Thymidine Zidovudine

C24H2,BN402 144873-97-2) see Losartan potassium 5 -0-(triphenylmethyl)thymidine 3 -methanesulfonate (CjoH,0N2O7S 42214-24-4) see Zidovudine... 

C24H25NO 127927-43-9) see Saquinavir tris(trimethylsilyloxy)ethylene (CiiH2g03Si3 69097-20-7) see Saquinavir (-)-(S)-l-trityl-2-(aminomethyl)pyrrolidine (C24H26N2 98598-84-6) see Remoxipride 5 -0-trityl-2,3 -anhydro thymidine (C29H24N2O4 25442-42-6) see Zidovudine trityl chloride... 

Human immunodeficiency virus (HIV) is a retrovirus, i.e. its RNA is converted in human cells by the en me reverse transcriptase to DNA which is incorporated into the human genome and is responsible for producing new HIV particles. Zidovudine (azidothymidine, AZT Fig. 5.22F) is a stmctural analogue of thymidine (Fig. 5.22A) and is used to treat AIDS patients. Zidovudine is converted in both infected and uninfected cells to the mono-, di- and eventually triphosphate derivatives. Zidovudine triphosphate, the aetive form, is a potent inhibitor of HIV replication, being mistaken for thymidine by reverse transeriptase. Premature ehain termination of viral DNA ensues. However, AZT is relatively toxic because, as pointed out above, it is converted to the triphosphate by eellular enzymes and is thus also aetivated in uninfected cells. 

Fig. 5.22 Thymidine (A), guanosine (B) and some nucleoside analogues (C-J). C, idoxuridine D, cytarabine E, ribavirin F, zidovudine (AZT) G, dideoxycytidine (DDC) H, dideoxyinosine (DDI) I, acyclovir J, ganciclovir.

Zidovudine is an antiretroviral drug that is clinically active against HIV-1 and is intended to treat HIV-infected patients. Zidovudine is an analog of thymidine that inhibits replication of the AIDS virus. It also turned into mono-, di-, and triphosphates by the same cellular enzymes that catalyze phosphorylation of thymidine and thymidine nucleosides. Zidovudine-triphosphate is then included in the terminal fragment of the growing chain of viral DNA by viral reverse transcriptase, thus causing the viral DNA chain to break apart in cells infected with the virus. 

Pharmacology Zidovudine is a synthetic nucleoside analog of the naturally occurring nucleoside thymidine. The active metabolite, zidovudine 5 -triphosphate (AztTP), inhibits the activity of the HIV reverse transcriptase by competing for utilization with the natural substrate deoxythymidine 5 -triphosphate (dTTP) and by its... 

Stavudine is an other thymidine analogue with a similar mechanism of action and activity as zidovudine. It can be used in AIDS patients who responded insufficiently to zidovudine or who cannot tolerate zidovudine. Its most prominent dose dependent toxicity is d4T induced neuropathy. 

More recently, Glaxo SmithKline patented an efficient fermentation rente for the biosynthetic prodnetion of thymidine (thymine-2-desoxyriboside). Key to the invention is a recombinant strain that efficiently produces high titers of thymidine by blocking some enzymes in the thymidine regulating pathway. This microbial process has now replaced the chemical route and has enabled gsk to supply the anti-AIDS drug AZT (zidovudine) to third-world countries at low cost. 

It is a thymidine analogue. After phosphorylation in body zidovudine triphosphate selectively inhibits viral reverse transcriptase i.e. RNA dependent DNA polymerase. It is effective against retrovirus only. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

TIs also inhibit the reverse transcriptase enzyme s ability to perform one of the initial steps in HIV replication. The NNRTIs, however, directly inhibit the active (catalytic) site on this enzyme, whereas zidovudine and other NRTIs serve as false substrates that take the place of the substance (thymidine) normally acted on by this enzyme (see Reverse Transcriptase Inhibitors Mechanism of Action ). Hence, NNRTIs provide another way to impair one of the key steps in HIV replication, and these drugs can be used along with other agents (NRTIs, protease inhibitors) to provide optimal benefits in preventing HIV replication and proliferation (see the next section). 

