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Antiviral Agents

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Drug Toxicity in Embryonic Development II

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 124 / 2))

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Abstract

As a result of extensive research activities during the last two decades, a considerable number of antiviral agents are now available for therapeutic use. As a matter of fact, we still face the unsatisfactory situation that none of the currently used antiviral drugs is effective in elimination of nonreplicating or latent viruses. In principle, the development of antiviral agents is more difficult than the development of drugs against other infectious agents, because viral replication depends crucially on the metabolic processes of the infected cell. However, an increasing need for antiviral agents arises from the increasing incidences of viral diseases such as genital herpes, cytomegalovirus (CMV) infections in immunocompromised patients, and last but not least the acquired immunodeficiency syndrome (AIDS) epidemic.

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References

  • Andrews EB, Yankaskas BC, Cordero JF, Schoeffler K, Hampp S (1992) Acyclovir in pregnancy registry: six years’ experience. Obstet Gynecol 79: 7–13.

    PubMed  CAS  Google Scholar 

  • Ayers KM (1988) Preclinical toxicology of zidovudine. An overview. Am J Med 85: 186–188.

    CAS  Google Scholar 

  • Bayer R (1994) Ethical challenges posed by zidovudine treatment to reduce vertical transmission of HIV. N Engl J Med 331: 1223–1225.

    Article  PubMed  CAS  Google Scholar 

  • Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ (1995) Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 39: 1546–1553.

    PubMed  CAS  Google Scholar 

  • Bridgen D, Rosling AE, Woods NC (1982) Renal function after aciclovir intravenous injection. Am J Med 73 Suppl: 182.

    Article  Google Scholar 

  • Caracatsanis M, Fouda N, Hammsarstrom L (1989) Effects of phosphonoformic and phosphonoacetic acids on developing enamel of rat molars. Scand J Dent Res 97: 139–149.

    PubMed  CAS  Google Scholar 

  • Chahoud I, Stahlmann R, Bochert G, Dillmann I, Neubert D (1988) Gross-structural defects in rats after aciclovir application on day 10 of gestation. Arch Toxicol 62: 8–14.

    Article  PubMed  CAS  Google Scholar 

  • Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, Jimenez E, O’ Neill E, Bazin B, Delfraissy J-F, Culnane M, Coombs R, Elkins M, Moye J, Stratton P, Balsley J (1994) Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 331: 1173–1180.

    Article  PubMed  CAS  Google Scholar 

  • Douglas RG (1990) Prophylaxis and treatment of influenza. N Engl J Med 322: 443–450.

    Article  PubMed  Google Scholar 

  • Eldrige RR, White AD, Tennis PS, Andrews EB, Dai WS, Cordero JF (1993) Three prospective registries to monitor prenatal maternal exposures: the acyclovir in pregnancy, the antiretroviral pregnancy and the lamotrigine in pregnancy registries. Reprod Toxicol 7: 637.

    Article  Google Scholar 

  • Eldrige RR, White AD, Andrews EB (1995) Monitoring birth outcomes in the aciclovir pregnancy registry (Abstr k97). Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, San Francisco.

    Google Scholar 

  • Faulds D, Brogden RN (1992) Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs 44: 94–116.

    Article  PubMed  CAS  Google Scholar 

  • Faulds D, Heel RC (1990) Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 39: 597–638.

    Article  PubMed  CAS  Google Scholar 

  • Ferm VH, Willhite C, Kilham L (1978) Teratogenic effects of ribavirin on hamster and rat embryos. Teratology 17: 93–102.

    Article  PubMed  CAS  Google Scholar 

  • Foerster M, Kastner U, Neubert R (1992a) Effect of six virustatic nucleoside analogues on the development of fetal rat thymus in organ culture. Arch Toxicol 66: 688–699.

    Article  PubMed  CAS  Google Scholar 

  • Foerster M, Merker H-J, Stahlmann R, Neubert D (1992b) In vitro effect of aciclovir on lymphopoiesis in fetal rat thymus. Toxicol In Vitro 6: 207–217.

    Article  PubMed  CAS  Google Scholar 

  • Frenkel LM, Brown ZA, Bryson YJ, Corey L, Unadket JD, Hensleigh PA, Arvin AM, Prober CG, Connor JD (1991) Pharmacokinetics of acyclovir in the term human pregnancy and neonate. Am J Obstet Gynecol 164: 569–576.

