Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity

Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC(50) 70 nM), strategically assembled on a pyridinone scaffold. A focused structure-activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC(50) 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC(50) 9 ± 4 nM, CC(50) 135 ± 7 μM, therapeutic index = 15,000).     

Central venous catheter related infections

Infusion therapy carries a substantial risk of producing iatrogenic sepsis, bacteremia or fungemia originating from the device used for vascular access or from the contaminated infusate. This study, a semiquantitative assay of the central venous catheter tips (CVC) was carried out and correlated with the blood culture results to determine the probable cause of sepsis in our post operated patients. One thousand six hundred and thirty one surgeries were performed in the Institute of Cardio-Vascular Diseases from January to December 1997. We received 150 CVC tips which were in place for more than five days for culture. Fifty one (51) CVC tips showed growth in either contents or roll. There was associated blood stream infection in 23 patients. The age groups of patients ranged from two months to 67 years and male to female ratio was 109:41. Children below the age of 12 years were 62 in number. Candida spp. (32.4%) and Staphylococcus spp. (33.9%) formed the predominant isolates from the CVC tips.     

Clinical characteristics and survival experience of out-of-hospital cardiac arrest victims without coronary heart disease

Of 270 patients successfully resuscitated from out-of-hospital cardiac arrest, 16% had no evidence of coronary heart disease. In these 43 patients, other forms of heart disease were found in 81% (35/43): cardiomyopathy in 18 patients, valvular disease in six, congenital heart disease in two, and primary arrhythmia in nine. Seven patients had evidence of only pulmonary disease and one had pancreatitis as his precipitating event. Nineteen of the 43 patients (44%) had serum potassium less than 3.6 mEq l-1 in the initial blood sample after cardiac arrest. One- and two-year mortalities were 30% and 43%, respectively, for the group, which is similar to one-year (20%) and two-year (35%) mortalities of the 227 resuscitated patients with coronary heart disease. Patients who survive a sudden death experience and who have no evidence of coronary artery disease are a unique but heterogeneous group who usually have identifiable cardiac or pulmonary disease.