Wikipedia

Zidovudine

"AZT" redirects here. For other uses, seeAZT (disambiguation).

Zidovudine(ZDV), also known asazidothymidine(AZT), was the firstantiretroviral medicationused to prevent and treatHIV/AIDS.It is generally recommended for use in combination with other antiretrovirals.[6]It may be used to preventmother-to-child spread during birthor after aneedlestick injuryor other potential exposure.[6]It is sold both by itself and together aslamivudine/zidovudineandabacavir/lamivudine/zidovudine.[6]It can be used by mouth or by slowinjection into a vein.[6]

Zidovudine
Clinical data
Trade namesRetrovir, others
AHFS/DrugsMonograph
MedlinePlusa687007
License data
Pregnancy
category
  • AU:B3
Routes of
administration		By mouth,intravenous,rectal suppository
ATC code
Legal status
Legal status
Pharmacokineticdata
BioavailabilityComplete absorption, following first-pass metabolism systemic availability 75% (range 52 to 75%)
Protein binding30 to 38%
MetabolismLiver
Eliminationhalf-life0.5 to 3 hours
ExcretionKidneyandBile duct
Identifiers
  • 3'-deoxy-3'-azido-thymidine
    1-[(2R,4S,5S)-4-Azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione[5]
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.152.492Edit this at Wikidata
Chemical and physical data
FormulaC10H13N5O4
Molar mass267.245g·mol−1
3D model (JSmol)
  • O=C1NC(C(C)=CN1[C@@H]2O[C@H](CO)[C@@H](N=[N+]=[N-])C2)=O
  • InChI=1S/C10H13N5O4/c1-5-3-15(10(18)12-9(5)17)8-2-6(13-14-11)7(4-16)19-8/h3,6-8,16H,2,4H2,1H3,(H,12,17,18)/t6-,7+,8+/m0/s1checkY
  • Key:HBOMLICNUCNMMY-XLPZGREQSA-NcheckY
☒NcheckY(what is this?)(verify)

Common side effects include headaches, fever, and nausea.[6]Serious side effects includeliver problems,muscle damage,andhigh blood lactate levels.[6]It is commonly used inpregnancyand appears to be safe for the fetus.[6]ZDV is of thenucleoside analog reverse-transcriptase inhibitor(NRTI) class.[6]It works by inhibiting theenzymereverse transcriptasethat HIV uses to make DNA and therefore decreases replication of the virus.[6]

Zidovudine was first described in 1964.[7]It was resynthesized from a public-domain formula byBurroughs Wellcome.[8]It was approved in the United States in 1987 and was the first treatment for HIV.[6][9]It is on theWorld Health Organization's List of Essential Medicines.[10][11]It is available as ageneric medication.[6]

Medical uses

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HIV treatment

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AZT was usually dosed twice a day in combination with other antiretroviral therapies. This approach is referred to as Highly Active Antiretroviral Therapy (HAART) and is used to prevent the likelihood of HIV resistance.[12][13]As of 2019, the standard is a three-drug once-daily oral treatment that can include AZT.[14]

HIV prevention

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AZT has been used forpost-exposure prophylaxis(PEP) in combination with another antiretroviral drug calledlamivudine.Together they work to substantially reduce the risk of HIV infection following the first single exposure to the virus.[15]More recently, AZT has been replaced by other antiretrovirals such astenofovirto provide PEP.[16] Before tenofovir, a principal part of theclinical pathwayfor both pre-exposure prophylaxis and post-exposure treatment ofmother-to-child transmissionof HIV during pregnancy, labor, and delivery and has been proven to be integral to uninfected siblings'perinatalandneonataldevelopment.[17][18]Without AZT, 10–15% of fetuses with HIV-infected mothers will themselves become infected.[19]AZT has been shown to reduce this risk to 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%.[20][21][22]

During 1994 to 1999, AZT 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.[23]In the U.S. at that time, the accepted standard of care for HIV-positive mothers was known as the 076 regimen and involved five daily doses of AZT from the second trimester onwards, as well as AZT intravenously administered during labour.[24]As this treatment was lengthy and expensive, it was deemed unfeasible in theGlobal 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.[25]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 the care and survival of impoverished subjects.[25]

