Zalcitabine Didanosine

NRTls are structural analogues of the natural nucleotides that form the building blocks of RNA and DNA in human cells. Their use as part of HAART has dramatically modified the natural history of HIV infection. They, however, cause a range of drag- or tissue-specific toxicides zidovudine (AZT) causes myopathy zalcitabine (ddC), didanosine (ddl), and lamivudine (3TC) cause neuropathy stavudine (d4T) causes neuropathy or myopathy and lactic acidosis (Dalakas 2001). During phase 1 and 11 trials, the dose-limiting toxicity of didanosine, zalcitabine, and stavudine was identified as peripheral neuropathy (Dalakas 2001). 

Didanosine3 NRTI 150-200 mg bid, depending on weight. Enteric-coated 250-400 mg qd, depending on weight 30 minutes before or 2 hours after meals Peripheral neuropathy, pancreatitis, diarrhea, hyperuricemia Contains antacid avoid alcohol avoid concurrent neuropathic drugs (eg, didanosine, zalcitabine, isoniazid)... 

Antiretroviral nucleoside analogues have been associated with hepatic steatosis and lactic acidosis. These compounds require phosphorylation to active triphosphate derivatives by cellular phosphokinases. The triphosphate nucleotide inhibits the growing proviral DNA chain, but it also inhibits host DNA polymerases, and this can result in compensatory glycolysis and lactic acidosis. Abnormal mitochondrial oxidation of free fatty acids causes the accumulation of neutral fat in liver cells, and this manifests as hepatomegaly with macrovesicular steatosis. Hepatic steatosis and lactic acidosis have been reported previously with zidovudine, didanosine, zalcitabine, Combivir (zidovudine plus lamivudine), and lamivudine. 

Inhibit viral reverse transcriptase Zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine... 

Subsequent reports described a syndrome of type B lactic acidosis in patients treated with zidovudine and other nucleoside reverse transcriptase inhibitors, including stavudine, lamivudine, zalcitabine, and didanosine which has also been attribute to mitochondrial DNA toxicity [82-93]. There are five types of DNA polymerase in human cells that catalyze the synthesis of new complementary DNA from the original DNA template (HIV encodes a reverse transcriptase DNA polymerase which uses RNA as the template). The active triphosphate metabolites of zidovudine, didanosine, zalcitabine, and stavudine inhibit DNA polymerase gamma in mitochondria, block the elongation of mitochondrial DNA, and deplete mitochondrial DNA [78-80, 87, 92-94, 94a]. The link between NRH effects on mitochondrial DNA and lactic acidosis is not entirely clear but is most likely related to disturbances of oxidative phosphorylation and impaired pyruvate metabolism leading to lactate accumulation. 

MacGregor TR, Lamson MJ, C 1, Pav JW, Saag MS, Elvin AT, Scmmadossi J-P, Myers M, Keims JJ. Steady state pharmacokinetics of nevirapine, didanosine, zalcitabine, and zidovudine combination therapy in HIV-1 positive patients. PharmRes (1995) 12 (9 Si pl), S-101. 

This drug is used cautiously in patients with peripheral vascular disease, neuropathy, chronic pancreatitis, or impaired liver function. Didanosine is a Pregnancy Category B drug and is used cautiously during pregnancy and lactation. There may be a decrease in the effectiveness of dapsone in preventing Pneumocystis carinii pneumonia when didanosine is administered with dapsone Use of didanosine with zalcitabine may cause additive neuropathy. Absorption of didanosine is decreased when it is administered with food. 

At present there are seven NRTIs, which have been formally approved for the treatment of AIDS 3 -azido-2, 3 -dideoxythymidine (AZT, zidovudine), 2, 3 -dideoxyinosine (ddl, didanosine), 2, 3 -dideoxycytidine (ddC, zalcitabine), 2, 3 -didehydro-2, 3 -dideoxythymidine (d4T, stavudine), (—)-L-3 -thia-2, 3 -dideoxycytidine (3TC, lamivudine), cyclopentenyl V -cyclopropylaminopurine (abacavir, ABC), and (—)-L-5-fluoro-3 -thia-2, 3 -dideoxycytidine ((—)FTC, emtricitabine) (De Clercq 2004a) (Fig. 3). 

Didanosine, 1-asparaginase, lamivudine, metformin, pentamidine, statins, stavudine, sulindac, valproic acid, and zalcitabine... 

Drugs that should not be combined due to overlapping toxi-cities include amprenavir oral solution plus ritonavir oral solution, atazanavir plus indinavir (due to enhanced hyperbilirubinemia), and any combination of didanosine, stavudine, and zalcitabine. Emtricitabine and lamivudine should not be combined because of their similar chemical structures, and antagonism can result when lamivudine is combined with zalcitabine, or stavudine is combined with zidovudine. 

APV, amprenavir ATV, atazanavir CNS, central nervous system CVD, cardiovascular disease D/C, discontinue ddC, zalcitabine ddl, didanosine DEXA, dual-energy x-ray absorptiometry d4T, stavudine EFV, efavirenz HDL, high-density lipoprotein HIV, human immunodeficiency virus HTN, hypertension IDV, indinavir LDL, low-density lipoprotein LPV/r, lopinavir+ ritonavir MRI, magnetic resonance imaging NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor RTV, ritonavir SQV, saquinavir TDF, tenofovir disoproxil fumarate TG, triglyceride TPV/r, tipranivir + ritonavir ZDV, zidovudine. 

