"AZT" redirects here. For other uses, see AZT (disambiguation).
Zidovudine
|
|
| Systematic (IUPAC) name |
| 1-[(2R,4S,5S)-4-Azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione[1] |
| Clinical data |
| Trade names |
Retrovir |
| AHFS/Drugs.com |
|
|
Pregnancy
category
|
- AU: B3
- US: C (Risk not ruled out) (AZT)
|
|
Legal status
|
|
|
Routes of
administration
|
Oral, serum, suppository |
| Pharmacokinetic data |
| Bioavailability |
Complete absorption, following first-pass metabolism systemic availability 75% (range 52 to 75%) |
| Protein binding |
30 to 38% |
| Metabolism |
Hepatic |
| Half-life |
0.5 to 3 hours |
| Excretion |
Renal/Rectal |
| Identifiers |
|
CAS Registry Number
|
30516-87-1 Y |
|
ATC code
|
J05AF01 |
| PubChem |
CID 35370 |
| DrugBank |
DB00495 Y |
| ChemSpider |
32555 Y |
| UNII |
4B9XT59T7S Y |
| ChEBI |
CHEBI:10110 N |
| ChEMBL |
CHEMBL129 Y |
| NIAID ChemDB |
000001 |
| PDB ligand ID |
AZZ (PDBe, RCSB PDB) |
| Chemical data |
| Formula |
C10H13N5O4 |
|
Molecular mass
|
267.242 g/mol |
SMILES
- O=C1NC(C(C)=CN1[C@@H]2O[C@H](CO)[C@@H](N=[N+]=[N-])C2)=O
|
InChI
-
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 Y
Key:HBOMLICNUCNMMY-XLPZGREQSA-N Y
|
| N (what is this?) (verify) |
Zidovudine (INN) or azidothymidine (AZT) (also called ZDV) is a nucleoside analog reverse-transcriptase inhibitor (NRTI), a type of antiretroviral drug used for the treatment of HIV/AIDS infection. AZT inhibits the enzyme (reverse transcriptase) that HIV uses to synthesize DNA, thus preventing viral DNA from forming.
AZT is the first U.S. government-approved treatment for HIV, marketed under the brand name Retrovir. AZT was the first breakthrough in AIDS therapy, significantly reducing the replication of the virus in patients and leading to clinical and immunologic improvements.[2] It can also be used to prevent HIV transmission, such as from mother to child during the period of birth or after a needle stick injury. Used by itself in HIV-infected patients, AZT slows HIV replication in patients, but does not stop it entirely.[3] HIV may become AZT-resistant over time, and therefore AZT is now usually used in conjunction with other anti-HIV drugs in the combination therapy called highly active antiretroviral therapy (HAART). AZT is included in Combivir and Trizivir, and is included in the World Health Organization's Model List of Essential Medicines, which suggests the minimum medicinal needs for a basic health care system.[4]
Contents
- 1 Medical uses
- 1.1 HIV treatment
- 1.2 HIV prevention
- 2 Side effects
- 3 Mechanism of action
- 4 Chemistry
- 5 History
- 6 Society and culture
- 7 References
- 8 External links
Medical uses
HIV treatment
In May 1984, shortly after the human immunodeficiency virus (HIV) had been unambiguously proven as the cause of AIDS,[5][6] Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan of the United States National Cancer Institute (NCI) initiated a program to develop therapies for HIV/AIDS.[7] Using a CD4+ cell line that they had made, they developed an assay to screen drugs for their ability to protect CD4+ T cells from being killed by HIV.[8] This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells. In order to get drugs into the clinic as soon as possible, they started with compounds that were either in clinical use or for which they could get a pharmaceutical partner. As part of this effort, they initiated a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). Burroughs-Wellcome had expertise in nucleoside analogs and viral diseases, led by researchers including Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts were focused in part on the viral enzyme reverse transcriptase. Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. One compound that they were working with (AZT), which they had given the code name "BW A509X", was tested and demonstrated remarkable efficacy against certain mouse viruses. However, the scientists at Burroughs-Wellcome were not working with HIV themselves, and sent 11 compounds to the NCI team for testing against HIV in their newly developed assay.
