Details

Autor(en) / Beteiligte

• Lambert, John S
• Seidlin, Mindell
• Reichman, Richard C
• Plank, Carol S
• Laverty, Maura
• Morse, Gene D
• Knupp, Catherine
• McLaren, Colin
• Pettinelli, Carla
• Valentine, Fred T
• Dolin, Raphael

Titel

2′,3′-Dideoxyinosine (ddI) in Patients with the Acquired Immunodeficiency Syndrome or AIDS-Related Complex: A Phase I Trial

Ist Teil von

• The New England journal of medicine, 1990-05, Vol.322 (19), p.1333-1340

Ort / Verlag

United States: Massachusetts Medical Society

Erscheinungsjahr

1990

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 2′,3′-dideoxyinosine (ddI) is a purine analogue that after intracellular metabolic conversion suppresses the replication of the human immunodeficiency virus (HIV). We conducted a Phase I dose-escalation study of ddI in 17 patients with the acquired immunodeficiency syndrome (AIDS) and 20 patients with AIDS-related complex. The drug was administered twice daily over a dose range of 0.4 to 66 mg per kilogram of body weight per day for 2 to 44 weeks. The maximal tolerated oral dose of ddI was estimated to be 12 mg per kilogram per day. The major dose-limiting toxic effects were a painful peripheral neuropathy (in eight patients) and pancreatitis (in five). Asymptomatic elevations of the serum aminotransferase levels (in 13 patients) and the serum urate level (in 10) were also noted, but there was no dose-related hematologic toxicity. At the maximal tolerated dose, the peak plasma levels of ddI were 6.3 to 9.6 μmol per liter 0.6 to 1 hour after oral administration; the mean plasma half-life was 1.5 hours. The administration of ddI was associated with statistically significant decreases in serum level of p24 antigen and increases in the numbers of CD4 cells at 2, 6, 10, and 20 weeks. These changes were seen at all dose levels studied. Either a clinical improvement or a weight gain of ≥2 kg was observed in 25 of 34 patients at six weeks. We conclude that ddI is a promising therapeutic agent in patients with AIDS or AIDS-related complex. Its efficacy is currently being evaluated in large-scale, controlled clinical trials. (N Engl J Med 1990; 322:1333–40.) SEVERAL dideoxynucleoside analogues are potent inhibitors of the human immunodeficiency virus (HIV) in vitro. 1 One member of this class of compounds, 2′,3′-dideoxyinosine (ddI), is a purine nucleoside analogue that has in vitro activity against HIV in both T cells 2 and monocytes. 3 This drug also appears to have relatively little toxicity in vitro for cells in tissue culture, including human bone marrow progenitor cells. 4 The drug is converted through a complex metabolic pathway to a triphosphorylated intracellular moiety, 2′,3′-dideoxyadenosine triphosphate (ddA-TP), which preferentially inhibits HIV reverse transcriptase and suppresses HIV replication by blocking the synthesis of viral DNA. 5 6 7 Unlike the triphosphates . . .