Antibacterial properties

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Zidovudine also has antibacterial properties,[26]though not routinely used in clinical settings. It acts on bacteria with a mechanism of action still not fully explained. Promising results fromin vitroandin vivostudies showed the efficacy of AZT also against multidrug-resistantgram-negative bacteria(includingmcr-1carrying and metallo-β-lactamaseproducing isolates), especially in combination with other active agents (e.g.fosfomycin,colistin,tigecycline).[27][28]

Side effects

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Most common side effects include nausea, vomiting,acid reflux(heartburn), headache, cosmetic reduction in abdominal body fat, trouble sleeping, and loss of appetite. Less common side effects include faint discoloration of fingernails and toenails, mood elevation, occasional tingling or transient numbness of the hands or feet, and minor skin discoloration. Allergic reactions are rare.[29]

Early long-term higher-dose therapy with AZT was initially associated with side effects that sometimes limited therapy, includinganemia,neutropenia,hepatotoxicity,cardiomyopathy,andmyopathy.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 ofmitochondrial DNA,sensitivity of the γ-DNA polymerase in some cellmitochondria,[30]the depletion ofthymidine triphosphate,oxidative stress,reduction of intracellularL-carnitineorapoptosisof the muscle cells.[31]Anemia due to AZT was successfully treated usingerythropoetinto stimulatered blood cellproduction.[32][33]Drugs that inhibithepaticglucuronidation,such asindomethacin,nordazepam,acetylsalicylic acid(aspirin) andtrimethoprimdecreased the elimination rate and increased the therapeutic strength of the medication.[34]Today, side effects are much less common with the use of lower doses of AZT.[35] According to IARC, there is sufficient evidence in experimental animals for thecarcinogenicityof zidovudine; it is possibly carcinogenic to humans (Group 2B).[36]In 2009, the State of California added zidovudine to its list of chemicals "known to the state of California to cause cancer and other reproductive harm."[37]

Viral resistance

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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 progression of the disease. Prolonged AZT treatment can lead to HIV developing resistance to AZT bymutationof itsreverse transcriptase.[38][39]To slow the development of resistance, physicians generally recommend that AZT be given in combination with anotherreverse-transcriptase inhibitorand an antiretroviral from another group, such as aprotease inhibitor,non-nucleoside reverse-transcriptase inhibitor,orintegrase inhibitor;this type of therapy is known asHAART(Highly Active Anti Retroviral Therapy).

Mechanism of action

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AZT in oral, injectable, and suppository form

AZT is athymidineanalogue. AZT works by selectively inhibiting HIV'sreverse transcriptase,theenzymethat the virus uses to make aDNAcopy of itsRNA.Reverse transcription is necessary for production of HIV's double-stranded DNA, which would be subsequently integrated into the genetic material of the infectedcell(where it is called aprovirus).[40][41][42]

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.[43]

At very high doses, AZT's triphosphate form may also inhibitDNA polymeraseused by human cells to undergocell division,but regardless of dosage AZT has an approximately 100-fold greater affinity for HIV's reverse transcriptase.[44]The selectivity has been suggested to be due to the cell's ability to quickly repair its own DNA chain if it is disrupted by AZT during its formation, whereas the HIV virus lacks that ability.[45]Thus AZT inhibits HIV replication without affecting the function of uninfected cells.[40]At sufficiently high dosages, AZT begins to inhibit the cellular DNA polymerase used bymitochondriato replicate, accounting for its potentially toxic but reversible effects oncardiacandskeletal muscles,causingmyositis.[46][47][48][49][50]

Chemistry

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A crystal of AZT, viewed under polarized light

Enantiopure AZT crystallizes in themonoclinicspace group P21.The primary intermolecular bonding motif is a hydrogen bonded dimeric ring formed from two N-H...O interactions.[51][52]

History

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Initial cancer research

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In the 1960s, the theory that mostcancerswere caused by environmentalretrovirusesgained clinical support and funding. It had recently become known, due to the work of Nobel laureatesHoward TeminandDavid Baltimore,[53]that nearly all avian cancers were caused by bird retroviruses, but corresponding human retroviruses had 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 laureatesGeorge H. HitchingsandGertrude Elion,leading to the development of the antitumor agent6-mercaptopurine.[54]

Richard E. Beltz first synthesized AZT in 1961, but did not publish his research.[55][56]Jerome Horwitzof the Barbara Ann Karmanos Cancer Institute andWayne State University School of Medicinesynthesized AZT in 1964 under aUSNational Institutes of Health(NIH)grant.[57][58][59]Development was shelved after it proved biologically inert in mice.[57][60]In 1974, Wolfram Ostertag of theMax Planck Institute for Experimental MedicineinGöttingen,Germany, reported that AZT specifically targetedFriend virus(strain ofmurine leukemia virus).[61]

