Open Access Articles- Top Results for Zidovudine


"AZT" redirects here. For other uses, see AZT (disambiguation).
Systematic (IUPAC) name
Clinical data
Trade names Retrovir
  • AU: B3
  • US: C (Risk not ruled out) (AZT)
  • (Prescription only)
Oral, serum, suppository
Pharmacokinetic data
Bioavailability Complete absorption, following first-pass metabolism systemic availability 75% (range 52 to 75%)
Protein binding 30 to 38%
Metabolism Hepatic
Half-life 0.5 to 3 hours
Excretion Renal/Rectal
30516-87-1 7pxY
PubChem CID 35370
DrugBank DB00495 7pxY
ChemSpider 32555 7pxY
UNII 4B9XT59T7S 7pxY
ChEBI CHEBI:10110 7pxN
NIAID ChemDB 000001
Chemical data
Formula C10H13N5O4
267.242 g/mol
 14pxN (what is this?)  (verify)

Zidovudine (INN) or azidothymidine (AZT) (also called ZDV) is a nucleoside analog reverse-transcriptase inhibitor (NRTI), a type of antiretroviral drug used for the treatment of HIV/AIDS infection. AZT inhibits the enzyme (reverse transcriptase) that HIV uses to synthesize DNA, thus preventing viral DNA from forming.

AZT is the first U.S. government-approved treatment for HIV, marketed under the brand name Retrovir. AZT was the first breakthrough in AIDS therapy, significantly reducing the replication of the virus in patients and leading to clinical and immunologic improvements.[2] It can also be used to prevent HIV transmission, such as from mother to child during the period of birth or after a needle stick injury. Used by itself in HIV-infected patients, AZT slows HIV replication in patients, but does not stop it entirely.[3] HIV may become AZT-resistant over time, and therefore AZT is now usually used in conjunction with other anti-HIV drugs in the combination therapy called highly active antiretroviral therapy (HAART). AZT is included in Combivir and Trizivir, and is included in the World Health Organization's Model List of Essential Medicines, which suggests the minimum medicinal needs for a basic health care system.[4]

Medical uses

HIV treatment

In May 1984, shortly after the human immunodeficiency virus (HIV) had been unambiguously proven as the cause of AIDS,[5][6] Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan of the United States National Cancer Institute (NCI) initiated a program to develop therapies for HIV/AIDS.[7] Using a CD4+ cell line that they had made, they developed an assay to screen drugs for their ability to protect CD4+ T cells from being killed by HIV.[8] This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells. In order to get drugs into the clinic as soon as possible, they started with compounds that were either in clinical use or for which they could get a pharmaceutical partner. As part of this effort, they initiated a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). Burroughs-Wellcome had expertise in nucleoside analogs and viral diseases, led by researchers including Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts were focused in part on the viral enzyme reverse transcriptase. Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. One compound that they were working with (AZT), which they had given the code name "BW A509X", was tested and demonstrated remarkable efficacy against certain mouse viruses. However, the scientists at Burroughs-Wellcome were not working with HIV themselves, and sent 11 compounds to the NCI team for testing against HIV in their newly developed assay.

In February 1985, the NCI scientists found that BW A509X, one of these compounds, had potent efficacy in vitro. Burroughs-Wellcome scientists had previously shown that it was active against bacterial infection in rodents.[8][9] Several months later, Broder, Mitsuya, and Yarchoan started the initial phase 1 clinical trial of AZT at the NCI, in collaboration with the scientists from Burroughs-Wellcome and Duke University.[10][11] In doing this Phase I trial, they built on their experience in doing an earlier trial, with suramin, another drug that had shown effective anti-HIV activity in the laboratory. This initial trial of AZT proved that the drug could be safely administered to patients with HIV, that it increased their CD4 counts, restored T cell immunity as measured by skin testing, and that it showed strong evidence of clinical effectiveness, such as inducing weight gain in AIDS patients. It also showed that levels of AZT that worked in vitro could be injected into patients in serum and suppository form, and that the drug penetrated deeply only into infected brains.

A rigorously maintained double-blind, placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome. The study, which was commended by the CDC and the NIH for its standards,[12] proved that AZT safely prolongs the lives of patients with HIV.[13] Burroughs-Wellcome filed for a patent for AZT in 1985. The Anti-Infective Advisory Committee to United States Food and Drug Administration (FDA) voted ten to one to recommend the approval of AZT.[14] The FDA approved the drug (via the then-new FDA accelerated approval system) for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-obsolete medical term for pre-AIDS illness) on March 20, 1987.[15] The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months, the shortest period of drug development in recent history.

