Multiple drug effect analysis with confidence interval

Belen'kii, Mikhail S.; Schinazi, Raymond F.

doi:10.1016/0166-3542(94)90089-2

Cited by 73 publications

(66 citation statements)

References 12 publications

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“…The program allows automated simulation of synergism and antagonism at all dose and effect levels and displays the methods of Chou and Talalay [19], including dose-effect curve, median effect plot, combination index (CI), isobologram, dose-reduction index (DRI) and the Monte Carlo algorithm plot of Belen'kii and Schinazi [20]. We chose the constant ratio drug combination design proposed by Chou and Talalay [19] because it offers several advantages, such as reduction of required data points and generation of maximal useful information on both dual and triple combinations.…”

Section: Drug Combination Analysesmentioning

confidence: 99%

Combinations of 2'-C-Methylcytidine Analogues with Interferon-α2b and Triple Combination with Ribavirin in the Hepatitis C Virus Replicon System

Bassit

Grier

Bennett

et al. 2008

Antivir Chem Chemother

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Background: Hepatitis C virus (HCV) polymerase is an essential enzyme for HCV replication and has multiple inhibitor binding sites making it a major target for antiviral intervention. It is apparent that no single drug can inhibit HCV replication in humans. Hence, combinations of nucleoside analogues β-d-2'-C-methylcytidine (2'-C-MeC; NM-107) or β-d-2'-deoxy-2'-fluoro-2'-C-methylcytidine (2'-F-C-MeC; PSI-6130) with interferon-a2b (IFN-a2b) or triple combination with ribavirin (RBV) were evaluated. Methods: Huh-7 cells containing the self-replicating subgenomic HCV replicon (Clone B) were used for drug combination studies. After drug treatment for 5 days, total cellular RNA was then extracted and both ribosomal RNA and HCV replicon RNA were amplified in a singlestep multiplex real-time PCR assay. Drug interaction analyses were performed using the CalcuSyn program. The current standard of care for chronic hepatitis C virus (HCV) infection is a combination of pegylated interferon (IFN)-a and ribavirin (RBV), which results in a sustained virological response in about a half of infected individuals; however, this combined modality is associated with considerable side effects [1,2]. Several new HCV inhibitors have been identified and some are being evaluated in controlled clinical trials [3]. Recently, promising 2′-modified nucleoside analogues with activity against HCV have been reported; for instance, valopicitabine (NM-283), the 3′-valine ester of β-d-2′-Cmethylcytidine (2′-C-MeC; NM-107), is a prodrug nucleoside that after intracellular phosphorylation to its 5′-triphosphate metabolite, selectively inhibits HCV RNA-dependent RNA polymerase [4,5]. Although valopicitabine was recently evaluated in clinical trials and the combination of valopicitabine with IFN-a (plus RBV) has led to successful viral RNA suppression in a number of HCV-infected individuals, this drug was found to have gastrointestinal toxicity leading to its discontinuation in its present form [6]. Another novel cytidine analogue, β-d-2′-deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130, 2′-F-C-MeC has demonstrated potent and specific in vitro anti-HCV activity with no apparent cytotoxicity [7,8]. Recently, in a 14 day Phase I monotherapy study, a new prodrug of 2′-F-C-MeC named R7128 was shown to be highly potent at lowering levels of HCV RNA, with a 2.7-log reduction in the viral load of individuals infected with HCV genotype 1 who had failed prior IFN therapy [9,10]. These nucleoside analogues have demonstrated excellent anti-HCV activity in vitro in both antireplicon and infectious HCV systems [11]. Furthermore, nucleoside analogue prodrugs can be administered in combination with IFN, with or without Results: Double combinations of 2'-C-MeC or 2'-F-C-

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Section: Drug Combination Analysesmentioning

confidence: 99%

Combinations of 2'-C-Methylcytidine Analogues with Interferon-α2b and Triple Combination with Ribavirin in the Hepatitis C Virus Replicon System

Bassit

Grier

Bennett

et al. 2008

Antivir Chem Chemother

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“…human peripheral blood mononuclear cells (PBMCs) have been published previously (Schinazi et al, 1988(Schinazi et al, , 1990 (Belen'kii & Schinazi, 1994 (Model EL 312e;Inc.,Winooski,VT,USA). The 50% inhibition concentration (IC 50 ) was determined from the concentration-response curve using the median effect method (Stuyver et al, 2002;Belen'kii & Schinazi, 1994).…”

Section: Antiviral Assays the Procedures For The Antiviral Assays Inmentioning

confidence: 99%

“…The 50% inhibition concentration (IC 50 ) was determined from the concentration-response curve using the median effect method (Stuyver et al, 2002;Belen'kii & Schinazi, 1994). Table 1).…”

Section: Antiviral Assays the Procedures For The Antiviral Assays Inmentioning

confidence: 99%

PAMAM Dendrimers and Branched Polyethyleneglycol (Nanoparticles) Prodrugs of (-)-β-D-(2R, 4R)-dioxolane-thymine (DOT) and Their Anti-HIV Activity

Liang

Janarthanan

Rapp

et al. 2006

Antivir Chem Chemother

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The synthesis, characterization, anti-HIV activity and cytotoxicity of dendrimers of (-)-β β-D-(2R,4R)-dioxolane-thymine (DOT) and polyethylene glycol (PEG)-DOT conjugates are described. Dendrimers in this study were polyamidoamine (PAMAM) generation 2.0, 3.0, 5.0 and 6.0, along with 8.0-branched PEG with a molecular weight of 40 kDa. DOT was attached to PAMAM dendrimers or branched PEG via ester or phosphate groups. Size exclusion chromatography was used to purify the dendrimers and PEG conjugates, which were characterized by NMR and MALDI-TOF mass spectrometry. The synthesized PAMAM dendrimers and PEG conjugates were evaluated for anti-HIV activity against HIV-1 LAI in primary human peripheral blood mononuclear cells (PBMCs) and cytotoxicity in PBMCs, CEM and Vero cells. PAMAM dendrimers of DOT with ester linkages and particularly phosphate linkers showed an increase in anti-HIV potency in comparison with DOT alone (140-and 56-fold, respectively). Unfortunately, the PAMAM dendrimers also exhibited increased cytotoxicity. Anti-HIV activity of PEG-DOT conjugates was found to be lower than that of DOT.

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“…The toxicity of the compounds was assessed in human PBM cells as previously described (41). The antiviral 50% effective concentration (EC 50 ) and 50% cytotoxic concentration were determined from the concentration-response curve using the median effect method (1).…”

Section: Chemicalsmentioning

confidence: 99%