more specific drug category |
Tightened up and added Duesberg references. |
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==History== |
==History== |
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Zidovudine was the first drug |
Zidovudine was the first FDA-approved drug for the treatment of AIDS and HIV infection. [[Jerome Horwitz]] of 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]]. Originally intended for use as [[chemotherapy]], AZT failed to show efficacy and had what was then viewed as an unacceptably high [[side effect]] profile. The drug then faded from view until November 1984, when Dr Marty St Clair, working for [[British]] pharmaceutical company GSK discovered that HIV-infected cells stored on petri dishes and treated with AZT didn't die as untreated HIV-infected cells had. [http://news.bbc.co.uk/1/hi/health/7117651.stm] |
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⚫ | |||
⚫ | In February [[1985]], [[Samuel Broder]], [[Hiroaki Mitsuya]], and [[Robert Yarchoan]], three scientists in the [[National Cancer Institute]] (NCI), collaborating with Janet Rideout and several other scientists at Burroughs Wellcome (now [[GlaxoSmithKline]]), began testing AZT as an AIDS drug. After showing that this drug was an effective agent against HIV [[in vitro]], the team conducted the initial [[clinical trial]] that showed the human body’s tendency to temporarily increase [[CD4]] counts in response to trauma or infection was not inhibited in AIDS patients undergoing AZT treatment. <ref>Inventing the AIDS Virus, Peter H. Duesberg</ref> |
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⚫ | A |
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⚫ | A more extensive trial of AZT was subsequently conducted by Burroughs-Wellcome, but AZT's toxicity quickly defeated standard [[double-blind]], placebo-controlled protocols and the trial’s objectivity remains disputed on these and other grounds. <ref>Inventing the AIDS Virus, Peter H. Duesberg</ref> Claiming nevertheless that AZT prolonged the lives of the trial-patients with AIDS, Burroughs Wellcome Co. filed for a patent on AZT in [[1985]]. On March 20, [[1987]], the [[Food and Drug Administration]] (FDA) approved the drug, using its then-new accelerated approval system, for use against both HIV and AIDS, as well as Aids Related Complex (ARC), a now-obsolete medical term for pre-AIDS illnesses. In [[1990]] AZT was approved as a prophylactic treatment for immediate use following exposure to HIV (see Prophylaxis, below). AZT was initially administered in much higher dosages than today, typically 400 mg every four hours around the clock. For some, the unavailability of less-toxic, FDA-approved alternatives biased the perceived risk/benefit ratio towards AZT, given HIV’s uncertain infection-risk versus benefits said to derive from the very toxicity that had led to AZT’s being left unpatented in 1964. |
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Modern treatment regimens typically use lower dosages (e.g. 300 mg) two to three times a day. [[As of 1996]], AZT, like other [[antiretroviral drug]]s, is almost always used as part of ''[[highly active antiretroviral therapy]]'' (HAART). That is, it is combined with other drugs in order to prevent mutation of HIV into an AZT-resistant form.<!-- |
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Early trials showed one of AZT's side effects to be [[anemia]]. As the chemotherapy it was developed to be, AZT is most effective against cells that are continually dividing, as young cancer-cells, hair, and bone-marrow cells do. Current treatment regimens typically use lower dosages (e.g. 300 mg) two to three times a day. Since a lower dose necessarily reduces AZT’s stated effectiveness, as of [[1996]] it and other [[antiretroviral drugs]] are typically combined as part of what is named [[highly active antiretroviral therapy]] (HAART). That is, the drugs are combined with the goal of slowing HIV’s fast and persistent mutations into AZT-resistant forms. <!-- |
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--><ref>{{cite journal | author=De Clercq E | title=HIV resistance to reverse transcriptase inhibitors. | journal=Biochem Pharmacol | volume=47 | issue=2 | pages=155-69 | year=1994 | id=PMID 7508227}}</ref><!-- |
