Zidovudine: Difference between revisions
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{{Short description|Antiretroviral medication}} |
{{Short description|Antiretroviral medication}} |
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{{Redirect|AZT}} |
{{Redirect|AZT}} |
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| legal_UK = POM |
| legal_UK = POM |
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| legal_UK_comment = <ref>{{cite web | title=Retrovir 100mg Capsules |
| legal_UK_comment = <ref>{{cite web | title=Retrovir 100mg Capsules – Summary of Product Characteristics (SmPC) | website=(emc) | date=December 14, 2018 | url=https://www.medicines.org.uk/emc/product/6811/smpc | access-date=January 23, 2021}}</ref> |
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| legal_US = Rx-only |
| legal_US = Rx-only |
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| legal_US_comment = <ref>{{cite web | title=Retrovir |
| legal_US_comment = <ref>{{cite web | title=Retrovir – zidovudine capsule Retrovir – zidovudine solution Retrovir – zidovudine injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6df09f15-b102-431c-adde-d7aeef6f5d84 | access-date=January 23, 2021}}</ref> |
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| legal_EU = Rx-only |
| legal_EU = Rx-only |
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| legal_EU_comment = <ref>https://www.ema.europa.eu/en/documents/psusa/zidovudine-list-nationally-authorised-medicinal-products-psusa/00003143/201703_en.pdf |
| legal_EU_comment = <ref>{{cite web | title = Active substance: Zidovudine | url = https://www.ema.europa.eu/en/documents/psusa/zidovudine-list-nationally-authorised-medicinal-products-psusa/00003143/201703_en.pdf | work = European Medicines Agency | date = November 30, 2017 }}</ref> |
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<!-- Definition and uses --> |
<!-- Definition and uses --> |
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'''Zidovudine''' ('''ZDV'''), also known as '''azidothymidine''' ('''AZT'''), |
'''Zidovudine''' ('''ZDV'''), also known as '''azidothymidine''' ('''AZT'''), was the first [[antiretroviral medication]] used to prevent and treat [[HIV/AIDS]]. It is generally recommended for use in combination with other antiretrovirals.<ref name=AHFS2016/> It may be used to prevent [[vertical transmission|mother-to-child spread during birth]] or after a [[needlestick injury]] or other potential exposure.<ref name=AHFS2016/> It is sold both by itself and together as [[lamivudine/zidovudine]] and [[abacavir/lamivudine/zidovudine]].<ref name=AHFS2016/> It can be used by mouth or by slow [[intravenous|injection into a vein]].<ref name=AHFS2016>{{cite web|title=Zidovudine|url=https://www.drugs.com/monograph/zidovudine.html|publisher=The American Society of Health-System Pharmacists|access-date=November 28, 2016|url-status=live|archive-url=https://web.archive.org/web/20161221005642/https://www.drugs.com/monograph/zidovudine.html|archive-date=December 21, 2016}}</ref> |
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<!-- Side effects and mechanism --> |
<!-- Side effects and mechanism --> |
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Common side effects include headaches, fever, and nausea.<ref name=AHFS2016/> Serious side effects include [[liver problems]], [[myopathy|muscle damage]], and [[lactic acidosis|high blood lactate levels]].<ref name=AHFS2016/> It is commonly used in [[pregnancy]] and appears to be safe for the |
Common side effects include headaches, fever, and nausea.<ref name=AHFS2016/> Serious side effects include [[liver problems]], [[myopathy|muscle damage]], and [[lactic acidosis|high blood lactate levels]].<ref name=AHFS2016/> It is commonly used in [[pregnancy]] and appears to be safe for the fetus.<ref name=AHFS2016/> ZDV is of the [[nucleoside analog reverse-transcriptase inhibitor]] (NRTI) class.<ref name=AHFS2016/> It works by inhibiting the [[enzyme]] [[reverse transcriptase]] that HIV uses to make DNA and therefore decreases replication of the virus.<ref name=AHFS2016/> |
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<!-- History and culture --> |
<!-- History and culture --> |
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Zidovudine was first described in 1964.<ref>{{cite book| |
Zidovudine was first described in 1964.<ref>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=505|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA505|url-status=live|archive-url=https://web.archive.org/web/20170908213935/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA505|archive-date=September 8, 2017}}</ref> It was resynthesized from a public-domain formula by [[Burroughs Wellcome]].<ref name="latimes.com">[https://www.latimes.com/archives/la-xpm-1993-06-20-tm-10183-story.html Linda Marsa, 'Toxic Hope', ''Los Angeles Times'', 20 June 1993]</ref> It was approved in the United States in 1987 and was the first treatment for HIV.<ref name=AHFS2016/><ref>{{cite book | vauthors = Reeves JD, Derdeyn CA |title=Entry Inhibitors in HIV Therapy |date=2007 |publisher=Springer Science & Business Media |isbn=9783764377830 |page=179 |url=https://books.google.com/books?id=zNCJmuWgHAoC&pg=PA179 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2016/> |
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==Medical uses== |
==Medical uses== |
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===HIV treatment=== |
===HIV treatment=== |
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AZT |