In February 1985, the NCI scientists found that BW A509X, one of these compounds, had potent efficacy in vitro. Burroughs-Wellcome scientists had previously shown that it was active against bacterial infection in rodents.[8][9] Several months later, Broder, Mitsuya, and Yarchoan started the initial phase 1 clinical trial of AZT at the NCI, in collaboration with the scientists from Burroughs-Wellcome and Duke University.[10][11] In doing this Phase I trial, they built on their experience in doing an earlier trial, with suramin, another drug that had shown effective anti-HIV activity in the laboratory. This initial trial of AZT proved that the drug could be safely administered to patients with HIV, that it increased their CD4 counts, restored T cell immunity as measured by skin testing, and that it showed strong evidence of clinical effectiveness, such as inducing weight gain in AIDS patients. It also showed that levels of AZT that worked in vitro could be injected into patients in serum and suppository form, and that the drug penetrated deeply only into infected brains.
A rigorously maintained double-blind, placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome. The study, which was commended by the CDC and the NIH for its standards,[12] proved that AZT safely prolongs the lives of patients with HIV.[13] Burroughs-Wellcome filed for a patent for AZT in 1985. The Anti-Infective Advisory Committee to United States Food and Drug Administration (FDA) voted ten to one to recommend the approval of AZT.[14] The FDA approved the drug (via the then-new FDA accelerated approval system) for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-obsolete medical term for pre-AIDS illness) on March 20, 1987.[15] The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months, the shortest period of drug development in recent history.
AZT was subsequently approved unanimously for infants and children in 1990.[16] AZT was initially administered in somewhat higher dosages than today, typically 400 mg every four hours, day and night. The paucity of alternatives for treating HIV/AIDS at that time unambiguously affirmed the health risk/benefit ratio, with inevitable slow, disfiguring, and painful death from HIV outweighing the drug's side-effect of transient anemia and malaise.
Current treatment regimens involve relatively lower dosages (e.g., 300 mg) of AZT taken just twice a day, almost always as part of highly active antiretroviral therapy (HAART), in which AZT is combined with other drugs (known affectionately as "the triple cocktail") in order to prevent the selection of HIV into an AZT-resistant form.[17][18]
HIV prevention
AZT has been used as post-exposure prophylaxis (PEP) in combination with another antiretroviral, lamivudine, substantially reducing the risk of HIV infection following the first single exposure to the virus (such as a needle-stick injury involving blood or body fluids from an individual known or suspected of being infected with HIV)[19] (though its use in PEP has largely been replaced by tenofovir as a component of a three drug combination[20]).