This report attracted little interest from other researchers as the Friend leukemia virus is a retrovirus, and at the time, there were no known human diseases caused by retroviruses.[62]

HIV/AIDS research

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In 1983, researchers at the Institut Pasteur in Paris identified the retrovirus now known as the Human Immunodeficiency Virus (HIV) as the cause of acquired immunodeficiency syndrome (AIDS) in humans.[63][64]Shortly thereafter,Samuel Broder,Hiroaki Mitsuya,andRobert Yarchoanof the United StatesNational Cancer Institute(NCI) initiated a program to develop therapies for HIV/AIDS.[65]Using a line ofCD4+T cellsthat they had made, they developed an assay to screen drugs for their ability to protect CD4+T cells from being killed by HIV. In order to expedite the process of discovering a drug, the NCI researchers actively sought collaborations with pharmaceutical companies having access to libraries of compounds with potential antiviral activity.[40]This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells.

In June 1984, Burroughs-Wellcome virologist Marty St. Clair set up a program to discover drugs with the potential to inhibit HIV replication. Burroughs-Wellcome had expertise in nucleoside analogs and viral diseases, led by researchers includingGeorge Hitchings,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 enzymereverse transcriptase.Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. Secondary testing was performed in mouse cells infected with the retroviruses Friend virus or Harvey sarcoma virus, as the Wellcome group did not have a viable in-house HIV antiviral assay in place at that time, and these other retroviruses were believed to represent reasonable surrogates. AZT proved to be a remarkably potent inhibitor of both Friend virus and Harvey sarcoma virus, and a search of the company's records showed that it had demonstrated low toxicity when tested for its antibacterial activity in rats many years earlier. Based in part on these results, AZT was selected by nucleoside chemist Janet Rideout as one of 11 compounds to send to the NCI for testing in that organization's HIV antiviral assay.[62]

In February 1985, the NCI scientists found that AZT had potent efficacy in vitro.[40][57] Several months later, a phase 1clinical trialof AZT at the NCI was initiated at the NCI and Duke University.[41][46][66] 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 theirCD4counts, 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.

Patent filed and FDA approval

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A flaweddouble-blind,placebo-controlledrandomized trialof AZT was subsequently conducted by Burroughs-Wellcome and suggested that AZT safely prolongs the lives of people with HIV. However, it was quickly unblinded and several more in the drug receiving group later perished.[67][68]Burroughs-Wellcome filed for a patent for AZT in 1985. The Anti-Infective Advisory Committee to United StatesFood and Drug Administration(FDA) voted ten to one to recommend the approval of AZT.[69]The FDA approved the drug (via the then-newFDA 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.[70]The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months.

AZT was subsequently approved unanimously for infants and children in 1990.[71]AZT was initially administered in significantly higher dosages than today, typically 400 mg every four hours, day and night, compared to modern dosage of 300 mg twice daily.[72]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 transientanemiaand malaise.

Society and culture

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See also:Cost of HIV treatment

Until 1991, 80% of the $420 million allocated to the National Institute of Health's AIDS Clinical Trials Group, went toward studies of AZT. Aside from two similarly designed chemotherapies, ddI and ddC, from approval of the drug until 1993, no other drugs against AIDS were approved, leading to criticism that research preoccupation with AZT and its close relatives, and the massive diverting of funds to such, had delayed the development of more efficacious drugs.[8]

In 1991, the advocacy groupPublic Citizenfiled 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 WellcomeCo. filed a lawsuit against the two companies. TheUnited States Court of Appeals for the Federal Circuitruled 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. This suit was appealed up to the Supreme Court of the US, but in 1996 the Court declined to formally review it.[73]The case,Burroughs Wellcome Co. v. Barr Laboratories,was a landmark in US law of inventorship.[74]

In 2002, another lawsuit was filed challenging the patent by theAIDS Healthcare Foundation,which also filed an antitrust case againstGSK.[75]The patent case was dismissed in 2003 and AHF filed a new case challenging the patent.[75]

GSK's patents on AZT expired in 2005, and in September 2005, the FDA approved threegenericversions.[76]