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.<ref>{{cite journal | vauthors = De Clercq E | title = HIV resistance to reverse transcriptase inhibitors | journal = Biochemical Pharmacology | volume = 47 | issue = 2 | pages = 155–169 | date = January 1994 | pmid = 7508227 | doi = 10.1016/0006-2952(94)90001-9 }}</ref><ref>{{cite journal | vauthors = Yarchoan R, Mitsuya H, Broder S | title = AIDS therapies | journal = Scientific American | volume = 259 | issue = 4 | pages = 110–119 | date = October 1988 | pmid = 3072667 | doi = 10.1038/scientificamerican1088-110 | bibcode = 1988SciAm.259d.110Y }}</ref> As of 2019, the standard is a three-drug once-daily oral treatment that can include AZT.<ref>{{cite journal | vauthors = Phanuphak N, Gulick RM | title = HIV treatment and prevention 2019: current standards of care | journal = Current Opinion in HIV and AIDS | volume = 15 | issue = 1 | pages = 4–12 | date = January 2020 | pmid = 31658110 | doi = 10.1097/COH.0000000000000588 | s2cid = 204952772}}</ref> |
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===HIV prevention=== |
===HIV prevention=== |
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AZT has been used for [[post-exposure prophylaxis]] (PEP) in combination with another antiretroviral drug called [[lamivudine]]. Together they work to substantially reduce the risk of HIV infection following the first single exposure to the virus.<ref>{{cite journal |vauthors=Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS |title=Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis |journal=MMWR Recomm Rep |volume=54 |issue=RR-9 |pages=1–17 |date=September 2005 |pmid=16195697 |url=https://www.cdc.gov/mmwr/PDF/rr/rr5409.pdf}}</ref> More recently, AZT has been replaced by other antiretrovirals such as [[Tenofovir disoproxil|tenofovir]] to provide PEP.<ref>{{cite web | url = http://www.bhiva.org/PEPSE.aspx | title = UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011) | access-date = April 7, 2014 | url-status = live | archive-url = https://web.archive.org/web/20140408214056/http://www.bhiva.org/PEPSE.aspx | archive-date = April 8, 2014 |
AZT has been used for [[post-exposure prophylaxis]] (PEP) in combination with another antiretroviral drug called [[lamivudine]]. Together they work to substantially reduce the risk of HIV infection following the first single exposure to the virus.<ref>{{cite journal |vauthors=Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS |title=Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis |journal=MMWR Recomm Rep |volume=54 |issue=RR-9 |pages=1–17 |date=September 2005 |pmid=16195697 |url=https://www.cdc.gov/mmwr/PDF/rr/rr5409.pdf}}</ref> More recently, AZT has been replaced by other antiretrovirals such as [[Tenofovir disoproxil|tenofovir]] to provide PEP.<ref>{{cite web | url = http://www.bhiva.org/PEPSE.aspx | title = UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011) | access-date = April 7, 2014 | url-status = live | archive-url = https://web.archive.org/web/20140408214056/http://www.bhiva.org/PEPSE.aspx | archive-date = April 8, 2014}}</ref> |
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⚫ | Before tenofovir, a principal part of the [[clinical pathway]] for both pre-exposure prophylaxis and post-exposure treatment of [[vertical transmission|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.<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 | date = November 17, 2005 | access-date = March 29, 2006 | url-status = dead | archive-url = https://web.archive.org/web/20060422113223/http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf | archive-date = April 22, 2006 | work = AIDSinfo | publisher = U.S. Department of Health and Human Services }}</ref><ref name="pmid17476315">{{cite journal | vauthors = Briand N, Lallemant M, Jourdain G, Techapalokul S, Tunthanathip P, Suphanich S, Chanpoo T, Traisathit P, McIntosh K, Le Coeur S | display-authors = 6 | title = Haematological safety of perinatal zidovudine in pregnant HIV-1-infected women in Thailand: secondary analysis of a randomized trial | journal = PLOS Clinical Trials | volume = 2 | issue = 4 | pages = e11 | date = April 2007 | pmid = 17476315 | pmc = 1863515 | doi = 10.1371/journal.pctr.0020011 | doi-access = free }}</ref> Without AZT, 10–15% of fetuses with HIV-infected mothers will themselves become infected.<ref>Science Codex.</ref> 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%.<ref>CIDRZ. Prevention of AIDS Transmission (PMTCT). {{cite web |url=http://www.cidrz.org/pmtct |title=Prevention of mother-to-child HIV transmission (PMTCT) | CIDRZ |access-date=March 31, 2012 |url-status=dead |archive-url=https://web.archive.org/web/20120214203337/http://www.cidrz.org/pmtct |archive-date=February 14, 2012 }}</ref><ref>Transmission of HIV from infants {{cite web |url=http://aidsperspective.net/blog/?p=868 |title=Transmission of HIV from infants to women who breastfeed them. | work = Aids Perspective | date = July 1, 2012 |access-date=August 3, 2012 |url-status=dead |archive-url=https://web.archive.org/web/20131203030636/http://aidsperspective.net/blog/?p=868 |archive-date=December 3, 2013 }}</ref><ref>{{cite journal |vauthors=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| s2cid=13457499 | doi-access=free }}</ref> |
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⚫ | 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.<ref name="pmid16741877">{{cite journal | vauthors = Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, Weinstein MC, Freedberg KA | display-authors = 6 | title = The survival benefits of AIDS treatment in the United States | journal = The Journal of Infectious Diseases | volume = 194 | issue = 1 | pages = 11–19 | date = July 2006 | pmid = 16741877 | doi = 10.1086/505147 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Morris K | title = Short course of AZT halves HIV-1 perinatal transmission | journal = Lancet | volume = 351 | issue = 9103 | pages = 651 | date = February 1998 | pmid = 9500334 | doi = 10.1016/S0140-6736(05)78436-1 | s2cid = 8293828 }}</ref> 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.<ref name="Crane, Johanna 2010">{{cite journal | vauthors = Crane J | title = Adverse events and placebo effects: African scientists, HIV, and ethics in the 'global health sciences' | journal = Social Studies of Science | volume = 40 | issue = 6 | pages = 843–870 | date = December 2010 | pmid = 21553555 | doi = 10.1177/0306312710371145 | s2cid = 26027925 }}</ref> 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.<ref name="Crane, Johanna 2010"/> |
