Structure-activity relationship of purine ribonucleosides for inhibition of hepatitis C virus RNA-dependent RNA polymerase

As part of a continued effort to identify inhibitors of hepatitis C viral (HCV) replication, we report here the synthesis and evaluation of a series of nucleoside analogues and their corresponding triphosphates. Nucleosides were evaluated for their ability to inhibit HCV RNA replication in a cell-based, subgenomic replicon system, while nucleoside triphosphates were evaluated for their ability to inhibit in vitro RNA synthesis mediated by the HCV RNA-dependent RNA polymerase, NS5B. 2'-C-Methyladenosine and 2'-C-methylguanosine were identified as potent inhibitors of HCV RNA replication, and the corresponding triphosphates were found to be potent inhibitors of HCV NS5B-mediated RNA synthesis. The data generated in the cell-based assay demonstrated a fairly stringent structure-activity relationship around the active nucleosides. Increase in steric bulk beyond methyl on C2, change in the stereo- or regiochemistry of the methyl substituent, or change of identity of the heterobase beyond that of the endogenous adenine or guanine was found to lead to loss of inhibitory activity. The results highlight the importance of the ribo configuration 2'- and 3'-hydroxy pharmacophores for inhibition of HCV RNA replication in the cell-based assay and demonstrate that inclusion of the 2'-C-methylribonucleoside pharmacophore leads to increased resistance to adenosine deaminase and purine nucleoside phosphorylase mediated metabolism.     

Recurrent urinary tract infection in girls. Group with lower tract findings and a benign course

A group of girls is described with recurrent urinary tract infections characterized by predominantly lower tract symptoms. Clinical, laboratory, and radiography findings during the period of follow-up are presented. Infection persisted in most patients over several years. Response to medical and surgical treatment was unsatisfactory. The mean interval between the initial and most recent radiological study was 6 1/2 years. No case of renal parenchymal scarring was seen.     

Beverage-induced enhanced bioavailability of carbamazepine and its consequent effect on antiepileptic activity and toxicity

The present study was undertaken to investigate the food–drug interaction of carbamazepine (CBZ). Common fruit juices [grapefruit juice (GFJ), lime juice (LJ)], known to inhibit the enzyme cytochrome P450 3A4 (CYP3A4), and some widely consumed beverages [milk (M), black tea (BT)] were involved in this study in the presence of CBZ, as might happen during clinical therapy. The effects of the beverages on the pharmacokinetics and drug-induced toxicity of CBZ was observed after concomitant administration for a period of 28 days. Accordingly, the influence of altered bioavailability of CBZ on its antiepileptic activity was investigated. A significant shift in the C_max as well as T_max of CBZ was observed in the presence of LJ and GFJ. This increase in bioavailability significantly enhanced hepatotoxicity and delayed the onset of tremor and piloerection against pentylene tetrazole (PTZ)-induced seizure in experimental animals. However, increased toxicity of CBZ was found to be absent with BT. Thus, from our observation, LJ or GFJ in the presence of CBZ significantly increased the bioavailability of CBZ, which might lead to increased toxicity and antiepileptic activity of the drug.     

Development of a High-Performance Liquid Chromatographic Method for Determination of Letrozole in Wistar Rat Serum and its Application in Pharmacokinetic Studies

A fast, sensitive, and specific reversed-phase high-performance liquid chromatographic (RP–HPLC) method for the determination of letrozole in Wistar rat serum was developed. In this method, liquid–liquid extraction of letrozole was achieved using diethyl ether as the extracting solvent. The analysis was carried out on a reversed-phase C18 (250 mm × 4.6 mm, 5 μm) column with an isocratic mobile phase of methanol–water (70:30,v/v), at a flow rate of 1.0 mL min⁻¹. Detection was carried out at 239 nm with a UV–visible spectrophoto-metric detector. The method was shown to be selective and linear over the concentration range of 0.15–100 μg mL⁻¹. The intra-day and inter-day precision studies showed good reproducibility with coefficients of variation less than 11% for the analyte. The relative errors of intra– and inter–day accuracy were within −11.52 to −2.26%. The limit of quantification was evaluated to be 0.15 μg mL⁻¹. The method was successfully applied for the pharmacokinetic study of letrozole after oral administration of 10 mg kg⁻¹ of letrozole in six healthy Wistar rats.     

DA8 Evaluating Health Outcomes and Pharmacoeconomic Literature

In 1997, the United States Pharmacopeia (USP) established an Ad Hoc Outcomes/Cost Effectiveness Advisory Panel to consider the development of specifications for compiling, indexing, and evaluating outcomes research/cost-effectiveness literature on a disease-specific basis. Such a resource could be used to support pharmaceutical therapy choice decision making by a variety of potential users. The USP had developed a protype health outcomes and pharmacoeconomic annotated registry of the literature on the disease state, congestive heart failure. Other organizations have established and are marketing pharmacoeconomic and health outcome literature registries, with two examples being the HEED database (OHE-IFPMA Database Ltd.) and the University of York NHS Centre for Reviews and Dissemination (DARE).
OBJECTIVE: To share experiences and to identify the needs of decision makers for outcome/pharmacoeconomic information and to discuss whether they are being met by currently available literature sources. Decision makers include health care practitioners, managed care organizations, third party payers, industry and governments.
WORKSHOP FORMAT: The USP congestive heart failure protype literature registry will be described and compared to currently available pharmacoeconomic/outcome databases. Participants will share their assessment of the currently available abstracting service/databases and determine if there is a role for further developments.
DESIRED OUTCOME: To determine if there is a need for a collaborative approach among interested parties to make relevant health outcome/pharmacoeconomic information more accessible to the drug therapy decision makers in a format that is "user friendly."     

Synthesis and in vitro Evaluation of 1,2,4‐Triazolo[1,5‐a][1,3,5]triazine Derivatives as Thymidine Phosphorylase Inhibitors

In our lead finding program, a series of 1,2,4‐triazolo[1,5‐a][1,3,5]triazine derivatives were synthesized, and their in vitro thymidine phosphorylase inhibitory potential was explored. Among the different derivatives, compounds having keto group (C = O) at C7 and thioketo group (C = S) at C5 positions showed varying degrees of TP inhibitory activity comparable with positive control, 7‐deazaxanthine ( 7‐DX , 2 ) (IC₅₀ value = 42.63 μm ). Enzyme inhibition kinetics study suggested that compound IVn behaved as a mixed‐type inhibitor of the enzyme with respect to thymidine (dThd) as a variable substrate. Compound IVn was also found to inhibit PMA‐induced MMP‐9 expression in MDA‐MB‐231 cells at sublethal concentrations. Computational docking study was performed to illustrate the enzyme inhibition kinetics and to explore the ligand–enzyme interactions.