Zalcitabine NRTIs

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). 

Zalcitabine (ddC) Hivid (anticipated discontinuation of distribution in 2006) 0.375-, 0.75-mg tab 0.75 mg tid CrCI Dose (mL/minute) 10-40 0.75 mg bid less than 10 0.75 mg qday No data on hemodialysis None Peripheral neuropathy stomatitis, lactic acidosis with hepatic steatosis (rare but potentially life-threatening toxicity with use of NRTIs) pancreatitis Renal excretion... 

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. 

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. 

Zidovudine (ZDV or AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) and it was the first anti-HIV agent to be introduced. Other NRTIs include stavudine (d4T), lamivudine (3TC), didano-sine (ddl), abacavir (ABC) and zalcitabine (ddC). Recent additions to this class are emtricitabine (FTC) which has a molecular structure similar to 3TC and tenofovir (TDF) a nucleotide reverse transcriptase inhibitor. 

As a class effect NRTIs are associated with lactic acidosis and hepatic steatosis, conditions which may occur more frequently in pregnant women. The individual NRTIs have their own adverse reactions. Pancreatitis is seen with lamivudine, stavudine, di-danosine and rarely with zalcitabine while the latter three agents can also induce peripheral neuropathy. 

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)... 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

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)... 

Nevirapine = Viramune] (dipyridodiazepinone) [NRTIs in clinical use Abacavir (ABC) Adefovir dipivoxil (9-[2-Phosphonomethoxy)ethyl] -adenine PMEA) AZT Didanosine (= 2, 3 -Dideoxyinosine) Lamivudine Stavudine Zalcitabine (2, 3 -Dideoxycytidine]... 

The nucleoside analogue reverse transcriptase inhibitors (NRTIs) include abacavir, didanosine, lamivudine, stavu-dine, tenofovir, zalcitabine, and zidovudine (all rINNs). The following abbreviations have been used and may still be encountered in published papers ... 

There are currently a variety of nucleoside analogs (i.e., AZT [zidovudine] [3], DDC [zalcitabine] [4], DDI [didanosine] [4], D4T [stavudine] [5], and 3TC [lamivudine] [6] [also designated NRTIs or nucleoside RT inhibitors]) and two nonnucleoside RT inhibitors (i.e., nevirapine [viramune] and BHAP [delavirdine] [also designated NNRTIs] [7,8]) officially approved for treatment of HIV-infected individuals. It should be noted that the NNRTIs are uniquely active against HIV-1, but not HIV-2 RT, whereas the NRTIs inhibit both HIV-1 and HIV-2 RTs. In addition, several other structural classes of... 

The demonstration that combination regimens of two NRTIs (e.g., zidovudine and didanosine or zalcitabine) are superior to zidovudine monotherapy in immunologic and virologic parameters, particularly in patients with no previous antiretroviral therapy, and confer a superior survival benefit (ACTG 175). ... 

Mechanisms Zalcitabine is a pyrimidine nucleoside with mechanisms of action and resistance similar to those of other NRTIs. Depending on specific sites of mutation on the pol gene, resistance may emerge to ddC alone or cross-resistance between other RT inhibitors may occur. 

Antiviral nucleoside inhibitor of HIV reverse transcriptase (NRTI). Used in combination regimens. Tox peripheral neuropathy, pancreatitis. Other NRTIs latnivudine (3TC), stavudine (d4T), zalcitabine (ddC), and the prototype, zidovudine (see below). 

NRTIs are faulty version reverse transcriptase. Reproduction of HIV is stalled when HIV uses NRTI instead of the normal reverse transcriptase. Dmgs within this category include Abacavir (Ziagen, ABC), Abacavir, Lamivudine (Epzicom), Abacavir, Lamivudine, Zidovudine (Trizivir), Didanosine (Videx, ddl, Videx EC), Emtricitabine (Emtriva, FTC, Coviracil), Emtricitabine, Tenofovir DF (Truvada), Lamivudine (Epivir, 3TC), Lamivudine, Zidovudine (Combivir), Stavudine (Zerit, d4T), Tenofovir DF (Viread, TDF), Zalcitabine (Hivid, ddC), and Zidovudine (Retrovir, AZT, AZV). 

DDC (zalcitabine) NRTI The first clinical trial of multiple drugs Is held... 

NRTIs are water soluble, and are mainly eliminated by the kidneys (di-danosine, lamivudine, stavudine, and zalcitabine) or undergo hepatie glu-curonidation (abacavir, zidovudine). The few important interactions with these drugs primarily involve altered renal clearance. For zidovudine (and possibly abacavir) some interactions occur via altered glucuronidation, but the clinical relevance of these are less clear (e.g. rifampicin , (p.792)). Cytochrome P450-mediated interactions are not important for this class of drugs. 

There is no pharmacokinetic interaction between stavudine and fluconazole. No interaction would be expected with other similar NRTIs such as lamivudine and zalcitabine (see Antivirals , (p.772)). 

Of the NRTIs, didanosine, stavudine and zalcitabine have been associated with fatal pancreatitis. " ... 

Some combinations of NRTIs are potentially antagonistic (stavudine with zidovudine, lamivudine with zalcitabine) and some are expected to result in additive toxicity (didanosine with stavudine or zalcitabine, and possibly stavudine with zalcitabine). Some do not appear to result in additional benefits (emtricitabine with lamivudine), and some are considered inferior to other combinations (stavudine with lamivudine, zidovudine with zalcitabine or didanosine). None of these combinations are recommended. Combinations that are specifically recommended (with other antiretrovirals) include lamivudine with abacavir, didanosine or zidovudine, or didanosine with emtricitabine. Sole use of all triple NRTI regimens should generally be avoided, with the possible exception of abacavir or tenofovir , (p.806) with zidovudine and lamivudine. 

In vitro, stavudine had no significant effect on the intracellular activation ofzalcitabine. Both stavudine and zalcitabine have the potential to cause peripheral neuropathy and pancreatitis. Combined use of drugs causing these serious adverse effects should be closely monitored (see also NRTIs + Drugs that cause pancreatitis , p.797). US guidelines say that the combination of stavudine and zalcitabine should not be recommended at any time because of additive peripheral neuropathy. ... 

The protease inhibitors indinavir, ritonavir, and saquinavir had no effect on intracellular activation of various NRTIs (didanosine, lamivu-dine, stavudine, zalcitabine and zidovudine). No interaction would be expected by this mechanism. Other potential interactions are discussed below. 

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