Nucleic Acids. III. Antiviral Activity of Nucleotides and Dinucleoside Phosphates Containing <i>ara</i>-Cytidine

Renis, Harold E.; Hollowell, C A; Underwood, Gerald E.

doi:10.1021/jm00317a005

Cited by 25 publications

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“…The experimental conditions used have included intraperitoneal injection of both herpesvirus and ara-C (28), intracranial inoculation of vaccinia virus and intraperitoneal injection of ara-C (33), and intranasal inoculation of herpes (type 2) virus in newborn mice and intraperitoneal injection of ara-C (23). In the mouse models which have been reported, antiviral activity with ara-C has only been observed when the virus was administered intracranially, and the drug was given by the same route 3 h later (30).…”

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confidence: 99%

“…In mice, ara-C has been shown to be effective when herpesvirus and drug were both given by intracerebral inoculation (30). However, if the virus or the drug is given by other routes, the antiviral activity is no longer detectable (28; E. R. Kern, J. C. Overall, and L. A. Glasgow, Abstr.…”

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confidence: 99%

“…The results reported herein are from a series of experiments demonstrating in vivo activity in rats experimentally infected with herpesvirus and treated with ara-C subcutaneously. (30).…”

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Antiviral Activity of Cytarabine in Herpesvirus–Infected Rats

Renis

1973

Antimicrob Agents Chemother

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Intranasal inoculation of herpesvirus (approximately 1.8 mean lethal doses [LD 50 ] in 0.1 ml) into 105- to 115-g rats produces paralytic disease in 4 to 5 days and 80 to 100% mortality in 8 to 12 days. Cytarabine (ara-C) (40 to 320 mg/kg), administered subcutaneously to inoculated rats, delays the onset of paralysis and protects the animals from death. Drug treatments were given twice daily for 5 days. Beneficial drug effects were observed even when initiation of therapy was delayed for 3 days after virus inoculation. A dose-response relationship existed when therapy was initiated at 4 h after virus inoculation. However, when therapy was delayed for 3 days, it appeared that the highest drug level (320 mg/kg twice daily) was somewhat less effective than the lower doses (160 and 80 mg/kg twice daily). Virus could be detected in homogenates of brain beginning 3 days after inoculation, and the titer increased through 7 days. Ara-C treatment, initiated 4 h after inoculation, caused a delay in the appearance of virus, and a reduction in the titer in the brain homogenates. No virus was detected in blood serum, or in homogenates prepared from lung, kidney, thymus, or spleen of infected rats. The virus titration studies are in agreement with the illness and mortality produced by herpesvirus infection.

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Antiviral Activity of Cytarabine in Herpesvirus–Infected Rats

Renis

1973

Antimicrob Agents Chemother

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“…The virus dilution was that necessary to cause 90% lethality in the control group. For intracerebral inoculation, 0.03 ml of HSV-1 diluted in BME-3% FBS was used (12).…”

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“…In mice with HSV-1 infection, Ara-C was active only when virus and drug were given by intracerebral injection (12), although systemic (s.c.) administration of Ara-C protected rats infected intranasally with HSV-1 (8). Both 5-iodo-2'-deoxyuridine and Ara-C were effective when applied topically to rabbits with experimental herpetic keratitis (3).…”

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Activities of 5,6-Dihydro-5-Azathymidine Against Herpes Simplex Virus Infections in Mice