--><ref>{{cite journal | author=De Clercq E | title=HIV resistance to reverse transcriptase inhibitors. | journal=Biochem Pharmacol | volume=47 | issue=2 | pages=155-69 | year=1994 | id=PMID 7508227}}</ref><!-- |
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--><ref>{{cite journal | author=Yarchoan R, Mitsuya H, Broder S | title=AIDS therapies. | journal=Sci Am | volume=259 | issue=4 | pages=110-9 | year=1988 | id=PMID 3072667}}</ref> |
--><ref>{{cite journal | author=Yarchoan R, Mitsuya H, Broder S | title=AIDS therapies. | journal=Sci Am | volume=259 | issue=4 | pages=110-9 | year=1988 | id=PMID 3072667}}</ref> |
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Whether combined or taken singly, the biological action undertaken by these antiretroviral drugs remains unchanged: prevention of DNA synthesis during cell division. Thus AZT has over the years been commonly described as a DNA chain terminator. |
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⚫ | |||
In the solid state AZT forms a [[hydrogen bond]] network. |
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==Prophylaxis== |
==Prophylaxis== |
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==Mode of action== |
==Mode of action== |
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[[Image:Azt pills.JPG|thumb|right|250px|AZT in oral and injectable form]] |
[[Image:Azt pills.JPG|thumb|right|250px|AZT in oral and injectable form]] |
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Like other [[reverse transcriptase inhibitor]]s, AZT works by inhibiting the action of [[reverse transcriptase]], the [[enzyme]] that HIV uses to make a [[DNA]] copy of its [[RNA]]. The viral double-stranded DNA is subsequently spliced into the [[DNA]] of a target [[cell (biology)|cell]], where it is called a [[provirus]].<!-- |
Like other [[reverse transcriptase inhibitor]]s, AZT works by inhibiting the action of [[reverse transcriptase]], the [[enzyme]] that HIV uses to make a [[DNA]] copy of its [[RNA]]. The viral double-stranded DNA is subsequently spliced into the [[DNA]] of a target, i.e. dividing, [[cell (biology)|cell]], where it is called a [[provirus]].<!-- |
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--><ref>{{cite journal | author=Mitsuya H, Yarchoan R, Broder S | title=Molecular targets for AIDS therapy. | journal=Science | volume=249 | issue=4976 | pages=1533-44 | year=1990 | id=PMID 1699273}}</ref><!-- |
--><ref>{{cite journal | author=Mitsuya H, Yarchoan R, Broder S | title=Molecular targets for AIDS therapy. | journal=Science | volume=249 | issue=4976 | pages=1533-44 | year=1990 | id=PMID 1699273}}</ref><!-- |
||
--><ref>{{cite journal | author=Mitsuya H, Weinhold K, Furman P, St Clair M, Lehrman S, Gallo R, Bolognesi D, Barry D, Broder S | title=3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus ''in vitro''. | journal=Proc Natl Acad Sci U S A | volume=82 | issue=20 | pages=7096-100 | year=1985 | id=PMID 2413459 | url=http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=2413459}}</ref><!-- |
--><ref>{{cite journal | author=Mitsuya H, Weinhold K, Furman P, St Clair M, Lehrman S, Gallo R, Bolognesi D, Barry D, Broder S | title=3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus ''in vitro''. | journal=Proc Natl Acad Sci U S A | volume=82 | issue=20 | pages=7096-100 | year=1985 | id=PMID 2413459 | url=http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=2413459}}</ref><!-- |
Revision as of 23:49, 4 January 2008
Clinical data | |
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Routes of administration | Oral |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | near complete absoprtion, following first-pass metabolism systemic availability 65% (range 52 to 75%) |
Protein binding | 30 to 38% |
Metabolism | Hepatic |
Elimination half-life | 0.5 to 3 hours |
Excretion | Renal |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
DrugBank | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.152.492 |
Chemical and physical data | |
Formula | C10H13N5O4 |
Molar mass | 267.242 g/mol g·mol−1 |
Zidovudine (INN) or azidothymidine (AZT) (also called ZDV) is an antiretroviral drug, the first approved for treatment of HIV. It is also sold under the names Retrovir® and Retrovis®, and as an ingredient in Combivir® and Trizivir®. It is an analog of thymidine.
