View source for Zidovudine

{{Redirect|AZT}}
{{drugbox | Watchedfields = changed
| verifiedrevid = 310033590
|fat
| IUPAC_name = 1-[(2''R'',4''S'',5''S'')-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione
| image = Zidovudine.svg
| image2 = Zidovudine-3D-balls.png
| CASNo_Ref = {{cascite}}
| CAS_number = 30516-87-1
| ChemSpiderID = 32555
| ATC_prefix = J05 
| ATC_suffix = AF01
| PubChem = 35370
| DrugBank = DB00495
| C = 10 | H = 13 | N = 5 | O = 4
| molecular_weight = 267.242 g/mol
| smiles = OC[C@H]1O[C@H](C[C@@H]1N=[N+]=[N-])n1cc(C)c(=O)[nH]c1=O	
| bioavailability = near complete absoprtion, following first-pass metabolism systemic availability 65% (range 52 to 75%)
| protein_bound =30 to 38%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 0.5 to 3 hours
| excretion = [[Kidney|Renal]]
| pregnancy_US = C
| pregnancy_AU = B3
| legal_status = 
| routes_of_administration = Oral
}}

'''Zidovudine''' ([[International Nonproprietary Name|INN]]) or '''azidothymidine''' ('''AZT''') (also called ZDV) is a [[reverse transcriptase inhibitor|nucleoside analog reverse transcriptase inhibitor]] (NRTI), a type of [[antiretroviral drug]] used for the treatment of HIV/AIDs. It is an [[analog (chemistry)|analog]] of [[thymidine]]. 

AZT was the first approved treatment for [[HIV]], sold under the names '''Retrovir''' and '''Retrovis'''. AZT use was a major breakthrough in [[AIDS]] therapy in the 1990s that significantly altered the course of the illness and helped destroy the notion that HIV/AIDS was an instant death sentence. AZT slows HIV spread significantly, but does not stop it entirely. This allows HIV to become AZT resistant over time, and for this reason AZT is usually used in conjunction with other NRTIs and anti-viral drugs. In this form, AZT is used as an ingredient in [[Combivir]]  and [[Trizivir]], among others. Zidovudine is included in the [[World Health Organization]]'s "[[WHO Model List of Essential Medicines|Essential Drugs List]]", which is a list of minimum medical needs for a basic health care system.<ref name="essentialWHO">{{cite web
 | year = March 2005
 | url = http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf
 | title = WHO Model List of Essential Medicines
 | format = PDF
 | publisher = World Health Organization
 | accessdate = 2006-03-12
}}</ref>

==History==
===Development===
In the 1950s the theory that most cancers were caused by environmental [[retrovirus]]es gained currency. It had long been known that most avian cancers were caused by retroviruses, but this knowledge was of limited use in clinical settings due to a lack of drugs that were effective against them. The development of the first anti-retroviral drugs in the 1950s and 60s led to increasing efforts to isolate the expected human analogs of these avian viruses, and then develop suitable drugs to kill them and produce a universal cure for cancer. These efforts eventually culminated in the "[[War on Cancer]]" in the 1970s.

AZT was originally studied as one of many attempts to block the action of these [[oncovirus]]es. [[Jerome Horwitz]] of the Barbara Ann Karmanos Cancer Institute and [[Wayne State University School of Medicine]] first synthesized AZT in [[1964]] under a [[United States|US]] [[National Institutes of Health]] (NIH) [[Federal grant|grant]].<ref name=pmid20018391>{{Cite pmid|20018391}}</ref><ref name=horwitz64>{{cite journal | title = The monomesylates of 1-(2-deoxy-bd-lyxofuranosyl) thymines
| last = Horowitz | first = JP | coauthors = Chua J; Noel MJ | journal = Org. Chem. Ser. Monogr | year = 1964 | volume = 29 | pages = 2076-9 |doi=10.1021/jo01030a546 |accessdate = 2010-07-02}}</ref><ref name=filmazt2002>{{Cite video  | people = Detours V; Henry D (writers/directors) | title = I am alive today (history of an AIDS drug) | medium = Film | publisher = ADR Productions/Good & Bad News | location =   | date = 2002 }}</ref> Development was shelved after it proved insufficiently effective against tumors in mice.<ref name=pmid20018391/><ref name="nytimes">{{cite news | url = http://query.nytimes.com/gst/fullpage.html?sec=health&res=9A0DE4D81F3CF933A1575AC0A960948260 | title = A Failure Led to Drug Against AIDS | work = [[The New York Times]] | date = 1986-09-20 | accessdate = 2010-06-30 }}</ref> In [[1974]], Wolfram Ostertag of the [[Max Planck Institute]] in [[Germany]] reported that AZT was active against Friend murine leukaemia virus, a [[retrovirus]], in a mouse culture system.<ref>{{cite pmid | 4531031 }}</ref>