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⚫ | |||
⚫ | 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.<ref name="pmid16741877">{{cite journal | |
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=== Antibacterial properties === |
=== Antibacterial properties === |
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Zidovudine also has antibacterial properties,<ref>{{ |
Zidovudine also has antibacterial properties,<ref>{{cite journal | vauthors = DeSarno AE, Parcell BJ, Coote PJ | title = 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 | journal = Pathogens and Disease | volume = 78 | issue = 9 | pages = ftaa063 | date = December 2020 | pmid = 33053176 | doi = 10.1093/femspd/ftaa063 | doi-access = free | hdl = 10023/24137 | hdl-access = free }}</ref> though not routinely used in clinical settings. It acts on bacteria with a mechanism of action still not fully explained. Promising results from ''[[in vitro]]'' and ''[[in vivo]]'' studies showed the efficacy of AZT also against multidrug-resistant [[gram-negative bacteria]] (including [[mcr-1]] carrying and metallo-[[β-lactamase]] producing isolates), especially in combination with other active agents (e.g. [[fosfomycin]], [[colistin]], [[tigecycline]]).<ref>{{cite journal | vauthors = Zhou YF, Liu P, Dai SH, Sun J, Liu YH, Liao XP | title = Activity of Tigecycline or Colistin in Combination with Zidovudine against Escherichia coli Harboring ''tet''(X) and ''mcr-1'' | journal = Antimicrobial Agents and Chemotherapy | volume = 65 | issue = 1 | date = December 2020 | pmid = 33020156 | pmc = 7927862 | doi = 10.1128/AAC.01172-20 }}</ref><ref>{{cite journal | vauthors = Antonello RM, Di Bella S, Betts J, La Ragione R, Bressan R, Principe L, Morabito S, Gigliucci F, Tozzoli R, Busetti M, Knezevich A, Furlanis L, Fontana F, Luzzaro F, Luzzati R, Lagatolla C | display-authors = 6 | title = Zidovudine in synergistic combination with fosfomycin: an in vitro and in vivo evaluation against multidrug-resistant Enterobacterales | journal = International Journal of Antimicrobial Agents | volume = 58 | issue = 1 | pages = 106362 | date = July 2021 | pmid = 34010710 | doi = 10.1016/j.ijantimicag.2021.106362 | s2cid = 234791392 }}</ref> |
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==Side effects== |
==Side effects== |
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Most common side |
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.<ref>{{cite web|url=http://www.medicinenet.com/zidovudine_azt-oral/page2.htm|title=zidovudine, Retrovir|date=August 12, 2010|publisher=Medicinenet.com|access-date=December 14, 2010|url-status=live|archive-url=https://web.archive.org/web/20101220035237/http://www.medicinenet.com/zidovudine_azt-oral/page2.htm|archive-date=December 20, 2010}}</ref> |
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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]],<ref>{{ |
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]],<ref>{{cite journal | vauthors = Sun R, Eriksson S, Wang L | title = Identification and characterization of mitochondrial factors modulating thymidine kinase 2 activity | journal = Nucleosides, Nucleotides & Nucleic Acids | volume = 29 | issue = 4–6 | pages = 382–385 | date = June 2010 | pmid = 20544523 | doi = 10.1080/15257771003741018 | s2cid = 13539181 }}</ref> the depletion of [[thymidine triphosphate]], [[oxidative stress]], reduction of intracellular <small>L</small>-[[carnitine]] or [[apoptosis]] of the muscle cells.<ref name="Scruggs">{{cite journal | vauthors = Scruggs ER, Dirks Naylor AJ | title = Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy | journal = Pharmacology | volume = 82 | issue = 2 | pages = 83–88 | year = 2008 | pmid = 18504416 | doi = 10.1159/000134943 | s2cid = 2044833 | doi-access = free }}</ref> Anemia due to AZT was successfully treated using [[Erythropoietin|erythropoetin]] to stimulate [[red blood cell]] production.<ref>{{cite journal | vauthors = Fisher JW | title = Erythropoietin: physiologic and pharmacologic aspects | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 216 | issue = 3 | pages = 358–369 | date = December 1997 | pmid = 9402140 | doi = 10.3181/00379727-216-44183 | s2cid = 26177904 }}</ref><ref>{{cite journal | vauthors = Fisher JW | title = Erythropoietin: physiology and pharmacology update | journal = Experimental Biology and Medicine | volume = 228 | issue = 1 | pages = 1–14 | date = January 2003 | pmid = 12524467 | doi = 10.1177/153537020322800101 | s2cid = 2829677 }}</ref> Drugs that inhibit [[liver|hepatic]] [[glucuronidation]], such as [[indomethacin]], [[nordazepam]], [[acetylsalicylic acid]] (aspirin) and [[trimethoprim]] decreased the elimination rate and increased the therapeutic strength of the medication.<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 | access-date=January 9, 2006 | publisher=MedicineNet | url-status=live | archive-url=https://web.archive.org/web/20050630080343/http://www.medicinenet.com/zidovudine_azt-oral/article.htm | archive-date=June 30, 2005 }}</ref> Today, side effects are much less common with the use of lower doses of AZT.<ref>Side Effects. NAM Aidsmap. {{cite web |url=http://www.aidsmap.com/Side-effects/page/1730907/ |title=Zidovudine (AZT, ''Retrovir'') |access-date=March 28, 2012 |url-status=live |archive-url=https://web.archive.org/web/20111226015716/http://www.aidsmap.com/Side-effects/page/1730907/ |archive-date=December 26, 2011 }}</ref> |
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According to IARC, there is sufficient evidence in experimental animals for the [[carcinogen]]icity of zidovudine; it is possibly carcinogenic to humans ([[Group 2B carcinogen|Group 2B]]).<ref>{{cite web|url=http://www.inchem.org/documents/iarc/vol76/zidovudine.html|title=Summary of Data Reported and Evaluation|year=2000|access-date=August 11, 2012|url-status=live|archive-url=https://web.archive.org/web/20120104162609/http://inchem.org/documents/iarc/vol76/zidovudine.html|archive-date=January 4, 2012}}</ref> |
