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The Annals of Pharmacotherapy May 1992To review the chemistry, intracellular metabolism, pharmacokinetics, and clinical experience with didanosine (2',3'-dideoxyinosine [ddI]). (Comparative Study)
Comparative Study Review
OBJECTIVE
To review the chemistry, intracellular metabolism, pharmacokinetics, and clinical experience with didanosine (2',3'-dideoxyinosine [ddI]).
DATA SOURCES
English-language articles and conference proceedings (indexing terms were didanosine, 2',3'-dideoxyinosine, and ddI).
STUDY SELECTION
Available Phase I studies and abstracts determined to have clinical significance were included.
DATA EXTRACTION
Clinical experience with ddI is limited to uncontrolled Phase I studies and a large "expanded-access" program. The primary outcome parameters used to evaluate ddI were the HIV surrogate markers: CD4+ lymphocytes and p24 antigen. Thus, the clinical data reviewed here must be evaluated critically and be considered preliminary until the results of studies comparing ddI with zidovudine (ZDV) and combination studies are available.
DATA SYNTHESIS
Didanosine has been approved for the treatment of HIV infection in patients who are unable to tolerate ZDV because of adverse effects (e.g., anemia and neutropenia) or who experience clinical or immunologic deterioration while receiving ZDV. Compared with ZDV, ddI has a long intracellular half-life and negligible bone-marrow toxicity. It also has in vitro activity against ZDV-resistant strains of HIV. Phase I studies indicate that ddI has a beneficial effect on the CD4+ cell counts and HIV p24 antigen concentrations. As a result of the acid-labile nature of ddI, oral formulations are buffered or must be mixed with antacid to neutralize gastric pH. Bioavailability then averages 20-40 percent, depending on the dose and formulation given. The plasma half-life, total body clearance, and volume of distribution of ddI are one to two hours, 0.7-1 L/kg/h, and 0.8-1 L/kg, respectively. Painful peripheral neuropathy and pancreatitis (dose-limiting toxicities of ddI) occurred in 34 and 9 percent of patients in Phase I studies, respectively.
CONCLUSIONS
Didanosine has demonstrated preliminary efficacy in the treatment of late-stage HIV infection; however, its effect on patient survival, its efficacy relative to ZDV, and its utility in combination with other agents are still under evaluation.
Topics: Acquired Immunodeficiency Syndrome; Adult; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Clinical Trials as Topic; Didanosine; Drug Evaluation; Drug Interactions; Female; Humans; Leukocyte Count; Male; Time Factors; Zidovudine
PubMed: 1350471
DOI: 10.1177/106002809202600511 -
Lancet (London, England) Jan 1993
Review
Topics: Adult; Antiviral Agents; Child; DNA Replication; DNA, Viral; Didanosine; Drug Interactions; HIV; HIV Infections; Humans; Virus Replication; Zalcitabine
PubMed: 8093278
DOI: 10.1016/0140-6736(93)92496-g -
Retina (Philadelphia, Pa.) Dec 2016To report nine new cases of retinal degeneration secondary to didanosine toxicity and to summarize the previously reported cases in the literature. (Observational Study)
Observational Study
PURPOSE
To report nine new cases of retinal degeneration secondary to didanosine toxicity and to summarize the previously reported cases in the literature.
METHODS
This was a multicenter, retrospective, observational case study from seven institutions. Medical records of patients who demonstrated well-demarcated severe midperipheral chorioretinal degeneration and who were previously treated with didanosine therapy were collected and the following information was reviewed: age, gender, medical history, detailed medication history including current and previous antiretroviral use, ocular and retinal examination findings, and multimodal imaging findings with optical coherence tomography, fundus photography, wide-field fundus autofluorescence, and wide-field fluorescein angiography. When available, findings with electrophysiology testing and automated perimetry were also collected and reviewed. A literature review was also performed to collect all reported cases of chorioretinal degeneration secondary to didanosine toxicity.