References

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  1. ^"FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)".nctr-crs.fda.gov.FDA.RetrievedOctober 22,2023.
  2. ^"Retrovir 100mg Capsules – Summary of Product Characteristics (SmPC)".(emc).December 14, 2018.RetrievedJanuary 23,2021.
  3. ^"Retrovir – zidovudine capsule Retrovir – zidovudine solution Retrovir – zidovudine injection, solution".DailyMed.RetrievedJanuary 23,2021.
  4. ^"Active substance: Zidovudine"(PDF).European Medicines Agency.November 30, 2017.
  5. ^"Zidovudine".PubChem Public Chemical Database.NCBI.Archivedfrom the original on October 25, 2012.RetrievedApril 10,2011.
  6. ^abcdefghijk"Zidovudine".The American Society of Health-System Pharmacists.Archivedfrom the original on December 21, 2016.RetrievedNovember 28,2016.
  7. ^Fischer J, Ganellin CR (2006).Analogue-based Drug Discovery.John Wiley & Sons. p. 505.ISBN9783527607495.Archivedfrom the original on September 8, 2017.
  8. ^abLinda Marsa, 'Toxic Hope',Los Angeles Times,20 June 1993
  9. ^Reeves JD, Derdeyn CA (2007).Entry Inhibitors in HIV Therapy.Springer Science & Business Media. p. 179.ISBN9783764377830.
  10. ^World Health Organization(2019).World Health Organization model list of essential medicines: 21st list.Geneva: World Health Organization.hdl:10665/325771.WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  11. ^World Health Organization(2021).World Health Organization model list of essential medicines: 22nd list.Geneva: World Health Organization.hdl:10665/345533.WHO/MHP/HPS/EML/2021.02.
  12. ^De Clercq E (January 1994). "HIV resistance to reverse transcriptase inhibitors".Biochemical Pharmacology.47(2): 155–169.doi:10.1016/0006-2952(94)90001-9.PMID7508227.
  13. ^Yarchoan R, Mitsuya H, Broder S (October 1988). "AIDS therapies".Scientific American.259(4): 110–119.Bibcode:1988SciAm.259d.110Y.doi:10.1038/scientificamerican1088-110.PMID3072667.
  14. ^Phanuphak N, Gulick RM (January 2020). "HIV treatment and prevention 2019: current standards of care".Current Opinion in HIV and AIDS.15(1): 4–12.doi:10.1097/COH.0000000000000588.PMID31658110.S2CID204952772.
  15. ^Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS (September 2005)."Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis"(PDF).MMWR Recomm Rep.54(RR-9): 1–17.PMID16195697.
  16. ^"UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011)".Archivedfrom the original on April 8, 2014.RetrievedApril 7,2014.
  17. ^"Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health"(PDF).AIDSinfo.U.S. Department of Health and Human Services. November 17, 2005. Archived fromthe original(PDF)on April 22, 2006.RetrievedMarch 29,2006.
  18. ^Briand N, Lallemant M, Jourdain G, Techapalokul S, Tunthanathip P, Suphanich S, et al. (April 2007)."Haematological safety of perinatal zidovudine in pregnant HIV-1-infected women in Thailand: secondary analysis of a randomized trial".PLOS Clinical Trials.2(4): e11.doi:10.1371/journal.pctr.0020011.PMC1863515.PMID17476315.
  19. ^Science Codex.
  20. ^CIDRZ. Prevention of AIDS Transmission (PMTCT)."Prevention of mother-to-child HIV transmission (PMTCT) | CIDRZ".Archived fromthe originalon February 14, 2012.RetrievedMarch 31,2012.
  21. ^Transmission of HIV from infants"Transmission of HIV from infants to women who breastfeed them".Aids Perspective.July 1, 2012. Archived fromthe originalon December 3, 2013.RetrievedAugust 3,2012.
  22. ^Connor E, Sperling R, Gelber R, Kiselev P, Scott G, O'Sullivan M, VanDyke R, Bey M, Shearer W, Jacobson R (1994)."Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group".N Engl J Med.331(18): 1173–80.doi:10.1056/NEJM199411033311801.PMID7935654.S2CID13457499.
