AZT

AZT
IUPAC name	1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione
Tradename	Retrovir
CAS number	30516-87-1
DrugBank	DB00495
UNII Ref	correct, FDA
UNII	4B9XT59T7S
ATC prefix	J05
ATC suffix	AF01

AZT. It is a nucleoside analog reverse-transcriptase inhibitor (NRTI) and was the first treatment approved by the Food and Drug Administration for combating HIV/AIDS. Its development and clinical use marked a pivotal turning point in the management of the AIDS epidemic, transforming a universally fatal diagnosis into a manageable chronic condition. The drug's approval in 1987 followed a landmark clinical trial conducted by the National Institutes of Health and researchers like Margaret Fischl.

History

The compound was first synthesized in 1964 by Jerome Horwitz at the Michigan Cancer Foundation as a potential anti-cancer agent, but it was shelved after showing little efficacy. Its activity against retroviruses was discovered in 1984 by researchers at the Duke University School of Medicine and the Burroughs Wellcome company, notably Marty St. Clair. The urgent need for therapies during the height of the AIDS crisis led to rapid clinical development. A pivotal double-blind trial, known as ACTG 016, demonstrated significant survival benefits, leading to expedited approval by the FDA under pressure from advocacy groups like ACT UP. The drug's manufacturer, Burroughs Wellcome, faced significant controversy over its pricing, which sparked protests and debates about drug access.

Medical uses

It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection. It is also used for the prevention of maternal-fetal HIV transmission during pregnancy, labor, and delivery, significantly reducing the risk of perinatal infection. Furthermore, it is recommended for post-exposure prophylaxis following occupational exposures, such as needlestick injuries, in healthcare settings. While largely superseded by newer agents with better tolerability, it remains a component of certain fixed-dose combination therapies available in resource-limited settings.

Mechanism of action

As a nucleoside analog, it is phosphorylated intracellularly by host cell kinases to its active triphosphate form. This active metabolite competitively inhibits the incorporation of thymidine triphosphate into viral DNA by the enzyme reverse transcriptase. Once incorporated into the growing DNA chain, it acts as a chain terminator because it lacks a 3'-hydroxyl group, preventing the formation of phosphodiester bonds with subsequent nucleotides. This halts the replication of the viral genome and prevents the infection of new cells.

Adverse effects

Significant side effects have limited its long-term use. The most serious is dose-dependent bone marrow suppression, leading to anemia and neutropenia, which often requires dose adjustment or discontinuation. Other common adverse reactions include myopathy, characterized by muscle wasting and weakness, and lactic acidosis, a potentially fatal metabolic disturbance. Gastrointestinal intolerance, manifesting as nausea, headache, and fatigue, was also frequently reported in early high-dose regimens. Long-term use has been associated with lipodystrophy and mitochondrial toxicity.

Pharmacology

It is administered orally or intravenously and demonstrates good bioavailability. The drug is metabolized primarily in the liver via glucuronidation by the enzyme UGT2B7 to an inactive glucuronide metabolite, which is then excreted by the kidneys. Its plasma half-life is approximately 1 hour, but the intracellular half-life of the active triphosphate form is much longer, allowing for twice-daily dosing. It crosses the blood-brain barrier and achieves concentrations in the cerebrospinal fluid, which contributed to its early use for treating HIV-associated dementia.

Society and culture

The approval and introduction of the drug had a profound societal impact, galvanizing the AIDS activist movement and reshaping the relationship between patients, physicians, and regulatory agencies. The high cost set by Burroughs Wellcome led to widespread protests by groups like ACT UP and legal battles, accelerating discussions about drug pricing and compassionate use programs. Its story is featured in numerous works, including the play and film The Normal Heart and the documentary How to Survive a Plague. The drug's development is considered a milestone in modern pharmacology and a catalyst for the rapid development of subsequent antiretroviral classes.

Category:Antiviral drugs Category:HIV/AIDS