According to IARC, there is sufficient evidence in experimental animals for the [[carcinogen]]icity of zidovudine; it is possibly carcinogenic to humans ([[Group 2B carcinogen|Group 2B]]).<ref>{{cite web|url=http://www.inchem.org/documents/iarc/vol76/zidovudine.html|title=Summary of Data Reported and Evaluation|year=2000|access-date=August 11, 2012|url-status=live|archive-url=https://web.archive.org/web/20120104162609/http://inchem.org/documents/iarc/vol76/zidovudine.html|archive-date=January 4, 2012}}</ref> 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."<ref>{{cite web |title=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 |url=https://tig.org.za/AZT_OEHHA_listing/6.AZT_listed_as_a_chemical_known_to_the_state_of_California_to_cause_cancer_or_reproductive_toxicity_18_December_2009.pdf|access-date=November 14, 2022|date=July 29, 2011}}</ref> |
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===Viral resistance=== |
===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 by [[mutation]] of its [[reverse transcriptase]].<ref>{{ |
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 by [[mutation]] of its [[reverse transcriptase]].<ref>{{cite journal | vauthors = Richman DD | title = Susceptibility to nucleoside analogues of zidovudine-resistant isolates of human immunodeficiency virus | journal = The American Journal of Medicine | volume = 88 | issue = 5B | pages = 8S–10S | date = May 1990 | pmid = 2186629 | doi = 10.1016/0002-9343(90)90414-9 }}</ref><ref>{{cite journal | vauthors = Wainberg MA, Brenner BG, Turner D | title = 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 | journal = Antimicrobial Agents and Chemotherapy | volume = 49 | issue = 5 | pages = 1671–1678 | date = May 2005 | pmid = 15855480 | pmc = 1087622 | doi = 10.1128/AAC.49.5.1671-1678.2005 }}</ref> 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 (pharmacology)|protease inhibitor]], [[Reverse-transcriptase inhibitor#Non-nucleoside reverse-transcriptase inhibitors (NNRTIs)|non-nucleoside reverse-transcriptase inhibitor]], or [[integrase inhibitor]]; this type of therapy is known as [[HAART]] (Highly Active Anti Retroviral Therapy). |
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==Mechanism of action== |
==Mechanism of action== |
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[[Image:Azt pills.JPG|thumb|right|250px|AZT in oral, injectable, and suppository form]] |
[[Image:Azt pills.JPG|thumb|right|250px|AZT in oral, injectable, and suppository form]] |
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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 |
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 (biology)|cell]] (where it is called a [[provirus]]).<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"/><ref>{{cite journal |vauthors=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|bibcode = 1990Sci...249.1533M | url=https://zenodo.org/record/1230944 | type=Submitted manuscript }}</ref> |
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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.<ref>{{cite journal | |
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.<ref>{{cite journal | vauthors = Quan Y, Rong L, Liang C, Wainberg MA | title = 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 = Journal of Virology | volume = 73 | issue = 8 | pages = 6700–6707 | date = August 1999 | pmid = 10400767 | pmc = 112754 | doi = 10.1128/JVI.73.8.6700-6707.1999 }}</ref> |
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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.<ref name=FurmanPNAS>{{cite journal |vauthors=Furman |
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.<ref name=FurmanPNAS>{{cite journal | vauthors = Furman PA, Fyfe JA, St Clair MH, Weinhold K, Rideout JL, Freeman GA, Lehrman SN, Bolognesi DP, Broder S, Mitsuya H | display-authors = 6 | title = Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 21 | pages = 8333–8337 | date = November 1986 | pmid = 2430286 | pmc = 386922 | doi = 10.1073/pnas.83.21.8333 | doi-access = free | bibcode = 1986PNAS...83.8333F }}</ref> 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.<ref>Induction of Endogenous Virus and of Thymidline Kinase. {{cite web |url=http://www.pnas.org/content/71/12/4980.full.pdf |title=Induction of Endogenous Virus and of Thymidline Kinase by Bromodeoxyuridine in Cell Cultures Transformed by Friend Virus|access-date=November 14, 2022 |url-status=live |archive-url=https://web.archive.org/web/20150924164155/http://www.pnas.org/content/71/12/4980.full.pdf |archive-date=September 24, 2015 }}</ref> Thus AZT inhibits HIV replication without affecting the function of uninfected cells.<ref name=MitsuyaPNAS/> 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 muscle|cardiac]] and [[skeletal muscle]]s, causing [[myositis]].<ref name="Yarchoan R, Mitsuya H, Myers C, Broder S 1989 726–38"/><ref>{{cite journal | vauthors = Collins ML, Sondel N, Cesar D, Hellerstein MK | title = Effect of nucleoside reverse transcriptase inhibitors on mitochondrial DNA synthesis in rats and humans | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 37 | issue = 1 | pages = 1132–1139 | date = September 2004 | pmid = 15319672 | doi = 10.1097/01.qai.0000131585.77530.64 | s2cid = 20020419 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Parker WB, White EL, Shaddix SC, Ross LJ, Buckheit RW, Germany JM, Secrist JA, Vince R, Shannon WM | display-authors = 6 | 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 = The Journal of Biological Chemistry | volume = 266 | issue = 3 | pages = 1754–1762 | date = January 1991 | pmid = 1703154 | doi = 10.1016/S0021-9258(18)52360-7 | doi-access = free }}</ref><ref>{{cite book | vauthors = Rang HP, Dale MM, Ritter JM | title=Pharmacology | edition=3rd | publisher=Pearson Professional Ltd | year=1995 | isbn=978-0-443-05974-2}}</ref><ref>{{cite journal | vauthors = 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 = Molecular Pharmacology | volume = 56 | issue = 6 | pages = 1354–1361 | date = December 1999 | pmid = 10570065 | doi = 10.1124/mol.56.6.1354 | url = http://molpharm.aspetjournals.org/cgi/content/full/56/6/1354 | url-status = live | s2cid = 25678740 | archive-url = https://web.archive.org/web/20070921090344/http://molpharm.aspetjournals.org/cgi/content/full/56/6/1354 | archive-date = September 21, 2007 }}</ref> |
