Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been hypothesized that didanosine has a low efficacy in the prevention and treatment of patients with the dementia complex of acquired immunodeficiency syndrome (AIDS) because "... the drug has not been detected in the cerebrospinal fluid". We investigated didanosine concentrations in cerebrospinal fluid (CSF) and plasma of four patients with AIDS who were using didanosine chronically. Didanosine levels, 4 h after the last drug administration, averaged 0.16 (+/- 0.03) mumol/l in CSF and 0.70 (+/- 0.27) mumol/l in plasma. When compared with historical data from patients using zidovudine, didanosine concentrations in CSF appeared to be approximately half (on a molar base) those of zidovudine concentrations in the CSF. Whether this difference in CSF levels is the explanation for the presumed lower efficacy of didanosine in the prevention and treatment of AIDS dementia complex remains to be proven. However, it is clear from this study, in contrast with earlier suggestions, that didanosine is able to pass the blood-CSF barrier in human immunodeficiency virus-infected individuals.
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PMID:Study on didanosine concentrations in cerebrospinal fluid. Implications for the treatment and prevention of AIDS dementia complex. 859 80

A nonrandomized trial was undertaken to evaluate the combination of didanosine and interferon-alpha (INF-alpha) in human immunodeficiency virus (HIV)-infected patients. Thirty-six volunteers with >200 x 10(6) CD4 cells/L received didanosine (one 100-, 250-, or 375-mg sachet twice daily) for at least 6 weeks, following which IFN-alpha (1, 5, 10, or 15 MU/day) was begun. Didanosine (one 375-mg sachet twice daily) was substituted for zidovudine in 14 additional patients who had received IFN-alpha and zidovudine for 7-45 months. Thirty-five patients completed the 34-week study. Clinical or chemical pancreatitis was the most common (6 patients) dose-limiting toxicity. CD4 cell counts increased with didanosine but declined following the addition of IFN-alpha; CD4 cell percents tended to increase and remain elevated. Thus, combination therapy with didanosine and IFN-alpha can be safely administered to patients with HIV infection. The clinical benefit of this combination therapy will require further evaluation.
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PMID:Combination therapy with didanosine and interferon-alpha in human immunodeficiency virus-infected patients: results of a phase I/II trial. 860 61

Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [+/- standard deviation] CD4+ cell count, 304 +/- 213/mm3) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (Cmax) was reduced from 7.22 +/- 4.0 to 3.51 +/- 1.9 microM, and the area under the concentration-time curve from 0 h to infinity (AUC0-->infinity) was reduced from 22.5 +/- 14 to 14 +/- 5.7 microM.h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC0-->infinity to the delavirdine AUC0-->infinity, was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a Cmax reduction from 4.65 +/- 2.0 to 3.22 +/- 0.59 microM and an AUC0-->infinity reduction from 7.93 +/- 3.9 to 6.54 +/- 2.3 microM.h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC0-->infinity of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady state.
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PMID:Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection. 898 Jul 74

In this multicenter study (ISS 902), 554 previously untreated patients with <500 CD4 cells/mm3 and mildly symptomatic human immunodeficiency virus disease were randomized to receive zidovudine or didanosine (ddI). After a mean follow-up of 20 months, 80 patients (40 zidovudine, 40 ddI) had died and 146 had at least one AIDS-defining event (73 zidovudine, 73 ddI). Overall, no difference was found between treatments with respect to progression to AIDS or death. The analysis of relative risk (RR) of progression over time, however, showed an initially minor risk for zidovudine patients and an inversion in the zidovudine-ddI RR in the second and third years of follow-up. Didanosine showed a greater effect on CD4 cell count response. The two drugs confirmed the toxicity patterns already reported in other trials, with a low occurrence of pancreatitis (ddI 1.3%, zidovudine 0.4%). The overall results suggest that, in this population, zidovudine and ddI monotherapies have comparable long-term clinical efficacy and that more powerful regimens should be preferred.
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PMID:A randomized trial (ISS 902) of didanosine versus zidovudine in previously untreated patients with mildly symptomatic human immunodeficiency virus infection. 920 45

