Comparison of the efficacy of vidarabine, its carbocyclic analog (cyclaradine), and cyclaradine-5'-methoxyacetate in the treatment of herpes simplex virus type 1 encephalitis in mice

Abstract

The relative therapeutic effects of vidarabine (9-,-D-arabinofuranosyladenine), cyclaradine (the adenosine deaminase-resistant carbocyclic analog of vidarabine), and cyclaradine-5'-methoxyacetate in the parenteral treatment of systemic herpes simplex virus type 1 infections in Swiss mice were determined. Among control mice inoculated intraperitoneally with virus, a mortality rate of 95% was observed. The intraperitoneal administration of nontoxic doses of vidarabine (125 to 250 mg/kg per day) or cyclaradine (113 to 450 mg/kg per day), by daily injections for 7 days beginning 4 h after virus inoculation, reduced mortality to 0 to 10%, Amnong control animals inoculated intracerebrally with 32 50% lethal doses of virus, 100%to mortality was observed, with a mean survival time of 4.6 days.Treatment with either drug at equimolar dose levels ranging from ca. 32 to 750 mg/kg per day produced significant (P < 0.0005), dose-dependent increases in the mean survival time of animals dying of herpesvirus encephalitis. Mice inoculated intracerebraily with 10 50o lethal doses of virus exhibited 97% mortality and a mean survival time of 5.5 to 6.4 days. Treatment with vidarabine, cyclaradine, or cyclaradine-5'-methoxyacetate significantly increased the mean survival time of dying animals and, at doses ranging from 250 to 750 mg/kg per day, produced significant increases in survival. The three drugs displayed equivalent antiviral efficacy in vivo. Drug toxicity (measured by weight loss) was not detected in mice treated with cyclaradine or cyclaradine-5'-methoxyacetate at 750 mg/kg per day, whereas severe toxicity (weight loss of -3 g) was observed in mice treated with vidarabine at an equivalent dose level. Thus, cyclaradine or its 5'-methoxyacetic acid ester may possess some advantage over vidarabine in the treatment of severe herpesvirus infections and should therefore be considered for clinical trials in humans.

Potent and selective activity of a new carbocyclic nucleoside analog (Carbovir: NSC 614846) against human immunodeficiency virus In vitro

“…These compounds were given priority for screening because of design features compatible with action as DNA chain terminators and because of previous evidence for antiviral activities of some carbocyclic nucleoside analogs in other viral systems. These include carbocyclic analogs of arabinofuranosylpurine nucleosides (10,11), aminonucleosides (12), lyxofuranosyladenine (13), and xylofuranosylpurine nucleosides (14,15). Carbocyclic nucleosides are structurally analogous to natural and synthetic nucleosides, the only difference being a methylene group which replaces the oxygen atom of the carbohydrate ring.…”

Activity of (+)-cyclaradine (Sch 31172) against herpes simplex virus in vitro and in vivo

“…They demonstrated the deamination of Ara-A to arabinosyl hypoxanthine with about a 100-fold activity loss. In in vivo studies that compared (+)-cyclaradine with Ara-A against murine encephalitis caused by HSV, both drugs were equivalently active (26). Thus, it is not certain that the prevention of deamination of (+)-cyclaradine, as observed in vitro, would result in an in vivo or clinical benefit over that of Ara-A.…”

“…(+)-Cyclaradine [carbocyclic (+)-9-P-D-arabinofuranosyladenine; carbocyclic adenosine arabinoside (Ara-A); Sch 31172] is a novel nucleoside derivative with anti-herpes simplex virus (HSV) activity in mice (26) and guinea pigs (28). A novel synthetic scheme for the preparation of (+)-cyclaradine has been presented (T. L. Nagabhushan, P. Reichert, H. Tsai, M. Ostrander, M. Lieberman, J. Schwartz, R. Vince, and G. H. Miller, Program Abstr.…”

Induction of biochemical active constituents of Jojoba (Simmondsia chinensis (Link) Schneider) callus affected by hormones

“…Therefore, we noticed that these major active constituents are divided into four fractions: 1.Triodecanoic acid, which has the following biological activity: it prevents the effect of bacteria and fungi fat, and has a role in getting rid of harmful pollutants, tolerant to salinity and so is grown on the banks of canals, used to get rid of contaminants (Agoramoorthy et al, 2007), used for the analysis of fat, and stimulates the working of lipase enzyme, which analyzes the cell walls of microbes (Enig, 2004); 2. Methoxyacetic acid with the following acid: it is used against harmful animals like mice (toxic baits), that inhibit fertilization processes and thus prevent the breeding and spread of these dangerous animals (Shannon et al, 1983); 3. Decanoic acid which is used in the manufacture of insect repellents; 4.…”