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==Chemistry== |
==Chemistry== |
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[[Image:Azt crystal.JPG|thumb|250px|A crystal of AZT, viewed under polarized light]] |
[[Image:Azt crystal.JPG|thumb|250px|A crystal of AZT, viewed under polarized light]] |
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Enantiopure AZT crystallizes in the [[monoclinic crystal system|monoclinic]] space group P2<sub>1</sub>. The primary intermolecular bonding motif is a hydrogen bonded dimeric ring formed from two N-H<sup>...</sup>O interactions.<ref>{{cite journal |vauthors=Dyer I, Low JN, Tollin P, Wilson HR, Howie RA |title=Structure of 3'-azido-3'-deoxythymidine, AZT |journal=Acta Crystallogr C |volume=44 |issue= 4|pages=767–9 |date=April 1988 |pmid=3271074 |doi= 10.1107/S0108270188000368}}</ref><ref>{{cite journal |journal= Proc Natl Acad Sci USA |year= 1987 |volume= 84 |issue= 23 |pages= 8239–8242 |title= Azidothymidine: crystal structure and possible functional role of the azido group |vauthors= Camerman A, Mastropaolo D, Camerman N |pmid= 2446321 |doi=10.1073/pnas.84.23.8239 |pmc=299517|bibcode= 1987PNAS...84.8239C |doi-access= free }}</ref> |
Enantiopure AZT crystallizes in the [[monoclinic crystal system|monoclinic]] space group P2<sub>1</sub>. The primary intermolecular bonding motif is a hydrogen bonded dimeric ring formed from two N-H<sup>...</sup>O interactions.<ref>{{cite journal |vauthors=Dyer I, Low JN, Tollin P, Wilson HR, Howie RA |title=Structure of 3'-azido-3'-deoxythymidine, AZT |journal=Acta Crystallogr C |volume=44 |issue= 4|pages=767–9 |date=April 1988 |pmid=3271074 |doi= 10.1107/S0108270188000368|bibcode=1988AcCrC..44..767D }}</ref><ref>{{cite journal |journal= Proc Natl Acad Sci USA |year= 1987 |volume= 84 |issue= 23 |pages= 8239–8242 |title= Azidothymidine: crystal structure and possible functional role of the azido group |vauthors= Camerman A, Mastropaolo D, Camerman N |pmid= 2446321 |doi=10.1073/pnas.84.23.8239 |pmc=299517|bibcode= 1987PNAS...84.8239C |doi-access= free }}</ref> |
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==History== |
==History== |
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===Initial cancer research=== |
===Initial cancer research=== |
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In the 1960s, the theory that most [[cancer]]s were caused by environmental [[retrovirus]]es gained clinical support and funding. It had recently become known, due to the work of Nobel laureates [[Howard Temin]] and [[David Baltimore]],<ref name="test75"> |
In the 1960s, the theory that most [[cancer]]s were caused by environmental [[retrovirus]]es gained clinical support and funding. It had recently become known, due to the work of Nobel laureates [[Howard Temin]] and [[David Baltimore]],<ref name="test75">{{cite web|url=https://www.nobelprize.org/prizes/medicine/1975/temin/lecture/|archiveurl=https://web.archive.org/web/20170103002308/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1975/temin-lecture.html|url-status=dead|title=The Nobel Prize in Physiology or Medicine 1975|archivedate=January 3, 2017|website=NobelPrize.org}}</ref> that nearly all avian cancers were caused by bird retroviruses, but corresponding human retroviruses had not yet been found. |
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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]].<ref name="test88"> |
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 H. Hitchings]] and [[Gertrude Elion]], leading to the development of the antitumor agent [[6-mercaptopurine]].<ref name="test88">{{cite web|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/elion-lecture.pdf|archiveurl=https://web.archive.org/web/20170808212611/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/elion-lecture.pdf|url-status=dead|title=The Purine Path To Chemotherapy|archivedate=August 8, 2017}}</ref> |
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[[Jerome Horwitz]] of the Barbara Ann Karmanos Cancer Institute and [[Wayne State University School of Medicine]] |
Richard E. Beltz first synthesized AZT in 1961, but did not publish his research.<ref>{{cite news |last1=Marsa |first1=Linda |title=Toxic Hope: Widely Embraced, the AIDS Drug is now under Heavy Fire |url=https://www.latimes.com/archives/la-xpm-1993-06-20-tm-10183-story.html |work=Los Angeles Times |date=June 20, 1993}}</ref><ref>{{cite web |last1=Brinck |first1=Anthony |title=Inventing AZT |url=http://www.tig.org.za/Inventing_AZT.pdf}}</ref>[[Jerome Horwitz]] of the Barbara Ann Karmanos Cancer Institute and [[Wayne State University School of Medicine]] synthesized AZT in 1964 under a [[United States|US]] [[National Institutes of Health]] (NIH) [[Federal grant|grant]].<ref name=pmid20018391>{{cite journal | vauthors = Broder S | title = The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic | journal = Antiviral Research | volume = 85 | issue = 1 | pages = 1–18 | date = January 2010 | pmid = 20018391 | pmc = 2815149 | doi = 10.1016/j.antiviral.2009.10.002 }}</ref><ref name=horwitz64>{{cite journal | title = The monomesylates of 1-(2-deoxy-bd-lyxofuranosyl) thymines| vauthors = Horwitz JP, Chua J, Noel MJ | journal = Org. Chem. Ser. Monogr | year = 1964 | volume = 29 | pages = 2076–9 |doi=10.1021/jo01030a546 | issue = 7}}</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 | date = 2002 }}</ref> Development was shelved after it proved biologically inert in mice.<ref name=pmid20018391/><ref name="nytimes">{{cite news | url = https://www.nytimes.com/1986/09/20/us/a-failure-led-to-drug-against-aids.html | title = A Failure Led to Drug Against AIDS | work = [[The New York Times]] | date = September 20, 1986 | access-date = June 30, 2010 | url-status = live | archive-url = https://web.archive.org/web/20090816081427/http://query.nytimes.com/gst/fullpage.html?sec=health | archive-date = August 16, 2009 }}</ref> 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]]).<ref>{{cite journal | vauthors = Ostertag W, Roesler G, Krieg CJ, Kind J, Cole T, Crozier T, Gaedicke G, Steinheider G, Kluge N, Dube S | display-authors = 6 | title = Induction of endogenous virus and of thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 12 | pages = 4980–4985 | date = December 1974 | pmid = 4531031 | pmc = 434023 | doi = 10.1073/pnas.71.12.4980 | doi-access = free | bibcode = 1974PNAS...71.4980O }}</ref> |