  23. ^Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, et al. (July 2006)."The survival benefits of AIDS treatment in the United States".The Journal of Infectious Diseases.194(1): 11–19.doi:10.1086/505147.PMID16741877.
  24. ^Morris K (February 1998). "Short course of AZT halves HIV-1 perinatal transmission".Lancet.351(9103): 651.doi:10.1016/S0140-6736(05)78436-1.PMID9500334.S2CID8293828.
  25. ^abCrane J (December 2010). "Adverse events and placebo effects: African scientists, HIV, and ethics in the 'global health sciences'".Social Studies of Science.40(6): 843–870.doi:10.1177/0306312710371145.PMID21553555.S2CID26027925.
  26. ^DeSarno AE, Parcell BJ, Coote PJ (December 2020)."Repurposing the anti-viral drug zidovudine (AZT) in combination with meropenem as an effective treatment for infections with multi-drug resistant, carbapenemase-producing strains of Klebsiella pneumoniae".Pathogens and Disease.78(9): ftaa063.doi:10.1093/femspd/ftaa063.hdl:10023/24137.PMID33053176.
  27. ^Zhou YF, Liu P, Dai SH, Sun J, Liu YH, Liao XP (December 2020)."Activity of Tigecycline or Colistin in Combination with Zidovudine against Escherichia coli Harboringtet(X) andmcr-1".Antimicrobial Agents and Chemotherapy.65(1).doi:10.1128/AAC.01172-20.PMC7927862.PMID33020156.
  28. ^Antonello RM, Di Bella S, Betts J, La Ragione R, Bressan R, Principe L, et al. (July 2021). "Zidovudine in synergistic combination with fosfomycin: an in vitro and in vivo evaluation against multidrug-resistant Enterobacterales".International Journal of Antimicrobial Agents.58(1): 106362.doi:10.1016/j.ijantimicag.2021.106362.PMID34010710.S2CID234791392.
  29. ^"zidovudine, Retrovir".Medicinenet. August 12, 2010.Archivedfrom the original on December 20, 2010.RetrievedDecember 14,2010.
  30. ^Sun R, Eriksson S, Wang L (June 2010). "Identification and characterization of mitochondrial factors modulating thymidine kinase 2 activity".Nucleosides, Nucleotides & Nucleic Acids.29(4–6): 382–385.doi:10.1080/15257771003741018.PMID20544523.S2CID13539181.
  31. ^Scruggs ER, Dirks Naylor AJ (2008)."Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy".Pharmacology.82(2): 83–88.doi:10.1159/000134943.PMID18504416.S2CID2044833.
  32. ^Fisher JW (December 1997). "Erythropoietin: physiologic and pharmacologic aspects".Proceedings of the Society for Experimental Biology and Medicine.216(3): 358–369.doi:10.3181/00379727-216-44183.PMID9402140.S2CID26177904.
  33. ^Fisher JW (January 2003). "Erythropoietin: physiology and pharmacology update".Experimental Biology and Medicine.228(1): 1–14.doi:10.1177/153537020322800101.PMID12524467.S2CID2829677.
  34. ^"ZIDOVUDINE (AZT) – ORAL (Retrovir) side effects, medical uses, and drug interactions".MedicineNet.Archivedfrom the original on June 30, 2005.RetrievedJanuary 9,2006.
  35. ^Side Effects. NAM Aidsmap."Zidovudine (AZT,Retrovir) ".Archivedfrom the original on December 26, 2011.RetrievedMarch 28,2012.
  36. ^"Summary of Data Reported and Evaluation".2000.Archivedfrom the original on January 4, 2012.RetrievedAugust 11,2012.
  37. ^"State of California Environmental Protection Agency Office of Environmental Hazard Assessment Safe Drinking Water and Toxic Enforcement Act of 1986 Chemicals Known to the State to Cause Cancer or Reproductive Toxicity July 29, 1011"(PDF).July 29, 2011.RetrievedNovember 14,2022.
  38. ^Richman DD (May 1990). "Susceptibility to nucleoside analogues of zidovudine-resistant isolates of human immunodeficiency virus".The American Journal of Medicine.88(5B): 8S–10S.doi:10.1016/0002-9343(90)90414-9.PMID2186629.
  39. ^Wainberg MA, Brenner BG, Turner D (May 2005)."Changing patterns in the selection of viral mutations among patients receiving nucleoside and nucleotide drug combinations directed against human immunodeficiency virus type 1 reverse transcriptase".Antimicrobial Agents and Chemotherapy.49(5): 1671–1678.doi:10.1128/AAC.49.5.1671-1678.2005.PMC1087622.PMID15855480.
