Zidovudine

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Zidovudine
Systematic (IUPAC) name
1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione
Identifiers
CAS number	30516-87-1
ATC code	J05AF01
PubChem	35370
DrugBank	APRD00449
ChemSpider	32555
Chemical data
Formula	C10H13N5O4
Mol. mass	267.242 g/mol
SMILES	eMolecules & PubChem
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 a nucleoside analog reverse transcriptase inhibitor (NRTI), a type of antiretroviral drug. It was the first approved treatment for 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.

AZT use was major breakthrough in AIDS therapy in the 1990s that significantly altered the course of the illness.

Contents 1 History 2 Prophylaxis 3 Side effects 4 Viral resistance 5 Mode of action 6 Patent issues 7 References

[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^[1][2], under a US National Institutes of Health (NIH) grant. AZT was originally intended as an anticancer drug, but was shelved after it proved insufficiently toxic to cancer tumours in mice.^[3]

In 1974 W. Ostertag from the Max Planck Institute in Germany showed that AZT was active against a mouse retrovirus^[4].

In 1984, shortly after the Human Immunodeficiency Virus (HIV) had been confirmed as the cause of AIDS, scientists at Burroughs Wellcome Co. (BW) began searching for compounds with activity against the virus. Burroughs Wellcome had expertise in antiviral disease led by researchers including Gertrude Elion, David Barry, Phil Furman, Marty St. Clair, Janet Rideout, Sandi Lehman and others. Their research effort focused on the viral enzyme reverse transcriptase. Reverse transcriptase is an enzyme that HIV utilizes to replicate itself. Scientists at BW began to identify and synthesize compounds and developed a screen to test for activity. One compound coded BW A509U was tested and demonstrated potent activity. With this activity identified, the coded compound was sent to the NIH for confirmatory testing.

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), started working on it as an AIDS drug. After showing that this drug was an effective agent against HIV in vitro, the Burroughs Wellcome and NCI team conducted the initial phase 1 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.^[5] 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,^[6] 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 is anemia, a common complaint in early trials.

Current treatment regimens involve lower dosages (e.g., 300 mg) of AZT taken twice a day, almost always as part of highly active antiretroviral therapy (HAART). AZT is combined with other drugs in order to prevent mutation of HIV into an AZT-resistant form.^[7][8]

The crystal structure of AZT was reported by Alan Howie (Aberdeen University) in 1988.^[9] In the solid state AZT forms a hydrogen bond network.

[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).^[10]

AZT is also recommended as part of a regimen to prevent mother-to-child transmission of HIV during pregnancy, labor, and delivery.^[11] 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.^[12] During the period from 1994-1999 when this was the primary form of prevention of mother-to-child HIV transmission, AZT prophylaxis prevented more than 1000 infant HIV infections.^[13] Use of appropriate combinations of antiretroviral medications, cesarean section and avoidance of breast feeding 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 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 antiviral agents such as acyclovir and interferon; however, ribavirin decreases 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.^[14]

[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, HIV has the ability to gain an increased resistance to AZT by mutation of its reverse transcriptase. A study^{[citation needed]} 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. 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.

[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. Reverse transcription is necessary for production of the viral double-stranded DNA, which is subsequently integrated into the genetic material of the infected cell (where it is called a provirus).^[15][16][17]

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.^[18][16][19] However, AZT has a 100-fold greater affinity for the HIV reverse transcriptase than for the human DNA polymerase alpha, accounting for its selective antiviral activity.^[16][18] 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).^{[20][21][22][23][24]}

[edit] Patent issues

AZT has been the target of some controversy due to the nature of the patent process.^[25]

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.^[26] 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. ^[27] 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.

[edit] References

v • d • e Antiviral drugs: antiretroviral drugs used against HIV (primarily J05) Entry/fusion inhibitors gp41 (Enfuvirtide) · CCR5 (Maraviroc, Vicriviroc†, PRO 140†) · CD4 (Ibalizumab†) Reverse transcriptase inhibitors (RTIs) Nucleoside & Nucleotide (NRTI) Nucleoside analogues/NARTIs: Abacavir (ABC)°# · Emtricitabine (FTC)°# · Lamivudine (3TC)°# · Didanosine (ddI)# · Zidovudine (AZT)# · Apricitabine† · Stampidine† · Elvucitabine† · Racivir† · Amdoxovir† · Stavudine (d4T)# · Zalcitabine (ddC)◊ Nucleotide analogues/NtRTIs: Tenofovir°# Non-Nucleoside (NNRTI) Efavirenz°# · Nevirapine# · diarylpyrimidines (Etravirine, Rilpivirine†) · Loviride◊ · Delavirdine◊ · Integrase inhibitors Raltegravir · Elvitegravir† · Globoidnan A (experimental) Maturation inhibitors Bevirimat† · Vivecon† Protease Inhibitors (PI) Atazanavir° · Fosamprenavir° · Lopinavir°# · Darunavir · Nelfinavir# · Ritonavir# · Saquinavir# · Tipranavir · Amprenavir◊ · Indinavir◊# Combined formulations Combivir · Atripla · Trizivir · Truvada · Kaletra · Epzicom Experimental agents Uncoating inhibitors TRIM5alpha (gene) Transcription inhibitors Tat antagonists Translation inhibitors Trichosanthin Other Abzyme · Calanolide A · Ceragenin · Cyanovirin-N · Diarylpyrimidines · Epigallocatechin gallate (EGCG) · Foscarnet · Griffithsin · Hydroxyurea · Miltefosine · Portmanteau inhibitors · Seliciclib† · Synergistic enhancers · Tre recombinase · Zinc finger protein transcription factor · KP-1461† Failed agents Dexelvucitabine · Capravirine · Emivirine · Lodenosine · Atevirdine · Brecanavir · Aplaviroc #WHO-EM. †Undergoing clinical trials, not FDA approved. ‡Withdrawn from market. §Development halted. °DHHS preferred first-line agent. ◊Formerly or rarely used agent.