Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans.

Objective To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase ( VKOR) and CYP2C9. Methods Warfarin maintenance dose, unbound plasma S-warfarin concentration [ Cu( S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset ( n=166), fully carboxylated plasma normal prothrombin levels ( NPT) were also measured. Genotyping for seven CYP2C9 ( CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement. Results The relationship between NPT and Cu( S) indicated Japanese are more susceptible to inhibition of NPT production by S- warfarin than the other two populations. VKORC1 1173 C > T had a greater frequency in Japanese ( 89.1%) than Caucasians ( 42.2%) and African-Americans ( 8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients ( 5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype- matched groups. Furthermore, VKORC1 1173C > T and CYP2C9 (* 2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage. Conclusions Both VKORC1 and CYP2C9 polymorphisms contribute to inter- population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population

Have lichenized fungi delivered promising anticancer small molecules?

This review, covering the literature from 1844 to present (end 2017), probes questions concerning small molecule metabolites derived from lichens (lichenized fungi) and their impact in terms of providing compounds with significant promise in oncology. The review gives an overview of lichenized fungi and summarizes the classes of compounds obtained as metabolites from these organisms. A definition of what characteristics an actual “promising” anticancer compound should possess is also delineated. The review reports a brief overview on human cancer and then goes into depth in listing compounds with so-called “anticancer properties” that have been isolated from lichenized fungi, according to their small molecule structural classes. Five “most promising” compounds are discussed in-depth, also considering the possibility of obtaining sufficient amounts for further investigations