Didanosine (ddI) is currently used in the management of patients infected by the human immunodeficiency virus. Rifabutin (RBT) is being extensively used for prophylaxis against Mycobacterium avium complex (MAC) infections. Due to its acid-labile characteristics, ddI must be administered with a buffer. Recent reports have indicated that absorption of ketoconazole, ciprofloxacin, and dapsone, etc., in the gut is altered by concomitant ddI dosing. We have assessed whether concomitant dosing of ddI as antiretroviral therapy modifies RBT absorption in the gut, its steady-state pharmacokinetics, and/or safety in 15 patients with AIDS. Of the 15 patients enrolled, 12 completed the study and 3 receiving 600 mg of RBT with concomitant ddI administration withdrew prematurely from the study. Steady-state RBT pharmacokinetics were assessed on day 13 (ddI plus RBT) and day 16 (RBT alone). The ddI doses (adjusted for body weight) were 167 to 375 mg twice daily, while RBT was administered as a single 300- or 600-mg daily dose. No statistically significant (P > 0.05) differences were seen in RBT absorption parameter estimates between days 13 and 16: maximum concentration in plasma (Cmax; 511 +/- 341 ng/ml versus 525 +/- 254 ng/ml) and the time at which Cmax was observed (3.0 versus 2.5 h). The mean RBT estimates for area under the concentration-time curve from 0 to 24 h (AUC(0-tau)) (5,650 versus 5,023 ng x h/ml) and for oral clearance (1.28 versus 1.18 liter/h/kg) on both study days were also similar. Assessment based on urinary recovery of RBT (3.1 versus 3.7 mg) and its predominant deacetyl metabolite, LM565 (1.6 versus 1.4 mg), showed no apparent effect of ddI. The fraction of the RBT dose converted to LM565, as suggested by the ratio of AUC of the metabolite to AUC of the parent drug, was also unaltered (0.15 versus 0.12). A ratio analysis (day 13/day 16) of the RBT pharmacokinetic estimates showed that the 95% confidence intervals for all parameters were inclusive of one. Furthermore, the brief interruption of ddI therapy over this short study period at steady state produced no clinically significant changes in body weight, hematology, and renal and pancreatic functions. Therefore, concomitant administration of ddI appears not to affect RBT absorption in the gut and its disposition or safety in patients with AIDS.
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PMID:Rifabutin absorption in the gut unaltered by concomitant administration of didanosine in AIDS patients. 921 Jun 86

Didanosine (ddI) that inhibits the reverse transcriptase of human immunodeficiency virus (HIV) causes steatosis and fulminant hepatitis in some patients with HIV. We studied hepatic histopathologic changes with particular attention to ddI-induced Mallory body formation. Three liver biopsies were performed on three patients with HIV who were treated with ddI; an autopsy was performed on a patient with HIV who was also treated with ddI. All hepatic specimens were studied with a routine liver immunohistochemical panel including antibodies to ubiquitin and cytokeratin (CAM 5.2). Morphologically, all hepatic specimens showed focal to diffuse steatosis with a predominance of macrovesicular fatty change. Fibrosis was minimal in three cases. No secondary bacterial and fungal infections were noted. Single or clusters of "empty cells" were present, and some contained Mallory bodies validated by ubiquitin stain. Empty cells are hepatocytes that fail to stain positive for cytokeratin. The Mallory bodies were different from the others because they were randomly distributed and occurred in noncirrhotic hepatic tissue. In the autopsy specimen, the Mallory bodies had a centrilobular location with central fibrosis (central sclerosing hyaline necrosis).
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PMID:2',3'-Dideoxyinosine-induced Mallory bodies in patients with HIV. 929 55

Hematologic abnormalities are often seen in patients infected with human immunodeficiency virus (HIV). The effect of HIV infection of bone marrow stroma on support of uninfected CD34 progenitor cells in long-term bone marrow culture (LTBMC) was investigated. Results show that HIV-infected bone marrow stroma was unable to adequately support CD34 progenitor cells in vitro. Zidovudine or didanosine was added to cultures in an attempt to reverse the suppressive effects exerted by HIV and to determine whether such suppression was mediated by transfer of HIV infection to progenitor cells. Didanosine failed to reduce the suppressive effects of HIV, whereas zidovudine compounded the observed suppression. HIV infection of bone marrow stroma, while reducing the production of nonadherent cells, did not increase apoptosis and cell death in such cells. In contrast, zidovudine enhanced apoptosis and cell death in nonadherent cells produced by both HIV-infected and control LTBMC.
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PMID:Human immunodeficiency virus infection impairs hemopoiesis in long-term bone marrow cultures: nonreversal by nucleoside analogues. 939 62

