Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The effects of vehicles and enhancers on the skin permeation of the dideoxynucleoside-type anti-HIV drugs Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT) were studied using hairless rat skin at 37 degrees C. After each drug was saturated in various volume fractions of ethanol (EtOH)/water or EtOH/tricaprylin (TCP) cosolvent system for 48 h at 37 degrees C, an in vitro skin permeation study was conducted using Valia-Chien permeation cells for 30 h. The skin permeation rates of DDC, DDI, and AZT from both EtOH/water and EtOH/TCP cosolvent systems increased as the volume fraction of ethanol was increased, reached maximum values at 50-60% (v/v) of ethanol, and then decreased with further increase of ethanol volume fraction. The EtOH/water cosolvent system seems to enhance the skin permeation of these drugs by increasing both the solubility of drug in the vehicles and partitioning of drug into the skin. The skin permeation enhancing effect of EtOH/TCP seems to be solely due to the increase in partitioning of drug into the skin. Addition of 1.0% (v/v) of permeation enhancers, such as oleic acid (OA) and N-methyl-2-pyrrolidone (NMP), in the EtOH/TCP (50:50) cosolvent system could not significantly increase the permeation rate of these drugs. Incorporation of viscous TCP into ethanol probably reduced the thermodynamic activity of enhancers to distribute from the vehicle to the skin. However, incorporation of 1.0% (v/v) of OA in the EtOH/water (60:40) cosolvent system dramatically enhanced the skin permeation of these drugs while reducing the lag time. The permeation rates of these drugs increased as OA concentration was increased up to 0.3% (v/v) in the EtOH/water (60:40) cosolvent system and reached a plateau with further addition of OA. Using a saturated solution in the EtOH/water (60:40) cosolvent system containing 1.0% (v/v) OA, DDC, and AZT reached the target permeation rate required to maintain a therapeutic system level across hairless rat skin. Although only DDC reached the target permeation rate across human cadaver skin, these results suggest that the mutual enhancement effect of ethanol and OA may make transdermal delivery of dideoxynucleoside-type anti-HIV drugs feasible.
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PMID:Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 2. The effect of vehicle and enhancer on skin permeation. 868 51

This study was carried out to assess the safety and efficacy of a combination of lentinan, an immune modulator, and didanosine (ddI) in a controlled study in HIV positive patients with CD4 levels of 200-500 cells/mm3. Didanosine was administered to HIV patients at doses of 400 mg/day (po) for six weeks (bid), then 2 mg of lentinan i.v. was added per week for 24-80 weeks. A control group (20%) received ddI only. A total of 107 patients were enrolled at three sites, and 88 patients started the ddI/lentinan phase. The combination caused significant increases in CD4 levels up to 38 weeks, whereas ddI alone was significant at the 5% level at 14 weeks. Based on these data, lentinan qualifies as a participant in future multi-drug studies in HIV.
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PMID:A phase II controlled study of a combination of the immune modulator, lentinan, with didanosine (ddI) in HIV patients with CD4 cells of 200-500/mm3. 872 97

Didanosine is commonly prescribed as monotherapy or as part of a combination regimen for patients with human immunodeficiency virus infection. The use of lower doses, either as part of a combination regimen or as a result of dose reduction secondary to clinical intolerance, requires that a sensitive assay method be available for either traditional or population-based pharmacokinetic evaluations. We evaluated a radioimmunoassay technique with a standard curve range of 0 to 100 ng/ml in human plasma, urine, and cerebrospinal fluid and assessed its accuracy and precision for use in pharmacokinetic studies.
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PMID:Didanosine measurement by radioimmunoassay. 872 95

Didanosine is a dideoxynucleoside analogue, which is phosphorylated to the active metabolite dideoxyadenosine triphosphate (ddATP) intracellularly. At therapeutic concentrations, ddATP inhibits HIV replication by inhibiting HIV reverse transcriptase. Didanosine is established as a first-line treatment for patients with HIV disease and has recently been shown to be superior to zidovudine monotherapy in the treatment of patients with intermediate-stage HIV infection. In clinical practice, however, combination regimens of antiretroviral drugs are generally considered preferable to monotherapy as first-line treatment for most patients with HIV disease. Importantly, 2 large multicentre studies have demonstrated that combination therapy with didanosine and zidovudine was more effective than zidovudine monotherapy in delaying disease progression and death in patients with intermediate or advanced HIV disease. In other comparative studies, improvements in surrogate markers of HIV disease were generally greater in patients who received combination therapy than in recipients of antiretroviral drug monotherapy. Improvements in surrogate markers were also observed in children who received didanosine monotherapy in several clinical trials. Although the efficacy of combination antiretroviral drug therapy has not yet been investigated extensively in children, a combination regimen of didanosine and zidovudine was well tolerated and achieved beneficial effects on surrogate markers if HIV disease. In addition, preliminary findings of a larger study have shown that disease progression was delayed in children and adolescents who received didanosine plus zidovudine combination therapy compared with those receiving zidovudine monotherapy. Didanosine has a tolerability profile that is distinctly different from that of zidovudine. In particular, didanosine exhibits only minimal haematological toxicity when administered either as a single agent or in combination with zidovudine. The most serious dose-limiting adverse effects associated with didanosine treatment are peripheral neuropathy and pancreatitis. In conclusion, didanosine monotherapy is an effective treatment of HIV infection. However, combination antiretroviral therapy is the optimal treatment strategy for most patients, and didanosine is now firmly established as a component of combination antiretroviral drug regimens for the first-line treatment of patients with HIV disease.
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PMID:Didanosine. An update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV disease. 895 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