In the past, various serendipitous discoveries have capitalized on the differential expression of enzymes by host and viral infected cells. For example, the prodrug Acyclovir, used widely for the treatment of herpes simplex and herpes zoster infections, is selectively activated through phosphorylation by viral thymidine kinase to acyclovir monophosphate which is then converted to the triphosphate, which inhibits DNA polymerase, by host cellular enzymes. Similarly several 2, 3 -dideoxynucleoside analogs such as Zidovudine (azidothymidine, AZT) and 2, 3 -didehydro-3 -deoxythymidine (D4T) have potent antiviral activity against human immunodeficiency vims (HIV). These compounds are selectively phosphoiylated intracellularly to the 5 -triphosphate derivatives which inhibit the viral reverse transcriptase. 

STAVUDINE ZIDOVUDINE Possibly 1 efficacy -l cellular activation of stavudine and antagonism in vivo. Both are phosphorylated to the active form by thymidine kinase, which preferentially phosphorylates zidovudine therefore causes i phosphorylation of stavudine Avoid co-administration... 

Successful treatment of human immunodeficiency virus (HIV-1) infection has been achieved through successful implementation of highly active antiretroviral therapy, frequently referred to as HAART. This involves simultaneous administration of both nucleoside and nonnucleoside reverse transcriptase inhibitors and one or more protease inliibitors. The common nucleoside reverse transcriptase inhibitors are the thymidine analogs didanosine (ddl), lamivudine (3TC), and zalcitabine (ddC) and the non-thymidine analogs abacavir (Ziazen), stavudine (d4T), and zidovudine (AZT). The nonnucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. The protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Response to therapy is monitored by quantification of HIV-RNA copies (viral load) and CD-4+ T-lymphocyte count. Successful therapy is indicated when viral load is reduced to <50 copies/mL and CD-4+ count >500 per mL. 

Zidovudine is a thymidine (a nucleoside) analogue and was the first drug introduced that inhibits reverse transcriptase. This action terminates the growing viral DNA strand. Because of HIV resistance, several similar drugs have been developed, including abacavir and lamivudine. 

Zidovudine (200 mg every 4 hours) is indicated in the management of patients with HIV infection who show evidence of impaired immunity. Trimethoprim-sulfamethoxazole, pyrimethamine, and acyclovir may be necessary for the management or prevention of opportunistic infections. Zidovudine (3 -azido-3 -deoxythymidine, commonly referred to as AZT) is a thymidine analog with antiviral activity against HIV-1, HIV-2, human T-lymphotropic (or leukemia) virus (HTLV)-I, and other retroviruses. Low concentrations (<0.001 to 0.04 pg/ml) inhibit acute HIV-1 infection in human T-cell lines and peripheral blood lymphocytes. Zidovudine is less active in human monocyte-macrophages or quiescent cells but inhibits HIV replication in human brain macrophages. Zidovudine is also inhibitory for HBV and EBV... 

Zidovudine. 3 -Azido-3 -deoxythymidine azido-thymidine AZT BW A509U Retrovir. mol... 

Zidovudine is a synthetic thymidine analog with potent activity against a broad spectrum of retroviruses including HIV-1, HlV-2, and human T-ceU lymphotrophic viruses (HTLV) 1 and II. The drug has no impact in cells already infected with HIV. It is most effective in activated lymphocytes because the phosphorylating enzyme, thymidine kinase, is S-phase specific. 

Stavudine is a synthetic thymidine analog reverse transcriptase inhibitor that is active against HIV-1 and HIV-2. After entering the cell, it is phosphorylated to its active form, stavudine 5 -triphosphate. Unlike zidovudine, the monophosphate does not accumulate within the cell. 

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