Efficacy and safety of Cannabidiol and Tetrahydrocannabivarin on glycemic and lipid parameters in patients with Type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel group pilot study

OBJECTIVE Cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDL-cholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and tolerability end points were also evaluated. RESULTS Compared with placebo, THCV significantly decreased fasting plasma glucose (estimated treatment difference [ETD] = −1.2 mmol/L; P < 0.05) and improved pancreatic β-cell function (HOMA2 β-cell function [ETD = −44.51 points; P < 0.01]), adiponectin (ETD = −5.9 × 106 pg/mL; P < 0.01), and apolipoprotein A (ETD = −6.02 μmol/L; P < 0.05), although plasma HDL was unaffected. Compared with baseline (but not placebo), CBD decreased resistin (−898 pg/ml; P < 0.05) and increased glucose-dependent insulinotropic peptide (21.9 pg/ml; P < 0.05). None of the combination treatments had a significant impact on end points. CBD and THCV were well tolerated. CONCLUSIONS THCV could represent a new therapeutic agent in glycemic control in subjects with type 2 diabetes

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P&lt;5 × 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis

An Effective-Medium Tight-Binding Model for Silicon

A new method for calculating the total energy of Si systems is presented. The method is based on the effective-medium theory concept of a reference system. Instead of calculating the energy of an atom in the system of interest a reference system is introduced where the local surroundings are similar. The energy of the reference system can be calculated selfconsistently once and for all while the energy difference to the reference system can be obtained approximately. We propose to calculate it using the tight-binding LMTO scheme with the Atomic-Sphere Approximation(ASA) for the potential, and by using the ASA with charge-conserving spheres we are able to treat open system without introducing empty spheres. All steps in the calculational method is {\em ab initio} in the sense that all quantities entering are calculated from first principles without any fitting to experiment. A complete and detailed description of the method is given together with test calculations of the energies of phonons, elastic constants, different structures, surfaces and surface reconstructions. We compare the results to calculations using an empirical tight-binding scheme.Comment: 26 pages (11 uuencoded Postscript figures appended), LaTeX, CAMP-090594-

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p &lt; 5 × 10−8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy

Ensayo de neutralización in vitro de aplicación en la evaluación de inmunógenos contra la hepatitis A, obtenidos mediante la tecnología de expresión en fagos filamentosos [In vitro neutralization assay to evaluate new hepatitis A vaccine candidates]

The immunity against hepatitis A virus (HAV) is primarily due to the induction of neutralizing antibodies. Having neutralization assays is essential to evaluate new vaccine candidates against this pathogen. In this paper we developed a neutralization assay in vitro was used for evaluating the immunogenicity of HAV mimotopes obtained by phage display technology to be immunized BALB / c. Different dilutions of antibodies were incubated with 10 3 or 10 2 Dose Tissue Culture Infectious 50% (TCID 50 ) of clone cytopathic HM175/18f of HAV, and inoculated into plates with FRhK4 cells. After 7 days of incubation the neutralizing titer was determined as the reciprocal of the serum dilution capable of reducing the viral multiplication by 50%. Both 10 3 and 10 2 TCID 50 were neutralized by the monoclonal antibody 7E7 and human sera (A12 and A31) were positive for anti-HAV. Test Negative controls did not neutralize the virus. The neutralizing titers in the sera of mice immunized with mimotopes phage bearing HAV ranged between 4 and 16, whereas the preimmune sera from immunized mice and wild phage M13 did not neutralize viral infectivity. The neutralization assay was suitable for the evaluation of the immunogens proposed

Analysis of health outcome time series data in epidemiological studies

Several recent studies have reported significant health effects of air pollution even at low levels of air pollutants. These studies have been criticized for the statistical methods and for inconsistency in results between cities. An important development in air pollution epidemiology has come from multicenter studies. Within the APHEA-2 project we have developed a statistical methodology to evaluate short-term health effects of air pollution using data from 30 cities across Europe. For the analysis, a hierarchical modelling approach was adopted and implemented in two stages: (a) data from each city were analyzed separately to allow for local differences, using generalized additive Poisson regression models; (b) city-specific effects estimates were regressed on city-specific covariates to obtain an overall estimate and to explore heterogeneity across cities. In order to illustrate our methodology we present results for PM10 effects. It was found that a 10 mug/m(3) increase in PM10 or NO2 concentrations is associated with a 0.67% (95% Cl: 0.50 to 0.90) and 0.33% (0.20 to 0.40) increase in total mortality, respectively. After mutual adjustment, the PM10 effect was reduced by 40% and that of NO2 by 20%, but both pooled estimates remained significant. Long-term mean NO2 concentrations act as an effect modifier for PM10 effects, even after adjustment for NO2 confounding effects. In the second stage we explored two different models for combining the adjusted for NO2, PM10 effects across cities: bivariate, which accounts for within-city correlation of PM10 and NO2; and univariate, which ignores this correlation. Both models gave broadly the same results. Copyright (C) 2004 John Wiley Sons, Ltd