The pharmacokinetics of didanosine and ciprofloxacin were evaluated following the administration of multiple oral doses of each drug as a single agent or in combination. Didanosine was dosed as the Videx chewable/dispersible tablet, which contains the antacids dihydroxyaluminum sodium carbonate and magnesium hydroxide. Sixteen HIV-seropositive male subjects were randomly assigned to two groups of eight each. Group A received didanosine (200 mg q 12h) for 3d, followed by didanosine (200 mg q 12h) and ciprofloxacin (750 mg q 12h) for 3d, and finished with another course of didanosine (200 mg q 12h for 3 d). Group B began with ciprofloxacin, followed by the combination, and finished with ciprofloxacin using the same doses and schedule as utilized in group A. During the combination phase of the study, ciprofloxacin was administered 2 h prior to didanosine. Serial blood and urine samples were collected on study days 4, 8, and 12 for the quantitative determination of didanosine and ciprofloxacin using validated HPLC methods. The plasma and urine data were subjected to noncompartmental pharmacokinetic analysis. A statistically significant decrease in the average AUC and UR values of ciprofloxacin was noted when it was given with didanosine, relative to administration as a single agent. However, the magnitude of the decrease in these parameters, approximately 26 and 29%, respectively, was not considered clinically significant. The apparent decrease in the bioavailability of ciprofloxacin was probably due to the formation of a chelation complex between it and the aluminum- and magnesium-containing antacids found in the didanosine tablet. Other than an approximately 16% decrease in AUC, ciprofloxacin did not alter the pharmacokinetics of didanosine. The data from the present study demonstrate that didanosine or ciprofloxacin can be added to a treatment regimen consisting of the other single agent and that cessation of treatment with one agent does not have an impact on the pharmacokinetics of the other drug. The dose of ciprofloxacin must be taken at least 2h prior to didanosine to avoid a clinically significant interaction with the antacids present in the didanosine formulation.
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PMID:A multiple-dose pharmacokinetic interaction study between didanosine (Videx) and ciprofloxacin (Cipro) in male subjects seropositive for HIV but asymptomatic. 900 70

The aim of the present study, a multicentre trial of didanosine (ddI) compassionate use, was to identify factors associated with a better outcome in patients given ddI monotherapy. Enrolled were 1047 HIV-positive patients intolerant of and/or unresponsive to zidovudine (ZDV) therapy, with CD4+ cell counts of < 200/microliter or AIDS. Didanosine was given at a dose of 250 mg b.i.d. (patients > or = 60 kg) or 167 mg b.i.d. (patients < 60 kg). Clinical examinations and laboratory tests were performed every two months. Endpoints included death, the occurrence of a new AIDS-defining disease, or permanent discontinuation of ddI for a severe adverse event. At entry, the median CD41 cell count was 47/microliter and the median duration of prior ZDV treatment 19 months; 446 patients (43%) were classified as having AIDS. Severe toxicity occurred in 143 subjects (14%); the frequency of pancreatitis was very low (0.2%). The benefit in terms of CD4+ cell counts was greater for patients whose counts exceeded 100/microliter at entry and remained at this level until month 12 in those patients still receiving treatment. Death and/or new AIDS-defining events were observed in 374 cases (36%) over a median follow-up of eight months. AIDS dementia was observed in 11 patients (1%). Multivariate analysis of survival without disease progression showed that the factors associated with a worse outcome include the severity of immunodepression, a diagnosis of AIDS at entry, and a history of both intolerance of and clinical resistance to ZDV. Surprisingly, the patients who had received previous prolonged treatment with ZDV had a better outcome. In conclusion, severely immunodepressed patients previously administered long-term monotherapy may receive a short-term benefit from being switched to another antiretroviral drug.
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PMID:Italian multicentre study of didanosine compassionate use in advanced HIV infection. Italian BMS-906 Study Group. 910 40

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

Administration of anti-retroviral drugs induces a decrease of viral load associated with increase of CD4+ cell count in most HIV-infected patients. To investigate the early changes in CD4+ cell phenotype induced by anti-retroviral therapy, six patients with CD4+ cell count > 100/mm3 and never treated with anti-HIV therapy were enrolled and blood samples collected several times within 14 days from the initiation of therapy with Zidovudine plus Didanosine. CD4+ cell count and HIV viraemia were investigated at each time point, as well as the expression of CD45RA, CD45RO and CD95/Fas molecules on CD4+ cells, and the T cell receptor (TCR) Vbeta repertoire of CD4+ cells. All patients showed a rapid and dramatic decrease in viral load with a corresponding increase of CD4+ cell count. The main remodelling of CD4+ cell subpopulations took place in the first 14 days of therapy, and consisted of: (i) increased CD4+CD45RA+/CD4+CD45RO+ ratio; (ii) decrease of CD95/Fas expression. The rise in absolute number of CD4+CD45RA+ cells was paralleled by an increase of CD4+CD95/Fas- cells and accounted for most of the early increment of CD4+ cell count. The TCR Vbeta repertoire of CD4+ cells was conserved after anti-HIV therapy, with the exception of two patients with expanded CD4+Vbeta12+ cells, which also tested CD45RA+ and CD95/Fas-. These experiments show that newcomer CD4+ lymphocytes are CD45RA+CD95/Fas- cells, suggesting that blocking HIV replication causes an early and antigen-independent proliferation of possibly 'naive' cells unprimed for CD95/Fas-mediated apoptosis. These cells expressed a conserved and widespread TCR repertoire, suggesting that their capability for antigenic recognition is intact.
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PMID:Early increase of CD4+ CD45RA+ and CD4+ CD95- cells with conserved repertoire induced by anti-retroviral therapy in HIV-infected patients. 947 55


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