CLINICAL-PHARMACOLOGY OF ZIDOVUDINE AND OTHER 2',3'-DIDEOXYNUCLEOSIDEANALOGS

Since the discovery of the acquired immunodeficiency syndrome (AIDS) i n 1981, considerable progress has been made in the development of agen ts with anti-HIV activity. Zidovudine was one of the first 2'-3'-dideo xynucleosides to cause inhibition of human immunodeficiency virus (HIV ) replication in vitro, by inhibiting the viral reverse transcriptase. Early trials showed that zidovudine results in clinical and immunolog ical improvements and prolonged life in patients with AIDS or AIDS-rel ated complex. However, haematological toxicity is the main drawback as sociated with zidovudine therapy. The initial recommended dose of zido vudine was 1500 mg per day, but recent studies have shown that dosages as low as 300 mg per day could be just as effective, without the seve re haematological toxicity. Because zidovudine readily crosses the blo od-brain barrier, it is used for the treatment of neurological disease s associated with HIV disease with some success. However, Kaposi's sar coma does not respond to therapy with the drug. Apart from haematologi cal toxicity, patients on long-term therapy with zidovudine may also d evelop resistance. Zidovudine use has also been associated with improv ements in neurodevelopmental and growth velocity in HIV-infected child ren. The use of zidovudine as a prophylaxis has also been suggested, b ut the value of this is questionable. The combination of zidovudine wi th other agents, such as acyclovir and interferon, has a synergistic e ffect on the anti-HIV activity, with reduced drug toxicity. Other 2',3 '-dideoxynucleoside analogues, such as dideoxycytidine (ddC) and dideo xyinosine (ddI) are effective anti-HIV agents and their use is also as sociated with both clinical and immunological improvements. The toxici ty profiles of ddC and ddI are, however, different to that of zidovudi ne and are associated mainly with neurotoxicity. The different toxicit y profiles of ddC and ddI to zidovudine has provided the rationale for testing these agents in combination, in an attempt to retain the anti -retroviral activity of each compound against HIV, while reducing thei r toxicity. Zidovudine in combination with ddC has been shown to reduc e the progression of HIV disease in patients with AIDS or AIDS-related complex.