Zidovudine

From Free net encyclopedia

Zidovudine (INN) or azidothymidine (AZT) (also called ZDV) is an antiretroviral drug, the first one approved for treatment of HIV. It is also sold under the names Retrovir® and Retrovis®, and as an ingredient in Combivir® and Trizivir®. It is an analog of thymidine.

Image:AZT.jpg AZT
3'-Azido-2'-deoxythymidine
Empirical Formula	C10H13N5O4
Molecular Weight	267.24
Half-life	Approx. 3.3hours
Excretion	Renal
Pregnancy category	FDA Pregnancy category C

Contents 1 History 2 Prophylaxis 3 Side effects 4 Mode of action 5 Controversy 5.1 Patent issues 5.2 Peter Duesberg's claims 6 References

History

Zidovudine was the first drug approved for the treatment of AIDS and HIV infection. Jerome Horwitz first synthesized AZT in 1964, under a US National Institutes of Health (NIH) grant. It was originally intended to treat cancer, but failed to show efficacy and had an unacceptably high side effect profile. The drug then faded from view until February 1985, when Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan, three scientists in the National Cancer Institute (NCI), collaborating with Janet Rideout and several other scientists in Burroughs Wellcome Co., started working on it as an AIDS drug. After showing that this drug was an effective agent against HIV in vitro, the team conducted the initial clinical trial that provided evidence that it could increase CD4 counts in AIDS patients. <ref>{{cite web

| title=In Their Own Words-Bios: Samuel Broder, describing AZT development
| url=http://history.nih.gov/NIHInOwnWords/docs/page_09.html
| accessdate=2006-01-18
| publisher=NIH
| author=Samuel Broder

}}</ref><ref>{{cite web

| url=http://history.nih.gov/NIHInOwnWords/docs/page_25.html
| title=In Their Own Words-Bios: Robert Yarchoan, describing AZT development
| accessdate=2006-01-18
| publisher=NIH
| author=Robert Yarchoan

}}</ref>

A placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome (now GlaxoSmithKline), in which it was shown that it could prolong the life of patients with AIDS. Burroughs Wellcome Co. filed for a patent on AZT in 1986. The Food and Drug Administration (FDA) approved the drug (via the then-new FDA accelerated approval system) for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-defunct medical term for pre-AIDS illness) on March 20, 1987, and then as a preventive treatment in 1990. It was initially administered in much higher dosages than today, typically one 400mg dose every four hours (even at night). However, the unavailability at that time of alternatives to treat AIDS affected the risk/benefit ratio, with the certain toxicity of HIV infection outweighing the risk of drug toxicity. One of AZT's side-effects includes anemia, a common complaint in early trials.

Modern treatment regimens typically use lower dosages two to three times a day in order to improve the overall quality of life. Like other antiretroviral drugs, AZT is also almost always used in highly active antiretroviral therapy (HAART). That is, it is combined with other drugs in order to prevent mutation of the HIV into an AZT-resistant form.<ref>De Clercq, E: HIV resistance to reverse transcriptase inhibitors. Biochemical Pharmacology 1994; Vol. 47, No 2 pp. 155-169</ref><ref>Yarchoan R, Mitsuya H, Broder S. AIDS therapies. Sci Am 1988;259(4):110-9</ref>

The crystal structure of AZT was reported by Alan Howie (Aberdeen University) in 1988.<ref>{{cite web

| url=http://www.abdn.ac.uk/chemistry/research/rah/rah.hti
| accessdate=2006-01-18
| title=Dr Alan Howie
| publisher=University of Aberdeen
| author=Dr. Alan Howie

}}</ref> In the solid state AZT forms a hydrogen bond network. Note that AZT is based upon a sugar.

Prophylaxis

AZT may be used in combination with other antiretroviral medications to substantially reduce the risk of HIV infection following a significant exposure to the virus (such as a needle-stick injury involving blood or body fluids from an individual known to be infected with HIV).<ref>{{cite web | url = http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm | title = Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV | accessdate = 2006-03-29}}</ref>

AZT is also recommended<ref>{{cite web | url = http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf | title = Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health | accessdate = 2006-03-29}}</ref> as part of a regimen to prevent mother-to-child transmission of HIV during pregnancy, labor and delivery. With no treatment, approximately 25% of infants whose mothers are infected with HIV will become infected. AZT has been shown<ref>{{cite web | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7935654&query_hl=4&itool=pubmed_docsum | title = Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. | accessdate = 2006-03-29}}</ref> to reduce this risk to approximately 8% when given in a three-part regimen during pregnancy, delivery and to the infant for 6 weeks after birth. Use of appropriate combinations of antiretroviral medications and cesarean section when necessary can further reduce mother-child transmission of HIV to 1-2%.

