Studies on Propafenone-type Modulators of Multidrug-Resistance IV: Synthesis and Pharmacological Activity of 5-Hydroxy and 5-Benzyloxy Derivatives

A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3 . Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a–d . Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a–d . Structure activity relationship studies showed, that the 5-hydroxy derivates 6a–d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a–d showed almost identical EC₅₀ values, independent of their log P value.     

Inborn errors of the urea cycle

Inborn errors of the urea cycle are an important cause of hyperammonaemia throughout childhood, and are associated with high morbidity and mortality rates. If they are diagnosed early and treated appropriately, the outcome for affected children is significantly improved.     

Gastric emptying and anaesthesia

An understanding of factors which influence gastric emptying rate is important for anaesthetists. In the absence of pyloric stenosis or other mechanical obstruction to the gastric outlet, opioid drugs constitute the most important cause of delayed emptying in the perioperative period.     

Subfractionation of human peripheral blood lymphocytes by partitioning in two-polymer aqueous phase systems. Characteristics of a small subpopulation of cells with high partition coefficient

Mixtures of aqueous solutions of dextran and poly(ethylene glycol) form immiscible 2-phase systems that are suitable for the separation of viable, functionally-competent cells on the basis of their surface properties. With the appropriate choice of ionic composition, these systems will separate cells on the basis of charge-related surface characteristics. We have previously shown that in charge-sensitive phase systems, human B lymphocytes have a low partition coefficient (K) and T cells have an intermediate K. The cell subpopulation with the highest K values contains large null lymphocytes that have most of the antibody-dependent and natural killer activities. The present study further characterizes this latter cell subpopulation. 8-33% of peripheral blood lymphocytes in normal persons had high K values. About 50% of these cells had typical Giemsa-staining granules characteristic of killer cells and one third had Fc receptors, but lacked complement receptors. Although 15-30% of the cells with high K values formed rosettes with sheep erythrocytes, there was virtually no response to T-cell mitogens such as PHA and Con A. Mixing cells having high K values with mitogen-responsive T cells from intermediate cell fractions revealed no evidence of suppressor-cell activity to explain the poor mitogen response. The studies indicate that a heterogeneous population of cells share charge-related surface properties resulting in a high partition coefficient. These cells comprise a significant proportion of human peripheral blood lymphocytes and include virtually all of the large granular lymphocytes as well as a large population without this morphology that shares the feature of unresponsiveness to T-cell mitogens.     

Adiposity and sex hormones in girls.

Greater body fatness during childhood is associated with reduced risk of premenopausal breast cancer, but few studies have addressed the relation of adiposity with sex hormones in girls. We prospectively examined associations between adiposity and circulating levels of sex hormones and sex hormone-binding globulin (SHBG) among 286 girls in the Dietary Intervention Study in Children. Participants were 8 to 10 years old at baseline and were followed for an average of 7 years. Anthropometric measurements were taken at baseline and at subsequent annual visits, and blood samples were collected every 2 years. Concentrations of dehydroepiandrosterone sulfate (DHEAS) during follow-up were higher among girls with greater body mass index (BMI) at baseline. The mean for the lowest BMI quartile was 63.0 microg/dL compared with 78.8 microg/dL for the highest quartile, and each kg/m(2) increment in baseline BMI was associated with a 4.3% increase (95% confidence interval, 1.6-7.0%) in DHEAS levels during follow-up (P(trend) = 0.002). Concentrations of SHBG during follow-up were lower among girls with greater BMI at baseline. The mean for the lowest BMI quartile was 94.8 nmol compared with 57.5 nmol for the highest quartile, and each kg/m(2) increment in baseline BMI was associated with an 8.8% decrease (95% confidence interval, 7.0-10.6%) in SHBG levels during follow-up (P(trend) < 0.0001). Estrogen and progesterone concentrations were similar across BMI quartiles. These findings suggest that adiposity may alter DHEAS and SHBG levels in girls. Whether and how these differences affect breast development and carcinogenesis requires further research.