Zidovudine: Encyclopedia - Zidovudine

Zidovudine

AZT

3'-Azido-2'-deoxythymidine

Zidovudine (INN) or azidothymidine (abbreviated to AZT) is an antiretroviral drug, the first antiviral treatment to be approved for use against HIV. It is also sold under the names Retrovir and Retrovis, and as an ingredient in Combivir and Trizivir.

Zidovudine - History

Zidovudine was the first drug approved for the treatment of AIDS and HIV infection. Jerome Horowitz 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 scientists in Burroughs Wellcome Co., started working on it as an AIDS drug. After showing that this drug worked against HIV in the test tube, this team conducted the initial clinical trial that provided evidence that it could increase CD4 counts in AIDS patients. AZT inhibits HIV replication by blocking the action of "reverse transcriptase", the enzyme that HIV uses to replicate its RNA for splicing into the DNA of a target cell.

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 approved the drug for use against HIV on March 20, 1987, and then as a preventive treatment in 1990. When it was first administered dosages tended to be much higher than today, typically one 400mg dose every four hours (even at night) and one of AZT's side-effects includes anemia which was a common complaint. Modern treatment regimens typically use lower dosages two to three times a day in order to improve the overall quality of life. AZT is also almost always combined with other drugs in order to prevent in-situ mutation of the HIV into an AZT-resistant form. Such regimens of three or more drugs are called highly active antiretroviral therapy (HAART); such regimens delay or prevent the development of resistance because it is much more difficult to develop resistance to two or more drugs at once and because the regimens can effectively prevent HIV replication in the body.

The crystal structure of AZT was reported by Alan Howie (Aberdeen University) in 1988. In the solid state AZT forms a hydrogen bond network. Note that AZT is based upon a sugar.

Zidovudine - Treatment

When used as a preventative treatment, AZT has proven to be particularly effective. If treatment is started before the total amount of virus, known as the viral load, reaches a critical point of 50 million parts per millilitre of blood serum, the chance of AIDS developing is effectively zero. This is widely used with medical practitioners who receive accidental infections (please see discussion).

Zidovudine - 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 . At present, 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. 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.

Zidovudine - Mode of action

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. The triphosphate form then has the ability both to inhibit the HIV reverse transcriptase by working as a substrate to it and to terminate the viral DNA synthesis by incorporation into DNA. The termination is caused by the absence of 3’-hydroxyl group in AZT, so that other nucleotides cannot attach to it. Studies have shown that the chain termination is the specific factor in inhibitory effect. Whilst competing with natural thymidine AZT inhibits the viral reverse transcriptase 100 times more effectively than the cellular DNA polymerase.

Zidovudine - Patent Issues

AZT has been the target of some controversy due to the nature of the patent process. The drug is easy to produce in bulk, costing about $0.63 per daily dose, 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 in this case the drug was developed to a large extent by taxpayers.

In 1991, Public Citizen filed a lawsuit claiming that the AZT/Zidovudine patent was invalid. The US 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.

AZT is also the source of another controversy; there are some who claim that in fact AZT, not HIV, causes AIDS. The most vocal proponent of this argument has been Dr. Peter Duesberg. This has been part of his larger challenge of the virus-AIDS hypothesis. However, the fact that AIDS appeared before the development of AZT undermines this line of thinking.

Adapted from the Wikipedia article "Zidovudine", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki