Zidovudine , also known as azidothymidine ( AZT ), is an antiretroviral drug used to prevent and treat HIV/AIDS. Generally recommended for use with other ARVs. This can be used to prevent mother-to-child transmission during birth or after needle injury or other potential exposure. It is sold well by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. Can be used by mouth or by slow injection into the blood vessels.
Common side effects include headache, fever, and nausea. Serious side effects include liver problems, muscle damage, and high blood lactate levels. Usually used in pregnancy and seems safe for babies. ZDV is a nucleoside analogue NRTI (NRTI) class. It works by inhibiting the reverse transcriptase enzymes that HIV uses to make DNA and thereby decrease viral replication.
Zidovudine was first described in 1964. It was approved in the United States in 1986 and was the first treatment for HIV. It's in the List of Essential Medicines of the World Health Organization, the most effective and safe drugs needed in the health system. It is available as a generic drug. The cost of wholesale in developing countries is 5.10 to 25.60 USD per month. By 2015, the cost for one month of typical medicine in the United States is over 200 USD.
Video Zidovudine
Medical use
HIV treatment
AZT is usually given twice daily in combination with other antiretroviral therapy. This approach is referred to as Active Antiretroviral Therapy (ART) and is used to prevent the possibility of HIV resistance.
HIV prevention
AZT has been used for post-exposure prophylaxis (PPP) in combination with other antiretroviral drugs called lamivudine. Together they work to substantially reduce the risk of HIV infection after the first single exposure to the virus. Recently, AZT has been replaced by other antiretroviral drugs such as tenofovir to provide PEP.
AZT is now a major part of the clinical pathway for pre-exposure prophylaxis and post-exposure treatment of mother-to-child transmission of HIV during pregnancy, labor and delivery and has proven to be an integral part of perinatal uninfected siblings and neonatal development. Without AZT, as many as 10 to 15% of fetuses with HIV-infected mothers themselves will be infected. AZT has been shown to reduce this risk by as little as 8% when administered in a three-part post-conception, delivery, and six weeks postpartum regimen. Consistent and proactive precautions, such as the use of strict antiretroviral drugs, caesarean section, face mask, heavy rubber gloves, clinically disposable diapers, and avoidance of mouth contact will further reduce HIV transmission from child laborers to as few as 1 -2%.
During 1994 to 1999, AZT was a major form of prevention of mother-to-child transmission of HIV. AZT prophylaxis prevents more than 1000 parental and infant deaths from AIDS in the United States. In the US today, the standard of care received for HIV-positive mothers is known as regimen 076 and involves 5 daily doses of AZT from the second trimester and beyond, and AZT given intravenously during labor. Because the treatment is long and expensive, it is considered unfeasible in the global south, where mother-to-child transmission is a significant problem. A number of studies began in the late 1990s trying to test the effectiveness of shorter, simpler regimens for use in 'resource-poor' countries. This short course of AZT is an inferior standard of care and will be considered malpractice if tested in the US; However, it remains a treatment that will improve the care and survival of a poor subject.
Maps Zidovudine
Side effects
The most common side effects include nausea, vomiting, acid reflux (heartburn), headache, cosmetic reduction in abdominal fat, light sleep, and loss of appetite. Less common side effects include discoloration of the toenails and weak toenails, increased mood, occasional tingling or numbness in the hands or feet, and mild skin tone changes. Allergic reactions are rare.
Early, high-dose long-term therapy with AZT was initially associated with sometimes limited therapy side effects, including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. All of these conditions are commonly found to be reversible in AZT dose reduction. They have been linked to several possible causes, including temporary depletion of mitochondrial DNA, polymerase-DNA sensitivity in cell mitochondria, thinning of thymidine triphosphate, oxidative stress, intracellular reduction L -carnitine. or apoptosis of muscle cells. Anemia due to AZT is successfully treated using erythropoetin to stimulate the production of red blood cells. Drugs that inhibit liver glucuronidation, such as indomethacin, nordazepam, acetylsalicylic acid (aspirin) and trimethoprim decrease the rate of elimination and increase the strength of drug therapy. Today, side effects are less common in low-dose AZT. According to the IARC, there is considerable evidence in animal experiments for zidovudine carcinogenicity; it may be carcinogenic in humans (Group 2B).
