Pyrazolopyrimidinone Based Selective Inhibitors of PDE5 for the Treatment of Erectile Dysfunction

Continuing research with our earlier finding of sildenafil based analogs in the search of new inhibitors of PDE5 for erectile dysfunction suggested that there is a scope of modifications at N-methylpiperazine ring with hydrophobic region followed by hydrogen bond donor or acceptor region. However, the leads identified earlier had some limitations like poor pharmacokinetic (PK) profile, low aqueous solubility and poor bioavailability. In this direction, a new series of sildenafil based analogs were designed, synthesized and screened for their PDE5 inhibitory activity. In this series compound 18 was found to have excellent in vitro activity with selectivity towards PDE5 isozyme, also the in vivo activity and pharmacokinetic profile was excellent. The cyp inhibition and CaCO₂ permeability was also excellent for compound 18 .     

Partition coefficient of bovine serum albumin in two-phase aqueous systems

Summary We measured partition coefficients of bovine serum albumin in the following two-phase aqueous systems: polyethylene glycol-dextran and polyethylene glycol-potassium phosphate. We report the effects on partition coefficients of variables such as relative molecular masses of polyethylene glycol and dextran, phase composition and temperature.Contribution of National Bureau of Standards, not subject to copyright.     

Synergistic effect of two β globin gene cluster mutations leading to the hereditary persistence of fetal hemoglobin (HPFH) phenotype

Co-inheritance of gamma and beta globin gene mutations in a compound heterozygous state is rare but of clinical interest as it provides an important data on understanding the HbF expression. Hematological analysis was carried out (Sysmex KX-21). F-cells were enumerated using flow cytometry. Beta globin gene was analysed by CRDB technique and by DNA sequencing. Gamma globin promoter region was sequenced and expression studies were carried out using real time Taqman assay. We report a family, where two inherited defects of the β globin gene cluster segregate. The proband and her sibling were compound heterozygotes for a novel ^Gγ promoter mutation and the 619 bp deletion a common Indian β thalassemia mutation. Molecular characterization revealed that the father (HbA₂ 5.1%, HbF 5.4%), proband (HbA₂ 3.6%, HbF 31.7%) and her brother (HbA₂ 3.9%, HbF 23.6%) were heterozygous for the 619 bp deletion. The mother (HbA₂ 2.1%, HbF 3.4%) had a normal β globin gene. As both the children showed high HbF levels, the γ globin gene work up was carried out. The ^Gγ-globin gene promoter analysis revealed that the mother and the two children were heterozygous for a 5 bp deletion -ATAAG (-533 to -529) that resides in the GATA binding site. These findings suggest that the 5 bp deletion in the ^Gγ globin promoter has a functional role in silencing the γ-globin gene expression in adults by disrupting GATA-1 binding and the associated repressor complex and results in the up-regulation of gamma globin gene expression. When co-inherited with β -thalassemia trait it leads to a phenotype of HPFH.     

Studies on triacylglycerol ester hydrolase from bat adipose tissue

Triacylglycerol ester hydrolase was isolated from bat adipose tissue and characterized. The partially purified enzyme had pH optimum of 8.6 and a K_m value of 0.6 mM. The enzyme was denaturated upon freezing and thawing, which was prevented by 25% glycerol. The enzyme was activated by EDTA and NaCl, while it was inhibited by serum and bovine serum albumin. Heparin, sodium fluoride and diisopropyl fluorophosphate had no effect on triacylglycerol ester hydrolase activity. It hydrolyzed triglycerides partially. Triacylglycerol ester hydrolase lost its activity during delipidation but it was reactivated by endogenous lipids and phospholipids, viz. phosphatidyl ethanolamine, phosphatidyl choline and sphingomyelin. The enzyme shows kinetic properties altogether different from lipoprotein lipase and hormone sensitive lipase     

Radiopacity additives in silicone stent materials reduce in vitro bacterial adherence

In vitro adherence of the nosocomial pathogensPseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens, andCandida albicans to select radiopaque silicone compounds was lower than that observed for the base silicone (p<0.03). Except forE. coli ATCC 11775 andCandida albicans, all microorganisms showed significantly lower adherence to a silicone compound impregnated with tantalum in comparison with a silicone compound impregnated with barium sulfate (p<0.05). Surface hydrophobicity of the silicone compounds did not show a direct correlation with the concentration of radiopacity additives or with degree of bacterial adherence. Scatchard analyses of data indicated that the number of adherence sites forP. aeruginosa on the base silicone, BaSO₄-silicone, and Ta-silicone were 9.2×10⁶ per mm², 6.1×10⁶ per mm², and 3.7×10⁶ per mm² respectively. As determined by the Langmuir adsorption isotherm, the dissociation constants for adheredP. aeruginosa to the base silicone, BaSO₄-silicone, and Ta-silicone were 2.50×10³ mm⁴, 1.45×10³ mm⁴, and 6.27×10³ mm⁴ respectively.Pseudomonas aeruginosa demonstrated first order kinetics of adherence to the silicone compounds with a half saturation time of 4.15 h for the base silicone, 1.06 h for the BaSO₄-silicone, and 2.14 h for the Ta-silicone. The use of Ta-silicone stents may delay the development of ascending urinary tract infections.