Zidovudine

From Wikipedia, the free encyclopedia

Zidovudine chemical structure
Zidovudine
Systematic (IUPAC) name
1-[(2R,4S,5S)- 4-azido-5-(hydroxymethyl) oxolan-2-yl]- 5-methyl-pyrimidine-2,4-dione
Identifiers
CAS number 30516-87-1
ATC code J05AF01
PubChem 35370
DrugBank APRD00449
Chemical data
Formula C10H13N5O4 
Mol. weight 267.242 g/mol
Pharmacokinetic data
Bioavailability near complete absoprtion, following first-pass metabolism systemic availability 65% (range 52 to 75%)
Protein binding 30 to 38%
Metabolism Hepatic
Half life 0.5 to 3 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat.

C(US)
Legal status
Routes Oral

Zidovudine (INN) or azidothymidine (AZT) (also called ZDV) is an antiretroviral drug, the first one 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.

Contents

[edit] History

Zidovudine was the first drug approved 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. It was originally intended to treat cancer, but failed to show efficacy and had an unacceptably high side effect profile. The drug then faded from view until February 1985, when 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), started working on it 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 provided evidence that it could increase CD4 counts in AIDS patients.

A placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome, in which it was shown that AZT could prolong the life of patients with AIDS. Burroughs Wellcome Co. filed for a patent on AZT in 1986. The 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-defunct medical term for pre-AIDS illness) on March 20, 1987, and then as a preventive treatment in 1990. It was initially administered in much higher dosages than today, typically 400 mg every four hours (even at night). However, the unavailability at that time of alternatives to treat AIDS affected the risk/benefit ratio, with the certain toxicity of HIV infection outweighing the risk of drug toxicity. One of AZT's side effects includes anemia, a common complaint in early trials.

Modern treatment regimens typically use lower dosages (e.g. 300 mg) two to three times a day. As of 1996, AZT, like other antiretroviral drugs, 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 the HIV into an AZT-resistant form.[1][2]

The crystal structure of AZT was reported by Alan Howie (Aberdeen University) in 1988.[3] In the solid state AZT forms a hydrogen bond network. Note that AZT is based upon a sugar.

[edit] 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).[4]

AZT is also recommended as part of a regimen to prevent mother-to-child transmission of HIV during pregnancy, labor and delivery.[5] 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.[6] Use of appropriate combinations of antiretroviral medications and cesarean section when necessary can further reduce mother-child transmission of HIV to 1-2%.

[edit] 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 anaemia and bone marrow suppression. 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.[7]

[edit] 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 the HIV-virus 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.

[edit] 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 cell, where it is called a provirus.[8][9][10]

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.[11][12][13] 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.[14] A special kind of cellular DNA polymerase that replicates the DNA in mitochondria is relatively more sensitive to inibition by AZT, and this accounts for certain toxicities such as damage to cardiac and other muscles (also called myositis).[15][16][17][18][19]

[edit] Controversy

AZT has been the target of some controversy due to the nature of the patent process[20] and as part of Dr. Peter Duesberg's challenge to the virus-AIDS hypothesis.

[edit] 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 1994 in favour of GlaxoSmithKline. In 2002, another lawsuit was filed over the patent by the AIDS Healthcare Foundation.

However, the patent expired in March 2006 (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.

[edit] Peter Duesberg's claims

See also: AIDS reappraisal
See also: Duesberg hypothesis

Dr. Peter Duesberg claims that AZT or other immunosuppressive drugs (nitrite inhalants, cocaine, amphetamines, etc.), rather than HIV, cause AIDS in Western countries.[21] Most scientists believe that Duesberg's claims are contradicted by an overwhelming amount of clinical and epidemiological evidence.[22]

[edit] Footnotes

  1. ^ De Clercq E (1994). "HIV resistance to reverse transcriptase inhibitors.". Biochem Pharmacol 47 (2): 155-69. PMID 7508227.
  2. ^ Yarchoan R, Mitsuya H, Broder S (1988). "AIDS therapies.". Sci Am 259 (4): 110-9. PMID 3072667.
  3. ^ Dr. Alan Howie. Dr Alan Howie. University of Aberdeen. Retrieved on 2006-01-18.
  4. ^ Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV. Retrieved on 2006-03-29.
  5. ^ Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health. Retrieved on 2006-03-29.
  6. ^ 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.
  7. ^ ZIDOVUDINE (AZT) - ORAL (Retrovir) side effects, medical uses, and drug interactions. MedicineNet. Retrieved on 2006-01-09.
  8. ^ Mitsuya H, Yarchoan R, Broder S (1990). "Molecular targets for AIDS therapy.". Science 249 (4976): 1533-44. PMID 1699273.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ Plessinger M, Miller R. "Effects of zidovudine (AZT) and dideoxyinosine (ddI) on human trophoblast cells.". Reprod Toxicol 13 (6): 537-46. PMID 10613402.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ Rang H.P., Dale M.M., Ritter J.M. (1995). Pharmacology, 3rd edition, Pearson Professional Ltd.
  18. ^ 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.
  19. ^ 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.
  20. ^ The Best Democracy Money Can Buy by Greg Palast (2002)
  21. ^ Peter H. Duesberg. Duesberg on AIDS. Peter H. Duesberg. Retrieved on 2006-01-18.
  22. ^ The Evidence That HIV Causes AIDS. Retrieved on 2006-03-29.


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Antivirals (primarily J05A, also S01AD and D06BB) edit
Anti-herpesvirus agents   Aciclovir, Cidofovir, Docosanol, Famciclovir, Fomivirsen, Foscarnet, Ganciclovir, Idoxuridine, Penciclovir, Trifluridine, Tromantadine, Valaciclovir, Valganciclovir, Vidarabine
Anti-influenza agents Amantadine, Oseltamivir, Peramivir, Rimantadine, Zanamivir
 
Antiretroviral drugs   NRTIs Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Zalcitabine, Zidovudine
NtRTIs   Tenofovir
NNRTIs   Efavirenz, Delavirdine, Nevirapine
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Fusion inhibitors Enfuvirtide
 
Other antiviral agents Adefovir, Fomivirsen, Imiquimod, Inosine,Interferon, Podophyllotoxin, Ribavirin, Viramidine
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