Efficacy and Toxicity of Long-Term Administration of 2′,3′-dideoxycytidine in the LP-BM5 Murine-Induced Immunodeficiency Model

Brandi, Giorgio; Casabianca, Anna; Schiavano, Giuditta Fiorella; Rossi, Luigia; Fraternale, Alessandra; Albano, A; Magnani, Mauro

doi:10.1177/095632029500600304

Cited by 9 publications

(3 citation statements)

References 28 publications

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“…The fluorescent monoclonal antibodies used for fluorescenceactivated cell sorting (FACS) analysis were purchased from PharMingen, Becton Dickinson Co. (Milan, Italy). Blood samples were stained with fluorescent monoclonal antibody and analysed by FACS (Becton Dickinson, San Jose, CA, USA) as described in the study by Palamara et al 19 Lymphocyte proliferative index [ 3 H]Thymidine incorporation on lymphocytes stimulated by either phytohaemagglutinin (PHA) for T cells or lipopolysaccharide for B cells was determined as described by Brandi et al 24…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

“…Infection of C57BL/6 mice with the LP-BM5 retrovirus complex causes a disease with a pathology that resembles that of human AIDS; 25 as a result, this animal model has been used extensively for preclinical studies of antiviral drugs. 24,26 In the present study, LP-BM5-infected mice were treated with the antiviral agent PMEA, or its prodrug Bis-PMEA, by oral gavage administration. Drugs were administered at equi-molar doses of PMEA at a concentration of 50 mg/kg.…”

Section: Inhibition Of Murine Aids (Maids) Development In Vivomentioning

confidence: 99%

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Pharmacokinetic and antiretroviral activity in mice of oral [P1,P2-bis[2-(adenin-9-yl)ethoxymethyl]phosphonate], a prodrug of 9-(2-phosphonylmethoxyethyl)adenine

Rossi

Dominici²,

Serafini³

et al. 2002

Journal of Antimicrobial Chemotherapy

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9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is an antiviral drug with activity against herpes viruses, Epstein-Barr virus and retroviruses, including the human immunodeficiency virus. Unfortunately, oral PMEA administration, as required for long-term therapy, is hindered by its low bioavailability. In the present study, the synthesis, oral bioavailability and antiretroviral activity of a new prodrug of PMEA, consisting of two molecules of PMEA bound together by a P-O-P bond (Bis-PMEA), are reported. Pharmacokinetic experiments in mice showed that the oral bioavailabilities of PMEA following oral gavage of Bis-PMEA or PMEA (at a dose equivalent to 28 mg of PMEA/kg) were 50.8 and 13.5%, respectively. These results correlate with the antiviral efficacy of Bis-PMEA administered orally at a dose equivalent to 50 mg/kg of PMEA in C57 BL/6 mice infected with the retroviral complex LP-BM5. Oral treatment with Bis-PMEA proved to be more effective than oral treatment with PMEA given at equimolar doses. Moreover, oral Bis-PMEA was more effective than intraperitoneal PMEA (50 mg/kg) in reducing lymphoadenopathy, hypergammaglobulinaemia and lymph node proviral DNA content, overall in the first weeks post virus inoculation. Bis-PMEA thus appears to be an efficient oral prodrug of PMEA without significant toxicity, at least in this mouse model.

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Section: Flow Cytometric Analysismentioning

confidence: 99%

Section: Inhibition Of Murine Aids (Maids) Development In Vivomentioning

confidence: 99%

Pharmacokinetic and antiretroviral activity in mice of oral [P1,P2-bis[2-(adenin-9-yl)ethoxymethyl]phosphonate], a prodrug of 9-(2-phosphonylmethoxyethyl)adenine

Rossi

Dominici²,

Serafini³

et al. 2002

Journal of Antimicrobial Chemotherapy

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“…For this purpose 15 C57BL/6 mice were infected with the retroviral complex LP-BM5. The sources of the animals and the virus strain have been reported previously (2,6). Three of the mice received 0.25 mg of AZT (zidovudine)/ml in drinking water for the duration of the experiment, beginning 24 h after infection, as described previously (6).…”

mentioning

confidence: 99%

Competitive PCR for Quantification of BM5d Proviral DNA in Mice with AIDS

1998

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Murine AIDS in C57BL/6 mice is caused by a unique mixture of murine leukemia viruses. We report the use of a competitive PCR to detect and quantitate BM5d proviral DNA. This assay allowed discrimination among endogenous wild-type murine retroviruses and BM5d sequences. Furthermore, the method was subsequently used to evaluate the amount of BM5d in infected mice and in infected AZT (zidovudine)-treated mice, providing an effective way to quantitatively evaluate drug efficacy in the murine AIDS model.

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