Biomedical subjects

Elaine S Krul

Publications and source records attributed to Elaine S Krul.

3 recordsLinked to original sources

PubMed2007

Using genetic variation to optimize nutritional preemption.

One of the promises of nutritional genomics is a set of dietary recommendations that leverage our understanding of nutrient-gene interaction in the preemptive dietary management of complex chronic diseases. Whether nutritional genomics can deliver on this promise is a matter of debate and controversy. Although nutritional genomics is often viewed as an extension of pharmacogenomics, the pharmacogenomics paradigm is a disease-centric reductionistic model that overshadows both the complexities and opportunities to be leveraged in preemptive nutritional pharmacology. Moreover, the pharmacogenomics model tends to set clinical expectations that nutritional genomics may not be able to achieve. The biological boundaries of nutritional pharmacology are being tested in many areas of preventive medicine such as cardiovascular disease and cancer. In this regard, the lessons learned in one disease may be germane to the other. Recent results from the Vitamin Intervention for Stroke Prevention (VISP), the Norwegian Vitamin (NORVIT), and the Heart Outcomes Prevention Evaluation (HOPE) 2 trials underscore the incertitude of translating epidemiologic data into preemptive nutritional guidance. Moving ahead, the genetic determinism of the nutrigenomic model needs to take on a more holistic and phenotypic focus. To the extent this can be done, preemptive nutrition may one day become a safe and practical reality.

Diet↗

PubMed2003

Inhibition of both the apical sodium-dependent bile acid transporter and HMG-CoA reductase markedly enhances the clearance of LDL apoB.

Discovery of the ileal apical sodium-dependent bile acid transporter (ASBT) permitted development of specific inhibitors of bile acid reabsorption, potentially a new class of cholesterol-lowering agents. In the present study, we tested the hypothesis that combining the novel ASBT inhibitor, SC-435, with the HMG-CoA reductase inhibitor, atorvastatin, would potentiate reductions in LDL cholesterol (LDL-C) and LDL apolipoprotein B (apoB). ApoB kinetic studies were performed in miniature pigs fed a typical human diet and treated with the combination of SC-435 (5 mg/kg/day) plus atorvastatin (3 mg/kg/day) (SC-435+A) or a placebo. SC-435+A decreased plasma total cholesterol by 23% and LDL-C by 40%. Multicompartmental analysis (SAAM II) demonstrated that LDL apoB significantly decreased by 35% due primarily to a 45% increase in the LDL apoB fractional catabolic rate (FCR). SC-435+A significantly decreased hepatic concentrations of free cholesterol and cholesteryl ester, and increased hepatic LDL receptor mRNA consequent to increased cholesterol 7alpha-hydroxylase expression and activity. In comparison, SC-435 (10 mg/kg/day) monotherapy decreased LDL apoB by 10% due entirely to an 18% increase in LDL apoB FCR, whereas atorvastatin monotherapy (3 mg/kg/day) decreased LDL apoB by 30% due primarily to a 22% reduction in LDL apoB production. We conclude that SC-435+A potentiates the reduction of LDL-C and LDL apoB due to complementary mechanisms of action.

Animals↗

PubMed2002

Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein.

A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [(3)H]cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline analogues. Activity was substantially reduced by oxidation or substitution in the methylene of the benzylic group, implying that the benzyl ring orientation was important for activity. In the benzylic group, substitution at the 3-position was preferred over either the 2- or the 4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best 3-benzylic substituents were OCF(2)CF(2)H (42, IC(50) 0.14 microM in buffer, 5.6 microM in human serum), cyclopentyl (39), 3-iso-propoxy (27), SCF(3) (67), and C(CF(3))(2)OH (36). Separation of 42 into its enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent (IC(50) 0.02 microM in buffer, 0.6 microM in human serum) than the major S(-) enantiomer 1b, demonstrating that the R-chirality at the propanol 2-position is key to high potency in this series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with submicromolar potency in plasma. A chiral synthesis of 1a is reported.

Aniline Compounds↗