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Trizivir (abacavir + zidovudine + lamivudine) hivandhepatitis.com | Zidovudine (Retrovir) - Intravenous (IV) Dilution globalrph.com |
"AZT" redirects here. For other uses, see AZT (disambiguation).
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 a major breakthrough in AIDS therapy in the 1990s that significantly altered the course of the illness and helped destroy the notion of the 1980s and early 90s that HIV/AIDS was a death sentence.
[edit] HistoryZidovudine 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 effective against tumors in mice.[3] In 1974 W. Ostertag from the Max Planck Institute in Germany provided some evidence that AZT was active in a mouse retrovirus culture system [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 to treat the disease. Burroughs Wellcome had expertise in viral diseases, 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 retroviruses, including HIV, utilize to replicate themselves. Scientists at BW began to identify and synthesize compounds and developed a screen to test for activity against murine (mouse) retroviruses. One compound coded BW A509U was tested and demonstrated potent activity against those mouse viruses. At the same time, Drs. Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan in the US National Cancer Institute (NCI) had initiated an independent program to develop therapy for AIDS. The scientists at BW were not themselves working with HIV, and so the two groups decided to work together. In February 1985, the NCI scientists showed that BW A509U had potent activity against HIV in the test tube, and several months later, they started the initial phase 1 clinical trial of AZT at the NCI, in collaboration with scientists from Burroughs Wellcome and Duke University [5][6] [7]. This trial showed that the drug could be safely administered to patients with HIV and that it could increase CD4 counts in AIDS and other HIV-infected 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.[8] 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,[9]. The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was only 25 months, which is one of the shortest periods of drug development in recent history. AZT was subsequently approved 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.[10][11] The crystal structure of AZT was reported by Alan Howie (Aberdeen University) in 1988.[12] 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).[13] AZT is also recommended as part of a regimen to prevent mother-to-child transmission of HIV during pregnancy, labor, and delivery.[14] 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.[15] During the period from 1994 to 1999 when this was the primary form of prevention of mother-to-child HIV transmission, AZT prophylaxis prevented more than 1000 infant HIV infections.[16] 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 effectsCommon 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.[17] [edit] Viral resistanceAZT 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).[18][5][7] 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.[19][5][20] 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.[5][19] 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).[21][22][23][24][6] [edit] Patent issuesThe patents on AZT have been the target of some controversy. In 1991, Public Citizen filed a lawsuit claiming that the patents were invalid. Subsequently, Barr Laboraties and Novopharm Ltd. also challenged the patent, in part based on the assertion that the NCI scientists should have been named as inventors, and those two companies applied to the FDA to sell AZT as a generic drug. In response, Burroughs Wellcome Co. filed a lawsuit against the two companies. The United States Court of Appeals for the Federal Circuit ruled in 1992 in favour of Burroughs Wellcome, claiming that even though they had never tested it against HIV, they had conceived of it working before they sent it to the NCI scientists.[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. [edit] References
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