History
Zidovudine was the first FDA-approved drug for the treatment of AIDS and HIV infection. Jerome Horwitz of 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. Originally intended for use as chemotherapy, AZT failed to show efficacy and had what was then viewed as an unacceptably high side effect profile. The drug then faded from view until November 1984, when Dr Marty St Clair, working for British pharmaceutical company GSK discovered that HIV-infected cells stored on petri dishes and treated with AZT didn't die as untreated HIV-infected cells had. [1]
In February 1985, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan, three scientists in the National Cancer Institute (NCI), collaborating with Janet Rideout and several other scientists at Burroughs Wellcome (now GlaxoSmithKline), began testing AZT as an AIDS drug. After showing that this drug was an effective agent against HIV in vitro, the team conducted the initial clinical trial that showed the human body’s tendency to temporarily increase CD4 counts in response to trauma or infection was not inhibited in AIDS patients undergoing AZT treatment. [2]
A more extensive trial of AZT was subsequently conducted by Burroughs-Wellcome, but AZT's toxicity quickly defeated standard double-blind, placebo-controlled protocols and the trial’s objectivity remains disputed on these and other grounds. [3] Claiming nevertheless that AZT prolonged the lives of the trial-patients with AIDS, Burroughs Wellcome Co. filed for a patent on AZT in 1985. On March 20, 1987, the Food and Drug Administration (FDA) approved the drug, using its then-new accelerated approval system, for use against both HIV and AIDS, as well as Aids Related Complex (ARC), a now-obsolete medical term for pre-AIDS illnesses. In 1990 AZT was approved as a prophylactic treatment for immediate use following exposure to HIV (see Prophylaxis, below). AZT was initially administered in much higher dosages than today, typically 400 mg every four hours around the clock. For some, the unavailability of less-toxic, FDA-approved alternatives biased the perceived risk/benefit ratio towards AZT, given HIV’s uncertain infection-risk versus benefits said to derive from the very toxicity that had led to AZT’s being left unpatented in 1964.
Early trials showed one of AZT's side effects to be anemia. As the chemotherapy it was developed to be, AZT is most effective against cells that are continually dividing, as young cancer-cells, hair, and bone-marrow cells do. Current treatment regimens typically use lower dosages (e.g. 300 mg) two to three times a day. Since a lower dose necessarily reduces AZT’s stated effectiveness, as of 1996 it and other antiretroviral drugs are typically combined as part of what is named highly active antiretroviral therapy (HAART). That is, the drugs are combined with the goal of slowing HIV’s fast and persistent mutations into AZT-resistant forms. [4][5] Whether combined or taken singly, the biological action undertaken by these antiretroviral drugs remains unchanged: prevention of DNA synthesis during cell division. Thus AZT has over the years been commonly described as a DNA chain terminator.
The crystal structure of AZT was reported by Alan Howie (Aberdeen University) in 1988. [6] In the solid state AZT forms a hydrogen bond network.
Prophylaxis
AZT may be used in combination with other antiretroviral medications to substantially reduce the risk of HIV infection following a significant exposure to the virus (such as a needle-stick injury involving blood or body fluids from an individual known to be infected with HIV).[7]
AZT is also recommended as part of a regimen to prevent mother-to-child transmission of HIV during pregnancy, labor and delivery.[8] With no treatment, approximately 25% of infants whose mothers are infected with HIV will become infected. AZT has been shown to reduce this risk to approximately 8% when given in a three-part regimen during pregnancy, delivery and to the infant for 6 weeks after birth.[9] Use of appropriate combinations of antiretroviral medications and cesarean section when necessary can further reduce mother-child transmission of HIV to 1-2%.
Side effects
Common side effects of AZT include nausea, headache, changes in body fat, and discoloration of fingernails and toenails. More severe side effects include anemia and bone marrow suppression, which can be overcome using erythropoietin or darbepoetin treatments.23 These unwanted side effects might be caused by the sensitivity of the γ-DNA polymerase in the cell mitochondria. AZT has been shown to work additively or synergistically with many anti-HIV agents; however, acyclovir and ribavirin decrease the antiviral effect of AZT. Drugs that inhibit hepatic glucuronidation, such as indomethacin, acetylsalicylic acid (Aspirin) and trimethoprim, decrease the elimination rate and increase the toxicity.[10]
Viral resistance
AZT does not destroy the HIV infection, but only delays the progression of the disease and the replication of virus, even at very high doses. During prolonged AZT treatment HIV has the ability to gain an increased resistance to AZT by mutation of the reverse transcriptase. A study showed that AZT could not impede the resumption of virus production, and eventually cells treated with AZT produced viruses as much as the untreated cells. So as to slow the development of resistance, it is generally recommended 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.