AZT was subsequently approved unanimously for infants and children in 1990.[16] AZT was initially administered in somewhat higher dosages than today, typically 400 mg every four hours, day and night. The paucity of alternatives for treating HIV/AIDS at that time unambiguously affirmed the health risk/benefit ratio, with inevitable slow, disfiguring, and painful death from HIV outweighing the drug's side-effect of transient anemia and malaise.

Current treatment regimens involve relatively lower dosages (e.g., 300 mg) of AZT taken just twice a day, almost always as part of highly active antiretroviral therapy (HAART), in which AZT is combined with other drugs (known affectionately as "the triple cocktail") in order to prevent the selection of HIV into an AZT-resistant form.[17][18]

HIV prevention

AZT has been used as post-exposure prophylaxis (PEP) in combination with another antiretroviral, lamivudine, substantially reducing the risk of HIV infection following the first single exposure to the virus (such as a needle-stick injury involving blood or body fluids from an individual known or suspected of being infected with HIV)[19] (though its use in PEP has largely been replaced by tenofovir as a component of a three drug combination[20]).

AZT is now a principal part of the clinical pathway for both pre-exposure prophylaxis and post-exposure treatment of mother-to-child transmission of HIV during pregnancy, labor, and delivery and has been proven to be integral to uninfected siblings' perinatal and neonatal development.[21][22] Without AZT, as many as 10 to 15% of fetuses with HIV-infected mothers will themselves become infected.[23] AZT has been shown to reduce this risk to as little as 8% when given in a three-part regimen post-conception, delivery, and six weeks post-delivery. Consistent and proactive precautionary measures, such as the rigorous use of antiretroviral medications, cesarean section, face masks, heavy-duty rubber gloves, clinically segregated disposable diapers, and avoidance of mouth contact will further reduce child-attendant transmission of HIV to as little as 1–2%.[24][25][26]

During the period from 1994 to 1999 when this was the primary form of prevention of mother-to-child HIV transmission, AZT prophylaxis prevented more than 1000 parental and infant deaths from AIDS in the United States.[27] In the US at this time, the accepted standard of care for HIV-positive mothers was known as the 076 regimen and involved 5 daily doses of AZT from the second trimester onwards as well as AZT intravenously administered during labour.[28] As this treatment was lengthy and expensive, it was deemed unfeasible in the global south, where mother-to-child transmission was a significant problem. A number of studies were initiated in the late 1990s that sought to test the efficacy of a shorter, simpler regimen for use in ‘resource-poor’ countries.[29] This AZT short course was an inferior standard of care and would have been considered malpractice if trialed in the US; however it was nonetheless a treatment that would improve (at least to some extent) the care and survival of impoverished subjects, given local realities and the “shortages of staffing, medication and equipment that bound the possibilities of care” in such settings.[30] The trials were highly controversial and highlighted the inability of researchers to align the local realities, such as the inaccessibility of the AZT, with the scientific and ethical protocols designed in ‘resource-rich’ countries.[29]

Side effects

Early long-term higher-dose therapy with AZT was initially associated with side effects that sometimes limited therapy, including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. All of these conditions were generally found to be reversible upon reduction of AZT dosages. They have been attributed to several possible causes, including transient depletion of mitochondrial DNA, sensitivity of the γ-DNA polymerase in some cell mitochondria,[31] the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells.[32] Anemia due to AZT was successfully treated using vitamins to stimulate red blood cell production.[33][34] Drugs that inhibit hepatic glucuronidation, such as indomethacin, nordazepam, acetylsalicylic acid (aspirin) and trimethoprim, decreased the elimination rate and increased the therapeutic strength of the medication.[35] Most common side-effects included upset stomach and acid reflux (heartburn), headache, cosmetic reduction in abdominal body fat, light sleeping, and occasional loss of appetite; while less-common complaints included faint discoloration of fingernails and toenails, mood elevation, occasional tingling or transient numbness of the hands or feet, and minor skin discoloration. Allergic reactions were rare.[36] Today, side-effects are much less common with the use of lower doses of AZT.[37] According to IARC, there is sufficient evidence in experimental animals for the carcinogenicity of zidovudine; it is possibly carcinogenic to humans (Group 2B).[38]

Viral resistance

Even at the highest doses that can be tolerated in patients, AZT is not potent enough to prevent all HIV replication, and may only slow the replication of the virus and the progression of the disease. During prolonged AZT treatment, HIV has the potential to develop resistance to AZT by mutation of its reverse transcriptase.[39][40] To slow the development of resistance, physicians generally recommend that AZT be given in combination with another reverse transcriptase inhibitor and an antiretroviral from another group, such as a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy).

