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Zidovudine

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"AZT" redirects here. For other uses, see AZT (disambiguation).
Zidovudine
Clinical data
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: B3
Routes of
administration		Oral, Serum, Suppository
ATC code
Legal status
Legal status
  • US: WARNING[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailabilitycomplete absorption, following first-pass metabolism systemic availability 75% (range 52 to 75%)
Protein binding30 to 38%
MetabolismHepatic
Elimination half-life0.5 to 3 hours
ExcretionRenal/Rectal
Identifiers
  • 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione[2]
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.152.492 Edit this at Wikidata
Chemical and physical data
FormulaC10H13N5O4
Molar mass267.242 g/mol g·mol−1
3D model (JSmol)
  • O=C/1NC(=O)N(\C=C\1C)[C@@H]2O[C@@H]([C@@H](\N=[N+]=[N-])C2)CO
  • 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/s1 checkY
  • Key:HBOMLICNUCNMMY-XLPZGREQSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Zidovudine (INN) or azidothymidine (AZT) (also called ZDV) is a nucleoside analog reverse-transcriptase inhibitor (NRTI), a type of antiretroviral drug used for the treatment of HIV/AIDS infectiousness.

AZT is the first U.S. government-approved treatment for HIV therapy, prescribed under the names Retrovir and Retrovis. AZT was the first breakthrough in AIDS therapy, significantly reducing the replication of the virus in patients and leading to clinical and immunologic improvements.[3] It can also be used to prevent HIV transmission, such as from mother to child during the period of birth or after a needle stick. Used by itself in HIV-infected patients, AZT safely slows HIV replication in patients, but generally does not stop it entirely.[4] This may allow HIV to become AZT-resistant over time, and for this reason AZT is usually used in conjunction with the other anti-HIV drugs in combination therapy called highly active antiretroviral therapy (HAART).

To simplify its use in combination, AZT is included in Combivir and Trizivir, among others. Zidovudine is included in the World Health Organization's Model List of Essential Medicines, which suggests the minimum medicinal needs for a basic health care system.[5]

Chemistry

A salt crystal of AZT, viewed under polarized light

AZT crystallizes into an asymmetric nucleated monoclinic salt structure, forming an equalized hydrogen-nitrogen-oxygen bonded protease network of triple base-paired excimer dimers; its multiscaled crystallized lattice superstructure and surfactant headgroup electrostatic bond polarity was reported in 1988 and 1987.[6][7]

History

Development

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,[8] that nearly all avian cancers were caused by bird retroviruses, but corresponding human retroviruses were not known yet.

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.[8]

Jerome Horwitz of the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine first synthesized AZT in 1964 under a US National Institutes of Health (NIH) grant.[9][10][11] Development was shelved after it proved biologically inert in mice.[9][12] In 1974, Wolfram Ostertag of the Max Planck Institute in Germany reported that AZT specifically targeted Friend virus (strain of murine leukemia virus).[13]

Successful HIV Treatment

In May 1984, shortly after the human immunodeficiency virus (HIV) had been unambiguously proved as the cause of AIDS, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan of the United States National Cancer Institute (NCI) initiated a program to develop therapies for HIV/AIDS.[14] Using a CD4+ cell line that they had made, they developed an assay to screen drugs for their ability to protect CD4+ T cells from being killed by HIV.[15] This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells. In order to get drugs into the clinic as soon as possible, they started with compounds that were either in clinical use or for which they could get a pharmaceutical partner. As part of this effort, they initiated a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). Burroughs-Wellcome had expertise in nucleoside analogs and viral diseases, led by researchers including Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts were focused in part on the viral enzyme reverse transcriptase. Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. One compound that they were working with (AZT), which they had given the code name "BW A509X", was tested and demonstrated remarkable efficacy against certain mouse viruses. However, the scientists at Burroughs-Wellcome were not working with HIV themselves, and sent 11 compounds to the NCI team for testing against HIV in their newly developed assay. In February 1985, the NCI scientists found that BW A509X, one of these compounds, had potent efficacy in vitro and in rodents.[9][15] Several months later, Broder, Mitsuya, and Yarchoan started the initial phase 1 clinical trial of AZT at the NCI, in collaboration with the scientists from Burroughs-Wellcome and Duke University.[16][17] 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 the test tube could be injected into patients in serum and suppository form, and that the drug penetrated deeply only into infected brains.

A rigorously maintained double-blind, placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome. The study, which was commended by the CDC and the NIH for its standards,[18] proved that AZT safely prolongs the lives of patients with HIV.[19] Burroughs-Wellcome filed for a patent for AZT in 1985. The United States Food and Drug Administration (FDA) approved the drug (via the then-new FDA 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.[20] The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months, the shortest period of drug development in recent history.

