Canadian population. It was determined that maternal diabetes does not produce false-positive results in testing for in-utero ethanol exposure. Furthermore, heavy in-utero ethanol exposure was detected in 15.5% of samples and was associated with an increased exposure to amphetamines (OR=3.30) and opiates (OR=2.01), but a decreased exposure to cannabinoids (OR=0.61) when compared to neonates with no heavy in-utero ethanol exposure.

We investigated the efficacy of standard (8-week nicotine, 16-week placebo) vs extended (24-week nicotine) patch therapy for smoking cessation, and the effect of slow nicotine metabolism, indicated by CYP2A6 reduced metabolizer (RM) genotype or low 3-hydroxycotinine/cotinine ratio (3HC/COT), on abstinence. RM versus normal genotype predicted lower 3HC/COT. Extended vs standard treatment produced higher abstinence at 24 weeks (32% vs 20%), but not at 52 weeks (both 14%). Low 3HC/COT and RM genotype predicted higher abstinence on extended versus standard treatment at 24 (47% vs 25%, 38% vs 17%) and 28 weeks (34% vs 19%, 23% vs 11%), while high 3HC/COT or normal genotype did not. Within extended treatment, low versus high 3HC/COT predicted higher abstinence at 8 (48% vs 29%), 24 (47% vs 25%), and 28 weeks (34% vs 16%), with similar trends for the genotype effect. Overall, extending nicotine treatment increased abstinence during therapy, particularly for slow metabolizers.

Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.

Several lines of evidence implicate oxidative stress in the pathophysiology of bipolar disorder (BPD). The mood stabilizers lithium and valproate have been shown to protect against oxidative stress-induced cell death. This study examined whether an increase in cellular reductive potential due to glutathione (GSH) synthesis up-regulation underlies this neuroprotective effect. Using primary rat cortical neurons as a model, this study demonstrated that unlike lithium and valproate, carbamazepine and lamotrigine do not exert neuroprotective effects against H2O2-induced cell death. Moreover, the level of GSH and the GSH:GSSG ratio in neurons and in rat brain remained unchanged following chronic treatment with either lithium or valproate. Similarly, this study did not find a significant effect of treatment on the expression of genes encoding γ-glutamylcysteine ligase sub-units, Gclc and Gclm, in both neurons and the rat brain. These findings suggest that other molecular targets of lithium and valproate likely mediate the observed neuroprotective effects.

Targeting angiogenic vasculature has been validated as a viable approach for cancer imaging and therapy. The tumour vasculature-specific ligand asparagine-glycine-arginine (NGR) peptide targets the isoform of aminopeptidase N (CD13) expressed on endothelial cells lining angiogenic vessels. CD13 has become widely recognized as a rational target for therapeutic development and several NGR-conjugated agents are now in pre-clinical and clinical development. In the current study, a CT image-based approach is used to evaluate the in vivo performance of several NGR-conjugated liposome formulations that vary in terms of NGR density and PEG spacer arm length. Indeed, for the first time it is demonstrated that CT imaging can be used for quantitative and longitudinal assessment of the pharmacokinetics and biodistribution of an actively targeted liposome formulation. In comparison to conventional methods, CT imaging enables visualization of the intratumoural distribution of liposomes and quantification of the fraction of tumour occupied by the vesicles over time.

The aryl hydrocarbon receptor (AHR) mediates the toxic effects of halogenated aromatic hydrocarbons (HAHs), including 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran and 2,3,7,8-tetrachlorodibenzofuran. Y322 is believed to play a role in binding-independent activation of AHR by atypical inducers, such as omeprazole. I examined AHR-mediated regulation of and coactivator recruitment to CYP1A1, CYP1B1, HES1 and TiPARP in T-47D and HuH7 cells. All compounds induced expression of each gene in both cell lines, with some temporal differences between the HAHs and omeprazole. Chromatin immunoprecipitation assays demonstrated activator-, cell line- and gene-selectivity in AHR coactivator recruitment. Omeprazole induced AHR degradation which was prevented by MG-132 pre-treatment. Y322 was found to be important for maximal AHR activation by 2,3,7,8-TCDD and 2,3,4,7,8-PeCDF, but required for 2,3,7,8-TCDF and Omp in an AHR-deficient MCF-7 cells. My findings provide further evidence for cell-, gene- and ligand-dependent differences in AHR-mediated gene expression and coactivator recruitment, and a role for Y322 in AHR activation.

Obesity in pregnancy has been associated with an elevated risk for neural tube defects, though it is unknown if this is linked to a lower folate status in obese women. Studies have identified a reduced folate status among obese women even after controlling for folate intake. Thus, it is possible that folic acid pharmacokinetics are altered in the obese body. In this study, we compared the pharmacokinetics of folic acid in obese and non-obese women of childbearing age, following administration of a weight-adjusted dose. Area under the concentration-time curve was found to be significantly higher in the obese group, with the dose per kilogram lean body weight most strongly predicting systemic exposure. Estimation of the daily dose required to achieve protective blood concentrations did not identify a need to change supplementation recommendations for obese women. Accordingly, current guidelines appear to suggest adequate doses for obese women of childbearing age.

Early diagnosis represents an effective way to improve patient prognosis in cancer. New opportunities for cancer diagnosis and screening may arise from identification of cancer-specific epigenetic alterations in the cell-free circulating DNA (cirDNA). This study investigated biomarkers at the level of DNA methylation in the plasma cirDNA of individuals affected with prostate cancer or colorectal cancer. A methylation-sensitive restriction enzyme-based method was used to enrich methylated DNA fractions, which were interrogated on CpG island and human genome tiling microarrays. A number of genes and non-coding loci exhibited differential methylation between prostate cancer patients and controls. The candidate loci identified from these microarray experiments underwent verification by bisulfite modification coupled with pyrosequencing. Our results suggest that microarray-based studies of DNA methylation in the cirDNA can be a promising avenue for the identification of epigenetic biomarkers in cancer.

We investigated the efficacy of standard (8-week nicotine, 16-week placebo) vs extended (24-week nicotine) patch therapy for smoking cessation, and the effect of slow nicotine metabolism, indicated by CYP2A6 reduced metabolizer (RM) genotype or low 3-hydroxycotinine/cotinine ratio (3HC/COT), on abstinence. RM versus normal genotype predicted lower 3HC/COT. Extended vs standard treatment produced higher abstinence at 24 weeks (32% vs 20%), but not at 52 weeks (both 14%). Low 3HC/COT and RM genotype predicted higher abstinence on extended versus standard treatment at 24 (47% vs 25%, 38% vs 17%) and 28 weeks (34% vs 19%, 23% vs 11%), while high 3HC/COT or normal genotype did not. Within extended treatment, low versus high 3HC/COT predicted higher abstinence at 8 (48% vs 29%), 24 (47% vs 25%), and 28 weeks (34% vs 16%), with similar trends for the genotype effect. Overall, extending nicotine treatment increased abstinence during therapy, particularly for slow metabolizers.

Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.