    PubMed  CAS  Google Scholar 

  • Furman PA, St Clair MH, Fyfe JA, Rideout JL, Keller PM, Elion GB (1979) Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl) guanine and its triphosphate. J Virol 32: 72–77.

    PubMed  CAS  Google Scholar 

  • Furman PA, de Miranda P, St Clair MH, Elion GB (1981) Metabolism of acyclovir in virus-infected and uninfected cells. Antimicrob Agents Chemother 20: 518–524.

    PubMed  CAS  Google Scholar 

  • Gogu SR, Beckman BS, Agrawal KC (1989) Anti HIV-drugs: comparative toxicities in murine fetal liver and bone marrow erythroid progenitor cells. Life Sei 45: iii–vii.

    Article  CAS  Google Scholar 

  • Gogu SR, Beckman BS, Agrawal KC (1992) Amelioration of zidovudine-induced fetal toxicity in pregnant mice. Antimicob Agents Chemother 36: 2370–2374.

    CAS  Google Scholar 

  • Greene JA, Ayers KM, DeMiranda P, Tucker WE Jr (1991) Postnatal survival in Wistar rats following oral dosage with zidovudine on gestation day 10. Fundam Appl Toxicol 15: 201–206.

    Article  Google Scholar 

  • Gubbels JL, Gold WR, Bauserman S (1991) Prenatal diagnosis of fetal diastemato-myelia in a pregnancy exposed to acyclovir. Reprod Toxicol 5: 517–520.

    Article  PubMed  CAS  Google Scholar 

  • Ha JC, Nosbisch C, Conrad SH, Ruppenthal GC, Sackett GP, Abkowitz J, Unadkat JD (1994) Fetal toxicity of zidovudine (azidothymidine) In Macaca nemestrina: preliminary observations. J AIDS 7: 154–157.

    CAS  Google Scholar 

  • Hartman NR, Yarchoan R, Pluda JM, Thomas RV, Marczyk KS et al. (1990) Pharmacokinetics of 2′, 3′ dideoxyadenosine and 2′, 3′ dideoxyinosine in patients with severe human immunodeficiency virus infection. Clin Pharmacol Ther 47: 647–654.

    Article  PubMed  CAS  Google Scholar 

  • Hartmann J, Chahoud I, Buerkle B, Neubert D (1991) Testis hypoplasia in rat offspring prenatally exposed to ganciclovir (Abstr p 21) Teratology 44:25A.

    Google Scholar 

  • Hay AJ, Wolstenholme AJ, Skehel JJ, Smith MH (1985) The molecular basis of the specific anti-influenza action of amantadine. EMBO J 4: 3021–3024.

    PubMed  CAS  Google Scholar 

  • Hayden FG (1995) Antiviral agents. In: Mandell GL, Bennett JE, Dolin R (eds) Mandell, Douglas and Bennett’s principles and practice of infectious diseases, 4th edn. Churchill Livingstone, Edinburgh, pp 411–450.

    Google Scholar 

  • Heinrich-Hirsch B, Neubert D (1991) Effect of aciclovir on the development of the chick embryo in ovo. Arch Toxicol 65: 402–408.

    Article  PubMed  CAS  Google Scholar 

  • Henderson GI, Hu ZQ, Yang Y, Perez TB, Devi BG, Frosto TA, Schenker S (1993) Ganciclovir transfer by human placenta and its effects on rat fetal cells. Am J Med Sei 306: 151–156.

    Article  CAS  Google Scholar 

  • Hirsch MS, Swartz MN (1980) Antiviral agents. N Engl J Med 302: 903–907.

    Article  PubMed  CAS  Google Scholar 

  • Itoi M, Gefter JW, Kaneko N, Ishii Y, Ramer RM, Gasset AR (1975) Teratogenicities of ophthalmic drugs. I. Antiviral ophthalmic drugs. Arch Ophthalmol 93: 46–51.

    CAS  Google Scholar 

  • Kacmarek RM (1991) Care-giver protection from exposure to aerolized pharmacologic agents — is it necessary? Chest 100: 1104–1105.

    Article  PubMed  CAS  Google Scholar 

  • Khoo SH, Wilkins EGL (1995) Review: controversies in anti-retroviral therapy of adults. J Antimicrob Chemother 35: 245–262.

