Anti-CYP3A4 monoclonal antibody, clone FQS7313

In this article, we have established a highly promising approach for the synthesis of biscoumarins via domino Knoevenagel-Michael condensation of 4-hydroxycoumarin and aromatic aldehydes in 2:1 ratio using carbon-SO3H as a solid acid catalyst in H2O: EtOH (1:1). This new protocol produced alpha,alpha-benzylidene bis(4-hydroxycoumarin) derivatives in high to excellent yields. For this, carbon-SO3H solid acid catalyst has been prepared from glycerol and sulfuric acid and characterized by FT-IR, SEM, TGA, and X-ray diffraction methods. This approach has several advantages such as high atom-economy (96.05%), excellent yields (88-100%), no need of further purification techniques, that is, column chromatography, easy workup, less reaction time, cost-effective, avoid the use of hazardous solvents, recyclability of catalyst, etc. Moreover, molecular docking studies have been performed on selected proteins methylenetetrahydrohyrofolate reductase (MTHFR) and cytochrome P450 3A4 (CYP3A4) to identify the potency of the synthesized compounds(3a-j). Among the synthesized compounds3i,3e, and3bshowed the highest docking score against both the proteins.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5(star)1/(star)1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5(star)1(star)3 or CYP3A5(star)3/(star)3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.