Therapeutic activities of 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine and -thymine alone and in combination with acyclovir and vidarabine in mice infected intracerebrally with herpes simplex virus

evaluated for their efficacies in the treatment of genital infections with herpes simplex virus type 2 in guinea pigs. Intraperitoneal administration of these drugs in daily doses of 100 mg/kg of body weight initiated 24 h after virus inoculation and repeated 2 successive days thereafter inhibited development of genital lesions and reduced shedding of virus without evoking untoward reactions. In a comparative study with this 3-day dosage schedule, the efficacy of dgily doses of 50 mg of FMAU per kg was greater than that of the same doses of FIAC and FIAU, in that order; all these were more effective than daily doses of 50, 100, or 200 mg of acyclovir or of 500 mg of phosphonoformic acid per kg. These differences in efficacy were enhanced when treatment was delayed for 2 to 3 days after inoculation., and FMAU [1-(2'-deoxy-2'-fluoro-13-Darabinofuranosyl)-5-methyluracil] inhibit herpes simplex type 1 (HSV-1) and HSV-2 replication in cell culture (20; J. J. Fox, 185th Am. Chem. Soc. Natl. Meet., Seattle, Wash., 1983). FIAC and FMAU are equally active against HSV-1 and HSV-2 strains and have about the same potency as acyclovir (ACV) when assayed in rabbit kidney cells (2, 17). FIAU and FMAU are more active than ACV in the treatment of HSV encephalitis in mice (13). Topical application of FIAC and FMAU is also effective in the treatment of ocular infections in rabbits (17,18).Previous studies have shown that guinea pigs inoculated intravaginally with HSV-2 develop lesions of the external genitalia which follow a clinical course similar to that of herpes infections in human females; furthermore, this experimental infection may be used to evaluate the efficacy of various antiviral agents (8,14,16). Effective ACV and phosphonoformic acid (PFA) treatment of genital herpes in guinea pigs is well documented (1,4,6,10 laboratory (6, 10, 22) and is comparable to those used in other studies (8,14).Drug administration. All of the compounds were provided through the Antiviral Substances

supporting

confidence: 80%

“…FIAC and FMAU are equally active against HSV-1 and HSV-2 strains and have about the same potency as acyclovir (ACV) when assayed in rabbit kidney cells (2,17). FIAU and FMAU are more active than ACV in the treatment of HSV encephalitis in mice (13). Topical application of FIAC and FMAU is also effective in the treatment of ocular infections in rabbits (17,18).…”

mentioning

confidence: 99%

Treatment of primary acute genital herpes in guinea pigs by intraperitoneal administration of fluoropyrimidines

Mayo¹,

Hsiung²

1984

“…Thus, at the level of thymidylate kinase, IdUrd monophosphate has no selectivity for herpes simplex virus, and this may be reflected in the toxicity associated with this drug. Although previous studies have indicated that FIAC has antiviral activity in cell cultures and animals (14,16,19), the presence of FIAC triphosphate has not been reported in either in vitro or in vivo systems (13). However, metabolites of FIAC (principally 2'-fluoro-5-iodo-1-1-D-arabinofuranosyluracil) have been shown to be incorporated into cellular and viral DNAs (13).…”

mentioning

confidence: 99%

Kinetics of the interaction of monophosphates of the antiviral nucleosides 2'-fluoro-1-beta-D-arabinofuranosylpyrimidine and (E)-5-(2-bromovinyl)-2'-deoxyuridine with thymidylate kinases from Vero cells and herpes simplex virus types 1 and 2

Chen¹,

Amico²,

Speelman³

1984

The affinities of the monophosphates of 2'-fluoro-5-iodo-1-0-D-arabinofuranosyluracil and its 5smethyI analog for cellular thymidylate kinase were two or more orders of magnitude greater thap for the thymidine-thymidylate kinases from herpes simplex virus types 1 and 2. In contrpst, the monophosphate of (E)-5-(2-bromovinyl)-2'-deoxyuridine was found to have a higher affinity for the viral enzymes than for the cellular enzyme.Several nucleoside analogs developed during the past few years (7,9,17,20) show great promise for the chemotherapy of herpes simplex virus, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus infections. These antiherpes nucleoside analogs are preferential substrates for virally encoded thymidine-thymidylate kinase (1, 5). They exert their antiviral activity after being phosphorylated to their triphosphate derivatives, which inhibit viral DNA synthesis by competing with natural substrates (10,11,18). In some cases, the nucleoside analogs are also incorporated into viral DNA (10,11,13). The initial phosphorylation to their monophosphate derivatives is produced by viral thymidinethymidylate kinase; however, the subsequent conversion to their diphosphate derivatives may depend upon either viral or host enzymes or both. The phosphorylation of acyclovir monophosphate to its diphosphate was shown to be a function of host cell guanylate kinase activity (15), whereas (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd) monophosphate was preferentially phosphorylated by herpes simplex virus type 1 (HSV-1)-, herpes simplex virus type 2 (HSV-2)-, and varicella-zoster virus-encoded thymidine-thymidylate kinases (12). The HSV-2 thymidine-thymidylate kinase only poorly phosphorylates BVdUrd monophosphate to its diphosphate, distinguishing it from the enzymes of HSV-1 and varicella-zoster virus (12). The lower sensitivity of HSV-2 strains than of HSV-1 strains to BVdUrd inhibition was related to the lower levels of thymidylate kinase activity of the thymidine-thymidylate kinase found in HSV-2-infected cells. Although the rate of phosphorylation of BVdUrd monophosphate has been reported (12), the affinity of BVdUrd monophosphate for cellular and viral enzymes has not been described. Thymidylate kinase from rapidly dividing Vero cells and thymidine-thymidylate kinases from LMTK-cells infected with HSV-1 (KOS strain) and HSV-2 (MS strain) were purified as described by Cheng and Ostrander (6) and Chen and Prusoff (3). Enzymes were changed to the ATP. MG2' form before being used in kinetic studies by passage through a Sephadex G-25-40 column (Sigma Chemical Co., St. Louis, Mo.) equilibrated with 1 mM ATP. Mg2+-10 mM Tris (pH 7.5)-10% glycerol and were eluted with the same buffer. The assay for enzyme activities and analysis of kinetic data were done as described previously (2,4).The kinetic constants of the monophosphates of the nucleoside analogs for thymidylate kinase from Vero cells and thymidine-thymidylate kinases from HSV-1 and HSV-2 are shown in Table 1. Thymidylate kinase from Vero cells showed a h...

“…The compound has proven to be effective in the systemic and topical treatment of herpes simplex virus (HSV) type 2 (HSV-2) infections in both mice (11,25,31,38) and guinea pigs (39,43). Various clinical studies have demonstrated that acyclovir, when given systemically (either intravenously or perorally) or applied topically, is efficacious in the treatment of primary genital herpes (4,7,8,29,30) and, to a lesser extent, recurrent genital herpes (8,30,32,33).…”

mentioning

confidence: 99%

Xylotubercidin against herpes simplex virus type 2 in mice

Clercq¹,

Robins²

1986