The anti-retroviral approach to develop a "silver bullet" cancer cure ultimately failed. Contrary to early belief, today it is estimated that viruses account for only 10 to 20% of human cancers. However, these efforts advanced the knowledge of cancer considerably, and led to rapid development of many anti-retroviral drugs, which would later prove useful. Zidovudine(AZT) was approved for marketing by the FDA on March 20, 1987.<ref name="Cimons">{{cite news | last = Cimons | first = Marlene | title = U.S. Approves Sale of AZT to AIDS Patients | work = Los Angeles Times | pages = 1 | date = 21 March 1987 }}</ref>

===HIV===
In 1984, shortly after the [[human immunodeficiency virus]] (HIV) had been confirmed as the cause of AIDS, scientists at the [[GlaxoSmithKline|Burroughs-Wellcome Company]] (now GlaxoSmithKline) began searching for compounds to treat the disease. Burroughs-Wellcome had expertise in viral diseases, led by researchers including Gertrude Elion, David Barry, Phil Furman, Marty St. Clair, Janet Rideout, Sandi Lehman and others. Their research efforts focused on the viral enzyme [[reverse transcriptase]]. Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. Scientists at Burroughs-Wellcome began to identify and synthesize compounds and developed a screen to test for activity against murine (mouse) retroviruses. One compound, coded "BW A509U", was tested and demonstrated potent activity against mouse viruses.

At the same time, [[Samuel Broder]], [[Hiroaki Mitsuya]], and [[Robert Yarchoan]] of the United States [[National Cancer Institute]] (NCI) had initiated an independent program to develop therapies for HIV/AIDS. The Burroughs-Wellcome scientists were not working directly with HIV, so the two groups began a collaboration. In February 1985, the NCI scientists showed that BW A509U, one of 11 compounds sent to them by Burroughs-Wellcome, had potent activity against HIV in the test tube. Several months later, Broder, Mitsuya, and Yarchoan started the initial phase 1 [[clinical trial]] of AZT at the NCI, in collaboration with scientists from Burroughs-Wellcome and Duke University.<ref name=pmid20018391/><ref name=MitsuyaPNAS>{{cite journal | author=Mitsuya H, Weinhold K, Furman P, St Clair M, Lehrman S, Gallo R, Bolognesi D, Barry D, Broder S | title=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''. | journal=Proc Natl Acad Sci USA | volume=82 | issue=20 | pages=7096–100 | year=1985 | pmid=2413459 | doi=10.1073/pnas.82.20.7096 | pmc=391317}}</ref><ref name="Yarchoan R, Mitsuya H, Myers C, Broder S 1989 726–38">{{cite journal | author=Yarchoan R, Mitsuya H, Myers C, Broder S | title=Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides. | journal=N Engl J Med | volume=321 | issue=11 | pages=726–38 | year=1989 | pmid=2671731}}</ref><ref name="Yarchoan R, Klecker R, Weinhold K, Markham P, Lyerly H, Durack D, Gelmann E, Lehrman S, Blum R, Barry D 1986 575–80">{{cite journal | author=Yarchoan R, Klecker R, Weinhold K, Markham P, Lyerly H, Durack D, Gelmann E, Lehrman S, Blum R, Barry D | title=Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. | journal=Lancet | volume=1 | issue=8481 | pages=575–80 | year=1986 | pmid=2869302 | doi=10.1016/S0140-6736(86)92808-4}}</ref> This trial suggested that the drug could be safely administered to patients with HIV and that it could increase [[CD4]] counts in HIV-infected patients.

A [[placebo]]-controlled [[randomized trial]] of AZT was subsequently conducted by Burroughs-Wellcome. The study found that AZT could prolong the life of patients with AIDS.<ref>{{cite journal | author=Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, et al. | title=The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. | journal=N Engl J Med | volume=317 | issue=4 | pages=185–91 | year=1987 | pmid=3299089}}</ref> Burroughs-Wellcome filed for a patent for AZT in 1985. The [[United States Food and Drug Administration]] (FDA) approved the drug (via the then-new [[FDA Fast Track Development Program|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.<ref name="Cimons"/> The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was only 25 months, one of the shortest periods of drug development in recent history.  

AZT was subsequently approved as a preventive treatment in 1990. It was initially administered in much higher dosages than today, typically 400&nbsp;mg 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 is [[anemia]], a common complaint in early trials.