AZT is now a principal part of the clinical pathway for both pre-exposure prophylaxis and post-exposure treatment of mother-to-child transmission of HIV during pregnancy, labor, and delivery and has been proven to be integral to uninfected siblings' perinatal and neonatal development.[21][22] Without AZT, as many as 10 to 15% of fetuses with HIV-infected mothers will themselves become infected.[23] AZT has been shown to reduce this risk to as little as 8% when given in a three-part regimen post-conception, delivery, and six weeks post-delivery. Consistent and proactive precautionary measures, such as the rigorous use of antiretroviral medications, cesarean section, face masks, heavy-duty rubber gloves, clinically segregated disposable diapers, and avoidance of mouth contact will further reduce child-attendant transmission of HIV to as little as 1–2%.[24][25][26]
During the period from 1994 to 1999 when this was the primary form of prevention of mother-to-child HIV transmission, AZT prophylaxis prevented more than 1000 parental and infant deaths from AIDS in the United States.[27] In the US at this time, the accepted standard of care for HIV-positive mothers was known as the 076 regimen and involved 5 daily doses of AZT from the second trimester onwards as well as AZT intravenously administered during labour.[28] As this treatment was lengthy and expensive, it was deemed unfeasible in the global south, where mother-to-child transmission was a significant problem. A number of studies were initiated in the late 1990s that sought to test the efficacy of a shorter, simpler regimen for use in ‘resource-poor’ countries.[29] This AZT short course was an inferior standard of care and would have been considered malpractice if trialed in the US; however it was nonetheless a treatment that would improve (at least to some extent) the care and survival of impoverished subjects, given local realities and the “shortages of staffing, medication and equipment that bound the possibilities of care” in such settings.[30] The trials were highly controversial and highlighted the inability of researchers to align the local realities, such as the inaccessibility of the AZT, with the scientific and ethical protocols designed in ‘resource-rich’ countries.[29]
Side effects
Early long-term higher-dose therapy with AZT was initially associated with side effects that sometimes limited therapy, including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. All of these conditions were generally found to be reversible upon reduction of AZT dosages. They have been attributed to several possible causes, including transient depletion of mitochondrial DNA, sensitivity of the γ-DNA polymerase in some cell mitochondria,[31] the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells.[32] Anemia due to AZT was successfully treated using vitamins to stimulate red blood cell production.[33][34] Drugs that inhibit hepatic glucuronidation, such as indomethacin, nordazepam, acetylsalicylic acid (aspirin) and trimethoprim, decreased the elimination rate and increased the therapeutic strength of the medication.[35] Most common side-effects included upset stomach and acid reflux (heartburn), headache, cosmetic reduction in abdominal body fat, light sleeping, and occasional loss of appetite; while less-common complaints included faint discoloration of fingernails and toenails, mood elevation, occasional tingling or transient numbness of the hands or feet, and minor skin discoloration. Allergic reactions were rare.[36] Today, side-effects are much less common with the use of lower doses of AZT.[37] According to IARC, there is sufficient evidence in experimental animals for the carcinogenicity of zidovudine; it is possibly carcinogenic to humans (Group 2B).[38]
Viral resistance
Even at the highest doses that can be tolerated in patients, AZT is not potent enough to prevent all HIV replication, and may only slow the replication of the virus and the progression of the disease. During prolonged AZT treatment, HIV has the potential to develop resistance to AZT by mutation of its reverse transcriptase.[39][40] To slow the development of resistance, physicians generally recommend that AZT be given in combination with another reverse transcriptase inhibitor and an antiretroviral from another group, such as a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy).
Mechanism of action
AZT in oral, injectable, and suppository form
AZT is a thymidine analogue. AZT works by selectively inhibiting HIV's reverse transcriptase, the enzyme that the virus uses to make a DNA copy of its RNA. Reverse transcription is necessary for production of HIV's double-stranded DNA, which would be subsequently integrated into the genetic material of the infected cell (where it is called a provirus).[8][11][41]
Cellular enzymes convert AZT into the effective 5'-triphosphate form. Studies have shown that the termination of HIV's forming DNA chains is the specific factor in the inhibitory effect.
At very high doses, AZT's triphosphate form may also inhibit DNA polymerase used by human cells to undergo cell division, but regardless of dosage AZT has an approximately 100-fold greater affinity for HIV's reverse transcriptase.[42] The selectivity has been proven to be due to the cell's ability to quickly repair its own DNA chain if it is broken by AZT during its formation, whereas the HIV virus lacks that ability.[43] Thus AZT inhibits HIV replication without affecting the function of uninfected cells.[8] At sufficiently high dosages, AZT begins to inhibit the cellular DNA polymerase used by mitochondria to replicate, accounting for its potentially toxic but reversible effects on cardiac and skeletal muscles, causing myositis.[10][44][45][46][47]
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 network of base-paired dimers; its multiscaled crystallized lattice superstructure and surfactant headgroup electrostatic bond polarity was reported in 1988 and 1987.[48][49]
History
In the 1960s the theory that most cancers were caused by environmental retroviruses gained clinical support and funding. It had recently become known, due to the work of Nobel laureates Howard Temin and David Baltimore,[50] that nearly all avian cancers were caused by bird retroviruses, but corresponding human retroviruses have not yet been found.