RESULTS
Nine patients were identified who had findings consistent with peripheral retinal toxicity secondary to didanosine use. Eight of the 9 patients were men, and the median age was 54 years at the time of presentation (mean: 55 years, range, 42-71 years). Snellen distance acuity ranged from 20/20 to 20/32. At least three of the cases in the series demonstrated progression of the peripheral retinal pigment epithelium and photoreceptor atrophy despite didanosine cessation. A review of the literature revealed 10 additional cases of didanosine toxicity. Seven of the 10 cases were in men (70%), and the average age was 26 years with a wide range (2-54 years). Chorioretinal findings were very similar to this cohort.
CONCLUSION
Herein, we report the largest series of nine cases of peripheral chorioretinal degeneration secondary to didanosine toxicity in adults. When combined with the cases in the literature, 19 cases of didanosine toxicity, 4 of which occurred in children, were collected and analyzed. Three of the new cases presented showed clear progression of degeneration despite didanosine cessation. Newer nucleoside reverse transcriptase inhibitors may potentiate mitochondrial DNA damage and lead to continued chorioretinal degeneration.
Topics: Adult; Aged; Anti-HIV Agents; Choroid Diseases; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Retinal Degeneration; Retrospective Studies
PubMed: 28005674
DOI: 10.1097/IAE.0000000000001267 -
Pharmaceutisch Weekblad. Scientific... Oct 1992In this article the literature about didanosine, an antiretroviral drug, is reviewed. The mechanism of action, biochemical pharmacology, pharmacokinetics, and clinical... (Clinical Trial)
Clinical Trial Review
In this article the literature about didanosine, an antiretroviral drug, is reviewed. The mechanism of action, biochemical pharmacology, pharmacokinetics, and clinical results of phase-I trials are discussed. Serious adverse effects such as pancreatitis and peripheral neuropathy have occurred in these trials. An antiretroviral effect was observed in terms of an increase in CD4+ lymphocytes and a decrease in p24 antigen levels in HIV-infected individuals. Didanosine seems to be a promising drug against HIV infection, but knowledge about its clinical efficacy is scanty.
Topics: Animals; Antiviral Agents; Didanosine; HIV-1; Humans; Retroviridae
PubMed: 1437513
DOI: 10.1007/BF01977617 -
Drugs Dec 1999Didanosine, like zidovudine, stavudine and lamivudine, is a nucleoside analogue reverse transcriptase inhibitor (NRTI). In the target cell for HIV, didanosine is... (Review)
Review
UNLABELLED
Didanosine, like zidovudine, stavudine and lamivudine, is a nucleoside analogue reverse transcriptase inhibitor (NRTI). In the target cell for HIV, didanosine is converted to its active moiety, dideoxyadenosine-5'-triphosphate (ddATP), which inhibits HIV reverse transcriptase and terminates viral DNA growth. It is now well established that didanosine therapy produces beneficial effects on virological and immunological markers of HIV disease and improves clinical outcome in adults or children with HIV infection. In numerous clinical trials, pronounced and sustained decreases in plasma HIV RNA levels and increases in CD4+ cell counts occurred in previously untreated or antiretroviral therapy-experienced patients treated with didanosine in combination with at least 1 other antiretroviral drug; zidovudine, stavudine, lamivudine, nevirapine, nelfinavir and hydroxyurea (hydroxycarbamide) are among the drugs that have been given in combination with didanosine. Of note, HIV RNA levels decreased to below the limits of detection in some patients receiving triple or dual therapy with didanosine-containing regimens. In double-blind, placebo-controlled trials, triple therapy with didanosine, zidovudine and nevirapine was significantly more effective than dual therapy with various combinations of these agents in improving surrogate disease markers in treatment-naive patients and in delaying disease progression or death in treatment-experienced patients with advanced disease. Improvements in virological and immunological markers were greater with didanosine-containing triple regimens than with dual therapy or monotherapy in comparative trials. Triple therapy with didanosine, stavudine and indinavir showed efficacy similar to that of various other triple therapy regimens in nonblind comparative trials. Comparator regimens included combinations of stavudine, lamivudine plus indinavir, zidovudine, lamivudine plus indinavir and didanosine, stavudine and nevirapine. Combination therapy with didanosine plus hydroxyurea as dual therapy or with a third agent produced marked and sustained decreases in HIV RNA levels in the plasma and in lymph nodes. Combination therapy with didanosine and zidovudine delays disease progression and prolongs survival in patients with intermediate or advanced HIV infection. In large, randomised, double-blind, clinical trials, dual therapy with didanosine plus zidovudine was significantly more effective than zidovudine monotherapy in preventing disease progression and prolonging survival in previously untreated or antiretroviral therapy-experienced patients with intermediate or advanced HIV infection. Pancreatitis and peripheral neuropathy are serious adverse effects of didanosine. These effects are dose-related and usually reversible after discontinuation of treatment. Nausea, vomiting, diarrhoea and/or abdominal pain have been reported in patients receiving treatment with the drug.
