Zalcitabine
Encyclopedia
Zalcitabine also called dideoxycytidine, is a nucleoside analog reverse transcriptase inhibitor
(NARTI) sold under the trade name Hivid.
The recommended dosage is 0.750 mg (one tablet) every 8 hours, as part of a combination regimen.
Zalcitabine appears less potent than some other nucleoside RTIs, has an inconvenient three-times daily frequency and is associated with serious adverse events. For these reasons it is now rarely used to treat human immunodeficiency virus (HIV
), and even removed from pharmacies entirely in some countries.
and subsequently developed as an anti-HIV agent 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 or sell drugs. The National Institutes of Health
(NIH) thus licensed it to Hoffman LaRoche.
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 June 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.
The sale and distribution of zalcitabine has been discontinued since December 31, 2006.
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 T cell
s 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 retrovirus
es.
(3TC) significantly inhibits the intracellular phosphorylation of zalcitabine to the active form, and accordingly the drugs should not be administered together.
Additionally, zalcitabine should not be used with other drugs that can cause peripheral neuropathy, such as didanosine
and stavudine
.
, which can occur in up to 33% of patients with advanced disease, oral ulcers
, oesophageal ulcers and, rarely, pancreatitis
.
Reverse transcriptase inhibitor
Reverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
(NARTI) sold under the trade name Hivid.
The recommended dosage is 0.750 mg (one tablet) every 8 hours, as part of a combination regimen.
Zalcitabine appears less potent than some other nucleoside RTIs, has an inconvenient three-times daily frequency and is associated with serious adverse events. For these reasons it is now rarely used to treat human immunodeficiency virus (HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
), and even removed from pharmacies entirely in some countries.
History
Zalcitabine was first synthetized in the sixties by Jerome HorwitzJerome Horwitz
Dr. Jerome P. Horwitz is a globally renowned American scientist; his affiliations included the Barbara Ann Karmanos Cancer Institute, the Wayne State University School of Medicine and the Michigan Cancer Foundation.- Background :Dr...
and subsequently developed as an anti-HIV agent by Samuel Broder
Samuel Broder
Samuel Broder is an American oncologist and medical researcher. He was a co-developer of some of the first effective drugs for the treatment of AIDS and was Director of the National Cancer Institute from 1989 to 1995....
, Hiroaki Mitsuya
Hiroaki Mitsuya
is a Japanese virologist famous for his role in discovery of the anti-HIV drug zidovudine as well as other anti-AIDS drugs including didanosine and zalcitabine . Mitsuya obtained his M.D. and Ph.D. at Kumamoto University in Japan...
, and Robert Yarchoan
Robert Yarchoan
Robert Yarchoan is a medical researcher who played an important role in the development of the first effective drugs for AIDS. He is the Chief of the HIV and AIDS Malignancy Branch in the NCI and also coordinates AIDS and AIDS malignancy research throughout the NCI as Director of the Office of HIV...
at the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
(NCI). Like didanosine
Didanosine
Didanosine is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor, effective against HIV and used in combination with other antiretroviral drug therapy as part of highly active antiretroviral therapy .-History:The related pro-drug of didanosine,...
, it was then licensed because the NCI may not market or sell drugs. The National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH) thus licensed it to Hoffman LaRoche.
Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) for the treatment of HIV infection and AIDS. It was approved on June 19, 1992 as a monotherapy and again in 1996 for use in combination with Zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
(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
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
(PI) were not far off by this time.
The sale and distribution of zalcitabine has been discontinued since December 31, 2006.
Mechanism of action
Zalcitabine is an analogAnalog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of pyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
. It is a derivative of the naturally existing deoxycytidine
Cytidine
Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
, made by replacing the hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group in position 3' with a hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
.
It is phosphorylated in T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s and other HIV target cells into its active triphosphate form, ddCTP. This active metabolite works as a substrate for HIV reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
, 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
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
inhibitor it possess activity only against retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
es.
Pharmacokinetics
Zalcitabine has a very high oral absorption rate of over 80%. It is predominantly eliminated by the renal route, with a half-life of 2 hours.Drug interactions
LamivudineLamivudine
Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor .It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV...
(3TC) significantly inhibits the intracellular phosphorylation of zalcitabine to the active form, and accordingly the drugs should not be administered together.
Additionally, zalcitabine should not be used with other drugs that can cause peripheral neuropathy, such as didanosine
Didanosine
Didanosine is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor, effective against HIV and used in combination with other antiretroviral drug therapy as part of highly active antiretroviral therapy .-History:The related pro-drug of didanosine,...
and stavudine
Stavudine
Stavudine is a nucleoside analog reverse transcriptase inhibitor active against HIV.-History:...
.
Adverse events
The most common adverse events at the beginning of treatment are nausea and headache. More serious adverse events are peripheral neuropathyPeripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, which can occur in up to 33% of patients with advanced disease, oral ulcers
Mouth ulcer
A mouth or oral ulcer is an open sore in the mouth, or rarely a break in the mucous membrane or the epithelium on the lips or surrounding the mouth. The types of mouth ulcers are diverse, with a multitude of associated causes including: physical abrasion, acidic fruit, infection, other medical...
, oesophageal ulcers and, rarely, pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
.
Resistance
Resistance to zalcitabine develops infrequently compared with other nRTIs, and generally only occurs at a low level. The most common mutation observed in vivo is T69D, which does not appear to give rise to cross-resistance to other nRTIs; mutations at positions 65, 74, 75, 184 and 215 in the pol gene are observed more rarely.Further reading
- 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.html
- Moyle G. A re-evaluation of zalcitabine. Expert Opin Investig Drugs 1998;7:451-62