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The AZT
Molecule

(Zidovudine)

For 3D Structures

Zidovudine or azidothymidine (AZT)

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,
Epzicom and Trizivir. It is an analog of thymidine.

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 November 1984,
when Dr Marty St Clair, working for British pharmaceutical company GSK
discovered that AZT could retard the growth of the HIV virus on petri dishes.
[1] Later, in 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 1985. 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 HIV into an
AZT-resistant form.[2][3] The crystal structure of the AZT molecule was
reported by Alan Howie (Aberdeen University) in 1988.[4] In the solid state
AZT forms a hydrogen bond network.

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).[5] AZT is also recommended
as part of a regimen to prevent mother-to-child transmission of HIV during
pregnancy, labor and delivery.[6] 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.[7] 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 ?-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,
http://en.wikipedia.org/wiki/Zidovudinedecrease the elimination rate and
increase the toxicity.[8]

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

AZT in oral and injectable formLike 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.[9][10][11] 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.[12][13][14] 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.
[15] 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).[16][17][18][19][20]

Footnotes

8. ZIDOVUDINE (AZT) - ORAL

1. 'I thought I had made a mistake',
by Angus Crawford. Published
by the BBC on December 1,
2007; accessed Februrary 4
2008.
2. De Clercq E (1994). "HIV
resistance to reverse
transcriptase inhibitors.".
Biochem Pharmacol 47 (2):
155-69. PMID 7508227.
3. Yarchoan R, Mitsuya H, Broder
S (1988). "AIDS therapies.". Sci
Am 259 (4): 110-9. PMID
3072667.
4. Dr. Alan Howie. Dr Alan
Howie. University of Aberdeen.
Retrieved on 2006-01-18.
5. Updated U.S. Public Health
Service Guidelines for the
Management of Occupational
Exposures to HIV. Retrieved on
2006-03-29.
6. Recommendations for Use of
Antiretroviral Drugs in Pregnant
HIV-1-Infected Women for
Maternal Health. Retrieved on
2006-03-29.
7. 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.
(Retrovir) side effects, medical
uses, and drug interactions.
MedicineNet. Retrieved on
2006-01-09.
9. Mitsuya H, Yarchoan R, Broder
S (1990). "Molecular targets for
AIDS therapy.". Science 249
(4976): 1533-44. PMID
1699273.
10. 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.
11. 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.
12. 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.
13. 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.
14. Plessinger M, Miller R. "Effects
of zidovudine (AZT) and
dideoxyinosine (ddI) on human
trophoblast cells.". Reprod
Toxicol 13 (6): 537-46. PMID
10613402.
15. 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.
16. 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.
17. 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.
18. Rang H.P., Dale M.M., Ritter
J.M. (1995). Pharmacology, 3rd
edition, Pearson Professional
Ltd.
19. 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.
20. 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.
21. The Best Democracy Money
Can Buy by Greg Palast (2002)
22. People with Aids Health Group
v. Burroughs Wellcome Co.,
1992 U.S. Dist. LEXIS 578
23. 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 on
2007-02-28.

Katzung, Bertram G. Basic and Clinical Pharmacology, 10th edition.

New York: McGraw, Hill Lange Medical, 2007, pp.536-541

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