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Drugs online research references

J Pharmacol Exp Ther. 2000 Sep;294(3):844-9.
Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs.

Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, Endou H.

Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.

Organic anion transporter 1 (OAT1) is a p-aminohippurate/dicarboxylate exchanger that plays a primary role in the tubular secretion of endogenous and exogenous organic anions. OAT1 is located in the basolateral membrane of the proximal tubular cells and mediates the uptake of various organic anions from the peritubular fluid. In this study, we investigated the transport of antiviral nucleoside analogs via rat OAT1 (rOAT1) using a heterologous expression system in Xenopus laevis oocytes. Oocytes injected with rOAT1 cRNA showed significantly higher uptake of zidovudine (AZT) and acyclovir (ACV) than control oocytes. rOAT1-mediated uptake of AZT and ACV was probenecid-sensitive and increased by the outwardly directed gradient of glutarate. The affinity of rOAT1 for AZT and ACV was determined to be 68 and 242 microM, respectively. Five other antiviral agents that we studied (zalcitabine, didanosine, lamivudine, stavudine, and trifluridine) were also shown to be transported by rOAT1, whereas foscarnet, a phosphate analog, was not. The aforementioned nucleoside analogs lack a typical anionic group and are not very hydrophobic. This study demonstrates extension of the substrate spectrum of rOAT1 and provides a molecular basis for the pharmacokinetics of antiviral nucleoside analogs.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10945832&dopt=Abstract

Antiviral Res. 2002 Jun;54(3):163-74.
Establishment and use of a cell line expressing HSV-1 thymidine kinase to characterize viral thymidine kinase-dependent drug-resistance.

Kim JH, Park JB, Bae PK, Kim HS, Kim do W, Ahn JK, Lee CK.

Pharmaceutical Screening Center, Korea Research Institute of Chemical Technology, Taejon 305-600, South Korea.

To understand the mechanisms of antiviral drug resistance and to have a system to examine the cytotoxicity of herpes simplex virus type 1 (HSV-1) inhibitors that are thymidine kinase (TK)-dependent, we have constructed a plasmid pFTK1 by inserting a DNA fragment containing the TK gene of HSV-1 strain F into the eukaryotic expression vector pcDNA3.1/His A. TK-deficient 143B cells were transfected with this vector and neomycin-resistant cells were selected. Cell survival in HAT medium and TK activity of the cell lysates were examined to ascertain HSV-1 TK expression. A cell line expressing the viral TK gene, FTK143B (FTK), was established and used for characterization of two laboratory-derived TK-deficient drug-resistant HSV-1 mutants of strain F. The antiviral activities of several drugs, mostly nucleoside analogues, were compared in the Vero, 143B and FTK cell culture systems. We showed that both mutant viruses lost their resistance to acyclovir and to other HSV-1 TK-dependent compounds in FTK cells but not in Vero and 143B cells. Significantly increased cytotoxicity of ganciclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine was also observed in the FTK cells. This HSV-1 TK gene-transfected cell model is a useful tool to rapidly determine HSV-1 drug resistance at the viral TK level.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12062389&dopt=Abstract

J Pain Symptom Manage. 2002 Jun;23(6):510-6.
Clinical applications for change-point analysis of herpes zoster pain.

Desmond RA, Weiss HL, Arani RB, Soong SJ, Wood MJ, Fiddian PA, Gnann JW, Whitley RJ.

Medical Statistics Section, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294-3300, USA.

Pain is the most frequent and disabling complication of herpes zoster. The analysis of pain severity data is complicated by the nonlinear rate of resolution. Further, three distinct phases characterize pain resolution--acute, subacute, and chronic. Using two clinical trial datasets as the bases for analyses, the rates of baseline pain resolution were computed across each of three phases and compared for age, severity of pain at onset, and number of lesions at baseline. The results defined transition points of 24.4 +/- 3.34 for the subacute phase and 110.3 +/- 11.9 days for the chronic phase. The model demonstrated a treatment effect of valiciclovir (VACV) during the subacute phase as compared to acyclovir (ACV) (P = 0.006) and supports effects of age, baseline pain and number lesions on pain cessation rates in the acute phase. This model verifies three phases of zoster pain and delineates the impact of treatment and other factors on the phase-specific rates of pain cessation.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12067775&dopt=Abstract

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