Concentrations of bisphenol A in the composite food samples from the 2008 Canadian total diet study in Quebec City and dietary intake estimates.

A total of 154 food composite samples from the 2008 total diet study in Quebec City were analysed for bisphenol A (BPA), and BPA was detected in less than half (36%, or 55 samples) of the samples tested. High concentrations of BPA were found mostly in the composite samples containing canned foods, with the highest BPA level being observed in canned fish (106 ng g(-1)), followed by canned corn (83.7 ng g(-1)), canned soups (22.2-44.4 ng g(-1)), canned baked beans (23.5 ng g(-1)), canned peas (16.8 ng g(-1)), canned evaporated milk (15.3 ng g(-1)), and canned luncheon meats (10.5 ng g(-1)). BPA levels in baby food composite samples were low, with 2.75 ng g(-1) in canned liquid infant formula, and 0.84-2.46 ng g(-1) in jarred baby foods. BPA was also detected in some foods that are not canned or in jars, such as yeast (8.52 ng g(-1)), baking powder (0.64 ng g(-1)), some cheeses (0.68-2.24 ng g(-1)), breads and some cereals (0.40-1.73 ng g(-1)), and fast foods (1.1-10.9 ng g(-1)). Dietary intakes of BPA were low for all age-sex groups, with 0.17-0.33 µg kg(-1) body weight day(-1) for infants, 0.082-0.23 µg kg(-1) body weight day(-1) for children aged from 1 to 19 years, and 0.052-0.081 µg kg(-1) body weight day(-1) for adults, well below the established regulatory limits. BPA intakes from 19 of the 55 samples account for more than 95% of the total dietary intakes, and most of the 19 samples were either canned or in jars. Intakes of BPA from non-canned foods are low.

The new dioxolane, (-)-2'-deoxy-3'-oxacytidine (BCH-4556, troxacitabine), has activity against pancreatic human tumor xenografts.

There is a great need for new therapeutic agents for patients with advanced pancreatic cancer. The new dioxolane analogue troxacitabine was evaluated in two human pancreatic cancer xenograft models. The models used included the Panc-01 and MiaPaCa pancreatic cancer cell lines. Whereas there is certainly no absolute evidence that either of the in vivo models is predictive for clinical activity, there is at least some evidence that they may be helpful in selecting agents for clinical trials in patients with pancreatic cancer. Troxacitabine was administered i.v. to the animals at doses of 10 and 25 mg/kg on a daily x 5 regimen. Gemcitabine was used as a positive control. The end points for the study included tumor growth inhibition (TGI), final weight, and the number of partial and complete tumor responses in the animals. Troxacitabine was highly active against the Panc-01 model (n = 8), with TGI levels of 88.5% and 84.3% at the 10 and 25 mg/kg doses, respectively. The mean final tumor weights for animals given troxacitabine were also significantly smaller (P < 0.001) compared with vehicle controls. At the 10 mg/kg dose, there were three partial tumor shrinkages and one complete tumor shrinkage, whereas at the 25 mg/kg dose, there were three partial tumor shrinkages. Troxacitabine had less activity against the MiaPaCa model (n = 10) and, by traditional response criteria, would be considered inactive, with TGIs of 4% and 22.7% at the 10 and 25 mg/kg dose level, respectively. Of note is that in comparison with gemcitabine, troxacitabine was more efficacious against Panc-01 and was equally active against MiaPaCa. These in vivo results are encouraging and support the prospect of performing Phase II and perhaps Phase III trials with troxacitabine in patients with advanced pancreatic cancer.

Anti-human immunodeficiency virus type 1 activity, intracellular metabolism, and pharmacokinetic evaluation of 2'-deoxy-3'-oxa-4'-thiocytidine.

The racemic nucleoside analogue 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) is in clinical development for the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. dOTC is structurally related to lamivudine (3TC), but the oxygen and sulfur in the furanosyl ring are transposed. Intracellular metabolism studies showed that dOTC is phosphorylated within cells via the deoxycytidine kinase pathway and that approximately 2 to 5% of dOTC is converted into the racemic triphosphate derivatives, which had measurable half-lives (2 to 3 hours) within cells. Both 5'-triphosphate (TP) derivatives of dOTC were more potent than 3TC-TP at inhibiting HIV-1 reverse transcriptase (RT) in vitro. The K(i) values for dOTC-TP obtained against human DNA polymerases alpha, beta, and gamma were 5,000-, 78-, and 571-fold greater, respectively, than those for HIV RT (28 nM), indicating a good selectivity for the viral enzyme. In culture experiments, dOTC is a potent inhibitor of primary isolates of HIV-1, which were obtained from antiretroviral drug-naive patients as well as from nucleoside therapy-experienced (3TC- and/or zidovudine [AZT]-treated) patients. The mean 50% inhibitory concentration of dOTC for drug-naive isolates was 1.76 microM, rising to only 2.53 and 2.5 microM for viruses resistant to 3TC and viruses resistant to 3TC and AZT, respectively. This minimal change in activity is in contrast to the more dramatic changes observed when 3TC or AZT was evaluated against these same viral isolates. In tissue culture studies, the 50% toxicity levels for dOTC, which were determined by using [(3)H]thymidine uptake as a measure of logarithmic-phase cell proliferation, was greater than 100 microM for all cell lines tested. In addition, after 14 days of continuous culture, at concentrations up to 10 microM, no measurable toxic effect on HepG2 cells or mitochondrial DNA replication within these cells was observed. When administered orally to rats, dOTC was well absorbed, with a bioavailability of approximately 77%, with a high proportion (approximately 16.5% of the levels in serum) found in the cerebrospinal fluid.