Zidovudine
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3'-Azido-2'-deoxythymidine | |
| Empirical Formula | C10H13N5O4 |
| Molecular Weight | 267.24 |
| Half-life | Approx. 3.3hours |
| Excretion | Renal |
| Pregnancy category | FDA Pregnancy category C |
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.
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History
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 NIH's Hiroaki Mitsuya demonstrated the drug's effectiveness against HIV, due to its ability to block the action of the "reverse transcriptase" enzyme that HIV uses to replicate its RNA for splicing into the DNA of a target cell.
The formula was soon purchased by Burroughs-Wellcome (now GlaxoSmithKline), which 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 preventative 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 – it's much more difficult to develop two resistances at once.
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).
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, which makes the attachment of other nucleotides to it impossible. 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.
This drug doesn't actually target reverse-transcriptase, as the original researchers claimed. It blocks the reproductions of cells anywhere in the body, which could be useful for cancers in adults, in theory, but is devastating when prescribed to children with HIV and to pregnant women.
Side effects
However, AZT has common side effects such as nausea and headaches and possible severe side effects such as 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.
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 fully developed by taxpayers, so long ago that the patent would have already run out if the NIH had applied for one.
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 Glaxo Smith Kline. In 2002, another lawsuit was filed over the patent (which is due to expire in 2005) by the AIDS Healthcare Foundation.
AZT is also the source of another controversy; there are some who claim that in fact AZT, not HIV, causes AIDS. This sort of claim found itself easy to gain currency in the late 1980s and early 1990s before it became widely known that AIDS was actually considerably more widespread in Africa, where most of its victims had not been treated with AZT. This presents a problem of definition, however, as AIDS is defined by HIV in the presence of certain illnesses (AIDS defining illnesses). Western cases of AIDS present a very different set of illnesses. AIDS reappraisers have also pointed out that the effects of hunger and environment have taken the major toll in Africa.
References
- The Best Democracy Money Can Buy by Greg Palast (2002)
- AZT label (http://www.rethinking.org/aids/AZTLabel.html)
- De Clercq, E: HIV resistance to reverse transcriptase inhibitors. Biochemical Pharmacology 1994; Vol. 47, No 2 pp. 155-169
- Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3rd edition. Pearson Professional Ltd, 1995.
- 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