Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dideoxynucleosides currently in use for anti-HIV therapy have been found to be inefficient in passing through the blood-brain barrier to enter and maintain therapeutic drug levels in brain, a very significant reservoir of HIV. The low bioavailability of these drugs combined with the bone marrow toxicity of AZT (3'-azido, 3'-deoxythymidine, Zidovudine), resulting in anemia and leukopenia, pancreatitis with ddI (2',3'-dideoxyinosine, Didanosine) and painful peripheral neuropathy in case of ddC (2',3-dideoxycytosine, Zalcitabine) are the limiting factors in their use. In addition, the emergence of strains of HIV resistant to AZT, the most commonly used drug, further restricts its use. Thus the control of AIDS and its complications, needs special therapeutic approaches to combat the disease. In order to overcome these limitations, AZT and ddI have been synthesized as ester-linked ceramide- and phosphatidylcholine-linked prodrugs possessing therapeutic attributes lacking in the parent compounds. There is greater uptake and longer retention of these prodrugs in NIH/3T3 cells in vitro. Pretreatment with our prodrugs blocked infection of these cells by Moloney murine leukemia virus (M-MuLV) for an extended period, which the parent drugs failed to do. When human CD4+ HeLa cells were continuously exposed to the AZT prodrug, subsequent infection of these cells by HIV was blocked. Similar results were obtained with NIH/3T3 cells exposed to M-MuLV. AE(6)C, a prodrug of AZT linked to ceramide via a cleavable ester bond and a six carbon linker, was less toxic to both mouse and human bone marrow progenitor cells than free AZT. Most significantly, the prodrugs concentration was greater and the retention longer, in well known sanctuaries for HIV, such as the brain, testes and thymus.
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PMID:Improved uptake and retention of lipophilic prodrug to improve treatment of HIV. 1083 73

The Food and Drug Administration (FDA) used accelerated approval regulations to approve the use of Glaxo-Wellcome's lamivudine (Epivir/3TC) in combination with AZT. The FDA guidelines used for approval, including viral load and CD4 count benefits, are explained. The guidelines warn that 3TC should be used with extreme caution in pediatric patients who are at risk of developing pancreatitis. Glaxo Wellcome has been commended for testing the drug on children beyond the FDA requirements. Cross resistance to ddI and ddC is a concern if AZT is used after 3TC treatment. Despite controversy at the Antiviral Drugs Advisory Committee meeting, the FDA did not indicate any specific T-cell range for the 3TC/AZT combination therapy. The price of 3TC to wholesalers is $3.11 per 150 mg tablet. Glaxo-Wellcome will provide reimbursement assistance to patients who have no other means of purchasing the drug.
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PMID:Lamivudine (3TC) approved for combination use with AZT. 1136 49

A new notice was distributed to health care providers cautioning of the increased risk of fatal and nonfatal pancreatitis for patients taking didanosine (Videx) from Bristol-Meyers Squibb. Several patients enrolled in the clinical trials died from pancreatitis. Any incidences of pancreatitis should be disclosed to Bristol-Meyers Squibb, and the FDA through MEDWATCH. Contact information is provided.
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PMID:Extended warning on Didanosine-related pancreatitis. 1136 89

Physicians and researchers received a stronger warning from Bristol-Myers Squibb (BMS) this week about the risk of pancreatitis in patients taking ddI (Videx). The risk is higher if they are also taking d4T, with or without Hydroxyurea (Hydrea). There have been four deaths in recent clinical trials. Each of the four had CD4 counts greater than 500, viral loads below 200 copies, and were taking d4T. Two of the four were also enrolled in a study which included ddI, d4T, and Hydroxyurea, and three had known risk factors for pancreatitis. The new warning follows an October 27 letter from the FDA to BMS after an investigation found the drug company failed to disclose important safety information, and was promoting hydroxyurea for unapproved uses. The text of the warning letter, as well as a web site address for the full text of the FDA warning, is included.
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PMID:ddI, d4T, Hydroxyurea: new pancreatitis warning. 1136 25

The Food and Drug Administration (FDA) approved once-daily dosing of a new 200mg formulation of Bristol-Myers Squibb's nucleoside analog, ddI. The new tablet will be available in December 1999. Two tablets of ddI must always be taken together to minimize gastric acid degradation. The FDA will require the drug company to warn patients of the increased risk of developing pancreatitis, sometimes observed in persons on ddI therapy. The FDA also approved a 1,250mg twice-daily dosing of nelfinavir, a protease inhibitor manufactured by Agouron Pharmaceuticals.
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PMID:New dosing of ddI (Videx) and Nelfinavir (Viracept) approved. 1136 46

For the last several years, the combination of ddI (didanosine, Videx) and d4T (stavudine, Zerit) as a backbone of three-drug therapy has been popular both in treatment and in research. Together, the two nucleoside analog reverse transcriptase inhibitor (NARTI) drugs offered relatively high strength and fairly simple use. Despite this, some researchers have long questioned the wisdom of the combination as it violates one of the key rules of combining drugs: combine only drugs with different side effect profiles. Both drugs are associated with the development of peripheral neuropathy and pancreatitis. Pancreatitis is more commonly seen with ddI and neuropathy with d4T, but both occur to a significant degree with each drug and to a higher degree than was seen with other drugs of their class. However, few if any studies were run comparing the ddI/d4T combination to alternatives such as AZT/3TC (Combivir) or even 3TC/d4T. Both ddI and d4T come from the same company, Bristol Myers Squibb.
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PMID:New questions about an old combination--ddI + d4T. 1264 75

The aim of this prospective study was to determine the adverse effects of antiretroviral therapy in HIV-1 infected children and factors associated with adverse effects. The study was performed in a pediatric and perinatal HIV clinic in a tertiary general hospital. Forty-three HIV positive children from the age group of 5 months to 14 years were started on antiretroviral therapy ART. Thirteen patients (30%) had adverse effects related to the ART. Seven patients (16%) had hepatotoxicity, 5 patients (12%) had raised serum amylase without symptomatic pancreatitis, 5 patients (12%) had zidovudine AZT induced anemia, 4 patients (9%) had Nevirapine NVP induced rash, 1 patient (2%) had Didanosine ddI induced pain in abdomen, 1 patient (2%) had Stavudine d4T induced angioedema, and 1 patient (2%) had hepatic steatosis. Five patients (71%) with hepatotoxicity responded to dose adjustment of ART whereas in 2 patients (29%), the elevated liver enzymes resolved on its own. Two patients (40%) with AZT induced anemia required omission of AZT and remaining 3 patients (60%) responded to dosage adjustment. ddI induced abdominal pain, d4T induced angioedema and hepatic steatosis resolved on omitting the respective antiretroviral drug. NVP induced rash and raised serum amylase subsided without any intervention. Hepatotoxicity was seen at higher viral load (Mean = 118608 copies/ml) whereas elevated serum amylase was seen at lower viral load (mean = 37631 copies/ml), which was statistically significant (p < 0.0001). NVP induced rash was seen in early weeks of therapy, serum amylase abnormalities were seen at a mean interval of 0.9 years after starting therapy, hepatotoxicity was seen at a mean interval of 1.7 years and AZT induced anemia was seen at a mean interval of 2.0 years after starting therapy. Adverse effects with antiretroviral drugs in HIV-infected children are quite common. Hepatotoxicity is the commonest adverse effect noted followed by elevated serum amylase and zidovudine induced anemia. Hepatotoxicity is seen at higher viral load as compared to other adverse effects. Most of the adverse effects are reversible on dosage modification or omitting the offending drug.
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PMID:Adverse effects of antiretroviral therapy in HIV-1 infected children. 1612 3

The nucleoside analogues, 3'-azido-3'-deoxythymidine (AZT, zidovudine), 2',3'-dideoxyinosine (ddI, didanosine) and 2',3'-dideoxycytidine (ddC, zalcitabine), used in the treatment of human immunodeficiency virus (HIV) infection, have been associated with a number of dose-limiting toxicities in clinical studies. These include myelotoxicity (AZT), myopathy (AZT), peripheral neuropathy (ddC, ddI) and pancreatitis (ddI). Myopathy, peripheral neuropathy and pancreatitis are also observed in HIV-infected patients who have not been treated with the nucleoside analogues. Thus, nucleoside analogue toxicity can be confused with the adverse effects of HIV infection. Animal models exist for some, but not all, aspects of nucleoside analogue-related toxicity. In vitro studies have been used extensively to elucidate the mechanisms of nucleoside analogue toxicity. Cellular purine and pyrimidine metabolizing enzymes phosphorylate the analogues, which can then interact with DNA polymerases. Inhibition of one of these, HIV reverse transcriptase, is responsible for the antiviral activity of the nucleoside analogues. Toxicity is caused by inhibition of nuclear or mitochondrial DNA polymerases (or both) and by chain termination of replicating DNA at the point of insertion of the nucleoside analogue. The different toxicities observed in the case of each nucleoside analogue are most likely explained by different affinities for each of the cellular DNA polymerases.
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PMID:In vitro studies of the toxicity of nucleoside analogues used in the treatment of HIV infection. 2069 86


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