Side effects

Common side effects of AZT include nausea, headache, changes in body fat, and discoloration of finger and toenails. More severe side effects include anaemia and bone marrow suppression. These unwanted side effects might be caused by the sensitivity of the γ-DNA polymerase in the cell mitochondria. AZT has been shown to work additively or synergistically with many anti-HIV agents; however, acyclovir and ribavirin decrease the antiviral effect of AZT. AZT is recommended to be given in combination with another reverse transcriptase inhibitor and a protease inhibitor. Such drugs that inhibit hepatic glucoronidation, such as indomethacin, acetylsalicylic acid (Aspirin) and trimethoprim, decrease the elimination rate and increase the toxicity.<ref>{{cite web

| url=http://www.medicinenet.com/zidovudine_azt-oral/article.htm
| title=ZIDOVUDINE (AZT) - ORAL (Retrovir) side effects, medical uses, and drug interactions.
| accessdate=2006-01-09
| publisher=MedicineNet

}}</ref>

AZT does not destroy the HIV infection, but only delays the progression of the disease and the replication of virus, even at very high doses. During prolonged AZT treatment the HIV-virus has the ability to gain an increased resistance to AZT by mutation of the reverse transcriptase. A study showed that AZT could not impede the resumption of virus production, and eventually cells treated with AZT produced viruses as much as the untreated cells.

Mode of action

Like other reverse transcriptase inhibitors, AZT inhibits HIV replication by inhibiting the action of reverse transcriptase, the enzyme that HIV uses to make a DNA copy of its RNA and then a second DNA copy. The viral double-stranded DNA is subsequently spliced into the DNA of a target cell where it is called a provirus.<ref>Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science 1990;249(4976):1533-44</ref><ref>Mitsuya H, Weinhold KJ, Furman PA, et al. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A 1985;82(20):7096-100</ref><ref>Yarchoan R, Klecker RW, Weinhold KJ, et al. Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet 1986;1(8481):575-80</ref>

The azido group increases the lipophilic nature of AZT, allowing it cross cell membranes easily by diffusion and thereby also cross the blood-brain barrier. The cellular enzymes convert it into the effective 5’-triphosphate form. Studies have shown that the termination of the formed DNA chains is the specific factor in the inhibitory effect. The triphosphate form also has some ability to inhibit cellular DNA polymerase, which is used for replicating DNA as part of cell division.<ref>Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. PMID 2430286</ref> At relatively high concentrations, it can inhibit cell proliferation.<ref>3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. PMID 2413459</ref><ref>Effects of zidovudine (AZT) and dideoxyinosine (ddI) on human trophoblast cells. PMID 10613402</ref> However, it is much more active against reverse transcriptase than against cellular DNA polymerase, accounting for its selective antiviral activity. A special kind of cellular DNA polymerase that replicates the DNA in mitochondria is relatively more sensitive to inibition by AZT, and this accounts for certain toxicities such as damage to cardiac and other muscles (also called myositis).<ref>Effect of nucleoside reverse transcriptase inhibitors on mitochondrial DNA synthesis in rats and humans. PMID 15319672</ref><ref>Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases alpha, beta, and gamma by the 5'-triphosphates of carbovir, 3'-azido-3'-deoxythymidine, 2',3'-dideoxyguanosine and 3'-deoxythymidine. A novel RNA template for the evaluation of antiretroviral drugs. PMID 1703154</ref> <ref>Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3^rd edition. Pearson Professional Ltd, 1995.</ref><ref>Balzarini J., Naesens L., Aquaro S., Knispel T., Perno C.-F., De Clercq E., Meier C.: Intracellular Metabolism of CycloSaligenyl 3’-Azido-2’-3’-dideoxythymidine Monophosphate, a Prodrug of 3’-Azido-2’-3’-dideoxythymidine (Zidovudine). Molecular Pharmacology 1999; 56: pp. 1354-1361</ref><ref>Yarchoan R, Mitsuya H, Myers CE, Broder S. Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med 1989;321(11):726-38</ref>

Controversy

AZT has been the target of some controversy due to the nature of the patent process<ref>The Best Democracy Money Can Buy by Greg Palast (2002)</ref> and as part of Dr. Peter Duesberg's challenge to the virus-AIDS hypothesis.

Patent issues

AZT is easy to produce in bulk, costing about USD $0.63 per daily dose (pdd), but due to the patent protection, GlaxoSmithKline is able to sell it for about $8 pdd. Normally this would be considered a reasonable price given the high costs of developing a drug, but some believe the selling price is unreasonably high because AZT was developed with federal grant funds.

In 1991, Public Citizen filed a lawsuit claiming that the AZT/Zidovudine patent was invalid. The United States Court of Appeals for the Federal Circuit ruled in 1994 in favour of GlaxoSmithKline. In 2002, another lawsuit was filed over the patent by the AIDS Healthcare Foundation.

However, the patent expired in September 2005, allowing other drug companies to manufacture and market generic AZT without having to pay GlaxoSmithKline any royalties. The US Food and Drug Administration (FDA) has since approved 4 generic forms of AZT for sale in the US.

Peter Duesberg's claims

AZT is also the source of another controversy; Dr. Peter Duesberg claims that in fact AZT or other immunosuppressive drugs (nitrite inhalants, cocaine, amphetamines etc.), not HIV, cause AIDS in Western countries.<ref>{{cite web

| url=http://www.duesberg.com/
| title=Duesberg on AIDS
| accessdate=2006-01-18
| publisher=Peter H. Duesberg
| author=Peter H. Duesberg

}}</ref> That claim is part of his larger challenge of the virus-AIDS hypothesis. Duesberg's claims are contradicted by an overwhelming amount of clinical and epidemiological evidence.<ref>{{cite web | url = http://www.niaid.nih.gov/factsheets/evidhiv.htm | title = The Evidence That HIV Causes AIDS | accessdate = 2006-03-29}}</ref>

References

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