Virus resistance
Even at the highest tolerable dose in patients, AZT is not strong enough to prevent all HIV replication and may only slow the viral replication and progression of the disease. Prolonged treatment of AZT can cause HIV to develop resistance to AZT with reverse transcriptase mutations. To slow the development of resistance, doctors generally recommend that AZT be given in combination with other reverse transcriptase inhibitors and antiretrovirals from other groups, such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors, or integrase inhibitors; This type of therapy is known as HAART (Highly Active Anti Retroviral Therapy).
Action mechanism
AZT is analogous to thyroid. AZT works by inhibiting reverse HIV transcriptase, an enzyme that the virus uses to duplicate DNA RNAs. Inverted transcription is required for the production of double-stranded DNA HIV, which will then be integrated into the genetic material of the infected cell (where it is called provirus).
Cellular enzymes convert AZT to an effective 5'-triphosphate form. Studies have shown that the cessation of DNA chains that make up HIV is a specific factor in the inhibitory effect.
At very high doses, the AZT triphosphate form can also inhibit the DNA polymerase used by human cells to undergo cell division, but regardless of the dose of AZT has about 100 times greater affinity for HIV reverse transcriptase. Selectivity has been proven because of the cell's ability to repair its DNA chain quickly if it is damaged by AZT during its formation, whereas the HIV virus does not have that ability. Thus AZT inhibits HIV replication without affecting the function of non-infected cells. At fairly high doses, AZT begins to inhibit cellular DNA polymerases used by mitochondria to replicate, which are responsible for the toxic but reversible effects on cardiac and skeletal muscle, which cause myositis.
Chemistry
AZT crystallizes into the asymmetric core monoclinic salt structure, forming the corresponding hydrogen-nitrogen-oxygen bonding network of the paired-base dimer; the structure of its multiscaled crystal superstructure and the electrostatic bonding headgroup of bonded polarity reported in 1988 and 1987.
History
In the 1960s the theory that most cancers are caused by environmental retroviruses gain clinical and funding support. It has recently become known, for the work of Nobel Prize winner Howard Temin and David Baltimore, that almost all bird cancers are caused by bird retroviruses, but appropriate human retroviruses have not been found.
In parallel work, other compounds that successfully block nucleic acid synthesis have been shown to be antibacterial, antiviral, and anticancer agents, leading work done in Nobel Prize winning laboratories George Hitchings and Gertrude Elion, leading to the development of 6-mercapttopurin antitumor agents.
Jerome Horwitz from Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine first synthesized AZT in 1964 under the grant of the US National Institutes of Health (NIH). Development was accommodated after proven biologically inert in mice. In 1974, Wolfram Ostertag of the Max Planck Institute for Experimental Medicine in GÃÆ'¶ttingen, Germany reported that AZT specifically targets Friend's virus (murine leukemia virus strains).
Azidothymidine was first synthesized at the Michigan Cancer Foundation in 1964 as part of a program directed to the discovery of anticancer drugs. This gives negative results and attracts a bit more interest. In 1974, Wofram Ostertag at the Max Planck Institute demonstrated the ability of AZT to inhibit the replication of the leukemia virus in cell cultures. This report draws little interest from other researchers because the Leukemia friend's virus is a retrovirus, and at the time, no known human disease was caused by retroviruses.
In 1983 researchers at the Pasteur Institute in Paris identified a retrovirus now known as Human Immunodeficiency Virus (HIV) as the cause of acquired immunodeficiency syndrome (AIDS) in humans. Shortly thereafter, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan of the National Cancer Institute of the United States (NCI) began a program to develop therapy for HIV/AIDS. Using their CD4 T cells, they developed a drug-screening test because of their ability to protect CD4 T cells that were killed by HIV. To expedite the process of drug discovery, NCI researchers are actively seeking cooperation with pharmaceutical companies that have access to compound libraries with potential antiviral activity. This test can simultaneously test the anti-HIV effect of the compound and its toxicity to infected T cells.
