Synergistic Inhibition of Human Immunodeficiency Virus Type 1 in vitro by 6-0-butanoylcastanospermine (MDL 28574) in Combination with Inhibitors of the Virus-Encoded Reverse Transcriptase and Proteinase

Abstract

SummaryThe anti-human immunodeficie~yvirus type 1 (HIV-1) activity of the a-glucosidase 1~nhibitor 6-0-butanoylcastanospermine (MOL 28574) was assessed in combination with the 2',3'-dideoxynucleoside analogues zidovudine (AZT), didanosine (ddl) and zalcitabine (ddC). MOL 28574 was also evaluated in combination with the non-nucleoside reverse transcriptase (RT) inhibitor nevi rapine and the HIV proteinase inhibitor saquinavir (Ro-31-8959). Orug interactions were examined by the isobologram technique and by calculating combination indices (CJ.s). In all cases synergistic inhibition of HIV-1 replication was observed. In three-drug combinations, a marked synergistic antiviral effect was also observed, with Col. values in the range 0.35-0.44 for MOL 28574 in combination with AZT and nevirapine, and in the range 0.34-0.67 for MOL 28574 in combination with AZT and saquinavir. Moreover, the combination of MOL 28574 with other drugs did not produce detrimental effects on cell division. MOL 28574 is currently in clinical trials and may have an important role in combination chemotherapy for HIV infections.

Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication

“…In both PBMCs and CEM-SS cells, BMS-PI-d4T was additive, and one additional combination, d4T-saquinavir, showed synergy in PBMCs. Others have also published reports showing additive to synergistic interactions with different HIV protease inhibitors in combination with AZT or ddC in vitro (9,23,25,29,44). In one clinical trial, the combination AZT-ddC-saquinavir resulted in a significant and sustained reduction in viral load (19).…”

Nevirapine

“…[14] • Nevirapine exhibited a synergistic effect (HIV-I-infected MT-4 cells) in combination with the (Xglucosidase 1 inhibitor MDL 28 574, [15] an additive effect (HIV-l-induced syncytium formation in HT4-6C cells) with Ro 24-7429 (a Tat protein antagonist) [16] and only a slightly better than additive effect (tetrazolium viability assay using MT-4 cells) with MKC-442, a non-nucleoside RT inhibitor. [14] • Nevirapine exhibited a synergistic effect (HIV-I-infected MT-4 cells) in combination with the (Xglucosidase 1 inhibitor MDL 28 574, [15] an additive effect (HIV-l-induced syncytium formation in HT4-6C cells) with Ro 24-7429 (a Tat protein antagonist) [16] and only a slightly better than additive effect (tetrazolium viability assay using MT-4 cells) with MKC-442, a non-nucleoside RT inhibitor.…”

“…[2] Furthermore, when combined with other anti-HIV-I agents in vitro, nevirapine was not associated with detrimental effects in healthy (uninfected) PBMCs.ll, 15,20] • Nevirapine is not immunosuppressive. [2] Furthermore, when combined with other anti-HIV-I agents in vitro, nevirapine was not associated with detrimental effects in healthy (uninfected) PBMCs.ll, 15,20] • Nevirapine is not immunosuppressive.…”