Drugs that may affect valganciclovir include didanosine, imipenem-cilastin, nephrotoxic drugs, probenecid, trimethoprim, zalcitabine, and zidovudine. Drugs that may be affected by valganciclovir include cytotoxic drugs, didanosine, and zidovudine. 

Drugs that may interact with zalcitabine include antacids, chloramphenicol, cisplatin, dapsone, didanosine, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, vincristine, cimetidine, metoclopramide, amphotericin, aminoglycosides, foscarnet, antiretroviral nucleoside analogs, pentamidine, and probenecid. 

Pharmacology Abacavir is a synthetic carbocyclic synthetic nucleoside analog with inhibitory activity against HIV. Abacavir has synergistic activity in combination with amprenavir, nevirapine, and zidovudine and additive activity in combination with didanosine, lamivudine, stavudine, and zalcitabine in vitro. 

Walker, U.A. et al. (2004) Depletion of mitochondrial DNA in liver rmder antiretroviral therapy with didanosine, stavudine, or zalcitabine. Hepatology,... 

The present NRTIs available for the treatment of HIV are zidovudine (azidothymidine, AZT), stavu-dine (d4T), didanosine (ddl), lamivudine (3TC), dideoxycytidine (ddC, zalcitabine) and abacavir, emtricitabine and tenofovir disoproxil. Combination formulations are abcavir combined with zidovudine and lamivudine and the abacavir-lamivudine combination. 

TC Lamivudine ABC Abacavir d4T Stavudine ddC Zalcitabine ddl Didanosine TDF Tenofovir ZDV Zidovudine, also abbreviated as AZT FTC Emtricitabine NVP Nevirapine DLV Delavirdine EFV Efavirenz RTV, r Ritonavir Pl/r Ritonavir boosted protease inhibitor SQV Saquinavir IDV Indinavir LPV Lopinavir NEV Nelfinavir APV Amprenavir ATV Atazanavir DRV Darunavir... 

Buffering agents that are compounded with didanosine to counteract its degradation by gastric acid may interfere with the absorption of other drugs that require acidity (e.g., indinavir, delavirdine, ketoconazole, fluoroquinolones, tetracyclines, dapsone). An enteric-coated formulation Videx EC) that dissolves in the basic pH of the small intestine is not susceptible to these interactions. Ganciclovir and valganciclovir can increase blood levels of didanosine. The use of zalcitabine with didanosine is not recommended because that combination carries an additive risk of peripheral neuropathy. The combination of didanosine with stavudine increases the risk of pancreatitis, hepatotoxicity, and peripheral neuropa-... 

Peripheral neuropathy occurs in up to 50% of patients taking zalcitabine. Stomatitis, esophageal ulceration, hepatotoxicity, rash, and pancreatitis may occur. Zalcitabine should be used with caution in individuals with a history of pancreatitis, liver disease, or alcohol abuse. Dosage adjustment is necessary for individuals with renal impairment. Zalcitabine should not be used in combination with didanosine, lamivudine, or stavudine. 

A. The NRTIs can produce a potentially fatal syndrome of lactic acidosis and severe hepatomegaly with hepatic steatosis. Risk factors associated with the development of this syndrome include female sex, obesity, alcoholism, and prolonged exposure to NRTIs. Peripheral neuropathy is a common side effect of some NRTIs (e.g., stavudine., didanosine, and zalcitabine) but not associated with these risk factors. Stevens-Johnson syndrome is rarely associated with NNRTIs, such as nevirapine, and not with these risk factors. Hyperuricemia is not associated with these risk factors. Hypersensitivity reaction may oc-... 

NRTIs) abacavir sulfate didanosine (ddl) lamivudine (3TC) stavudine (d4T) zalcitabine (ddC) zidovudine (AZT)... 

CMV Cytomegalovirus CYP Cytochrome P450 d4T Stavudine ddC Zalcitabine ddl Didanosine EBV Epstein-Barr virus FTC Emtricitabine... 

Didanosine (ddl) NRTT1 Tablets, 400 mg daily,3 adjusted for weight. 30 min before or 2 h after meals. Separate dosing from fluoroquinolones and tetracyclines by 2 h Peripheral neuropathy, pancreatitis, diarrhea, nausea, hyperuricemia. Possible increase in myocardial infarction Avoid concurrent neuropathic drugs (eg, stavudine, zalcitabine, isoniazid), ribavirin, and alcohol. Do not administer with tenofovir... 

Saag MS, Sommadossi JP, Rainey D, Myers M, Cort S, Hall D, et al. A pharmacokinetic and antiretroviral activity study of nevirapine in combination with zidovudine plus zalcitabine (ZDV/ddC), zidovudine plus didanosine (ZDV/ddI), or didanosine (ddl) Alone. In The First National Conference on Human Retroviruses and Related Infections, Washington D.C., 1993 102. 

Zalcitabine does not interact with zidovudine, and lamivudine inhibits its phosphorylation. It should not be administered with other drugs that cause neuropathy or pancreatitis including didanosine and stavudine. 

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