SYNERGISTIC INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN-VITRO BY 6-0-BUTANOYLCASTANOSPERMINE (MDL-28-574) IN COMBINATION WITH INHIBITORS OF THE VIRUS-ENCODED REVERSE-TRANSCRIPTASE AND PROTEINASE

The anti-human immunodeficiency virus type 1 (HIV-1) activity of the a lpha-glucosidase 1 inhibitor 6-O-butanoyl-castanospermine (MDL 28 574) was assessed in combination with the 2',3'-dideoxynucleoside analogue s zidovudine (AZT), didanosine (ddl) and zalcitabine (ddC). MDL 28 574 was also evaluated in combination with the non-nucleoside reverse tra nscriptase (RT) inhibitor nevirapine and the HIV proteinase inhibitor saquinavir (Re-31-8959). Drug interactions were examined by the isobol ogram technique and by calculating combination indices (C.I.s). In all cases synergistic inhibition of HIV-1 replication was observed. In th ree-drug combinations, a marked synergistic antiviral effect was also observed, with C.I, values in the range 0.35-0.44 for MDL 28 574 in co mbination with AZT and nevirapine, and in the range 0.34-0.67 for MDL 28 574 in combination with AZT and saquinavir. Moreover, the combinati on of MDL 28 574 with other drugs did not produce detrimental effects on cell division, MDL 28 574 is currently in clinical trials and may h ave an important role in combination chemotherapy for HIV infections.