    Article  PubMed  CAS  Google Scholar 

  • Klug S, Lewandowski C, Blankenburg G, Merker HJ, Neubert D (1985a) Effect of acyclovir on mammalian embryonic development in culture. Arch Toxicol 58: 89–96.

    Article  PubMed  CAS  Google Scholar 

  • Klug S, Lewandowski C, Neubert D (1985b) Modification and standardization of the culture of early postimplantation embryos for toxicological studies. Arch Toxicol 58: 84–88.

    Article  PubMed  CAS  Google Scholar 

  • Klug S, Lewandowski C, Merker H-J, Stahlmann R, Wildi L, Neubert D (1991) In vitro and in vivo studies on the prenatal toxicity of five virustatic nucleoside analogues in comparison to aciclovir. Arch Toxicol 65: 283–291.

    Article  PubMed  CAS  Google Scholar 

  • Klug S, Stahlmann R, Golor G, Foerster M, Felies A, Bochert G, Rahm U, Neubert D (1992) Aciclovir in pregnant marmoset monkeys — oral treatment (Abstr). Teratology 45: A64.

    Google Scholar 

  • Kochhar DM (1982) Embryonic limb bud organ culture in assessment of teratogenicity of environmental agents. Teratogen Carcinogen Mutagen 2: 303–312.

    Article  CAS  Google Scholar 

  • Kochhar DM, Penner JD, Knudsen TB (1980) Embryotoxic, teratogenic, and metabolic effects of ribavirin in mice. Toxicol Appl Pharmacol 52: 99–112.

    Article  PubMed  CAS  Google Scholar 

  • Koren G, Ito S (1993) Exposures of pregnant health care workers to ribavirin through inhalation of contaminated air. Reprod Toxicol 7: 158.

    Google Scholar 

  • Kurtz SM (1975) Toxicology of adenine arabinoside. In: Pavan-Langston D, Buchanan RA, Alford CA (eds) Adenine arabinoside: an antiviral agent. Raven, New York, pp 145–157.

    Google Scholar 

  • Kurtz SM, Fitzgerald JE, Schardein JL (1977) Comparative animal toxicology of vidarabine and its 5′ monophosphate. Ann NY Acad Sei 284: 6–8.

    Article  CAS  Google Scholar 

  • Lamar JK, Calhoun FJ, Darr AG(1970) Effects of amantadine hydrochloride on cleavage and embryonic development in the rat and rabbit. Toxicol Appl Pharmacol 17: 272 (abstr).

    Article  Google Scholar 

  • Laskin OL, Longstreth JA, Saral R, de Miranda P, Keeney R, Lietman PS (1982) Pharmacokinetics and tolerance of acyclovir, a new anti-herpesvirus agent in humans. Antimicrob Agents Chemother 21: 393–398.

    PubMed  CAS  Google Scholar 

  • Levy M, Pastuszak A, Koren G (1991) Fetal outcome following intrauterine amantadine exposure. Reprod Toxicol 5: 79–81.

    Article  PubMed  CAS  Google Scholar 

  • Lindström P, Harris M, Hoberman AM, Dunnick JK, Morrissey RE (1990) Developmental toxicity of orally administered 2′,3′-dideoxycytidine in mice. Teratology 42: 131–136.

    Article  PubMed  Google Scholar 

  • Lubeck MD, Schulman JL, Palase P (1978) Susceptibility of influenza A virus to amantadine is influenced by the gene coding for M protein. J Virol 28: 710–716.

    PubMed  CAS  Google Scholar 

  • McLaren C, Datema R, Knupp CA, Buroker RA (1991) Review: didanosine. Antiviral Chem Chemother 2: 321–328.

    CAS  Google Scholar 

  • Moore HL Jr, Szczech GM, Rodwell DE, Kapp RW Jr, de Miranda P, Tucker WE Jr (1983) Preclinical toxicology studies with aciclovir: teratologic, reproductive and neonatal tests. Fundam Appl Toxicol 3: 560–568.

    Article  PubMed  CAS  Google Scholar 

  • Nora JJ, Nora AH, Way GL (1975) Cardiovascular maldevelopment associated with maternal exposure to amantadine. Lancet 2: 607.

    Article  PubMed  CAS  Google Scholar 

  • Nosbisch C, Ha JC, Sackett GP, Conrad SH, Ruppenthal GC, Unadkat JD (1994) Fetal and infant toxicity of zidovudine in Macaca nemestrina (Abstr p 115). Teratology 49: 415 (abstr).