Mechanism of action

File:Azt pills.JPG
AZT in oral, injectable, and suppository form

AZT is a thymidine analogue. AZT works by selectively inhibiting HIV's reverse transcriptase, the enzyme that the virus uses to make a DNA copy of its RNA. Reverse transcription is necessary for production of HIV's double-stranded DNA, which would be subsequently integrated into the genetic material of the infected cell (where it is called a provirus).[8][11][41]

Cellular enzymes convert AZT into the effective 5'-triphosphate form. Studies have shown that the termination of HIV's forming DNA chains is the specific factor in the inhibitory effect.

At very high doses, AZT's triphosphate form may also inhibit DNA polymerase used by human cells to undergo cell division, but regardless of dosage AZT has an approximately 100-fold greater affinity for HIV's reverse transcriptase.[42] The selectivity has been proven to be due to the cell's ability to quickly repair its own DNA chain if it is broken by AZT during its formation, whereas the HIV virus lacks that ability.[43] Thus AZT inhibits HIV replication without affecting the function of uninfected cells.[8] At sufficiently high dosages, AZT begins to inhibit the cellular DNA polymerase used by mitochondria to replicate, accounting for its potentially toxic but reversible effects on cardiac and skeletal muscles, causing myositis.[10][44][45][46][47]


File:Azt crystal.JPG
A salt crystal of AZT, viewed under polarized light

AZT crystallizes into an asymmetric nucleated monoclinic salt structure, forming an equalized hydrogen-nitrogen-oxygen bonded network of base-paired dimers; its multiscaled crystallized lattice superstructure and surfactant headgroup electrostatic bond polarity was reported in 1988 and 1987.[48][49]


In the 1960s the theory that most cancers were caused by environmental retroviruses gained clinical support and funding. It had recently become known, due to the work of Nobel laureates Howard Temin and David Baltimore,[50] that nearly all avian cancers were caused by bird retroviruses, but corresponding human retroviruses have not yet been found.

In parallel work, other compounds that successfully blocked the synthesis of nucleic acids had been proven to be both antibacterial, antiviral, and anticancer agents, the leading work being done at the laboratory of Nobel laureates George Hitchings and Gertrude Elion, leading to the development of the antitumor agent 6-mercaptopurine.[50]

Jerome Horwitz of the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine first synthesized AZT in 1964 under a US National Institutes of Health (NIH) grant.[9][51][52] Development was shelved after it proved biologically inert in mice.[9][53] In 1974, Wolfram Ostertag of the Max Planck Institute for Experimental Medicine in Göttingen, Germany reported that AZT specifically targeted Friend virus (strain of murine leukemia virus).[54]

Society and culture

The patents on AZT have been the target of some controversy. In 1991, the advocacy group Public Citizen filed a lawsuit claiming that the patents were invalid. Subsequently, Barr Laboratories and Novopharm Ltd. also challenged the patent, in part based on the assertion that NCI scientists Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan should have been named as inventors, and those two companies applied to the FDA to sell AZT as a generic drug. In response, Burroughs Wellcome Co. filed a lawsuit against the two companies. The United States Court of Appeals for the Federal Circuit ruled in 1992 in favor of Burroughs Wellcome, ruling that even though they had never tested it against HIV, they had conceived of it working before they sent it to the NCI scientists.[55] This suit was appealed up to the Supreme Court of the US, but they declined to formally review it. In 2002, another lawsuit was filed over the patent by the AIDS Healthcare Foundation.

However, the patent expired in 2005 (placing AZT in the public domain), allowing other drug companies to manufacture and market generic AZT without having to pay GlaxoSmithKline any royalties. The U.S. FDA has since approved four generic forms of AZT for sale in the U.S.

In November 2009 GlaxoSmithKline formed a joint venture with Pfizer which combined the two companies' HIV assets in one company called ViiV Healthcare. This included the rights to Zidovudine.


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External links

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