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

Abstract

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 mumol 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 greater than or equal to 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.

Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus

“…Systemic availability appears to be further compromised by a rate-limited absorption step (8,12,14), leading to recommendations that ddI be taken BID instead of once a day (3a, 8). With the ddI formulations used in this trial (taken BID under fasting conditions), mean systemic bioavailability has been reported to range from 33 to 41% (8,14,15,18,22). Since the AUC of ddI has been shown to correlate with both suppression of p24 antigen and the frequency of adverse effects (7,8,22), a prospective study to evaluate whether monitoring concentrations in serum improves response or reduces toxicity may be beneficial.…”

“…Approximately 50 to 70% of the absorbed dose of ddI appears in urine as various metabolites, although the full metabolic profile is unknown (3a, 11a, 14). Dose-related toxicities of ddI include peripheral neuropathy and pancreatitis (5,15,22). Since fluconazole and ddI are commonly coadministered, fluconazole has the potential to inhibit the metabolism of ddI, leading to higher levels in serum and an increase in toxicities or intolerance.…”

Didanosine-induced retinopathy in adults can be reversible

“…In Caucasians, there is an association between ODM and uveal melanoma. 1,2 The disease, on the other hand, is rare in blacks. We report here a case of ODM and uveal melanoma in a black patient.…”

Retinopatia associada ao uso de didanosina

“…Intracelularmente é convertida pela enzima 5-nucleotidase em dd-IMP (dideoxytinosina 5 monofosfato) que por fim é metabolizada em sua forma ativa dd-ATP (2-3 dideoxyadenosina trifosfato), funcionando como um competidor do substrato dATP da enzima transcriptase reversa viral (inibidor competitivo) (1) .…”

“…A neuropatia periférica e a pancreatite são considerados os principais efeitos colaterais dose dependentes da didanosina, ocorrendo geralmente nos primeiros 3 a 6 meses de uso (1) . Casos de retinopatia tóxica em crianças HIV positivas são relatados associados ao uso de altas doses de DDI, porém raros casos são relatados em adultos (2)(3) .…”