Renis

Eidson

1979

Antimicrob Agents Chemother

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5,6-Dihydro-5-azathymidine (DHAdT), a nucleoside antibiotic inhibitory for herpes simplex virus (HSV) in cell cultures (H. E. Renis, Antimicrob. Agents Chemother. 13: 613-617, 1978), was evaluated in mice with experimental HSV infections. DHAdT protected mice infected with HSV type 1 (HSV-1) when the virus was inoculated intravenously and the drug was given by subcutaneous or oral routes. The activity observed was dependent on the dose and schedule of treatment. Doses of 100 to 400 mg/kg given three to four times daily (at 4-h intervals) for 4 to 5 days gave greater protection than less frequent treatment for shorter time intervals. DHAdT treatment reduced the rate of isolation as well as the HSV-1 titers in homogenates prepared from spinal cords and brains, whereas the titers in kidney homogenates were only marginally affected. The above treatment regime with DHAdT afforded only partial protection to mice infected intracerebrally with HSV-1 or mice inoculated intravaginally with HSV-1 or HSV-2. The antiviral activity of DHAdT was reversed by the co-administration of thymidine. Under these conditions, DHAdT was not toxic in mice.The antibiotic nucleoside 5,6-dihydro-5-azathymidine (DHAdT) was shown to inhibit herpes simplex virus type 1 (HSV-1) and HSV-2 in infected cell cultures (10). It appeared that HSV-2 was less susceptible than HSV-1, but more susceptible than vaccinia virus. In addition, DHAdT was essentially noncytotoxic at concentrations which were inhibitory to HSV-1. The anti-HSV-1 activity of DHAdT was reversed by thymidine (dThd) and deoxyuridine and partially by deoxycytidine. DHAdT has been shown to be effective in hairless mice with cutaneous herpesvirus infection (16).The studies described herein were undertaken to determine the activity of DHAdT in mice infected with HSV. The effect of DHAdT, by different routes and schedules of therapy, was evaluated in mice infected with HSV-1 and -2 by different routes.MATERIALS AND METHODS Mice. Upj:TUC(ICR)spf mice, of both sexes, obtained from the Upjohn colony, were housed in the same room in stainless steel cages. Food and water were provided ad libitum. They weighed 18 to 20 g at the time of virus inoculation.Viruses. The propagation and assay on primary rabbit kidney (PRK) monolayers of the herpesviruses used in these studies have been described (11). The HSV-1 (MRS) had a titer of 3.4 x 107 plaque-forming units (PFU) per 1.0 ml on PRK, and the 50% lethal dose (LD50) was 1029/0.05 ml after intravenous (i.v.) injection of mice. The HSV-2 (35D) had a titer of 4.0 x 10' PFU/1.0 ml on PRK and 1024 LD5o/0.05 ml after i.v. injection of mice.Vaccinia virus was obtained originally from the Michigan Department of Health. The titer of the virus was 7.9 x 106 PFU/0.5 ml on PRK.Virus inoculation. HSV-1 was diluted in Eagle basal medium containing 3% fetal bovine serum (BME-3% FBS), and 0.05 ml was inoculated into the tail veins of male mice as previously described (11). The virus dilution was that necessary to cause 90% lethality in the control group. For intr...

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Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Wagner¹,

Iyer²,

McIntee³

2000

Med. Res. Rev.

264

215

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To overcome the many hurdles preventing the use of antiviral and anticancer nucleosides as therapeutics, the development of a prodrug methodology (i.e., pronucleotide) for the in vivo delivery of nucleotides has been proposed as a solution. The ideal pronucleotide should be non‐toxic, stable in plasma and blood, capable of being i.v. and/or orally dosed, and intracellularly convertible to the corresponding nucleotide. Although this goal has yet to be achieved, many clever and imaginative pronucleotide approaches have been developed, which are likely to be important pharmacological tools. This review will discuss the major advances and future directions of the emerging field of antiviral and anticancer pronucleotide design and development. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 6, 417–451, 2000

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Nucleic Acids. III. Antiviral Activity of Nucleotides and Dinucleoside Phosphates Containing ara-Cytidine

Cited by 25 publications

References 0 publications

Antiviral Activity of Cytarabine in Herpesvirus–Infected Rats

Antiviral Activity of Cytarabine in Herpesvirus–Infected Rats

Activities of 5,6-Dihydro-5-Azathymidine Against Herpes Simplex Virus Infections in Mice

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

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