Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant.

Background: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine.

Cigarette smoking and metabolic syndrome components: a cross-sectional study from Maracaibo City, Venezuela.

A growing body of evidence suggests that cigarette smoking can cause the onset of metabolic syndrome prior to cardiovascular diseases. Therefore, the objective of this study was to evaluate the relationship between smoking habit and metabolic syndrome components in an adult population from Maracaibo city, Venezuela. The Maracaibo City Metabolic Syndrome Prevalence Study is a descriptive, cross-sectional study with random and multi-stage sampling.

Methoxyoxalamido chemistry in the synthesis of tethered phosphoramidites and functionalized oligonucleotides.

A general approach to phosphoramidites tethered with single and multiple linkers through the use of methoxyoxalamido (MOX) chemistry is described. The approach utilizes readily available and inexpensive primary aliphatic amino alcohols and diamines to produce a rich and diverse variety of tethered phosphoramidites. Furthermore, the use of MOX chemistry in a modular fashion enables fairly rapid assembly of compound tethers.

High-throughput production of optimized primers (fimers) for whole-genome direct sequencing.

Fimers are specifically modified primers selected to inhibit nonspecific interactions occurring in cycle sequencing. They are postsynthetically derived from 2'-methoxyoxalamido or 2'-succinimido precursor oligonucleotides by treatment with appropriate small molecular weight modifiers (a primary aliphatic amine or hydroxide anion). We describe design, synthesis, and purification of fimers, and their use in protocols for direct sequencing of genomic deoxyribonucleic acid (DNA).

Biotin-labeled oligonucleotides with extraordinarily long tethering arms.

We describe synthesis of four novel biotin phosphoramidites with tethering arms ranging from 20 to 74 atoms in length. One of these phosphoramidites is a uridine derivative with a biotin moiety attached through the 2'-position. The biotin phosphoramidites were synthetized based on robust and efficient methoxyoxalamido (MOX) and succinimido (SUC) precursor strategies from MOX/SUC precursors containing a secondary hydroxyl.

Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in vitro.

Aims: To confirm the identity of the major metabolites of domperidone and to characterize the cytochrome P450s (CYPs) involved in their formation.

Methods: Human liver microsomes (HLMs) were used to characterize the kinetics of domperidone metabolism and liquid chromatography-mass spectrometry to identify the products. Isoform-specific chemical inhibitors, correlation analysis and expressed human CYP genes were used to identify the CYPs involved in domperidone oxidation.

Methoxyoxalamido chemistry in the synthesis of novel amino linker and spacer phosphoramidites: a robust means for stability, structural versatility, and optimal tether length.

We have developed a general route to the synthesis of novel amino linker and spacer phosphoramidites utilizing methoxyoxalamido (MOX) chemistry. The synthesis makes use of readily available and inexpensive primary aliphatic amino alcohols and diamines to produce a rich and diverse variety of phosphoramidites. Among these are monomers with exceptionally long (up to 56 atoms in length) amphipathic tethering arms.

Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine.

Background: Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes. Selective serotonin reuptake inhibitors (SSRIs), which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs. In a prospective clinical trial, we tested the effects of coadministration of tamoxifen and the SSRI paroxetine, an inhibitor of CYP2D6, on tamoxifen metabolism.

Novel biotin phosphoramidites with super-long tethering arms.

A number of novel biotin phosphoramidites, possessing exceptionally long and uncharged tethering arms, were synthesized from methoxyoxalamido (MOX) and succinimido (SUC) precursors. Included among these monomers is a uridine derivative with the biotin moiety attached through the 2'-position. Some of these phosphoramidites were used to make 5'-biotinylated primers, which were applied in direct sequencing of genomic DNA and capture of Sanger fragment pools.

Stability, vigor, and inherent versatility of novel amino linker and spacer phosphoramidites.

Novel amino linker and spacer phosphoramidites were synthesized from methoxyoxalamido (MOX) percursors possessing a secondary hydroxyl, which when phosphitylated endowed stability to the corresponding phosphoramidites. The synthetic strategy is robust, and the chemistry is reactive towards a variety of primary aliphatic diamines and amino alcohols to produce distinctly unique phosphoramidites. The selection of building blocks determines the length and physico-chemical properties of the phosphoramidite tethering arms, and the synthesis can be specifically tailored to suit individual requirement.

The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6.

Metoclopramide is increasingly prescribed for conditions previously treated with cisapride, but its metabolic enzymology and drug interactions are poorly understood. Using human liver microsomes (HLMs) and recombinant human cytochromes P450 (P450), we identified the major route of metoclopramide oxidation and the P450 isoforms involved. We also documented the ability of metoclopramide to inhibit the P450 system, using isoform-specific substrate reaction probes of CYP1A2, 2C19, 2C9, 2D6, 2E1, and 3A4.

Stereoselective metabolism of cisapride and enantiomer-enantiomer interaction in human cytochrome P450 enzymes: major role of CYP3A.

Cisapride is a chiral molecule that is marketed as a racemate consisting of two optical isomers, but little is known about its stereoselective metabolism. Studies with (-)-, (+)-, and (+/-)-cisapride were undertaken in human liver microsomes (HLMs) and recombinant cytochrome P450s (P450s) to determine the stereoselective metabolism and enantiomer-enantiomer interaction. Each enantiomer and racemic cisapride were N-dealkylated to norcisapride (NORCIS) and hydroxylated to 3-fluoro-4-hydroxycisapride (3-F-4-OHCIS) and 4-fluoro-2-hydroxycisapride (4-F-2-OHCIS).

Stereoselective determination of cisapride, a prokinetic agent, in human plasma by chiral high-performance liquid chromatography with ultraviolet detection: application to pharmacokinetic study.

We have developed a simple, sensitive, specific and reproducible stereoselective high-performance liquid chromatography technique for analytical separation of cisapride enantiomers and measurement of cisapride enantiomers in human plasma. A chiral analytical column (ChiralCel OJ) was used with a mobile phase consisting of ethanol-hexane-diethylamine (35:64.5:0.

On the rapid deprotection of synthetic oligonucleotides and analogs.

The efficiency of oligodeoxynucleotide deprotection is greatly enhanced using a combination of: (a) ethanolamine, and especially a mixture of hydrazine, ethanolamine and methanol, in place of the usual aqueous ammonia; (b) tert-butylphenoxyacetyl amino protecting groups, and (c) oxalyl link between the first nucleotide and the polymeric support. The extent of base modification, particularly of C, is shown to be extremely low, and the quality of deprotected oligonucleotides is as high as in the case of ammonia deprotection. This method is also shown to be applicable to the preparation of phosphorothioate and methylphosphonate oligodeoxynucleotides and oligoribonucleotides.

Synthesis of phosphorothioate-methylphosphonate oligonucleotide co-polymers.

We describe the synthesis and characterization of novel phosphorothioate-methylphosphonate backbone-modified oligodeoxynucleotide co-polymers. These may have potential use as antisense constructs.

Phospholipids chiral at phosphorus. Stereochemical mechanism for the formation of inositol 1-phosphate catalyzed by phosphatidylinositol-specific phospholipase C.

The phosphatidylinositol-specific phospholipase C (PI-PLC) from mammalian sources catalyzes the simultaneous formation of both inositol 1,2-cyclic phosphate (IcP) and inositol 1-phosphate (IP). It has not been established whether the two products are formed in sequential or parallel reactions, even though the latter has been favored in previous reports. This problem was investigated by using a stereochemical approach.