CONCLUSIONS
Didanosine is an effective and generally well tolerated drug in previously untreated and antiretroviral therapy-experienced patients with HIV infection. Given once or twice daily, it has an important role as a component of triple combination regimens for the treatment of patients with symptomatic or asymptomatic HIV infection.
Topics: Adult; Anti-HIV Agents; Child; Didanosine; HIV Infections; HIV-1; Humans
PubMed: 10651392
DOI: 10.2165/00003495-199958060-00009 -
Drugs 2007Didanosine, which is a synthetic nucleoside analogue intracellularly phosphorylated to the active metabolite, inhibits the activity of HIV-1 reverse transcriptase by... (Review)
Review
Didanosine, which is a synthetic nucleoside analogue intracellularly phosphorylated to the active metabolite, inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate. Currently, didanosine is mainly provided as an enteric-coated capsule. In vitro, the molecule is active against laboratory strains and clinical isolates of HIV-1 in resting and activated T cells and monocyte/macrophages. Didanosine may select for resistance mutations that may render the drug inactive against the virus; L74V and K65R remain as the main didanosine-related mutations. In vitro, phenotypic susceptibility to didanosine was decreased beyond a defined fold change clinical cut-off (1.7), and it is considered that genotypic resistance exists when five thymidine-associated mutations or four plus M184V are present. In vivo, clinical studies have shown that didanosine retains significant antiviral activity in patients who have up to five nucleoside analogue mutations at baseline. Didanosine is useful in patients with no previous therapy, as well as in experienced patients in whom one or more antiretroviral regimens has failed.Enteric-coated didanosine is taken once daily, its co-administration with food has been recently evaluated and a reduction of the efficacy of the antiretroviral treatment was not observed. Administered with lamivudine (or emtricitabine), it can be considered a good alternative for use in the nucleoside analogue backbone included in combination therapies for antiretroviral-naive patients. Didanosine could be used in initial treatments for patients intolerant of zidovudine, abacavir or tenofovir. It can be included in once-daily combination regimens, which are more convenient and patient friendly.Prospective, observational and open-label studies, as well as clinical trials (with durations between 24 and 96 weeks), have demonstrated the safety and efficacy of didanosine plus lamivudine (or emtricitabine) plus efavirenz (or nevirapine) in previously untreated HIV-1-infected patients. The administration of didanosine to treatment-experienced patients has been evaluated in two different contexts: patients in whom previous therapies have failed (rescue therapy) and those with controlled viraemia who are switched to a didanosine-containing regimen for simplification.Adverse events associated with the administration of didanosine have been well known since the initial clinical trials with the drug. Gastrointestinal intolerance, peripheral neuropathy and hyperamylasaemia/pancreatitis were the most frequently reported. In the highly active antiretroviral therapy (HAART) era, the rate of adverse events has decreased. The tolerability of didanosine has been clearly improved with the development of the enteric-coated capsule. Severe manifestations of mitochondrial toxicity, including lactic acidosis and abnormal fat distribution, are rare complications, and occur most frequently when didanosine is used in combination with stavudine.
Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Tablets, Enteric-Coated
PubMed: 17600392
DOI: 10.2165/00003495-200767100-00006 -
Drugs Dec 1996Didanosine is a dideoxynucleoside analogue, which is phosphorylated to the active metabolite dideoxyadenosine triphosphate (ddATP) intracellularly. At therapeutic... (Review)
Review
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.
Topics: Anti-Bacterial Agents; Anti-HIV Agents; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Randomized Controlled Trials as Topic
PubMed: 8957161
DOI: 10.2165/00003495-199652060-00014 -
Enfermedades Infecciosas Y... Oct 1995
Review
Topics: Adult; Antiviral Agents; Child; Didanosine; Digestive System Diseases; Female; HIV Infections; Humans; Incidence; Pancreatitis; Peripheral Nervous System Diseases; Pregnancy; Reverse Transcriptase Inhibitors
PubMed: 8555311
DOI: No ID Found -
Drugs Jul 1992Didanosine is a dideoxynucleoside analogue which undergoes intracellular conversion to the putative active triphosphate metabolite. The active metabolite appears to... (Clinical Trial)
Clinical Trial Review
Didanosine is a dideoxynucleoside analogue which undergoes intracellular conversion to the putative active triphosphate metabolite. The active metabolite appears to inhibit viral reverse transcriptase and terminate the proviral DNA, and produces virustatic inhibition of actively replicating human immunodeficiency virus (HIV) at clinically relevant concentrations. In phase I studies didanosine had beneficial effects on various surrogate markers of clinical efficacy and also improved clinical manifestations of HIV infection, with a 21-month survival rate of 80% in patients with acquired immune deficiency syndrome (AIDS) and 93% in patients with AIDS-related complex (ARC) in 1 study. Didanosine also improved CD4+ cell counts in a phase II/III trial in patients previously treated with zidovudine, whereas cell counts declined in patients continuing zidovudine therapy. However, the effects of didanosine on clinical end-points (disease progression, survival, HIV encephalopathy) remain to be established. Peripheral neuropathy and pancreatitis are the predominant dose-limiting adverse events and didanosine therapy should be withdrawn in patients developing signs or symptoms of pancreatitis and during acute treatment of Pneumocystis carinii pneumonia. However, at currently recommended clinical dosages didanosine is generally well tolerated with minimal haematological toxicity. Thus, in a therapeutic area with few treatment options, didanosine offers a welcome alternative for patients intolerant of, or resistant to, zidovudine. There are a number of clinical trials in progress evaluating didanosine alone or in combination with other antiviral agents, and these results are awaited with considerable interest.
Topics: Acquired Immunodeficiency Syndrome; Didanosine; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; Humans
PubMed: 1379914
DOI: 10.2165/00003495-199244010-00008 -
Journal of the International... 2002Didanosine (ddl) has been a cornerstone of HIV management since it was made available in October 1991. Didanosine was originally introduced as an alternative to... (Review)
Review
Didanosine (ddl) has been a cornerstone of HIV management since it was made available in October 1991. Didanosine was originally introduced as an alternative to zidovudine (ZDV) for patients who were intolerant of ZDV or experienced disease progression during ZDV monotherapy. Didanosine is now used extensively as an integral component of multidrug combination regimens in both adults and children with HIV infection, and is now available for once-daily administration in the United States, Canada, and Europe. The recently approved Videx EC is an enteric-coated didanosine capsule dosed as one capsule, once daily. This paper provides an update of recently published studies on the use of ddl in combination anti-HIV therapy. In particular, these studies examine the rationale for the use of ddl as first-line anti-HIV therapy, and describe newer findings concerning its long-term efficacy, side effects, compliance, resistance, and once-daily use. The increased survival of HIV-infected patients is largely attributed to the introduction of the triple combination drug therapy but is probably also due to the long-term clinical efficacy of ddl.
Topics: Adult; Anti-HIV Agents; Child; Didanosine; HIV Infections; Humans
PubMed: 12942665
DOI: 10.1177/154510970200100105