AZT was subsequently approved unanimously for infants and children in 1990.[21] AZT was initially administered in somewhat higher dosages than today, typically 400 mg every four hours, day and night. The paucity of alternatives for treating HIV/AIDS at that time unambiguously affirmed the health risk/benefit ratio, with inevitable slow, disfiguring, and painful death from HIV outweighing the drug's side-effect of transient anemia and malaise.

Current treatment regimens involve relatively lower dosages (e.g., 300 mg) of AZT taken just twice a day, almost always as part of highly active antiretroviral therapy (HAART), in which AZT is combined with other drugs (known affectionately as "the triple cocktail") in order to prevent the mutation of HIV into an AZT-resistant form. [22][23]

HIV Prophylaxis

AZT is used as post-exposure prophylaxis in combination with another antiretroviral, Lamivudine, substantially reducing the risk of HIV infection following the first single exposure to the virus (such as a needle-stick injury involving blood or body fluids from an individual known or suspected of being infected with HIV).[24]

AZT is now a principal part of the clinical pathway for both pre-exposure prophylaxis and post-exposure treatment of mother-to-child transmission of HIV during pregnancy, labor, and delivery and has been proven to be integral to uninfected siblings' perinatal and neonatal development.[25][26] Without AZT, as many as 10 to 15% of fetuses with HIV-infected mothers will themselves become infected.[27] AZT has been shown to reduce this risk to as little as 8% when given in a three-part regimen post-conception, delivery, and six weeks post-delivery. Consistent and proactive precautionary measures, such as the rigorous use of antiretroviral medications, cesarean section, face masks, heavy-duty rubber gloves, clinically segregated disposable diapers, and avoidance of mouth contact and breast feeding will further reduce child-attendant transmission of HIV to as little as 1–2%.[28][29][30] However, a new study now indicates that HIV+ mothers not taking antiretrovirals who breastfeed their children will help prevent HIV transmission to their infants.[31]

During the period from 1994 to 1999 when this was the primary form of prevention of mother-to-child HIV transmission, AZT prophylaxis prevented more than 1000 parental and infant deaths from AIDS in the United States.[32]

Side effects

AZT-based antiretroviral therapy has been proven to significantly reduce rates of certain AIDS-defining cancers (most dramatically, that of Kaposi's sarcoma and central nervous system lymphoma).[33][34][35]

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,[36] the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells.[37] Anemia due to AZT was successfully treated using vitamins to stimulate red blood cell production.[38][39] 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.[40] Most common side-effects included upset stomach and acid reflux (heartburn), headache, cosmetic reduction in abdominal body fat, light sleeping, and occasional loss of appetite; while less-common complaints included faint discoloration of fingernails and toenails, mood elevation, occasional tingling or transient numbness of the hands or feet, and minor skin discoloration. Allergic reactions were rare.[41] Today, side-effects are much less common with the use of lower doses of AZT.[42] According to IARC, there is sufficient evidence in experimental animals for the carcinogenicity of zidovudine; it is possibly carcinogenic to humans (Group 2B).[43]

Viral resistance

Even at the highest doses that can be tolerated in patients, AZT is not potent enough to prevent all HIV replication, and may only slow the replication of the virus and the progression of the disease. During prolonged AZT treatment, HIV has the potential to develop resistance to AZT by mutation of its reverse transcriptase.[44][45] To slow the development of resistance, physicians generally recommend that AZT be given in combination with another reverse transcriptase inhibitor and an antiretroviral from another group, such as a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy).

Mechanism of action

AZT in oral, injectable, and suppository form

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).[46][15][17]

The azido group increases the lipophilic nature of AZT, allowing it to cross infected cell membranes easily by diffusion and thereby also to cross the blood–brain barrier. Cellular enzymes convert AZT into the effective 5'-triphosphate form. Studies have proven that the termination of HIV's forming DNA chains is the specific factor in the inhibitory effect.

At very high doses, AZT's triphosphate form may also inhibit DNA polymerase used by human cells to undergo cell division, but regardless of dosage AZT has an approximately 100-fold greater affinity for HIV's reverse transcriptase.[47] The selectivity has been proven to be due to the cell's ability to quickly repair its own DNA chain if it is broken by AZT during its formation, whereas the HIV virus lacks that ability.[48] Thus AZT inhibits HIV replication without affecting the function of uninfected cells.[15] 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.[49][50][51][52][16]

Patent issues

See also: Cost of HIV treatment

The patents on AZT have been the target of some controversy. In 1991, Public Citizen filed a lawsuit claiming that the patents were invalid. Subsequently, Barr 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, claiming that even though they had never tested it against HIV, they had conceived of it working before they sent it to the NCI scientists.[53] This suit was appealed up to the Supreme Court of the US, but they declined to formally review it. In 2002, another lawsuit was filed over the patent by the AIDS Healthcare Foundation.