    Google Scholar 

  • Öberg B (1989) Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther 40: 213–285.

    Article  PubMed  Google Scholar 

  • Percy DH (1975) Teratogenic effects of the pyrimidine analogues 5-iododeoxyuridine and cytosine arabinoside in late fetal mice and rats. Teratology 11: 103–111.

    Article  PubMed  CAS  Google Scholar 

  • Percy DH, Albert DM, Amemiya T (1973) Ocular defects in newborn rats treated with 5-iododeoxyuridine. Proc Soc Exp Biol Med 142: 1272–1276.

    PubMed  CAS  Google Scholar 

  • Pons JC, Boubon MC, Taburet AM, Singlas E, Chambrin V, Frydman R, Papiernik E, Delfraissy JF (1991) Fetoplacental passage of 2,3-dideoxyinosine. Lancet 337: 732.

    Article  PubMed  CAS  Google Scholar 

  • Prusoff WH (1988) Idoxuridine or how it all began. In: DeClerq E (ed) Clinical use of antiviral drugs. Nijhoff, Norwell, pp 15–24.

    Chapter  Google Scholar 

  • Qamar IU, Pandit PB, Jefferies AL, Landes A, Koren G, Chitayat D (1993) Tibial hemimelia and tetralogy of Fallot associated with first trimester exposure to amantadine. Teratology 47: 345–381.

    Article  Google Scholar 

  • Rogers MF, Jaffe HW (1994) Reducing the risk of maternal-infant transmission of HIV: a door is opened. N Engl J Med 331: 1222–1223.

    Article  PubMed  CAS  Google Scholar 

  • Schardein JL, Hentz DL, Petrere JA, Fitzgerald JE, Kurtz SM (1977) The effect of vidarabine on the development of the offspring of rats, rabbits and monkeys. Teratology 15: 231–242.

    Article  PubMed  CAS  Google Scholar 

  • Sieh E, Coluzzi ML, Cusella de Angelis MG, Mezzogiorno A, Floridia M, Canipari R, Cossu G, Vella S (1992) The effects of AZT and DDI on pre- and postimplantation mammalian embryos: an in vivo and in vitro study. AIDS Res Hum Retroviruses 8: 639–649.

    Article  PubMed  CAS  Google Scholar 

  • Sikka SC, Gogu SR, Agrawal KC (1991) Effect of zidovudine (AZT) on reproductive and hematopoietic systems in the male rat. Biochem Pharmacol 42: 1293–1297.

    Article  PubMed  CAS  Google Scholar 

  • Skalko RG, Packard DS (1973) The teratogenic response of the mouse embryo to 5-iododeoxyuridine. Experientia 29: 198–200.

    Article  PubMed  CAS  Google Scholar 

  • Sperling RS, Stratton P, O’Sullivan MJ, Boyer P, Watts DH, Lambert JS, Hammill H, Livingston EG, Gloeb DJ, Minkoff H, Fox HE (1992) A survey of zidovudine use in pregnant women with human immunodeficiency virus infection. N Engl J Med 326: 857–861.

    Article  PubMed  CAS  Google Scholar 

  • Stahlmann R, Klug S, Lewandowski C, Chahoud I, Bochert G, Merker H-J, Neubert D (1987) Teratogenicity of acyclovir in rats. Infection 15: 261–262.

    Article  PubMed  CAS  Google Scholar 

  • Stahlmann R, Klug S, Lewandowski C, Bochert G, Chahoud I, Rahm U, Merker H-J, Neubert D (1988a) Prenatal toxicity of acyclovir in rats. Arch Toxicol 61: 468–479.

    Article  PubMed  CAS  Google Scholar 

  • Stahlmann R, Franz R, Merker H-J (1988b) Embryotoxicity of aciclovir in rats after single application. Naunyn Schmiedebergs Arch Pharmacol 337: R35 (abstr).

    Google Scholar 

  • Stahlmann R, Chahoud I, Bochert G, Klug S, Korte M, Neubert D (1988c) Prenatal toxicity of zidovudine in rats. Teratology 38: 28A (abstr).

    Google Scholar 

  • Stahlmann R, Chahoud I, Korte M, Thiel R, van Loveren H, Vos JG, Foerster M, Merker H-J, Neubert D (1991) Structural anomalies of thymus and other organs and impaired resistance to Trichinella spiralis infection in rats after prenatal exposure to aciclovir. In: (eds) Harwood Thymus update vol 4. Kendall MD Ritter MA (eds) Harwood, New York, pp 129–155.