In parallel work, other compounds that successfully blocked the synthesis of nucleic acids had been proven to be both antibacterial, antiviral, and anticancer agents, the leading work being done at the laboratory of Nobel laureates George Hitchings and Gertrude Elion, leading to the development of the antitumor agent 6-mercaptopurine.[50]
Jerome Horwitz of the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine first synthesized AZT in 1964 under a US National Institutes of Health (NIH) grant.[9][51][52] Development was shelved after it proved biologically inert in mice.[9][53] In 1974, Wolfram Ostertag of the Max Planck Institute for Experimental Medicine in Göttingen, Germany reported that AZT specifically targeted Friend virus (strain of murine leukemia virus).[54]
Society and culture
See also: Cost of HIV treatment
The patents on AZT have been the target of some controversy. In 1991, the advocacy group Public Citizen filed a lawsuit claiming that the patents were invalid. Subsequently, Barr Laboratories and Novopharm Ltd. also challenged the patent, in part based on the assertion that NCI scientists Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan should have been named as inventors, and those two companies applied to the FDA to sell AZT as a generic drug. In response, Burroughs Wellcome Co. filed a lawsuit against the two companies. The United States Court of Appeals for the Federal Circuit ruled in 1992 in favor of Burroughs Wellcome, ruling that even though they had never tested it against HIV, they had conceived of it working before they sent it to the NCI scientists.[55] This suit was appealed up to the Supreme Court of the US, but they declined to formally review it. In 2002, another lawsuit was filed over the patent by the AIDS Healthcare Foundation.
However, the patent expired in 2005 (placing AZT in the public domain), allowing other drug companies to manufacture and market generic AZT without having to pay GlaxoSmithKline any royalties. The U.S. FDA has since approved four generic forms of AZT for sale in the U.S.
In November 2009 GlaxoSmithKline formed a joint venture with Pfizer which combined the two companies' HIV assets in one company called ViiV Healthcare. This included the rights to Zidovudine.
References
- ^ "Zidovudine". PubChem Public Chemical Database. NCBI. Retrieved 2011-04-10.
- ^ Wright, K. (1986). "AIDS therapy: First tentative signs of therapeutic promise". Nature 323 (6086): 283. doi:10.1038/323283a0. PMID 3463865. edit
- ^ Jeffries, D. J. (1989). "Zidovudine resistant HIV". BMJ (Clinical research ed.) 298 (6681): 1132–1133. doi:10.1136/bmj.298.6681.1131. PMID 2500164. edit
- ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. March 2005. Retrieved 2006-03-12.
- ^ Weiss R (May 1993). "How does HIV cause AIDS?". Science 260 (5112): 1273–9. Bibcode:1993Sci...260.1273W. doi:10.1126/science.8493571. PMID 8493571
- ^ Douek D, Roederer M, Koup R (2009). "Emerging Concepts in the Immunopathogenesis of AIDS". Annu. Rev. Med. 60: 471–84.
- ^ NIH Clinical Center's 50th Anniversary. http://www.cc.nih.gov/about/news/anniver50/_pdf/CC_50th_Anniversary_Celebration.pdf
- ^ 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.
- ^ a b c Broder, S. (2009). "The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic". Antiviral Research 85 (1): 1–2. doi:10.1016/j.antiviral.2009.10.002. PMC 2815149. PMID 20018391. edit
- ^ 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.
- ^ 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.
- ^ Harvard Business Review. Burroughs Wellcome and AZT.http://hbr.org/product/burroughs-wellcome-and-azt-c/an/793115-PDF-ENG
- ^ 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.