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

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

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ "Zidovudine". PubChem Public Chemical Database. NCBI. Retrieved 2011-04-10.
  3. ^ AIDS therapy. First proof of therapeutic promise. Wright, K. http://www.ncbi.nlm.nih.gov/pubmed/3463865
  4. ^ Zidovudine resistant HIV. D.J. Jeffries. http://www.ncbi.nlm.nih.gov/pubmed/2500164
  5. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. March 2005. Retrieved 2006-03-12.{{cite web}}: CS1 maint: year (link)
  6. ^ Dyer I, Low JN, Tollin P, Wilson HR, Howie RA (1988). "Structure of 3'-azido-3'-deoxythymidine, AZT". Acta Crystallogr C. 44 (4): 767–9. PMID 3271074. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Azidothymidine: crystal structure and possible functional role of the azido group. http://worldwidescience.org/wws/result-list/fullRecord:Azidothymidine%3A+crystal+structure+and+possible+functional+role+of+the+azido+group/viewId:view0/
  8. ^ a b Link text, additional text. Cite error: The named reference "test" was defined multiple times with different content (see the help page).
  9. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 20018391, please use {{cite journal}} with |pmid=20018391 instead.
  10. ^ Horwitz, JP (1964). "The monomesylates of 1-(2-deoxy-bd-lyxofuranosyl) thymines". Org. Chem. Ser. Monogr. 29 (7): 2076–9. doi:10.1021/jo01030a546. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ Detours V; Henry D (writers/directors) (2002). I am alive today (history of an AIDS drug) (Film). ADR Productions/Good & Bad News.
  12. ^ "A Failure Led to Drug Against AIDS". The New York Times. 1986-09-20. Retrieved 2010-06-30.
  13. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 4531031 , please use {{cite journal}} with |pmid= 4531031 instead.
  14. ^ NIH Clinical Center's 50th Anniversary. http://www.cc.nih.gov/about/news/anniver50/_pdf/CC_50th_Anniversary_Celebration.pdf
  15. ^ a b c d Mitsuya H, Weinhold K, Furman P, St Clair M, Li, Lars, Lehrman S, Gallo R, Bolognesi D, Barry D, Broder S (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". Proc Natl Acad Sci USA. 82 (20): 7096–100. Bibcode:1985PNAS...82.7096M. doi:10.1073/pnas.82.20.7096. PMC 391317. PMID 2413459.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "MitsuyaPNAS" was defined multiple times with different content (see the help page).
  16. ^ a b Yarchoan 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. PMID 2671731.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ a b Yarchoan 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. PMID 2869302.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Harvard Business Review. Burroughs Wellcome and AZT.http://hbr.org/product/burroughs-wellcome-and-azt-c/an/793115-PDF-ENG
  19. ^ Fischl MA; Richman DD; Grieco MH; Gottlieb MS; Volberding PA; Laskin OL; Leedom JM; Groopman JE; Mildvan D (1987). "The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial". N Engl J Med. 317 (4): 185–91. doi:10.1056/NEJM198707233170401. PMID 3299089. {{cite journal}}: Invalid |display-authors=10 (help); Unknown parameter |author-separator= ignored (help)
  20. ^ Cimons, Marlene (21 March 1987). "U.S. Approves Sale of AZT to AIDS Patients". Los Angeles Times. p. 1.
  21. ^ AZT Approved for AIDS Children. http://articles.latimes.com/1990-05-03/news/mn-603_1_azt-approved-for-aids-children
  22. ^ De Clercq E (1994). "HIV resistance to reverse transcriptase inhibitors". Biochem Pharmacol. 47 (2): 155–69. doi:10.1016/0006-2952(94)90001-9. PMID 7508227.
  23. ^ Yarchoan R, Mitsuya H, Broder S (1988). "AIDS therapies". Sci Am. 259 (4): 110–9. doi:10.1038/scientificamerican1088-110. PMID 3072667.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ "Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV". Retrieved 2006-03-29.
  25. ^ "Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health" (PDF). Retrieved 2006-03-29.
  26. ^ PLOS Hub. Clinical Trials. http://clinicaltrials.ploshubs.org/article/info%3Adoi%2F10.1371%2Fjournal.pctr.0020011
  27. ^ Science Codex. Breastfeeding may protect infants from HIV transmission. http://www.sciencecodex.com/breastfeeding_may_protect_infants_from_hiv_transmission-96699
  28. ^ CIDRZ. Prevention of AIDS Transmission (PMTCT). http://www.cidrz.org/pmtct
  29. ^ Transmission of HIV from infants http://aidsperspective.net/blog/?p=868