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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.<ref name="Sneader 2006 260–261">{{cite book | |
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.<ref name="Sneader 2006 260–261">{{cite book | vauthors = Sneader W |title=Drug Discovery – A History |url=https://archive.org/details/drugdiscoveryhis00snea |url-access=limited |publisher=Wiley |year=2006 |pages=[https://archive.org/details/drugdiscoveryhis00snea/page/n273 260]–261 |isbn=978-0-471-89980-8 }}</ref> |
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===HIV/AIDS research=== |
===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.<ref>{{cite journal | |
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.<ref>{{cite journal | vauthors = Weiss RA | title = How does HIV cause AIDS? | journal = Science | volume = 260 | issue = 5112 | pages = 1273–1279 | date = May 1993 | pmid = 8493571 | doi = 10.1126/science.8493571 | bibcode = 1993Sci...260.1273W }}</ref><ref>{{cite journal | vauthors = Douek DC, Roederer M, Koup RA | title = Emerging concepts in the immunopathogenesis of AIDS | journal = Annual Review of Medicine | volume = 60 | pages = 471–484 | year = 2009 | pmid = 18947296 | pmc = 2716400 | doi = 10.1146/annurev.med.60.041807.123549 }}</ref> Shortly thereafter, [[Samuel Broder]], [[Hiroaki Mitsuya]], and [[Robert Yarchoan]] of the United States [[National Cancer Institute]] (NCI) initiated a program to develop therapies for HIV/AIDS.<ref>NIH Clinical Center's 50th Anniversary. {{cite web |url=http://www.cc.nih.gov/about/news/anniver50/_pdf/CC_50th_Anniversary_Celebration.pdf |title=Clinical Center 50th Anniversary Celebration |access-date=April 18, 2012 |url-status=dead |archive-url=https://web.archive.org/web/20130619093432/http://www.cc.nih.gov/about/news/anniver50/_pdf/CC_50th_Anniversary_Celebration.pdf |archive-date=June 19, 2013 }}</ref> Using a line of [[T helper cell|CD4<sup>+</sup> T cells]] that they had made, they developed an assay to screen drugs for their ability to protect CD4<sup>+</sup> 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.<ref name=MitsuyaPNAS>{{cite journal | vauthors = Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S | display-authors = 6 | 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 20 | pages = 7096–7100 | date = October 1985 | pmid = 2413459 | pmc = 391317 | doi = 10.1073/pnas.82.20.7096 | doi-access = free | bibcode = 1985PNAS...82.7096M }}</ref> This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells. |
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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 including [[George Hitchings]], [[Gertrude B. Elion|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. 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 |
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 including [[George Hitchings]], [[Gertrude B. Elion|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. 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.<ref name="Sneader 2006 260–261"/> |
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In February 1985, the NCI scientists found that AZT had potent efficacy in vitro.<ref name=MitsuyaPNAS/><ref name=pmid20018391/> |
In February 1985, the NCI scientists found that AZT had potent efficacy in vitro.<ref name=MitsuyaPNAS/><ref name=pmid20018391/> |
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Several months later, a phase 1 [[clinical trial]] of AZT at the NCI was initiated at the NCI and Duke University |
Several months later, a phase 1 [[clinical trial]] of AZT at the NCI was initiated at the NCI and Duke University.<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 |vauthors=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| s2cid=37985276 }}</ref><ref name="Yarchoan R, Mitsuya H, Myers C, Broder S 1989 726–38">{{cite journal | doi=10.1056/NEJM198909143211106 |vauthors=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>{{cite journal |vauthors=Yarchoan R, Klecker RW, Weinhold KJ, Markham PD, Lyerly HK, Durack DT, Gelmann E, Lehrman SN, Blum RM, Barry DW |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|s2cid=37985276 }}</ref> |
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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. |
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. |
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===Patent filed and FDA approval=== |
===Patent filed and FDA approval=== |
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A |