- ^ Approval of Zidovudine (AZT) for Acquired Immunodeficiency Syndrome, September 18, 1987, Brook 258 (11): 1517 – JAMA
- ^ Cimons, Marlene (21 March 1987). "U.S. Approves Sale of AZT to AIDS Patients". Los Angeles Times. p. 1.
- ^ AZT Approved for AIDS Children. http://articles.latimes.com/1990-05-03/news/mn-603_1_azt-approved-for-aids-children
- ^ 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.
- ^ Yarchoan R, Mitsuya H, Broder S (1988). "AIDS therapies". Sci Am 259 (4): 110–9. doi:10.1038/scientificamerican1088-110. PMID 3072667.
- ^ "Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV". Retrieved 2006-03-29.
- ^ "UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011)". Retrieved 2014-04-07.
- ^ "Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health" (PDF). Retrieved 2006-03-29.
- ^ PLOS Hub. Clinical Trials. http://clinicaltrials.ploshubs.org/article/info%3Adoi%2F10.1371%2Fjournal.pctr.0020011
- ^ Science Codex.
- ^ CIDRZ. Prevention of AIDS Transmission (PMTCT). http://www.cidrz.org/pmtct
- ^ Transmission of HIV from infants http://aidsperspective.net/blog/?p=868
- ^ 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.
- ^ Walensky RP; Paltiel AD; Losina E et al. (July 2006). "The survival benefits of AIDS treatment in the United States". J. Infect. Dis. 194 (1): 11–9. doi:10.1086/505147. PMID 16741877.
- ^ Morris K. Short course of AZT halves HIV-1 perinatal transmission. Lancet. 1998 Feb 28;351(9103):651. PubMed PMID 9500334.
- ^ a b Crane, Johanna. "Adverse events and placebo effects: African scientists, HIV, and ethics in the ‘global health sciences’." Social studies of science 40.6 (2010): 843–870.
- ^ Crane, Johanna. "Adverse events and placebo effects: African scientists, HIV, and ethics in the ‘global health sciences’." Social studies of science 40.6 (2010): 843–870. pp. 861
- ^ Sun, R.; Eriksson, S.; Wang, L. (2010). "Identification and Characterization of Mitochondrial Factors Modulating Thymidine Kinase 2 Activity". Nucleosides, Nucleotides and Nucleic Acids 29 (4–6): 382–385. doi:10.1080/15257771003741018. PMID 20544523. edit
- ^ Scruggs, E. R.; Dirks Naylor, A. J. (2008). "Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy" (PDF). Pharmacology 82 (2): 83–88. doi:10.1159/000134943. PMID 18504416. edit
- ^ Fisher, J. W. (1997). "Erythropoietin: physiologic and pharmacologic aspects". Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 216 (3): 358–369. doi:10.3181/00379727-216-44183. PMID 9402140. edit
- ^ Fisher, J. W. (2003). "Erythropoietin: physiology and pharmacology update". Experimental biology and medicine (Maywood, N.J.) 228 (1): 1–14. PMID 12524467. edit
- ^ "ZIDOVUDINE (AZT) – ORAL (Retrovir) side effects, medical uses, and drug interactions". MedicineNet. Retrieved 2006-01-09.
- ^ "zidovudine, Retrovir". Medicinenet.com. 2010-08-12. Retrieved 2010-12-14.
- ^ Side Effects. NAM Aidsmap. http://www.aidsmap.com/Side-effects/page/1730907/
- ^ "Summary of Data Reported and Evaluation". 2000. Retrieved 11 August 2012.
