Zalcitabine

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Image:Zalcitabine.png
ddC
2'-3'-dideoxycytidine
Molecular Weight 211.22
Empiric Formula C9H13N3O3
ATC code J05AF03
Metabolism Renal elimination (ca.80%)
Pregnancy category C (USA)
D (Aus)

Zalcitabine (2'-3'-dideoxycytidine, ddC), also called dideoxycytidine, is a nucleoside analog reverse transcriptase inhibitor (NARTI) sold under the trade name Hivid®.

Zalcitabine is the least potent of all antiretroviral drugs, is inconvenient to take, and has serious side effects. For these reasons it is now rarely used to treat human immunodeficiency virus (HIV).

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History

Zalcitabine was developed in the National Cancer Institute (NCI) by Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan at the National Cancer Institute (NCI). Like didanosine, it was then licensed because the NCI may not market drugs. The National Institutes of Health (HIH) thus licensed it to Hoffman LaRoche Co.

Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV infection and AIDS. It was approved on Jun 19, 1992 as a monotherapy and again in 1996 for use in combination with Zidovudine (AZT). Using combinations of NRTIs was in practice prior to the second FDA approval and the triple drug combinations with dual NRTIs and a protease inhibitor (PI) were not far off by this time.

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Mechanism of action

Zalcitabine is an analog of pyrimidine. It is a derivative of the naturally existing deoxycytidine, made by replacing the hydroxyl group in position 3' with a hydrogen.

It is phosphorylated in the T cell and other HIV target cells into its active triphosphate form, ddCTP. This active metabolite works as a substrate for HIV reverse transcriptase, and also by incorporation into the viral DNA, hence terminating the chain elongation due to the missing hydroxyl group. Since zalcitabine is a reverse transcriptase inhibitor it possess activity only against retroviruses. It is used for the treatment of HIV infection only in combination with zidovudine.

Zalcitabine has a very high oral absorption rate, of over 80%. The most common side effect in the beginning of the treatment is nausea and headache. The more serious side effects are peripheral neuropathy, oesophagitis and pancreatitis.

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References

  • Yarchoan R, Mitsuya H, Broder S. AIDS therapies. Scientific American 1988;259(4):110-9.
  • Harvey Stewart C. in Remington's Pharmaceutical Sciences 18th edition: (ed. Gennard, Alfonso R.) Mack Publishing Company, 1990
  • Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3rd edition. Pearson Professional Ltd, 1995.
  • Mitsuya H, Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy virus-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci USA 1986;83:1911-5.
  • Yarchoan R, Perno CF, Thomas RV, et al. Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988;1:76-81.
  • Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science 1990;249:1533-44.
  • NIH Bio and Oral History of Samuel Broder describing the development of anti-HIV drugs: http://aidshistory.nih.gov/transcripts/bios/Samuel_Broder.html
  • NIH Bio and Oral History of Robert Yarchoan describing the development of anti-HIV drugs: http://aidshistory.nih.gov/transcripts/bios/Robert_Yarchoan.htmlTemplate:Antivirals

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