A question-based approach to adopting pharmacogenetics to understand risk for clinical variability in pharmacokinetics in early drug development.

Understanding genetic variations that influence pharmacokinetics (PK) in humans is important for optimal clinical use of drugs. Guidances for making decisions on when to conduct pharmacogenetic research during drug development have been proposed by regulatory agencies, but their uniform adoption presents problems due to an inherent lack of flexibility. A questions-based approach (QBA) was developed to enable drug development teams at Merck to iteratively and flexibly evaluate the potential impact of pharmacogenetics (PGx) on clinical pharmacokinetic variability.

A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina.

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.

[Association of polymorphisms in SULT1A1 and UGT1A1 Genes with breast cancer risk and phenotypes in Russian women].

Estrogens are critical for breast cancer initiation and development. Sulfotransferase 1A1 (SULT1A1) and UDP-glucuronosyltransferase 1A1 (UGT1A1) conjugate and inactivate both estrogens and their metabolites, thus preventing estrogen-mediated mitosis and mutagenesis. SULT1A1 and UGT1A1 genes are both polymorphic, and different alleles encode functionally different allozymes. We hypothesize that low activity alleles SULT1A1*2 and UGT1A1*28 are associated with the higher risk for breast cancer and more severe breast tumor phenotypes. We performed a case-control study, which included 119 women of Russian ancestry with breast cancer and 121 age-matched Russian female controls. We used PCR, followed by pyrosequencing to determine SULT1A1 and UGT1A1 genotypes. Our data showed that UGT1A1*28 allele was presented at a higher frequency than the wild type UGT1A1*1 allele in breast cancer patients as compared to controls (p = 0.002, OR = 1.79, CI 1.23-2.63). Consistently, the frequency of genotypes that contain the UGT1A1*28 allele in the homozygous or heterozygous state was greater than the frequency of the wild type UGT1A1*1/*1 genotype in breast cancer patients as compared to controls (p = 0.003, OR = 4.00, CI 1.49-11.11 and p = 0.014, OR = 2.04, CI 1.14-3.57, respectively). The group of individuals, carrying the UGT1A1*28 allele in the homo- or heterozygous state also presented larger breast tumors (>2 cm) as compared to the group with high enzymatic activity genotypes p = 0.011, OR = 3.44, CI 1.42-8.36). No association was observed between any of the SULT1A1 genotypes and breast cancer risk or phenotypes. Our data suggest that UGT1A1 but not SULT1A1 genotype might be important for breast cancer risk and phenotype in Russian women.

Gastrointestinal tuberculosis in renal transplantation: a case report and review.

The pattern of tuberculosis has changed and in recent years: extrapulmonary tuberculosis has become more common, especially in immuno-compromised individuals. A case of primary intestinal tuberculosis in a patient with kidney transplant is reported. The patient presented with persistent fever and right-sided abdominal pain. Histopathology of colonic tissue showed granulomatous inflammation containing acid fast bacilli, and culture of the tissue grew Mycobacterium tuberculosis. Clinical improvement occurred after institution of appropriate anti-tubercular treatment.

Considerations of acidifying water samples for 99Tc analysis.

Environmental water samples are routinely acidified before radionuclide analysis to prevent adsorption of radionuclides on the container walls. This study addresses the concern for volatilizing 99Tc from acid solutions during evaporation before beta analysis has been addressed. Water samples can be acidified to pH 1.7 with nitric acid and evaporated to dryness on planchets without significant losses of technetium due to volatilization. However, the planchets should not be flamed unless a detergent is used, and control samples should be flamed to determine the loss of activity under the conditions used.

Radiological sampling and analytical methods for National Primary Drinking Water Regulations.

Radiological sampling and analysis performed under the National Interim Primary Drinking Water Regulations were evaluated for the U.S. Environmental Protection Agency (EPA) Office of Drinking Water to consider whether any changes should be recommended. The authors reviewed the analytical screening scheme; sample collection, storage and analysis procedures; selection of analytical methods; reliability of results; and possible future needs. The main problem in the program has been dependence on a screening scheme of gross alpha-particle activity measurement and 226Ra analysis for predicting elevated 228Ra levels to determine compliance with the maximum contaminant level (MCL) for Ra. In some aquifers, 228Ra levels have been found to be unrelated to 226Ra levels. Several alternatives are discussed to eliminate this problem. A secondary problem is that the measurement for assuring compliance with the MCL for gross alpha-particle activity minus Ra, Rn and U uses chemical U analysis and assumes equilibrium of 238U and 234U. Because some ground waters are known to be at disequilibrium, radiometric U analysis is needed for those gross alpha-particle activities and chemical U values that could result in an erroneous conclusion relative to the MCL. In addition, studies were recommended for determining analytical uncertainties and assuring reliable sampling and sample maintenance; improvements in the system for accepting methods were suggested; and methods were identified for several radionuclides not currently in the analytical program that may be needed to assure absence of elevated radiation doses and could be useful for identifying trace contaminants.