The mechanism of action of the anti-herpes virus compound 2,3-dimethyl-6(2-dimethylaminoethyl)-6H-indolo-(2,3-b)quinoxaline.

The compound 2,3-dimethyl-6(2-dimethylaminoethyl)6H-indolo-(2,3-b)quinoxaline (B-220) has been shown to exhibit potent antiviral activity against herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV) and cytomegalovirus (CMV). The mechanism of antiviral action of B-220 against HSV-1 has been studied; from the results it appears that B-220 binds by intercalation into the DNA helix and then disturbs steps that are vital for viral uncoating.

Inhibition of human herpesvirus 6 replication by 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (2HM-HBG) and other antiviral compounds.

The in vitro susceptibilities of human herpesvirus 6 to foscarnet; the guanosine analogs acyclovir, ganciclovir, and two isomers of 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine; and the thymidine analogs 3'-azido-3'-deoxythymidine and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil were investigated. All compounds except 3'-azido-3'-deoxythymidine and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil inhibited human herpesvirus 6 replication. The highest in vitro selectivity was obtained for 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine.

Synergistic inhibition of human immunodeficiency virus replication in vitro by combinations of 3'-azido-3'-deoxythymidine and 3'-fluoro-3'-deoxythymidine.

The antiviral activity against human immunodeficiency virus type 1 of the two structurally related thymidine analogs azidothymidine and fluorothymidine, both alone and in combination, was tested. Fluorothymidine was tenfold more active than azidothymidine. The selectivity indices of the two compounds were similar. The combination of azidothymidine and fluorothymidine showed clearly synergistic antiviral activity, and diminished cytotoxicity. The inhibition of reverse transcriptase from human immunodeficiency virus type 1 by the triphosphates of azidothymidine and fluorothymidine, both alone and in combination was also tested. Azidothymidine triphosphate was a fourfold stronger inhibitor than fluorothymidine triphosphate. The combination of the two showed only additive (and not synergistic) effects upon reverse transcriptase. The combination of azidothymidine and fluorothymidine showed both synergistic antiviral activity and diminished cytotoxicity, and may therefore represent a promising therapeutic strategy. The additive (and not synergistic) inhibition of reverse transcriptase by the combination of the triphosphates indicates that in cell culture additional factors other than inhibition of the reverse transcriptase by the triphosphates influence the antiviral activity of the combination. Such factors might include effects upon normal nucleoside metabolism or metabolism of the analogs. Alternatively, one of the nucleosides might have an additional mechanism of action besides inhibition of the reverse transcriptase.

Improved sample preparation method for high-performance liquid chromatography of deoxyribonucleoside triphosphates from cell culture extracts.

The accurate determination of deoxyribonucleoside triphosphates in cells is difficult owing to the high concentrations of interfering ribonucleoside triphosphates. The latter can be degraded to their respective bases by periodate oxidation of cell extracts. However, the large amount of bases so produced can interfere with subsequent high-performance liquid chromatographic (HPLC) analysis. The use of a weak ion-exchange cartridge to partially purify and concentrate deoxyribonucleoside triphosphates in periodate-treated cell extracts, prior to HPLC, thus allowing accurate determination is described. The recovery of the deoxyribonucleoside triphosphates is greater than 95%, and greater than 90% of the interfering bases are removed.

Evaluation by immune scanning electron microscopy of foscarnet treatment of cytomegalovirus infection in patients with renal transplants.

Eight patients, 7 renal and 1 combined renal and pancreas allograft recipients with generalized cytomegalovirus (CMV) infection were treated with continuous intravenous foscarnet infusion (0.15 mg/kg/min) for 10-14 days. Antiviral effect was studied by immune scanning electron microscopy for detection of CMV antigen in serum and urine, by virus isolation in tissue culture in samples from buffy coat, broncholavage and urine and by serology. CMV antigen was detected in serum samples in 8 patients and 5 had positive virus isolation from buffy coat, before institution of therapy. The 3 patients with negative virus isolation in tissue culture had serological evidence of a reactivated CMV infection. Virus replication was inhibited by foscarnet treatment in 7 patients within a week (p less than 0.01) (Wilcoxon log rank test). 7/8 patients had no detectable CMV antigen in serum or urine after 7-10 days of treatment (p less than 0.01) (Wilcoxon log rank test).

Sensitivity of cytomegalovirus to intravenous foscarnet treatment.

Intravenous foscarnet was given on an emergency basis to 30 immunosuppressed patients with cytomegalovirus (CMV) disease, of whom 28 were organ transplant recipients. Thirteen patients responded to foscarnet by cessation of CMV secretion. The in vitro sensitivity to foscarnet of the CMV isolates from non-responders before, during and after foscarnet treatment was similar to that of viral isolates from responders before or during foscarnet treatment and also to CMV isolates from non-treated patients, with mean in vitro IC50 values of 239-294 microM of foscarnet. Thus, there was no evidence of increased resistance of the CMV isolates obtained after foscarnet treatment. A higher total foscarnet dose appeared to favor response.