- ^ Richman, D. (1990). "Susceptibility to nucleoside analogues of zidovudine-resistant isolates of human immunodeficiency virus". The American Journal of Medicine 88 (5B): 8S–10S. doi:10.1016/0002-9343(90)90414-9. PMID 2186629. edit
- ^ Wainberg, M. A.; Brenner, B. G.; Turner, D. (2005). "Changing Patterns in the Selection of Viral Mutations among Patients Receiving Nucleoside and Nucleotide Drug Combinations Directed against Human Immunodeficiency Virus Type 1 Reverse Transcriptase". Antimicrobial Agents and Chemotherapy 49 (5): 1671–1678. doi:10.1128/AAC.49.5.1671-1678.2005. PMC 1087622. PMID 15855480. edit
- ^ 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.
- ^ 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.
- ^ Induction of Endogenous Virus and of Thymidline Kinase. http://www.pnas.org/content/71/12/4980.full.pdf
- ^ 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.
- ^ 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.
- ^ Rang H.P., Dale M.M., Ritter J.M. (1995). Pharmacology (3rd ed.). Pearson Professional Ltd. ISBN 0-443-05974-8.
- ^ 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.
- ^ Dyer I, Low JN, Tollin P, Wilson HR, Howie RA (April 1988). "Structure of 3'-azido-3'-deoxythymidine, AZT". Acta Crystallogr C 44 (4): 767–9. doi:10.1107/S0108270188000368. PMID 3271074.
- ^ Azidothymidine: crystal structure and possible functional role of the azido group
- ^ a b The DNA Provirus Hypothesis
- ^ Horwitz, JP; Chua J; Noel MJ (1964). "The monomesylates of 1-(2-deoxy-bd-lyxofuranosyl) thymines". Org. Chem. Ser. Monogr 29 (7): 2076–9. doi:10.1021/jo01030a546.
- ^ Detours V; Henry D (writers/directors) (2002). I am alive today (history of an AIDS drug) (Film). ADR Productions/Good & Bad News.
- ^ "A Failure Led to Drug Against AIDS". The New York Times. 1986-09-20. Retrieved 2010-06-30.
- ^ Ostertag, W.; Roesler, G.; Krieg, C. J.; Kind, J.; Cole, T.; Crozier, T.; Gaedicke, G.; Steinheider, G.; Kluge, N.; Dube, S. (1974). "Induction of endogenous virus and of thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus". Proceedings of the National Academy of Sciences of the United States of America 71 (12): 4980–4985. Bibcode:1974PNAS...71.4980O. doi:10.1073/pnas.71.12.4980. PMC 434023. PMID 4531031. edit
- ^ 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.
External links
|
Pharmacology portal |
|
Viruses portal |
- U.S. National Library of Medicine: Drug Information Portal – Zidovudine
|
Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
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Entry/fusion inhibitors
(Discovery and development) |
- gp41 (Enfuvirtide (ENF, T-20))
- CCR5 (Maraviroc (MVC)
- Vicriviroc†, Cenicriviroc†, PRO 140†)
- CD4 (Ibalizumab†)
- gp120 (Fostemsavir†)
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Reverse-transcriptase
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Nucleoside and
nucleotide (NRTI) |
- Nucleoside analogues/NARTIs: Abacavir (ABC)°#
- Emtricitabine (FTC)°#
- Lamivudine (3TC)°#
- Didanosine (ddI)#
- Zidovudine (AZT, ZDV)#
- Apricitabine†
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- Racivir†
- Amdoxovir†
- Stavudine (d4T)#
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Non-nucleoside (NNRTI)
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- Nevirapine (NVP)#
