Does Pharmacogenomics Account for Variability in Control of Acute Chemotherapy-Induced Nausea and Vomiting With 5-Hydroxytryptamine Type 3 Receptor Antagonists?

Does Pharmacogenomics Account for Variability in Control of Acute Chemotherapy-Induced Nausea and Vomiting with 5-Hydroxytryptamine Type 3 Receptor Antagonists?

Curr Oncol Rep. 2013 Mar 21;
Trammel M, Roederer M, Patel J, McLeod H

Chemotherapy-induced nausea and vomiting is one of the most concerning adverse drug effects from cytotoxic chemotherapy. Despite appropriate use of antiemetic guidelines, 20-30 % of patients experience breakthrough nausea and vomiting secondary to chemotherapy. To assess the variability of 5-hydroxytryptamine type 3 receptor antagonist efficacy caused by genetic variation, a review of the available literature was conducted. From the literature, three sources of pharmacogenomic variability were identified: polymorphisms associated with 5-hydroxytryptamine type 3 receptor subunits, drug metabolism via cytochromes P450, and drug transport in the body. Testing for receptor subunit polymorphisms is not applicable to a clinical setting at this time; however, cytochrome P450 2D6 testing is FDA-approved and widely accessible. Cytochrome P450 2D6 ultrarapid metabolizers and poor metabolizers displayed altered antiemetic efficacy when compared with intermediate metabolizers and extensive metabolizers. We postulate that testing for cytochrome P450 2D6 phenotypes may be the most accessible way to provide individualized antiemetic therapy in the future. HubMed – drug


Dynamic View on Affordability of Fixed-Dose Combination Antihypertensive Drug Therapy.

Am J Hypertens. 2013 Mar 18;
Hong SH, Wang J, Tang J

BackgroundThe use of fixed-dose combinations (FDCs) has been increasing since the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommended using ?2 drugs as the first-line drug therapy for patients with stage 2 hypertension. FDCs simplify the drug therapy regimen and reportedly lower the drug therapy cost compared with the free combination (FC) of 2 single-agent drugs. This study hypothesized that the affordability of FDCs over FCs would change over time depending on the availability of generic single-agent drugs.MethodsThis study used the 2009 Medical Expenditure Panel Survey. Antihypertensive drugs were identified based on the Food and Drug Administration national drug directory. Based on the 2 databases, regression models were run to predict average monthly drug cost as well as out-of-pocket cost for each prescription along with their 95% confidence intervals (CIs).ResultsOverall, FDCs (n = 26) had average monthly drug costs similar to respective FCs when FCs were not generically available. However, when FCs were generically available, FDCs (n = 11) had average drugs costs much higher than their respective FCs. For example, Lotrel as an FDC had an average monthly drug cost of $ 115.97 (95% CI = $ 96.59-$ 135.36), whereas its counterpart FC had an average monthly drug cost of $ 21.00 (95% CI = $ 18.23-$ 23.79).ConclusionsThe cost advantage of FDCs over FCs was reversed when FCs were generically available. The finding of this study informs patients, health-care providers, and drug plans of the importance of making dynamic decisions on preferred drug therapy options depending on the availability of generic drugs. HubMed – drug


Biotinylation of a propargylated cyclic (3′-5′) diguanylic Acid and of its mono-6-thioated analog under “click” conditions.

Curr Protoc Nucleic Acid Chem. 2013 Mar; Chapter 14: Unit14.9
Grajkowski A, Cie?lak J, Schindler C, Beaucage SL

Commercial N(2)-isobutyryl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(propargyl)guanosine is converted to its 3′-O-levulinyl ester in a yield of 91%. The reaction of commercial N(2)-isobutyryl-5′-O-(4,4′-dimethoxytrityl)-2′-O-tert-butyldimethylsilyl-3′-O-[(2-cyanoethyl)-N,N-diisopropylaminophosphinyl]guanosine with N(2)-isobutyryl-2′-O-propargyl-3′-O-(levulinyl)guanosine provides, after P(III) oxidation, 3′-/5′-deprotection, and purification, the 2′-O-propargylated guanylyl(3′-5′)guanosine 2-cyanoethyl phosphate triester in a yield of 88%. Phosphitylation of this dinucleoside phosphate triester with 2-cyanoethyl tetraisopropylphosphordiamidite and 1H-tetrazole, followed by an in situ intramolecular cyclization, gives the propargylated cyclic dinucleoside phosphate triester, which is isolated in a yield of 40% after P(III) oxidation and purification. Complete removal of the nucleobases, phosphates, and 2′-O-tert-butyldimethylsilyl protecting groups leads to the desired propargylated c-di-GMP diester. Cycloaddition of a biotinylated azide with the propargylated c-di-GMP diester under click conditions provides the biotinylated c-di-GMP conjugate in an isolated yield of 62%. Replacement of the 6-oxo function of N(2)-isobutyryl-5′-O-(4,4′-dimethoxytrityl)-3′-O-levulinyl-2′-O-(propargyl)guanosine with a 2-cyanoethylthio group is effected by treatment with 2,4,6-triisopropybenzenesulfonyl chloride and triethylamine to give a 6-(2,4,6-triisopropylbenzenesulfonic acid) ester intermediate. Reaction of this key intermediate with 3-mercaptoproprionitrile and triethylamine, followed by 5′-dedimethoxytritylation, affords the 6-(2-cyanoethylthio)guanosine derivative in a yield of 70%. The 5′-hydroxy function of this derivative is reacted with commercial N(2)-isobutyryl-5′-O-(4,4′-dimethoxytrityl)-2′-O-tert-butyldimethylsilyl-3′-O-[(2-cyanoethyl)-N,N-diisopropylaminophosphinyl]guanosine. The reaction product is then converted to the mono-6-thioated c-di- GMP biotinylated conjugate under conditions highly similar to those described above for the preparation of the biotinylated c-di-GMP conjugate, and isolated in similar yields. Curr. Protoc. Nucleic Acid Chem. 52:14.9.1-14.9.20. © 2013 by John Wiley & Sons, Inc. HubMed – drug


Synthesis of Privileged Scaffolds by Using Diversity-Oriented Synthesis.

Chem Asian J. 2013 Mar 19;
Surakanti R, Sanivarapu S, Thulluri C, Iyer PS, Tangirala RS, Gundla R, Addepally U, Murthy YL, Velide L, Sen S

An elegant reagent-controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In?silico studies were used to estimate the drug-like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14. HubMed – drug