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JAC Advance Access originally published online on October 8, 2002
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Journal of Antimicrobial Chemotherapy (2002) 50, 639-647
© 2002 The British Society for Antimicrobial Chemotherapy

Inhibition of murine AIDS by a heterodinucleotide of azidothymidine and 9-(R)-2-(phosphonomethoxypropyl)adenine

Luigia Rossi1, Sonja Serafini1, Palmarisa Franchetti2, Anna Casabianca1, Chiara Orlandi1, Giuditta Fiorella Schiavano3, Andrea Carnevali4 and Mauro Magnani1,*

1 Institute of Biochemistry ‘G. Fornaini’ and 3 Institute of Hygiene, University of Urbino, Via Saffi, 2-61029 Urbino (PU); 2 Department of Chemical Sciences, University of Camerino (MC), 62032 Camerino; 4 Hospital ‘San Salvatore’, 61100 Pesaro (PU), Italy

Received 27 March 2002; returned 12 June 2002; revised 23 July 2002; accepted 7 August 2002

Tenofovir [9-(R)-2-(phosphonomethoxypropyl)adenine (PMPA)] and zidovudine [azidothymidine (AZT)] are potent anti-HIV agents that have shown a strong synergy in in vitro studies. In this paper we have investigated both the potentiality of this synergy in vivo and the possibility to administer AZT and PMPA simultaneously as a single drug AZTpPMPA. The pharmacokinetic studies reported here have shown that AZTpPMPA administered intraperitoneally in mice performs as a prodrug, providing a slow delivery of AZT and PMPA in circulation. C57BL/6 mice infected with the retroviral complex LP-BM5 were used to evaluate the efficacy of AZTpPMPA in inhibiting disease progression. Furthermore, the effectiveness of the heterodinucleotide was compared with that of AZT and PMPA, administered as single drugs, or as a combination (AZT plus PMPA). The results obtained showed that AZTpPMPA is able to reduce lymphoadenopathy (88%), splenomegaly (64%), lymph node BM5 proviral DNA content (49%) and hypergammaglobulinaemia (40%). However, upon AZT plus PMPA administration, similar (splenomegaly and lymphoadenopathy reduction) or better results (64% hypergammaglobulinaemia reduction and 75% lymph node BM5 proviral DNA content inhibition) were obtained. Furthermore, these results overlapped those obtained upon PMPA administration. Thus, no synergy between PMPA and AZT was observed in murine AIDS and administration of AZT does not improve the antiviral results obtained by PMPA administration.

* Corresponding author. Tel: +39-0722-305-211; Fax: +39-0722-320-188; E-mail: magnani{at}uniurb.it


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