didanosine and Pancreatic-Diseases

The pancreas is frequently involved during HIV infection, especially by disseminated infections or neoplasms. These lesions are generally asymptomatic and are discovered at autopsy. However, hypoglycaemia secondary to massive pancreatic infiltration by a tumour or tuberculous necrosis may occur. The most important cause of pancreatic dysfunction in HIV-infected patients is a drug toxic effect (intravenous pentamidine, didanosine, zalcitabine). Hypoglycaemia, which may or may not be followed by diabetes, can develop during intravenous pentamidine therapy. In cases with increased serum amylase and/or lipase levels, potentially toxic drugs must be promptly discontinued to avoid major pancreatic involvement.

Topics: Acute Disease; AIDS-Related Opportunistic Infections; Didanosine; HIV Infections; Humans; Pancreas; Pancreatic Diseases; Pancreatitis; Pentamidine; Trimethoprim, Sulfamethoxazole Drug Combination; Zalcitabine

The hydroxyurea-didanosine combination has been shown to limit immune activation (a major pathogenic component of HIV/AIDS) and suppress viral load by both antiviral and cytostatic ('virostatic') activities. Virostatics action represent a novel approach to attack HIV/AIDS from multiple directions; however, the use of these drugs is limited by the lack of understanding of their dose-dependent mechanism of action and by fear of pancreatic toxicity, even though a large review of ACTG studies has shown that hydroxyurea does not increase the incidence of pancreatitis.. In vitro cytostatic and cytotoxic activity, inhibition of viral replication and immune activation by pharmacologically attainable plasma concentrations of hydroxyurea (10-100 micromol/l) and didanosine (1-5 micromol/l) were analyzed by cell proliferation, viability, apoptosis and infection assays using peripheral blood mononuclear cells. In vivo, 600, 900 and 1200 mg daily doses of hydroxyurea in combination with standard doses of didanosine and stavudine were studied in 115 randomized chronically infected patients.. A cytostatic low (10 micromol/l) concentration of hydroxyurea inhibited cell proliferation and HIV replication in vitro. A gradual switch from cytostatic to cytotoxic effects was observed by increasing hydroxyurea concentration to 50-100 micromol/l, predicting that lower doses of hydroxyurea would be less toxic and more potent in vivo. The clinical results confirmed that 600 mg hydroxyurea was better tolerated, had fewer side effects and was more potent in suppressing HIV replication than the higher doses.. A bimodal, dose-dependent, cytostatic-cytotoxic switch is an immune-based mechanism explaining the apparent paradox that lowering the dose of hydroxyurea to 600 mg daily induces maximal antiviral suppression in HIV-infected patients.

Topics: Anti-HIV Agents; Apoptosis; Cell Proliferation; Cells, Cultured; Didanosine; Dose-Response Relationship, Drug; Drug Combinations; HIV Infections; Humans; Hydroxyurea; Maximum Tolerated Dose; Nucleic Acid Synthesis Inhibitors; Pancreatic Diseases; Viral Load; Virus Replication

Pancreatic involvement has been studied in 70 HIV infected patients, in diverse stages, that were treated with didanosine (ddI), both as monotherapy or associated to zidovudine; 38% of patients presented adverse reaction that obliged to withdraw the medication: pancreatitis (4%), hyperamylasemia (21%) and abdominal pain and/or diarrhea (12%). The possible causes in presentation of adverse effects were evaluated: route of infection, stage of HIV infection, use of pentamidine or trimethoprim-sulfamethoxazole for preventing Pneumocystis carinii pneumonia, administration of ddI in monotherapy or in combined form with zidovudine, time of treatment and level of CD4 lymphocytes. The outcome of adverse effects is related significantly only with the most advanced stage of HIV infection.

Topics: Acute Disease; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Pancreatic Diseases; Pancreatitis; Zidovudine

To describe the incidence, clinical characteristics and dose relationship of dideoxyinosine (ddI)-associated pancreatitis.. Patients enrolled in a Phase I dose escalation trial of ddI [AIDS Clinical Trials Group (ACTG) 064] were evaluated for signs and symptoms of pancreatic dysfunction.. Two ACTG sites.. Forty-four patients with AIDS or AIDS-related complex (ARC) and a CD4 cell count less than or equal to 400 x 10(6)/l.. Seven patients developed pancreatitis that lasted from 1 to 7 weeks and varied in severity from mild to life-threatening. Seven other patients had evidence of hyperamylasemia or hypertriglyceridemia. Six patients who developed pancreatitis were able to tolerate rechallenge with lower doses of ddI.. Development of pancreatitis correlated with cumulative dose of ddI but not with stage of disease or concomitant medications. Cumulative dose was not significantly associated with development of hyperamylasemia or hypertriglyceridemia in patients without clinical pancreatitis.. The development of pancreatitis in AIDS or ARC patients receiving ddI varies in severity and time course and is associated with cumulative dose. Patients who develop pancreatitis may be able to tolerate therapy with a lower dose after resolution of their symptoms. Patients receiving ddI require careful monitoring for the development of this complication.

Topics: Acquired Immunodeficiency Syndrome; Didanosine; Female; Humans; Male; Pancreatic Diseases; Pancreatitis