  40. ^abcdMitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, et al. (October 1985)."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".Proceedings of the National Academy of Sciences of the United States of America.82(20): 7096–7100.Bibcode:1985PNAS...82.7096M.doi:10.1073/pnas.82.20.7096.PMC391317.PMID2413459.
  41. ^abYarchoan R, Klecker R, Weinhold K, Markham P, Lyerly H, Durack D, Gelmann E, Lehrman S, Blum R, Barry D (1986). "Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex".Lancet.1(8481): 575–80.doi:10.1016/S0140-6736(86)92808-4.PMID2869302.S2CID37985276.
  42. ^Mitsuya H, Yarchoan R, Broder S (1990)."Molecular targets for AIDS therapy".Science(Submitted manuscript).249(4976): 1533–44.Bibcode:1990Sci...249.1533M.doi:10.1126/science.1699273.PMID1699273.
  43. ^Quan Y, Rong L, Liang C, Wainberg MA (August 1999)."Reverse transcriptase inhibitors can selectively block the synthesis of differently sized viral DNA transcripts in cells acutely infected with human immunodeficiency virus type 1".Journal of Virology.73(8): 6700–6707.doi:10.1128/JVI.73.8.6700-6707.1999.PMC112754.PMID10400767.
  44. ^Furman PA, Fyfe JA, St Clair MH, Weinhold K, Rideout JL, Freeman GA, et al. (November 1986)."Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase".Proceedings of the National Academy of Sciences of the United States of America.83(21): 8333–8337.Bibcode:1986PNAS...83.8333F.doi:10.1073/pnas.83.21.8333.PMC386922.PMID2430286.
  45. ^Induction of Endogenous Virus and of Thymidline Kinase."Induction of Endogenous Virus and of Thymidline Kinase by Bromodeoxyuridine in Cell Cultures Transformed by Friend Virus"(PDF).Archived(PDF)from the original on September 24, 2015.RetrievedNovember 14,2022.
  46. ^abYarchoan R, Mitsuya H, Myers C, Broder S (1989). "Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides".N Engl J Med.321(11): 726–38.doi:10.1056/NEJM198909143211106.PMID2671731.
  47. ^Collins ML, Sondel N, Cesar D, Hellerstein MK (September 2004)."Effect of nucleoside reverse transcriptase inhibitors on mitochondrial DNA synthesis in rats and humans".Journal of Acquired Immune Deficiency Syndromes.37(1): 1132–1139.doi:10.1097/01.qai.0000131585.77530.64.PMID15319672.S2CID20020419.
  48. ^Parker WB, White EL, Shaddix SC, Ross LJ, Buckheit RW, Germany JM, et al. (January 1991)."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".The Journal of Biological Chemistry.266(3): 1754–1762.doi:10.1016/S0021-9258(18)52360-7.PMID1703154.
  49. ^Rang HP, Dale MM, Ritter JM (1995).Pharmacology(3rd ed.). Pearson Professional Ltd.ISBN978-0-443-05974-2.
  50. ^Balzarini J, Naesens L, Aquaro S, Knispel T, Perno C, De Clercq E, Meier C (December 1999)."Intracellular metabolism of CycloSaligenyl 3'-azido-2', 3'-dideoxythymidine monophosphate, a prodrug of 3'-azido-2', 3'-dideoxythymidine (zidovudine)".Molecular Pharmacology.56(6): 1354–1361.doi:10.1124/mol.56.6.1354.PMID10570065.S2CID25678740.Archivedfrom the original on September 21, 2007.
  51. ^Dyer I, Low JN, Tollin P, Wilson HR, Howie RA (April 1988). "Structure of 3'-azido-3'-deoxythymidine, AZT".Acta Crystallogr C.44(4): 767–9.Bibcode:1988AcCrC..44..767D.doi:10.1107/S0108270188000368.PMID3271074.
  52. ^Camerman A, Mastropaolo D, Camerman N (1987)."Azidothymidine: crystal structure and possible functional role of the azido group".Proc Natl Acad Sci USA.84(23): 8239–8242.Bibcode:1987PNAS...84.8239C.doi:10.1073/pnas.84.23.8239.PMC299517.PMID2446321.
  53. ^"The Nobel Prize in Physiology or Medicine 1975".NobelPrize.org.Archived fromthe originalon January 3, 2017.
  54. ^"The Purine Path To Chemotherapy"(PDF).Archived fromthe original(PDF)on August 8, 2017.
