In Vivo Activity Against HIV and Favorable Toxicity Profile of 2′,3′-Dideoxyinosine

Abstract

The purine analog 2',3'-dideoxyinosine (ddI), which has anti-retroviral activity in vitro was administered for up to 42 weeks to 26 patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex (ARC). Ten of these individuals were AZT-intolerant. Eight dose regimens were studied. The drug was orally bioavailable and penetrated into the cerebrospinal fluid (CSF). Comparatively little evidence of an effect against human immunodeficiency virus (HIV) was seen at the lowest four doses. However, patients in the four highest dose groups (ddI at 1.6 milligrams per kilogram intravenously and then greater than or equal to 3.2 milligrams per kilogram orally at least every 12 hours or higher) had increases in their circulating CD4+ T cells (P less than 0.0005), increased CD4/CD8 T cell ratios (P less than 0.01), and, where evaluable, more than an 80% decrease in serum HIV p24 antigen (P less than 0.05). The patients also had evidence of improved immunologic function, had reduced viremic symptomatology, and gained a mean of 1.6 kilogram with these comparatively infrequent dosing schedules (every 8 or 12 hours). The most notable adverse effects directly attributable to ddI administration at the doses used in this study included increases in serum uric acid (due to hypoxanthine release) and mild headaches and insomnia. These results suggest that serious short-term toxicity at therapeutic doses is not an inherent feature in the profile of agents with clinical anti-HIV activity. Further controlled studies to define the safety and efficacy of this agent may be worth considering.

Sulphated Sugar Alpha-Cyclodextrin Sulphate, a Uniquely Potent Anti-HIV Agent, Also Exhibits Marked Synergism with AZT, and Lymphoproliferative Activity

“…Several chemical agents, including interferon, have been tested for their therapeutic potential against HIV-1 (Ho et aI., 1985;McCormick et aI., 1985;Mitsuya et al, 1985;Narashima et al, 1986;Anand et aI., 1988). The dideoxynucleoside analogue 3'-azido-2' ,3'-dideoxythymidine (AZl) was found to be very efficacious in inhibiting the infectivity and cytopathic effect of HIV-1 in vitro (Mitsuya et al, 1985;Mitsuya et al, 1987).AZT has been shown to increase the survival and decrease the frequency of opportunistic infections in certain patients with AIDS and AIDS-related complex (ARC) (Yarchoan et al, 1988).AZT, however, is associated with toxicities that limit its use, particularly bone marrow suppression with megaloblastic changes though the decline in CD4-positive cells has been delayed in patients who have been taking AZT for prolonged periods (Richman et aI., 1987;Yarchoan et al, 1988;Yarchoan et al, 1989). In 1988, AZT-resistant strains of HIV were isolated from patients (Larder et aI., 1989).Thus, there is a great need for alternative drugs and combination therapies.…”

Enantiomeric Synthesis of Novel Apiosyl Nucleosides as Potential Antiviral Agents

“…Therefore, this study attempted to synthesize the (E)-isomer 2 via a 2-fluorobutenolide formation 1, which could be readily prepared from L-Gulonic γ-Lactone in a large scale by the known procedure (Scheme 1). 14 Usually, the lactones are rapidly reduced to the diol by various reducing agents such as LAH, LiAlH(OMe) 3 , DIBAL-H, and NaBH 4 . However, to our knowledge, there are only a few examples of the direct reduction of butenolide to the diol.…”

“…The key strategy for the synthesis of the target compounds was based on the implementation of a [3,3]-sigmatropic rearrangement to generate an optically active fluoroester 4, which provides two useful functionalities, such as alkene and carbonyl groups, to obtain the fluorinated apiosyl moiety 6. However, due to the difficulties in preparing the (E) or (Z)-fluorinated olefin in a large scale, the planning for the preparation of the intermediate for the Claisen rearrangement, was guided using the difference in the geometry between the (E)-and (Z)-isomers.…”

Synthesis and cycloaddition reactions of [2-deoxy-3,5-bis[O-(p-toluoyl)]-α-D-ribofuranosyl]ethyne

“…AZT, 3'-azido-2',3'-dideoxythymidine, 1 ddI, 2′,3′-dideoxyinosine, 2 and the anti-cancer activity of some C-glycosides such as pseudocytidine 3 ), we have now synthesized the first examples of 2-deoxy-C-glycosides which combine both structural properties. We used [4+2]-and [3+2]-cycloaddition reactions of suitable acetylenic carbohydrate derivatives.…”