Didanosine (2',3'-dideoxyinosine; ddI) requires intracellular metabolism to its active triphosphate, 2',3'-dideoxyadenosine 5'-triphosphate (ddATP), to inhibit the replication of human immunodeficiency virus (HIV). We have investigated the metabolism of ddI to ddATP in the presence and absence of a range of compounds. In addition, we determined the levels of the endogenous competitor of ddATP, 2'-deoxyadenosine 5'-triphosphate (dATP), and calculated ddATP/dATP ratios. None of the nucleoside analogs studied had any effect on ddI phosphorylation at 1 and 10 microM concentrations. At 100 microM concentrations, ddC reduced total ddA phosphates (82% of control total ddA phosphates; p < 0.001). ZDV significantly decreased the levels of dATP, whereas ddC significantly increased dATP pools (e.g., at 100 microM ZDV, 82% of control dATP levels; p < 0.001). Hence, the ddATP/dATP ratio was increased in the presence of ZDV, but was decreased in the presence of ddC. Neither d4T nor 3TC affected the ddATP/dATP ratio. Deoxyinosine (dI) significantly reduced ddA phosphate production at 100 microM concentrations, with ddATP reduced to undetectable levels (p < 0.001). Hydroxyurea (HU) did not affect the activation of ddI, but significantly reduced dATP pools at 100 microM concentrations (67% of control dATP levels; p < 0.001), enhancing the ddATP/dATP ratio. ddA phosphate production was significantly reduced by pentoxyfylline (PXF) at 10 and 100 microM concentrations. dATP levels were unaffected, but the ddATP/dATP ratio was reduced. Finally, 8-aminoguanosine (8-AMG) had no effect on either ddI activation or dATP pools. These studies demonstrate the importance of determining both the active TP and the competing endogenous TP, as changes to the resulting ratio could alter the efficacy of the nucleoside analog in question.
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PMID:Intracellular activation of 2',3'-dideoxyinosine and drug interactions in vitro. 1038 Nov 67

Didanosine (ddI) pharmacokinetics in antepartum and postpartum human immunodeficiency virus (HIV)-infected women and their neonates were studied. HIV-infected pregnant women received an intravenous (iv) ddI infusion (1.6 mg/kg/h) or an oral dose (200 mg bid or 125 mg bid) at 31 weeks antepartum and 6 weeks postpartum. Blood samples were obtained regularly up to 6 or 8 h after drug administration. The same oral dose of ddI (bid) was administered until labor began. Then, ddI was infused iv until delivery. An oral pharmacokinetic study (60 mg/m2) was conducted in infants at day 1 and at week 6 after birth. Plasma concentrations of ddI were measured by radioimmunoassay. After iv ddI administration, only the maternal plasma clearance was found to be significantly increased antepartum (1028+/-231 mL/min) versus postpartum (707+/-213 mL/min). No pharmacokinetic parameters after oral administration were significantly affected by pregnancy. The pharmacokinetics of ddI in the neonates were highly variable. We conclude that the oral ddI dose need not be adjusted during pregnancy.
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PMID:Pharmacokinetics of didanosine in antepartum and postpartum human immunodeficiency virus--infected pregnant women and their neonates: an AIDS clinical trials group study. 1051 13

Resistance mutations selected in reverse transcriptase (RT) by incompletely suppressive therapy with combination zidovudine and didanosine with or without nevirapine were identified in 141 human immunodeficiency virus type 1 isolates from peripheral blood mononuclear cells of 57 individuals in the AIDS Clinical Trials Group protocol 241. After prolonged treatment (16-48 weeks), the most common nevirapine-selected mutations were RT 181C (15/30 isolates [50%]), 190A (15/30 [50%]), and 101E (9/30 [30%]). RT 103N and 188L, which individually confer cross-resistance to all nonnucleoside RT inhibitors, were seen in a minority of viruses (6/30 [20%] and 4/30 [13%], respectively). Didanosine-resistance mutations arose rarely. A newly recognized mutation, RT 44D, was selected by the nucleosides. Two distinct zidovudine-resistance mutational patterns were noted. Mutations selected during treatment with zidovudine, didanosine, and nevirapine differed among individuals and changed over time. Resistance testing is necessary to identify which mutations are selected by nevirapine-containing combinations.
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PMID:Patterns of resistance mutations selected by treatment of human immunodeficiency virus type 1 infection with zidovudine, didanosine, and nevirapine. 1072 May 11


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