Abstract
The activity against Toxoplasma gondii of 2',3' dideoxyinosine (ddI), an anti-human immunodeficiency virus drug, was examined in an in vitro and in vivo study. Cell cultures infected with a strain known to cause chronic infections were used to show the dose-dependent effect of this drug compared with spiramycin and sulfadiazine. When a dose of 4 microg/ml was used, no infected THP-1 cells or parasites were found after 60 h of incubation. An electron-microscopic study confirmed that after 12 h at 1 microg/ml, the few parasites observed were severely altered. The treatment of chronically infected mice 3 months postinfection showed that a 30-day treatment with 2 mg of ddI/ml induced a significant reduction in the number of T. gondii cysts in the cerebral tissue. These cysts were not viable, as confirmed by immunofluorescence and reinfection experiments. These experiments suggest a possible role for ddI in the treatment of toxoplasmosis, and this possibility deserves further investigation.
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- Araujo F. G., Lin T., Remington J. S. The activity of atovaquone (566C80) in murine toxoplasmosis is markedly augmented when used in combination with pyrimethamine or sulfadiazine. J Infect Dis. 1993 Feb;167(2):494–497. doi: 10.1093/infdis/167.2.494. [DOI] [PubMed] [Google Scholar]
- Araujo F. G., Prokocimer P., Lin T., Remington J. S. Activity of clarithromycin alone or in combination with other drugs for treatment of murine toxoplasmosis. Antimicrob Agents Chemother. 1992 Nov;36(11):2454–2457. doi: 10.1128/aac.36.11.2454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blais J., Garneau V., Chamberland S. Inhibition of Toxoplasma gondii protein synthesis by azithromycin. Antimicrob Agents Chemother. 1993 Aug;37(8):1701–1703. doi: 10.1128/aac.37.8.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blais J., Tardif C., Chamberland S. Effect of clindamycin on intracellular replication, protein synthesis, and infectivity of Toxoplasma gondii. Antimicrob Agents Chemother. 1993 Dec;37(12):2571–2577. doi: 10.1128/aac.37.12.2571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brun-Pascaud M., Chau F., Garry L., Jacobus D., Derouin F., Girard P. M. Combination of PS-15, epiroprim, or pyrimethamine with dapsone in prophylaxis of Toxoplasma gondii and Pneumocystis carinii dual infection in a rat model. Antimicrob Agents Chemother. 1996 Sep;40(9):2067–2070. doi: 10.1128/aac.40.9.2067. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Canessa A., Del Bono V., De Leo P., Piersantelli N., Terragna A. Cotrimoxazole therapy of Toxoplasma gondii encephalitis in AIDS patients. Eur J Clin Microbiol Infect Dis. 1992 Feb;11(2):125–130. doi: 10.1007/BF01967063. [DOI] [PubMed] [Google Scholar]
- Carr A., Tindall B., Brew B. J., Marriott D. J., Harkness J. L., Penny R., Cooper D. A. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med. 1992 Jul 15;117(2):106–111. doi: 10.7326/0003-4819-117-2-106. [DOI] [PubMed] [Google Scholar]
- Clumeck N. Some aspects of the epidemiology of toxoplasmosis and pneumocystosis in AIDS in Europe. Eur J Clin Microbiol Infect Dis. 1991 Mar;10(3):177–178. doi: 10.1007/BF01964454. [DOI] [PubMed] [Google Scholar]
- Dannemann B., McCutchan J. A., Israelski D., Antoniskis D., Leport C., Luft B., Nussbaum J., Clumeck N., Morlat P., Chiu J. Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group. Ann Intern Med. 1992 Jan 1;116(1):33–43. doi: 10.7326/0003-4819-116-1-33. [DOI] [PubMed] [Google Scholar]
- Derouin F., Caroff B., Chau F., Prokocimer P., Pocidalo J. J. Synergistic activity of clarithromycin and minocycline in an animal model of acute experimental toxoplasmosis. Antimicrob Agents Chemother. 1992 Dec;36(12):2852–2855. doi: 10.1128/aac.36.12.2852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Derouin F., Piketty C., Chastang C., Chau F., Rouveix B., Pocidalo J. J. Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine. Antimicrob Agents Chemother. 1991 Feb;35(2):252–255. doi: 10.1128/aac.35.2.252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Farthing C., Rendel M., Currie B., Seidlin M. Azithromycin for cerebral toxoplasmosis. Lancet. 1992 Feb 15;339(8790):437–438. doi: 10.1016/0140-6736(92)90132-m. [DOI] [PubMed] [Google Scholar]