  30. ^ 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. PMID 7935654.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ Breastfeeding may protect infants from HIV transmission. Science Codex. http://www.sciencecodex.com/breastfeeding_may_protect_infants_from_hiv_transmission-96699
  32. ^ Walensky RP; Paltiel AD; Losina E; et al. (2006). "The survival benefits of AIDS treatment in the United States". J. Infect. Dis. 194 (1): 11–9. doi:10.1086/505147. PMID 16741877. {{cite journal}}: Unknown parameter |author-separator= ignored (help); Unknown parameter |month= ignored (help)
  33. ^ Biggar RJ, Chaturvedi AK, Goedert JJ, Engels EA (2007). "AIDS-related cancer and severity of immunosuppression in persons with AIDS". J. Natl. Cancer Inst. 99 (12): 962–72. doi:10.1093/jnci/djm010. PMID 17565153. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  34. ^ "Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults". J. Natl. Cancer Inst. 92 (22): 1823–30. 2000. PMID 11078759. {{cite journal}}: Unknown parameter |month= ignored (help)
  35. ^ Houri JJ, Ogier-Denis E, Bauvy C; et al. (1992). "Swainsonine is a useful tool to monitor the intracellular traffic of N-linked glycoproteins as a function of the state of enterocytic differentiation of HT-29 cells". Eur. J. Biochem. 205 (3): 1169–74. PMID 1577000. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  36. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 20544523, please use {{cite journal}} with |pmid= 20544523 instead.
  37. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18504416 , please use {{cite journal}} with |pmid= 18504416 instead.
  38. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 9402140, please use {{cite journal}} with |pmid=9402140 instead.
  39. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 12524467 , please use {{cite journal}} with |pmid=12524467 instead.
  40. ^ "ZIDOVUDINE (AZT) - ORAL (Retrovir) side effects, medical uses, and drug interactions". MedicineNet. Retrieved 2006-01-09.
  41. ^ "zidovudine, Retrovir". Medicinenet.com. 2010-08-12. Retrieved 2010-12-14.
  42. ^ Side Effects. NAM Aidsmap. http://www.aidsmap.com/Side-effects/page/1730907/
  43. ^ "Summary of Data Reported and Evaluation". 2000. Retrieved 11 August 2012.
  44. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 2186629, please use {{cite journal}} with |pmid=2186629 instead.
  45. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15855480, please use {{cite journal}} with |pmid=15855480 instead.
  46. ^ Mitsuya H, Yarchoan R, Broder S (1990). "Molecular targets for AIDS therapy". Science. 249 (4976): 1533–44. Bibcode:1990Sci...249.1533M. doi:10.1126/science.1699273. PMID 1699273.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  47. ^ Furman P, Fyfe J, St Clair M, Weinhold K, Rideout J, Freeman G, Lehrman S, Bolognesi D, Broder S, Mitsuya H (1986). "Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase". Proc Natl Acad Sci USA. 83 (21): 8333–7. Bibcode:1986PNAS...83.8333F. doi:10.1073/pnas.83.21.8333. PMC 386922. PMID 2430286.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  48. ^ Induction of Endogenous Virus and of Thymidline Kinase. http://www.pnas.org/content/71/12/4980.full.pdf
  49. ^ Collins M, Sondel N, Cesar D, Hellerstein M (2004). "Effect of nucleoside reverse transcriptase inhibitors on mitochondrial DNA synthesis in rats and humans". J Acquir Immune Defic Syndr. 37 (1): 1132–9. doi:10.1097/01.qai.0000131585.77530.64. PMID 15319672.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  50. ^ Parker W, White E, Shaddix S, Ross L, Buckheit R, Germany J, Secrist J, Vince R, Shannon W (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". J Biol Chem. 266 (3): 1754–62. PMID 1703154.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  51. ^ Rang H.P., Dale M.M., Ritter J.M. (1995). Pharmacology (3rd ed.). Pearson Professional Ltd. ISBN 0-443-05974-8.{{cite book}}: CS1 maint: multiple names: authors list (link)
  52. ^ Balzarini J, Naesens L, Aquaro S, Knispel T, Perno C, De Clercq E, Meier C (1 December 1999). "Intracellular metabolism of CycloSaligenyl 3'-azido-2', 3'-dideoxythymidine monophosphate, a prodrug of 3'-azido-2', 3'-dideoxythymidine (zidovudine)". Mol Pharmacol. 56 (6): 1354–61. PMID 10570065.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  53. ^ US Court of Appeals for the Federal Circuit. "Burroughs Wellcome Co. v. Barr Laboratories, 40 F.3d 1223 (Fed. Cir. 1994)". University of Houston -- Health Law and Policy Institute. Retrieved 2007-02-28.
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