  55. ^Marsa L (June 20, 1993)."Toxic Hope: Widely Embraced, the AIDS Drug is now under Heavy Fire".Los Angeles Times.
  56. ^Brinck A."Inventing AZT"(PDF).
  57. ^abcBroder S (January 2010)."The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic".Antiviral Research.85(1): 1–18.doi:10.1016/j.antiviral.2009.10.002.PMC2815149.PMID20018391.
  58. ^Horwitz JP, Chua J, Noel MJ (1964). "The monomesylates of 1-(2-deoxy-bd-lyxofuranosyl) thymines".Org. Chem. Ser. Monogr.29(7): 2076–9.doi:10.1021/jo01030a546.
  59. ^Detours V; Henry D (writers/directors) (2002).I am alive today (history of an AIDS drug)(Film). ADR Productions/Good & Bad News.
  60. ^"A Failure Led to Drug Against AIDS".The New York Times.September 20, 1986.Archivedfrom the original on August 16, 2009.RetrievedJune 30,2010.
  61. ^Ostertag W, Roesler G, Krieg CJ, Kind J, Cole T, Crozier T, et al. (December 1974)."Induction of endogenous virus and of thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus".Proceedings of the National Academy of Sciences of the United States of America.71(12): 4980–4985.Bibcode:1974PNAS...71.4980O.doi:10.1073/pnas.71.12.4980.PMC434023.PMID4531031.
  62. ^abSneader W (2006).Drug Discovery – A History.Wiley. pp.260–261.ISBN978-0-471-89980-8.
  63. ^Weiss RA (May 1993). "How does HIV cause AIDS?".Science.260(5112): 1273–1279.Bibcode:1993Sci...260.1273W.doi:10.1126/science.8493571.PMID8493571.
  64. ^Douek DC, Roederer M, Koup RA (2009)."Emerging concepts in the immunopathogenesis of AIDS".Annual Review of Medicine.60:471–484.doi:10.1146/annurev.med.60.041807.123549.PMC2716400.PMID18947296.
  65. ^NIH Clinical Center's 50th Anniversary."Clinical Center 50th Anniversary Celebration"(PDF).Archived fromthe original(PDF)on June 19, 2013.RetrievedApril 18,2012.
  66. ^Yarchoan R, Klecker RW, Weinhold KJ, Markham PD, Lyerly HK, Durack DT, Gelmann E, Lehrman SN, Blum RM, Barry DW (1986). "Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex".Lancet.1(8481): 575–80.doi:10.1016/s0140-6736(86)92808-4.PMID2869302.S2CID37985276.
  67. ^"Did Controversial AZT Treatment Kill More Patients than AIDS in '80s, '90s?".September 21, 2021.
  68. ^Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, et al. (July 1987). "The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial".The New England Journal of Medicine.317(4): 185–191.doi:10.1056/NEJM198707233170401.PMID3299089.
  69. ^Brook I (September 1987). "Approval of zidovudine (AZT) for acquired immunodeficiency syndrome. A challenge to the medical and pharmaceutical communities".JAMA.258(11): 1517.doi:10.1001/jama.1987.03400110099035.PMID3306004.
  70. ^Cimons M (March 21, 1987). "U.S. Approves Sale of AZT to AIDS Patients".Los Angeles Times.p. 1.
  71. ^AZT Approved for AIDS Children."HEALTH: AZT Approved for AIDS Children".Los Angeles Times.May 3, 1990.Archivedfrom the original on May 4, 2015.RetrievedMarch 30,2012– via From Times Wire Services.
  72. ^"Zidovudine (AZT) | Johns Hopkins ABX Guide".
  73. ^Greenhouse L (January 17, 1996)."Supreme Court Roundup;Justices Reject Challenge Of Patent for AIDS Drug".The New York Times.Archivedfrom the original on November 17, 2016.
  74. ^Armstrong M, Murphy Jr GM (April 26, 2012)."Inventorship and ownership considerations and pitfalls with collaborative research: patent highlight".ACS Medicinal Chemistry Letters.3(5): 349–51.doi:10.1021/ml300084e.PMC4025834.PMID24900477.
  75. ^abMeland M (May 3, 2004)."Judge Denies Request To Dismiss Patent Challenge Vs. Glaxo's AZT – Law360".Law360.Archivedfrom the original on November 17, 2016.
  76. ^"HIV/AIDS History of Approvals – HIV/AIDS Historical Time Line 2000 – 2010".U.S.Food and Drug Administration(FDA). August 8, 2014.Archivedfrom the original on October 23, 2016.
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