    Google Scholar 

  • Stahlmann R, Korte M, Van Loveren H, Vos JG, Thiel R, Neubert D (1992a) Abnormal thymus development and impaired function of the immune system in rats after prenatal exposure to aciclovir. Arch Toxicol 66: 551–559.

    Article  PubMed  CAS  Google Scholar 

  • Stahlmann R, Golor G, Klug S, Renschier C, Stürje H, Merker H-J, Neubert D (1992b) Aciclovir in pregnant marmoset monkeys — intravenous treatment. Teratology 45: A4 (abstr).

    Google Scholar 

  • Stahlmann R, Klug S, Foerster M, Neubert D (1993) Significance of embryo culture methods for studying the prenatal toxicity of virustatic agents. Reprod Toxicol 7: 129–143.

    Article  PubMed  CAS  Google Scholar 

  • Stahlmann R, Golor G, Thiel R, Chahoud I, Kuschel S, Baumann-Wilschke I (1995) Persistent changes of components of the immune system in rats after exposure to aciclovir during organogenesis. Teratology 51: 168–169 (abstr).

    Google Scholar 

  • Syntex (1988) CYMEVENE and cytomegalovirus infections. Syntex Pharmaceuticals

    Google Scholar 

  • Toltzis P, Marx CM, Kleinman N, Levine EM, Schmidt EV (1991) Zidovudine-associated embryonic toxicity in mice. J Infect Dis 163: 1212–1218.

    Article  PubMed  CAS  Google Scholar 

  • Toltzis P, Mourton T, Magnuson T (1993) Effect of zidovudine on preimplantation murine embryos. Antimicrob Agents Chemother 37: 1610–1613.

    PubMed  CAS  Google Scholar 

  • Toltzis O, Mourton T, Magnuson T (1994) Comparative embryonic cytotoxicity of antiretroviral nucleosides. J Infect Dis 169: 1100–1102.

    Article  PubMed  CAS  Google Scholar 

  • Vernier VG, Harmon JB, Stump JM, Lynes TE, Marvel JP, Smith DH (1969) The toxicologic and pharmacologic properties of amantadine hydrochloride. Toxicol Appl Pharmacol 15: 642–665.

    Article  PubMed  CAS  Google Scholar 

  • Wagstaff AJ, Bryson HM (1994) Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs 48: 199–226.

    Article  PubMed  CAS  Google Scholar 

  • Watts DH, Brown ZA, Tartaglione T, Burchett SK, Opheim K, Coombs R, Corey L (1991) Pharmacokinetic disposition of zidovudine during pregnancy. J Infect Dis 163: 226–232.

    Article  PubMed  CAS  Google Scholar 

  • Whitley R, Alford C, Hess F, Buchanan R (1980) Vidarabine: a preliminary review of its pharmacological properties and therapeutic use. Drugs 20: 267–282.

    Article  PubMed  CAS  Google Scholar 

  • Whitley RJ, Gnann JW (1992) Acyclovir: a decade later. N Engl J Med 327: 782–789.

    Article  PubMed  CAS  Google Scholar 

  • Whittington R, Brogden RN (1992) Zalcitabine. A review of its pharmacology and clinical potential in acquired immunodeficiency syndrome (AIDS). Drugs 44: 656–683.

    Article  PubMed  CAS  Google Scholar 

  • Yarachoan R, Mitsuya H, Myers CE, Broder S (1989) Clinical pharmacology of 3′- azido-2′, 3′-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med 321: 726–739.

    Article  Google Scholar 

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Authors
  1. R. Stahlmann
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  2. S. Klug
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Editors and Affiliations

  1. Reproductive Toxicology Division (MD-71) National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, 27711, NC, USA

    Robert J. Kavlock Ph.D. (Director) (Director)

  2. Miami Valley Laboratories, The Procter and Gamble Company, P.O. Box 538707, 53239, Cincinnati, OH, USA

    George P. Daston Ph.D.

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Stahlmann, R., Klug, S. (1997). Antiviral Agents. In: Kavlock, R.J., Daston, G.P. (eds) Drug Toxicity in Embryonic Development II. Handbook of Experimental Pharmacology, vol 124 / 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60447-8_6

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