In June 1984, virologist Burroughs-Wellcome Marty St. Clair created a program to find drugs that could potentially inhibit HIV replication. Burroughs-Wellcome has expertise in nucleoside analogs and viral diseases, led by researchers including George Hitchings, Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts are focused in part on viral reverse transcriptase enzymes. Reverse transcriptase is an enzyme that retroviruses, including HIV, use to self-replicate. Secondary testing was performed on mouse cells infected with the retrovirus virus virus or Harvey's sarcoma virus, as the Wellcome group had no in-house HIV test available at the time at the time, and this other retrovirus was believed to represent a reasonable substitute. AZT is shown to be a very powerful inhibitor of the virus Friend and Harvey sarcoma virus, and the search of company records shows that it has shown low toxicity when tested for antibacterial activity in mice many years earlier. Partly based on these results, AZT was selected by nucleoside chemist Janet Rideout as one of 11 compounds to be sent to NCI for testing in antiviral antiviral tests of the organization.
In February 1985, NCI scientists found that AZT has strong efficacy in vitro. A few months later, phase 1 AZT clinical trials in NCI began at NCI and Duke University,. In conducting this Phase I trial, they build on their experience in previous experiments, with suramine, another drug that has demonstrated effective anti-HIV activity in the laboratory. These early AZT experiments prove that these drugs can be safely administered to patients with HIV, that these drugs increase their CD4 cell count, restore T cell immunity as measured by skin tests, and show strong evidence of clinical effectiveness, such as encouraging weight gain. in AIDS patients. It also shows that AZT levels that work in vitro can be injected into the patient in the form of serum and suppository, and that the drug just penetrates into the infected brain.
A double-blind, placebo-controlled, randomized controlled trial of AZT was then performed by Burroughs-Wellcome and proved that AZT safely prolongs the lives of people with HIV. Burroughs-Wellcome filed a patent for AZT in 1985. The Anti-Infection Advisory Committee to the United States Food and Drug Administration (FDA) selected ten to one to recommend AZT approval. The FDA approved the drug (via the new FDA accelerated approval system) for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-defunct medical term for pre-AIDS diseases) on March 20, 1987. The time between the first demonstration AZT is active against HIV in the laboratory and approval is 25 months, the longest drug development period in recent history.
AZT was then approved unanimously for infants and children in 1990. AZT was initially given in slightly higher doses than today, usually 400 mg every four hours, day and night. The lack of an alternative to treat HIV/AIDS at that time clearly affirms the health risk/benefit ratio, with the inevitable, destructive, and painful death of HIV over the side effects of transient anemia and malaise anemia.
Society and culture
In 1991, Public Citizen advocacy group filed a lawsuit claiming that the patent was invalid. Furthermore, Barr Laboratories and Novopharm Ltd. also opposed the patent, partly based on the assertion that NCI scientist Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan should be crowned inventors, and both companies are applying to the FDA to sell AZT as a generic drug. In response, Burroughs Wellcome Co. filed a lawsuit against both companies. The US Court of Appeals for the Federal Circuit decided in 1992 in support of Burroughs Wellcome, who had the power that even though they had never tested him for HIV, they had thought about it before they sent it to the NCI scientists. The lawsuit was filed with the US Supreme Court, but in 1996 they refused to officially review. The case, Burroughs Wellcome Co. v. Barr Laboratories , is a landmark in US law of fellowship.
In 2002, another lawsuit filed challenged the patent by the AIDS Healthcare Foundation, which also filed an antitrust case against GSK as well. The patent case was dismissed in 2003 and AHF filed a new case challenging the patent.
The GSK patent on AZT ended in 2005 and in September 2005 the FDA approved three generic versions.
References
External links
- US. National Drug Library: Drug Information Portal - Zidovudine
Source of the article : Wikipedia
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