Current treatment regimens involve lower dosages (e.g., 300&nbsp;mg) of AZT taken twice a day, almost always as part of ''[[highly active antiretroviral therapy]]'' (HAART). AZT is combined with other drugs in order to prevent mutation of HIV into an AZT-resistant form.<!--
  --><ref>{{cite journal | author=De Clercq E | title=HIV resistance to reverse transcriptase inhibitors. | journal=Biochem Pharmacol | volume=47 | issue=2 | pages=155–69 | year=1994 | pmid=7508227 | doi=10.1016/0006-2952(94)90001-9}}</ref><!--
  --><ref>{{cite journal | author=Yarchoan R, Mitsuya H, Broder S | title=AIDS therapies. | journal=Sci Am | volume=259 | issue=4 | pages=110–9 | year=1988 | pmid=3072667 | doi=10.1038/scientificamerican1088-110}}</ref>

As a solid, AZT forms a [[hydrogen bond]]ed network of base-paired [[dimer]]s; its crystal structure was reported in 1988.<ref>{{cite journal |author=Dyer I, Low JN, Tollin P, Wilson HR, Howie RA |title=Structure of 3'-azido-3'-deoxythymidine, AZT |journal=Acta Crystallogr C |volume=44 ( Pt 4) |issue= |pages=767–9 |year=1988 |month=April |pmid=3271074 |doi= |url=}}</ref>

==Prophylaxis==
[[Image:Azt crystal.JPG|thumb|left|250px|A crystal of AZT, viewed under polarized light]]
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 as part of a regimen to prevent [[vertical transmission|mother-to-child transmission]] of HIV during pregnancy, labor, and delivery.<!--
  --><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>
With no treatment, approximately 25% of infants whose mothers are infected with HIV will become infected.  AZT has been shown 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.<!--
  --><ref>{{cite journal | author=Connor E, Sperling R, Gelber R, Kiselev P, Scott G, O'Sullivan M, VanDyke R, Bey M, Shearer W, Jacobson R | title=Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. | journal=N Engl J Med | volume=331 | issue=18 | pages=1173–80 | year=1994 | pmid=7935654 | doi=10.1056/NEJM199411033311801}}</ref>
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 infant HIV infections.<!--
  --><ref name="pmid16741877">{{cite journal |author=Walensky RP, Paltiel AD, Losina E, ''et al.'' |title=The survival benefits of AIDS treatment in the United States |journal=J. Infect. Dis. |volume=194 |issue=1 |pages=11–9 |year=2006 |month=July |pmid=16741877 |doi=10.1086/505147 |url=}}</ref> 
Use of appropriate combinations of antiretroviral medications, [[cesarean section]] and avoidance of breast feeding 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 fingernails and toenails.  More severe side effects include [[anemia]] and [[bone marrow suppression]], which can be overcome using [[erythropoietin]] or [[darbepoetin]] treatments.{{Citation needed|date=January 2010}}  These unwanted side effects might be caused by the sensitivity of the γ-DNA polymerase in the cell [[mitochondria]]. Drugs that inhibit [[liver|hepatic]] [[glucuronidation]], 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>

==Viral resistance==
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, HIV has the ability to gain an increased resistance to AZT by [[mutation]] of its [[reverse transcriptase]]. To slow the development of resistance, physicians generally recommend that AZT be given in combination with another [[Reverse transcriptase inhibitor#Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)|reverse transcriptase inhibitor]] and an antiretroviral from another group, such as a [[protease inhibitor]] or a [[Reverse transcriptase inhibitor#Non-nucleoside reverse transcriptase inhibitors (NNRTIs)|non-nucleoside reverse transcriptase inhibitor]], this type of therapy is known as [[HAART]] (Highly Active Anti Retroviral Therapy). AZT has been shown to work additively or synergistically with many antiviral agents such as [[acyclovir]] and [[interferon]]; however, [[ribavirin]] decreases the antiviral effect of AZT. 

==Mode of action==
[[Image:Azt pills.JPG|thumb|right|250px|AZT in oral and injectable form]]
Like other [[reverse transcriptase inhibitor]]s, AZT works by inhibiting the action of [[reverse transcriptase]], the [[enzyme]] that HIV uses to make a [[DNA]] copy of its [[RNA]]. Reverse transcription is necessary for production of the viral double-stranded [[DNA]], which is subsequently integrated into the genetic material of the infected [[cell (biology)|cell]] (where it is called a [[provirus]]).<!--
  --><ref>{{cite journal | author=Mitsuya H, Yarchoan R, Broder S | title=Molecular targets for AIDS therapy. | journal=Science | volume=249 | issue=4976 | pages=1533–44 | year=1990 | pmid=1699273 | doi=10.1126/science.1699273}}</ref><!--
  --><ref name=MitsuyaPNAS/><!--
  --><ref name="Yarchoan R, Klecker R, Weinhold K, Markham P, Lyerly H, Durack D, Gelmann E, Lehrman S, Blum R, Barry D 1986 575–80"/>

