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JAC Advance Access originally published online on March 28, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 1181-1189
© 2003 The British Society for Antimicrobial Chemotherapy

APHS can act synergically with clinically available HIV-1 reverse transcriptase and protease inhibitors and is active against several drug-resistant HIV-1 strains in vitro

Cândida F. Pereira*, Judith T. M. L. Paridaen, Marja van de Bovenkamp, Jeena Middel, Jan Verhoef and Hans S. L. M. Nottet

Eijkman-Winkler Center, Hp G04.614, University Medical Center Utrecht, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands

Received 24 September 2002; returned 17 December 2002; revised 23 December 2002; accepted 25 January 2003

Objectives: The use of multiple drug combinations in current anti-human immunodeficiency virus (HIV) therapy allows lower dosages of individual drugs and results in enhancement of the therapeutic effect due to synergic interactions between different drugs. We have shown that o - (acetoxyphenyl)hept-2-ynyl sulphide (APHS), a recently developed non-steroidal anti-inflammatory drug, shows anti-HIV activity in a dose-dependent manner. The first aim of this study was to investigate whether APHS can act synergically with the clinically available reverse transcriptase and protease inhibitors (RTIs and PIs, respectively) in vitro. Because of the increasing prevalence of RTI- and PI-resistant HIV-1 strains, the second aim of this study was to assess the antiviral activity of APHS against drug-resistant HIV-1 strains in vitro.

Materials and methods: HIV-infected peripheral blood mononuclear cells (PBMC) were treated for 7 days with different combinations of APHS and RTIs or PIs. The MT-2 cell line was infected with different HIV-1 strains and treated with APHS for 5 days.

Results: APHS showed synergic interactions with the RTIs zidovudine, lamivudine and efavirenz and with the PIs indinavir and ritonavir. The 50% inhibitory concentration (IC50) of APHS in this assay dropped from 13 µM when used alone, to 5 µM after combination with an RTI or PI. In combination with APHS the IC50 of the RTI and PI drugs tested also dropped. APHS inhibits the replication of HIV-1 strains resistant to zidovudine, lamivudine, stavudine, didanosine, zalcitabine and ritonavir.

Conclusions: These results indicate that APHS can be combined with RTIs and PIs and can inhibit several NRTI and PI-resistant HIV-1 strains.

Keywords: o-(acetoxyphenyl)hept-2-ynyl sulphide, Calcusyn, peripheral blood mononuclear cells, MT-2 cell line

* Corresponding author. Tel: +31-30-2506525; Fax: +31-30-2541770; E-mail: c.f.pereira{at}lab.azu.nl


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