Zidovudine

Zidovudine (thymidine.

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 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 CD4 counts in AIDS patients.

A 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 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.^[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.

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%.

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 trimethoprim, decrease the elimination rate and increase the toxicity.^[7]

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 non-nucleoside reverse transcriptase inhibitor.

Mode of action

  Like other DNA of a target cell, where it is called a provirus.^[8][9][10]

The azido group increases 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 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).^{[15][16][17][18][19]}

Controversy

AZT has been the target of some controversy due to the nature of the patent process.^[20]

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.^[21] 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. ^[22] 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 generic forms of AZT for sale in the U.S.

23. Katzung, Bertram G. Basic and Clinical Pharmacology, 10th edition. New York: McGraw, Hill Lange Medical, 2007, pp.536-541