The azido group increases the [[lipophilic]] nature of AZT, allowing it to cross [[cell membrane]]s easily by [[diffusion]] and thereby also to cross the [[blood-brain barrier]].  Cellular enzymes convert AZT 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 inhibits [[DNA polymerase]] used by human cells to undergo [[cell division]]<ref>{{cite journal | author=Plessinger M, Miller R | title=Effects of zidovudine (AZT) and dideoxyinosine (ddI) on human trophoblast cells. | journal=Reprod Toxicol | volume=13 | issue=6 | pages=537–46 | pmid=10613402 | doi=10.1016/S0890-6238(99)00052-0 | year=1999}}</ref> but is far more effective at inhibiting reverse transcriptase than it is at inhibiting DNA polymerase alpha making it much better at inhibiting HIV replication than interfering with human cell division.<ref name=FurmanPNAS>{{cite journal | author=Furman P, Fyfe J, St Clair M, Weinhold K, Rideout J, Freeman G, Lehrman S, Bolognesi D, Broder S, Mitsuya H | title=Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. | journal=Proc Natl Acad Sci USA | volume=83 | issue=21 | pages=8333–7 | year=1986 | pmid=2430286 | doi=10.1073/pnas.83.21.8333 | pmc=386922}}</ref><ref name=MitsuyaPNAS/>  The cellular DNA polymerase used by [[mitochondria]] to replicate is more sensitive to the inhibitory effects of AZT, accounting for its toxic effects on [[cardiac muscle|cardiac]] and [[skeletal muscle]]s, causing [[myositis]].<!--
  --><ref>{{cite journal | author=Collins M, Sondel N, Cesar D, Hellerstein M | title=Effect of nucleoside reverse transcriptase inhibitors on mitochondrial DNA synthesis in rats and humans. | journal=J Acquir Immune Defic Syndr | volume=37 | issue=1 | pages=1132–9 | year=2004 | pmid=15319672 | doi=10.1097/01.qai.0000131585.77530.64}}</ref><!--
  --><ref>{{cite journal | author=Parker W, White E, Shaddix S, Ross L, Buckheit R, Germany J, Secrist J, Vince R, Shannon W | title=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. | journal=J Biol Chem | volume=266 | issue=3 | pages=1754–62 | year=1991 | pmid=1703154}}</ref><!--
  --><ref>{{cite book | author=Rang H.P., Dale M.M., Ritter J.M. | title=Pharmacology | edition=3<sup>rd</sup> | publisher=Pearson Professional Ltd | year=1995 | isbn=0443059748}}</ref><!--
  --><ref>{{cite journal | author=Balzarini J, Naesens L, Aquaro S, Knispel T, Perno C, De Clercq E, Meier C | title=Intracellular metabolism of CycloSaligenyl 3'-azido-2', 3'-dideoxythymidine monophosphate, a prodrug of 3'-azido-2', 3'-dideoxythymidine (zidovudine). | journal=Mol Pharmacol | volume=56 | issue=6 | pages=1354–61 | date=1 December 1999| pmid=10570065 | url=http://molpharm.aspetjournals.org/cgi/content/full/56/6/1354 }}</ref><!--
  --><ref name="Yarchoan R, Mitsuya H, Myers C, Broder S 1989 726–38"/>

==Patent issues==
The patents on AZT have been the target of some controversy.  In 1991, [[Public Citizen]] filed a lawsuit claiming that the patents were invalid.  Subsequently, Barr Laboraties 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]], claiming that even though they had never tested it against HIV, they had conceived of it working before they sent it to the NCI scientists.<ref>{{cite web | url=http://www.law.uh.edu/healthlaw/law/FederalMaterials/FederalCases/BurroughsWellcomevBarrLaboratories.htm | accessdate=2007-02-28 | title=Burroughs Wellcome Co. v. Barr Laboratories, 40 F.3d 1223 (Fed. Cir. 1994) | publisher=University of Houston -- Health Law and Policy Institute | author=US Court of Appeals for the Federal Circuit}}</ref> 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 drug|generic]] forms of AZT for sale in the U.S.

==References==
{{Reflist|2}}

==External links==
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Zidovudine U.S. National Library of Medicine: Drug Information Portal - Zidovudine]

{{HIVpharm}}

[[Category:Nucleoside analog reverse transcriptase inhibitors]]
[[Category:World Health Organization essential medicines]]
[[Category:IARC Group 2B carcinogens]]
[[Category:Azides]]

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[[mn:Зидовудин]]
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[[pl:Azydotymidyna]]
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[[Category:2Fix]]