A flawed [[double-blind]], [[placebo]]-controlled [[randomized trial]] of 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.<ref>{{cite web | url=https://www.snopes.com/news/2021/09/21/did-azt-kill-more-patients-than-aids/#A%20Fast-Track%20Approval%20Rife%20with%20Controversy | title=Did Controversial AZT Treatment Kill More Patients than AIDS in '80s, '90s? | date=September 21, 2021 }}</ref><ref>{{cite journal | vauthors = Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT | display-authors = 6 | title = The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial | journal = The New England Journal of Medicine | volume = 317 | issue = 4 | pages = 185–191 | date = July 1987 | pmid = 3299089 | doi = 10.1056/NEJM198707233170401 }}</ref> 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.<ref>{{cite journal | vauthors = Brook I | title = Approval of zidovudine (AZT) for acquired immunodeficiency syndrome. A challenge to the medical and pharmaceutical communities | journal = JAMA | volume = 258 | issue = 11 | pages = 1517 | date = September 1987 | pmid = 3306004 | doi = 10.1001/jama.1987.03400110099035 }}</ref> The 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-obsolete medical term for pre-AIDS illness) on March 20, 1987.<ref name="Cimons">{{cite news | vauthors = Cimons M | title = U.S. Approves Sale of AZT to AIDS Patients | work = Los Angeles Times | page = 1 | date = March 21, 1987 }}</ref> The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months. |
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AZT was subsequently approved unanimously for infants and children in 1990.<ref>AZT Approved for AIDS Children. {{ |
AZT was subsequently approved unanimously for infants and children in 1990.<ref>AZT Approved for AIDS Children. {{cite news |url=https://articles.latimes.com/1990-05-03/news/mn-603_1_azt-approved-for-aids-children |title= HEALTH : AZT Approved for AIDS Children |journal=Los Angeles Times |access-date=March 30, 2012 |url-status=live |archive-url=https://web.archive.org/web/20150504000547/http://articles.latimes.com/1990-05-03/news/mn-603_1_azt-approved-for-aids-children |archive-date=May 4, 2015 |date=May 3, 1990 | via = From Times Wire Services}}</ref> 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.<ref>{{cite web | url=https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540597/all/Zidovudine__AZT_ | title=Zidovudine (AZT) | Johns Hopkins ABX Guide }}</ref> 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. |
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==Society and culture== |
==Society and culture== |
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{{See also|Cost of HIV treatment}} |
{{See also|Cost of HIV treatment}} |
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⚫ | 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 |
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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.<ref name="latimes.com"/> |
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⚫ | In 2002, another lawsuit was filed challenging the patent by the [[AIDS Healthcare Foundation]], which also filed an antitrust case against GSK |
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⚫ | 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. This suit was appealed up to the Supreme Court of the US, but in 1996 they declined to formally review it.<ref>{{cite news| vauthors = Greenhouse L | title=Supreme Court Roundup;Justices Reject Challenge Of Patent for AIDS Drug|url=https://www.nytimes.com/1996/01/17/us/supreme-court-roundup-justices-reject-challenge-of-patent-for-aids-drug.html|work=The New York Times|date=January 17, 1996|url-status=live|archive-url=https://web.archive.org/web/20161117145258/http://www.nytimes.com/1996/01/17/us/supreme-court-roundup-justices-reject-challenge-of-patent-for-aids-drug.html|archive-date=November 17, 2016}}</ref> The case, ''[https://openjurist.org/40/f3d/1223 Burroughs Wellcome Co. v. Barr Laboratories]'', was a landmark in US law of inventorship.<ref>{{cite journal| vauthors = Armstrong M, Murphy Jr GM |title=Inventorship and ownership considerations and pitfalls with collaborative research: patent highlight.|journal=ACS Medicinal Chemistry Letters|date=April 26, 2012|volume=3|issue=5|pages=349–51|pmid=24900477|pmc=4025834|doi=10.1021/ml300084e}}</ref> |
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⚫ | In 2002, another lawsuit was filed challenging the patent by the [[AIDS Healthcare Foundation]], which also filed an antitrust case against [[GSK Plc|GSK]].<ref name=Law3602004>{{cite news| vauthors = Meland M |title=Judge Denies Request To Dismiss Patent Challenge Vs. Glaxo's AZT – Law360|url=http://www.law360.com/articles/1396/judge-denies-request-to-dismiss-patent-challenge-vs-glaxo-s-azt|work=Law360|date=May 3, 2004|url-status=live|archive-url=https://web.archive.org/web/20161117212239/http://www.law360.com/articles/1396/judge-denies-request-to-dismiss-patent-challenge-vs-glaxo-s-azt|archive-date=November 17, 2016}}</ref> The patent case was dismissed in 2003 and AHF filed a new case challenging the patent.<ref name=Law3602004/> |
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GSK's patents on AZT expired in 2005, and in September 2005, the FDA approved three [[generic drug|generic]] versions.<ref>{{cite web|title=HIV/AIDS History of Approvals – HIV/AIDS Historical Time Line 2000 – 2010|url=https://www.fda.gov/ForPatients/Illness/HIVAIDS/History/ucm151081.htm|publisher=U.S. [[Food and Drug Administration]] (FDA)|date=August 8, 2014|url-status=live|archive-url=https://web.archive.org/web/20161023204558/https://www.fda.gov/ForPatients/Illness/HIVAIDS/History/ucm151081.htm|archive-date=October 23, 2016}}</ref> |
GSK's patents on AZT expired in 2005, and in September 2005, the FDA approved three [[generic drug|generic]] versions.<ref>{{cite web|title=HIV/AIDS History of Approvals – HIV/AIDS Historical Time Line 2000 – 2010|url=https://www.fda.gov/ForPatients/Illness/HIVAIDS/History/ucm151081.htm|publisher=U.S. [[Food and Drug Administration]] (FDA)|date=August 8, 2014|url-status=live|archive-url=https://web.archive.org/web/20161023204558/https://www.fda.gov/ForPatients/Illness/HIVAIDS/History/ucm151081.htm|archive-date=October 23, 2016}}</ref> |
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Revision as of 21:28, 20 March 2024
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Clinical data | |
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Trade names | Retrovir, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a687007 |
License data |
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Pregnancy category |