Mode of action
Like other reverse transcriptase inhibitors, AZT works by inhibiting the action of reverse transcriptase, the enzyme that HIV uses to make a DNA copy of its RNA. The viral double-stranded DNA is subsequently spliced into the DNA of a target, i.e. dividing, cell, where it is called a provirus.[11][12][13]
The azido group increases the lipophilic nature of AZT, allowing it to cross 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 shown that the termination of the formed DNA chains is the specific factor in the inhibitory effect.
The triphosphate form also has some ability to inhibit cellular DNA polymerase, which is used by normal cells as part of cell division.[14][15][16] However, AZT has a 100- to 300-fold greater affinity for the HIV reverse transcriptase, as compared to the human DNA polymerase, accounting for its selective antiviral activity.[17] A special kind of cellular DNA polymerase that replicates the DNA in mitochondria is relatively more sensitive to inhibition by AZT, and this accounts for certain toxicities such as damage to cardiac and other muscles (also called myositis).[18][19][20][21][22]
Controversy
AZT has been the target of some controversy due to the nature of the patent process.[23]
Patent issues
In 1991, Public Citizen filed a lawsuit claiming that the AZT/Zidovudine patent was invalid. The United States Court of Appeals for the Federal Circuit ruled in 1992 in favour of Burroughs-Wellcome, the licensee of the patent.[24] The court ruled that the challenge of the citizen group was not the correct approach to evaluate the underlying validity of the patent which was already being litigated in another suit. [25] 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.
Footnotes
- ^ "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.
- ^ Inventing the AIDS Virus, Peter H. Duesberg
- ^ Inventing the AIDS Virus, Peter H. Duesberg
- ^ De Clercq E (1994). "HIV resistance to reverse transcriptase inhibitors". Biochem Pharmacol. 47 (2): 155–69. PMID 7508227.
- ^ Yarchoan R, Mitsuya H, Broder S (1988). "AIDS therapies". Sci Am. 259 (4): 110–9. PMID 3072667.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Dr. Alan Howie. "Dr Alan Howie". University of Aberdeen. Retrieved 2006-01-18.
- ^ "Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV". Retrieved 2006-03-29.
- ^ "Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health" (PDF). Retrieved 2006-03-29.
- ^ 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. PMID 7935654.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ "ZIDOVUDINE (AZT) - ORAL (Retrovir) side effects, medical uses, and drug interactions". MedicineNet. Retrieved 2006-01-09.
- ^ Mitsuya H, Yarchoan R, Broder S (1990). "Molecular targets for AIDS therapy". Science. 249 (4976): 1533–44. PMID 1699273.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Mitsuya H, Weinhold K, Furman P, St Clair M, 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 U S A. 82 (20): 7096–100. PMID 2413459.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ 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. PMID 2869302.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ 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 U S A. 83 (21): 8333–7. PMID 2430286.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Mitsuya H, Weinhold K, Furman P, St Clair M, 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 U S A. 82 (20): 7096–100. PMID 2413459.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Plessinger M, Miller R. "Effects of zidovudine (AZT) and dideoxyinosine (ddI) on human trophoblast cells". Reprod Toxicol. 13 (6): 537–46. PMID 10613402.
- ^ Mitsuya H, Weinhold KJ, Furman PA, et al: 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. Med Sci 1985; 82:7096-7100.
- ^ 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. PMID 15319672.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ 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) - ^ Rang H.P., Dale M.M., Ritter J.M. (1995). Pharmacology (3rd edition ed.). Pearson Professional Ltd.
{{cite book}}
:|edition=
has extra text (help)CS1 maint: multiple names: authors list (link) - ^ Balzarini J, Naesens L, Aquaro S, Knispel T, Perno C, De Clercq E, Meier C (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) - ^ 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. PMID 2671731.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ The Best Democracy Money Can Buy by Greg Palast (2002)
- ^ People with Aids Health Group v. Burroughs Wellcome Co., 1992 U.S. Dist. LEXIS 578
- ^ 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.
23. Katzung, Bertram G. Basic and Clinical Pharmacology, 10th edition. New York: McGraw, Hill Lange Medical, 2007, pp.536-541