- Faulds D., Brogden R. N. Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs. 1992 Jul;44(1):94–116. doi: 10.2165/00003495-199244010-00008. [DOI] [PubMed] [Google Scholar]
- Frenkel J. K., Escajadillo A. Cyst rupture as a pathogenic mechanism of toxoplasmic encephalitis. Am J Trop Med Hyg. 1987 May;36(3):517–522. doi: 10.4269/ajtmh.1987.36.517. [DOI] [PubMed] [Google Scholar]
- Harvie P., Désormeaux A., Bergeron M. C., Tremblay M., Beauchamp D., Poulin L., Bergeron M. G. Comparative pharmacokinetics, distributions in tissue, and interactions with blood proteins of conventional and sterically stabilized liposomes containing 2',3'-dideoxyinosine. Antimicrob Agents Chemother. 1996 Jan;40(1):225–229. doi: 10.1128/aac.40.1.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holliman R. E. Clinical and diagnostic findings in 20 patients with toxoplasmosis and the acquired immune deficiency syndrome. J Med Microbiol. 1991 Jul;35(1):1–4. doi: 10.1099/00222615-35-1-1. [DOI] [PubMed] [Google Scholar]
- Huskinson-Mark J., Araujo F. G., Remington J. S. Evaluation of the effect of drugs on the cyst form of Toxoplasma gondii. J Infect Dis. 1991 Jul;164(1):170–171. doi: 10.1093/infdis/164.1.170. [DOI] [PubMed] [Google Scholar]
- Iannucci A. A., Hart L. L. Clindamycin in the treatment of toxoplasmosis in AIDS. Ann Pharmacother. 1992 May;26(5):645–647. [PubMed] [Google Scholar]
- Iannucci A. A., Hart L. L. Clindamycin in the treatment of toxoplasmosis in AIDS. Ann Pharmacother. 1992 May;26(5):645–647. [PubMed] [Google Scholar]
- Israelski D. M., Tom C., Remington J. S. Zidovudine antagonizes the action of pyrimethamine in experimental infection with Toxoplasma gondii. Antimicrob Agents Chemother. 1989 Jan;33(1):30–34. doi: 10.1128/aac.33.1.30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Khan A. A., Slifer T., Araujo F. G., Remington J. S. Trovafloxacin is active against Toxoplasma gondii. Antimicrob Agents Chemother. 1996 Aug;40(8):1855–1859. doi: 10.1128/aac.40.8.1855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lacassin F., Schaffo D., Perronne C., Longuet P., Leport C., Vilde J. L. Clarithromycin-minocycline combination as salvage therapy for toxoplasmosis in patients infected with human immunodeficiency virus. Antimicrob Agents Chemother. 1995 Jan;39(1):276–277. doi: 10.1128/aac.39.1.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leport C., Chêne G., Morlat P., Luft B. J., Rousseau F., Pueyo S., Hafner R., Miro J., Aubertin J., Salamon R. Pyrimethamine for primary prophylaxis of toxoplasmic encephalitis in patients with human immunodeficiency virus infection: a double-blind, randomized trial. ANRS 005-ACTG 154 Group Members. Agence Nationale de Recherche sur le SIDA. AIDS Clinical Trial Group. J Infect Dis. 1996 Jan;173(1):91–97. doi: 10.1093/infdis/173.1.91. [DOI] [PubMed] [Google Scholar]
- Lindsay D. S., Rippey N. S., Toivio-Kinnucan M. A., Blagburn B. L. Ultrastructural effects of diclazuril against Toxoplasma gondii and investigation of a diclazuril-resistant mutant. J Parasitol. 1995 Jun;81(3):459–466. [PubMed] [Google Scholar]
- Masur H., Polis M. A., Tuazon C. U., Ogata-Arakaki D., Kovacs J. A., Katz D., Hilt D., Simmons T., Feuerstein I., Lundgren B. Salvage trial of trimetrexate-leucovorin for the treatment of cerebral toxoplasmosis in patients with AIDS. J Infect Dis. 1993 Jun;167(6):1422–1426. doi: 10.1093/infdis/167.6.1422. [DOI] [PubMed] [Google Scholar]
- McGowan J. J., Tomaszewski J. E., Cradock J., Hoth D., Grieshaber C. K., Broder S., Mitsuya H. Overview of the preclinical development of an antiretroviral drug, 2',3'-dideoxyinosine. Rev Infect Dis. 1990 Jul-Aug;12 (Suppl 5):S513–S521. doi: 10.1093/clinids/12.supplement_5.s513. [DOI] [PubMed] [Google Scholar]
