Summary Background VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. Methods We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10−8 in the discovery cohort and p<0·0038 in the replication cohort. Findings The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10−8). This association was confirmed in the replication cohort (p=5·04×10−5); analysis of the two cohorts together produced a p value of 4·5×10−12. Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). Interpretation A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. Funding National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.

Background and objective Warfarin is a commonly used oral anticoagulant with a narrow therapeutic index and various genetic and clinical factors that influence interpatient variability in dose requirements. This study investigated the impact of genetic and nongenetic factors on warfarin dose requirements in Egyptians. Methods DNA was extracted from 207 patients taking warfarin for more than 2 months and genotyped for VKORC1 (3673 G> A), CYP2C9 *2*3*4*5*8, CYP4F2 (V33M; rs2108622), APOE (rs429358, rs7412), and CALU (rs339097) gene polymorphisms. Linear regression modeling was conducted to identify the genetic and nongenetic factors that independently influence warfarin dose requirements. Results VKORC1 3673 AA or GA genotype (P < 0.0001), one or two variant alleles of CYP2C9 gene (P= 0.0004), APOE ε2 haplotype (P = 0.01), and increasing age (P < 0.0001) were all associated with lower warfarin dose, whereas smoking (P = 0.025) and pulmonary embolism (P = 0.0059) showed association with higher warfarin doses. These factors explained 31% of the warfarin dose variability. This is the first independent confirmation of the association of the CALU rs339097 variant with higher warfarin dose requirement, although inclusion of this single nucleotide polymorphism in the multiple regression model failed to achieve significance (P = 0.066). CYP4F2 (V33M) polymorphism was not significant (P = 0.314), despite its high frequency in the studied population (42%). Conclusion The study shows that VKORC1, CYP2C9 polymorphisms, APOE ε2 variant, and several clinical/ demographic variables are important determinants of warfarin dose requirements in Egyptian patients. The percentage of variability explained by these factors is lower than in those of European ancestry, but similar to the variability explained in Asians and African ancestry.

A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

The natural cembranolide sarcophine (3) and its lactone ring-opened analogue (10) were oxidized using selenium dioxide under different reaction temperatures to prepare hydroxylated derivatives. Nine new compounds were obtained, six of them targeted hydroxylated derivatives. The determination of regio- and stereochemistry as well as the mechanistic considerations on the selectivity observed in these reactions are discussed on the basis of 2D NMR and molecular modeling. In preliminary in vitro tests on inhibition of EBV-EA activation, compounds 10 and 12-15 have shown higher activity than the known chemopreventive agent sarcophytol A.

Potent antifungal cyclic lipopeptides, burkholdines (Bk), were isolated from a culture of Burkholderia ambifaria 2.2N. Bk-1229 (1) and Bk-1097 (2) are octapeptides comprised of nonproteinogenic amino acids, including -hydroxytyrosine, -hydroxyasparagine, and a new fatty acyl amino acid. 1 and 2 are fungicidal against a panel of fungi with potencies 2-60-fold better than amphotericin B control.

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The utility of a species can be divided into its direct, indirect, and options values. In the marine environment, direct consumptive values predominate and often lead to overexploitation at the expense of significant options values derived through bioprospecting for natural products. We surveyed the waters of the Egyptian Red Sea coast (Gulf of Aqaba [north] and the Red Sea [south]) for species of sea cucumbers and analyzed extracts from species for a range of bioactivities with potential biomedical applications. All habitat types were surveyed within these regions. We found 22 species of sea cucumber of which two, Holothuria fuscogilva and Holothuria flavomaculata, were recorded in Egypt for the first time. Although none of the species identified were unique to the Gulf of Aqaba, 10 species were only found in the Red Sea sector. Bioassay results showed that although no species had antibacterial activity, most extracts exhibited activity against Candida and Leishmania but were most active against a LoVo mammalian carcinoma cell line. Our most significant finding was the intraspecific variation in bioactivity in individuals collected from different habitat types and sectors of the coast. This variation may reflect the effect of environment on secondary metabolite production or may indicate significant genetic diversity between populations within a species. Our results indicate a potentially significant options value to sea cucumbers through bioprospecting. Given the importance of economic development in countries such as Egypt and the perceived low conservation value of invertebrates such as sea cucumbers, the linking of these factors to conservation is vital for the maintenance and sustainable exploitation of these animals.

Objective. To assess pharmacy students' knowledge and perceptions of doping and anti-doping in sports and to explore the curricular needs for undergraduate pharmacy in the field of sports pharmacy. Methods. A cross-sectional, descriptive, web-based survey of pharmacy students was conducted at Qatar University College of Pharmacy from March to May 2014. Data were analyzed using descriptive and inferential statistics. Results. Eighty respondents completed the online survey (80% response rate). Sixty percent were unaware of the World Anti-Doping Agency, and 85% were unaware of the International Pharmaceutical Federation's statement on the pharmacist's role in anti-doping. Students' knowledge score regarding the prohibited status of drugs that may be used by athletes was around 50%. Fourth-year pharmacy students had significantly higher knowledge scores than the other groups of students. Respondents acknowledged the important role of health care professionals, including pharmacists, as advisors on the safe and effective use of drugs in sports. Ninety percent of the students supported the inclusion of sports pharmacy in the curriculum. Conclusion. Pharmacy students indicated a strong desire to play a role in doping prevention and ensure safe and rational use of drugs among athletes. They suggested requiring an education and training strategy for sports pharmacy in undergraduate pharmacy curricula.