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(2nd generation) diarylpyrimidines (Etravirine (ETR)- Rilpivirine (RPV)°)
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| Integrase inhibitors |
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Protease Inhibitors (PI)
(Discovery and development) |
| 1st generation |
- Fosamprenavir (FPV)
- Lopinavir (LPV)°#
- Nelfinavir (NFV)#
- Ritonavir (RTV)#
- Saquinavir (SQV)#
- Amprenavir (APV)◊
- Indinavir (IDV)◊#
- Telinavir
- Droxinavir
|
|
| 2nd generation |
- Atazanavir (ATV)°
- Darunavir (DRV)°
- Tipranavir (TPV)
|
|
|
| Combined formulations |
- Lamivudine/zidovudine
- Lopinavir/ritonavir°
- Abacavir/lamivudine/zidovudine
- Abacavir/lamivudine°
- Tenofovir/emtricitabine°
- Emtricitabine/tenofovir/efavirenz°
- Emtricitabine/rilpivirine/tenofovir°
- Elvitegravir/cobicistat/emtricitabine/tenofovir°
- Abacavir/dolutegravir/lamivudine°
- Atazanavir/cobicistat
- Darunavir/cobicistat
- Lamivudine/raltegravir
|
|
| Boosters |
- Ritonavir (r)
- Cobicistat (cobi)
|
|
| Experimental agents |
| Uncoating inhibitors |
|
|
| Transcription inhibitors |
|
|
| Translation inhibitors |
|
|
| Other |
- Abzyme
- Calanolide A
- Ceragenin
- Cyanovirin-N
- Diarylpyrimidines
- Epigallocatechin gallate (EGCG)
- Foscarnet
- Griffithsin
- Hydroxycarbamide
- Miltefosine
- Portmanteau inhibitors
- Scytovirin
- Seliciclib†
- Synergistic enhancers
- Tre recombinase
- Zinc finger protein transcription factor
- KP-1461†
- BIT225†
|
|
| Failed agents |
- Aplaviroc
- Atevirdine
- Brecanavir
- Capravirine
- Dexelvucitabine
- Emivirine
- Lersivirine
- Lodenosine
- Loviride
|
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
°DHHS recommended initial regimen options. ◊Formerly or rarely used agent.
|
Index of viral disease
|
|
| Description |
|
|
| Disease |
- Systemic
- Cutaneous
- Zoster
- Human papillomavirus
- Zoonotic
- Symptoms and signs
|
|
| Treatment |
|
|
|
|
GlaxoSmithKline
|
|
| Subsidiaries |
- GlaxoSmithKline Pakistan
- GlaxoSmithKline Pharmaceuticals Ltd
- Stiefel Laboratories
- ViiV Healthcare (85%)
|
|
Predecessors,
acquisitions |
- Allen & Hanburys
- Beecham Group
- Block Drug
- Burroughs Wellcome
- Glaxo
- Glaxo Wellcome
- Human Genome Sciences
- Recherche et Industrie Thérapeutiques
- Reliant Pharmaceuticals
- S. E. Massengill Company
- SmithKline Beecham
- Smith, Kline & French
|
|
| Products |
|
Current
|
|
Pharmaceuticals
|
- Advair
- Alli
- Augmentin
- Avandia
- Beconase
- Boniva
- Flixonase
- Hycamtin
- Lamictal
- Paxil/Seroxat
- Serlipet
- Tagamet
- Ventolin
- Wellbutrin/Zyban
- Zantac … more
|
|
|
Vaccines
|
- Hepatyrix
- Pandemrix
- Twinrix
|
|
|
Other
|
- Aquafresh
- Horlicks
- Nicoderm
- Nicorette
- NiQuitin
- Sensodyne
- Tums … more
|
|
|
|
Former
|
- BC Powder
- Geritol
- Goody's Powder
- Lucozade
- Ribena
|
|
|
| People |
|
Governance
|
- Chris Gent (chair)
- Andrew Witty (CEO)
|
|
|
Other
|
- Thomas Beecham
- Silas M. Burroughs
- Mahlon Kline
- John K. Smith
- Henry Wellcome
|
|
|
| Litigation |
- Canada v. GlaxoSmithKline Inc.
- Christopher v. SmithKline Beecham Corp.
- GlaxoSmithKline Services Unlimited v Commission
- United States v. Glaxo Group Ltd.
- United States v. GlaxoSmithKline
|
|
| Other |
- Drug Industry Document Archive
- GlaxoSmithKline Prize
- Side Effects (2008)
- Study 329
|
|
|
|
|