- McHugh T. D., Holliman R. E., Butcher P. D. The in vitro model of tissue cyst formation in Toxoplasma gondii. Parasitol Today. 1994 Jul;10(7):281–285. doi: 10.1016/0169-4758(94)90148-1. [DOI] [PubMed] [Google Scholar]
- Mitsuya H., Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1911–1915. doi: 10.1073/pnas.83.6.1911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mitsuya H., Broder S. Strategies for antiviral therapy in AIDS. 1987 Feb 26-Mar 4Nature. 325(6107):773–778. doi: 10.1038/325773a0. [DOI] [PubMed] [Google Scholar]
- Nordback I. H., Olson J. L., Chaisson R. E., Cameron J. L. Acute effects of a nucleoside analog dideoxyinosine (DDI) on the pancreas. J Surg Res. 1992 Dec;53(6):610–614. doi: 10.1016/0022-4804(92)90262-x. [DOI] [PubMed] [Google Scholar]
- Oksenhendler E., Charreau I., Tournerie C., Azihary M., Carbon C., Aboulker J. P. Toxoplasma gondii infection in advanced HIV infection. AIDS. 1994 Apr;8(4):483–487. doi: 10.1097/00002030-199404000-00010. [DOI] [PubMed] [Google Scholar]
- Perno C. F., Yarchoan R., Cooney D. A., Hartman N. R., Gartner S., Popovic M., Hao Z., Gerrard T. L., Wilson Y. A., Johns D. G. Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2',3'-dideoxynucleosides. J Exp Med. 1988 Sep 1;168(3):1111–1125. doi: 10.1084/jem.168.3.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Porter S. B., Sande M. A. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992 Dec 3;327(23):1643–1648. doi: 10.1056/NEJM199212033272306. [DOI] [PubMed] [Google Scholar]
- Raffi F., Struillou L., Ninin E., Reliquet V., Billaud E., Milpied B. Breakthrough cerebral toxoplasmosis in patients with AIDS who are being treated with clarithromycin. Clin Infect Dis. 1995 Apr;20(4):1076–1077. doi: 10.1093/clinids/20.4.1076. [DOI] [PubMed] [Google Scholar]
- Ray G. F., Mason W. D., Badr M. Z. Pharmacokinetics of the anti-AIDS drug 2',3'-dideoxyinosine in the rat. Drug Metab Dispos. 1990 Sep-Oct;18(5):654–658. [PubMed] [Google Scholar]
- Romand S., Della Bruna C., Farinotti R., Derouin F. In vitro and in vivo effects of rifabutin alone or combined with atovaquone against Toxoplasma gondii. Antimicrob Agents Chemother. 1996 Sep;40(9):2015–2020. doi: 10.1128/aac.40.9.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Romand S., Pudney M., Derouin F. In vitro and in vivo activities of the hydroxynaphthoquinone atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, or minocycline against Toxoplasma gondii. Antimicrob Agents Chemother. 1993 Nov;37(11):2371–2378. doi: 10.1128/aac.37.11.2371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith E., Pers C., Aschow C., Mathiesen L. Cerebral toxoplasmosis in Danish AIDS patients. Scand J Infect Dis. 1991;23(6):703–709. doi: 10.3109/00365549109024297. [DOI] [PubMed] [Google Scholar]
- Suzuki Y., Orellana M. A., Schreiber R. D., Remington J. S. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988 Apr 22;240(4851):516–518. doi: 10.1126/science.3128869. [DOI] [PubMed] [Google Scholar]
- Winstanley P., Khoo S., Szwandt S., Edwards G., Wilkins E., Tija J., Coker R., McKane W., Beeching N., Watkin S. Marked variation in pyrimethamine disposition in AIDS patients treated for cerebral toxoplasmosis. J Antimicrob Chemother. 1995 Aug;36(2):435–439. doi: 10.1093/jac/36.2.435. [DOI] [PubMed] [Google Scholar]
- Yarchoan R., Pluda J. M., Thomas R. V., Mitsuya H., Brouwers P., Wyvill K. M., Hartman N., Johns D. G., Broder S. Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex. Lancet. 1990 Sep 1;336(8714):526–529. doi: 10.1016/0140-6736(90)92085-v. [DOI] [PubMed] [Google Scholar]
- Zufferey J., Sugar A., Rudaz P., Bille J., Glauser M. P., Chave J. P. Prevalence of latent toxoplasmosis and serological diagnosis of active infection in HIV-positive patients. Eur J Clin Microbiol Infect Dis. 1993 Aug;12(8):591–595. doi: 10.1007/BF01973636. [DOI] [PubMed] [Google Scholar]
- el Dareer S. M., Tillery K. F., Kalin J. R., Hill D. L. Disposition of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine in mice. Invest New Drugs. 1989 Jul;7(2-3):139–146. doi: 10.1007/BF00170850. [DOI] [PubMed] [Google Scholar]