AZT drug

Cnti (Slc28al) Rat Adenosine, thymidine, uridine Drug AZT Drugs cytarabine, floxidine, gemcitabine, idoxuridine, zalcitabine... 

Other nucleosides such as 2, 3 -dideoxyinosine (ddl) also block the action of reverse transcriptase and are often combined with AZT in drug cocktails. Using a mixture of drugs makes it more difficult for a virus to develop resistance than using a single drug. 

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

In addition to the three anti-HIV agents [AZT (zidovudine), DDI (dida-nosine) and DDC (zalcitabine)] that have been formally approved by the U.S. Food and Drug Administration for the treatment of HIV infections, several other 2, 3 -dideoxynucleoside (ddN) analogues (Fig. 5), including 3 -fluoro-2, 3 -didcoxy-5-chlorouridine (FddClUrd) and 2, 3 -didehydro-... 

PMEA and its congeners are more effective in vivo than could be predicted from their in vitro potency. While less potent as an antiretrovirus agent than AZT in vitro, PMEA proved clearly superior to AZT when the two drugs were compared for their effectiveness in vivo, in mice infected with murine Moloney sarcoma virus [51,52]. PMEA was also shown to be effective against various other retrovirus infections, including Friend leukemia virus (FLV), Rauscher leukemia virus (RLV), and LP-BM5 (murine AIDS) virus infection in mice, feline leukemia virus (FeLV) or feline immunodeficiency virus (FIV) infection in cats, and SIV infection in macaque (rhesus) monkeys (for review, see Ref. 53). In the latter model [54], again PMEA proved far superior to AZT in suppressing several parameters of the disease. 

The 181 Tyr — Cys mutation, which is responsible for resistance to most NNRTIs, has been found to suppress the 215 mutation (Thr — Phe/ Tyr), which is responsible for resistance to AZT [94], and, vice versa, the 181 Tyr — Cys mutation can be suppressed by AZT, which thus means that the mutations at positions 181 and 215 counteract each other. Yet other mutations have proved to counteract each other 236 Pro — Leu vs 138 Glu —> Lys, and, as mentioned, 215 Thr > Phe/Tyr vs 184 Met > Val, and 215 Thr — Phe/Tyr vs 74 Leu > Val [47]. Based on the resistance mutations that counteract each other, combinations of different drugs could be envisaged—namely, combinations of AZT with either TIBO, a-APA, HEPT, nevirapine, or pyridinone—and these two drug combinations could be extended to three- or four-drug combinations by the addition of another ddN analogue (such as 3TC) and/or another NNRTI (such as BHAP or TSAO). 

An interesting idea was to use a monolith column to perform dual functions of online SPE and chromatographic separation. Because of the porous structure of a monolith column and its very low backpressure, plasma or diluted plasma can be directly injected. Plumb et al. (2001) used this approach to quantitate an isoquinoline drug and 3 -azido-3 -deoxy thymidine (AZT). Diluted plasma samples (plasma water 1 1) were injected directly into a Chromolith Speed ROD RP-18e column... 

AZT, which is an antiviral compound against HIV, is an effective drug in AIDS patients. The fact that this drug works means that agents that interfere with continued HIV infection in an AIDS patient will improve the clinical status. 

AZT works by specifically blocking DNA synthesis carried out by HIV reverse transcriptase. Other related compounds are also being tested to see if they specifically affect HIV reverse transcriptase. Such compounds might have equivalent antiviral effects. If they have fewer side effects than AZT, they may be even more effective in treating HIV-infected individuals. Two additional antivirals related to AZT have recently been approved for anti-HIV therapy, dideoxy-inosine (DDI) and dideoxycytosine (DDC). These drugs are predominantly recommended for individuals who cannot tolerate AZT, or for whom AZT has ceased to be effective although they are effective against HIV, they do have side effects. Nevertheless, they may be important because AZT does not indefinitely reduce the amount of virus in HIV-infected individuals. 

In addition to drugs such as AZT, other antivirals targeted at reverse transcriptase are also being developed. AZT (and its relatives DDI and DDC) inhibits HIV replication by mimicking normal building blocks of DNA and being selectively incorporated by reverse transcriptase into viral DNA as opposed to cellular DNA. Viral DNA that has incorporated these compounds cannot be completed, and virus replication is aborted. Other compounds have been developed that directly inhibit the activity of HIV reverse transcriptase, with relatively little effect on cellular DNA polymerases. The net effect of these compounds also is to selectively inhibit HIV replication. One class of reverse transcriptase inhibitors currently being tested is referred to as TIBO inhibitors. 

Peptidases encoded by many viruses play essential roles at various stages of viral replication, including the coordinated assembly and maturation of virons [7a]. Viral peptidases have become important drug targets in the treatment of viral infections. Of note are inhibitors of proteases of the human immunodeficiency virus (HIV), particularly HIV-1 protease (HIV-1 retropepsin, EC 3.4.23.16) and HIV-2 protease [47-50], Drugs in this class, which include indinavir, ritonavir, and saquinavir, are useful in the treatment of AIDS, especially when administered as a cocktail together with one of the drugs that act on the viral retrotranscriptase (e.g., didanosine, stavudine, and zidovudine (AZT)). 

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