Zidovudine (INN) أوazidothymidine (AZT) (أيضا يدعى ZDV)وهوnucleoside analog reverse transcriptase inhibitor (NRTI), a type of antiretroviral drug. وهوأول دواء أجيز لعلاج HIV. ويباع تحت الأسماء التالية Retrovir وRetrovis, وكمكون في Combivir وTrizivir. وهويعد[[نظير كيميائى thymidine.

التاريخ

Zidovudine أول دواء أجيز لعلاج عدوى AIDS وHIV . Jerome Horwitz باربارا آن كارمانوس معهد السرطان وWayne State University School of Medicine قاما بتخليق AZT في عام 1964, تحت US National Institutes of Health (NIH) grant. AZT صمم أساسا لعلاج to treat cancer, but was shelved after it proved ineffective in treating cancer in mice.

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 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. 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 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.

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

الوقاية

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).

AZT is also recommended as part of a regimen to prevent mother-to-child transmission of HIV during pregnancy, labor and delivery. 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 forستة weeks after birth. 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%.

الآثار الجانبية

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.

المقاومة الفيروسية

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 ^{[بحاجة لمصدر]} 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.

طريقة العمل

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 spliced into the genetic material of the infected cell (where it is called a provirus).

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. 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. 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).

موضوع الترخيص

AZT has been the target of some controversy due to the nature of the patent process.

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. 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. 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.

المراجع

نطقب:HIVpharm