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Routes of administration | By mouth, intravenous, rectal suppository |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | Complete absorption, following first-pass metabolism systemic availability 75% (range 52 to 75%) |
Protein binding | 30 to 38% |
Metabolism | Liver |
Elimination half-life | 0.5 to 3 hours |
Excretion | Kidney and Bile duct |
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ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
NIAID ChemDB | |
PDB ligand | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.152.492 |
Chemical and physical data | |
Formula | C10H13N5O4 |
Molar mass | 267.245 g·mol−1 |
3D model (JSmol) | |
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Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals.[6] It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure.[6] It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine.[6] It can be used by mouth or by slow injection into a vein.[6]
Common side effects include headaches, fever, and nausea.[6] Serious side effects include liver problems, muscle damage, and high blood lactate levels.[6] It is commonly used in pregnancy and appears to be safe for the fetus.[6] ZDV is of the nucleoside analog reverse-transcriptase inhibitor (NRTI) class.[6] It works by inhibiting the enzyme reverse transcriptase that 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 by Burroughs Wellcome.[8] It was approved in the United States in 1987 and was the first treatment for HIV.[6][9] It is on the World Health Organization's List of Essential Medicines.[10][11] It is available as a generic medication.[6]
Medical uses
HIV treatment
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
AZT has been used for post-exposure prophylaxis (PEP) in combination with another antiretroviral drug called lamivudine. 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 as tenofovir to provide PEP.[16] Before tenofovir, 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.[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 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.[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
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 from in vitro and in vivo studies showed the efficacy of AZT also against multidrug-resistant gram-negative bacteria (including mcr-1 carrying and metallo-β-lactamase producing isolates), especially in combination with other active agents (e.g. fosfomycin, colistin, tigecycline).[27][28]
Side effects
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, 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,[30] the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells.[31] Anemia due to AZT was successfully treated using erythropoetin to stimulate red blood cell production.[32][33] 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.[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 the carcinogenicity of 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
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 by mutation of its reverse transcriptase.[38][39] 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, non-nucleoside reverse-transcriptase inhibitor, or integrase inhibitor; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy).
Mechanism of action
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).[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 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.[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 by mitochondria to replicate, accounting for its potentially toxic but reversible effects on cardiac and skeletal muscles, causing myositis.[46][47][48][49][50]
Chemistry
Enantiopure AZT crystallizes in the monoclinic space group P21. The primary intermolecular bonding motif is a hydrogen bonded dimeric ring formed from two N-H...O interactions.[51][52]
History
Initial cancer research
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,[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 laureates George H. Hitchings and Gertrude Elion, leading to the development of the antitumor agent 6-mercaptopurine.[54]
Richard E. Beltz first synthesized AZT in 1961, but did not publish his research.[55][56]Jerome Horwitz of the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine synthesized AZT in 1964 under a US National 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 the Max Planck Institute for Experimental Medicine in Göttingen, Germany, reported that AZT specifically targeted Friend virus (strain of murine 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
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, and Robert Yarchoan of the United States National Cancer Institute (NCI) initiated a program to develop therapies for HIV/AIDS.[65] Using a line of CD4+ T cells that 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 including George 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 enzyme reverse 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 1 clinical trial of 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 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.
Patent filed and FDA approval
A flawed double-blind, placebo-controlled randomized trial of 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 States Food and Drug Administration (FDA) voted ten to one to recommend the approval of AZT.[69] 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.[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 transient anemia and malaise.
Society and culture
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 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. This suit was appealed up to the Supreme Court of the US, but in 1996 they 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 the AIDS Healthcare Foundation, which also filed an antitrust case against GSK.[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 three generic versions.[76]
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External links
- "Zidovudine". Drug Information Portal. U.S. National Library of Medicine.