Zidovudine
Encyclopedia
Zidovudine or azidothymidine (AZT) (also called ZDV) is a nucleoside analog reverse-transcriptase inhibitor (NRTI), a type of antiretroviral drug
used for the treatment of HIV
/AIDS
. It is an analog
of thymidine
.
AZT was the first approved treatment for HIV, sold under the names Retrovir and Retrovis. 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 that HIV/AIDS was a death sentence. AZT slows HIV spread significantly, but does not stop it entirely. This allows HIV to become AZT-resistant over time, and for this reason AZT is usually used in conjunction with other NRTIs and anti-viral drugs. In this form, AZT is used as an ingredient in Combivir
and Trizivir
, among others. Zidovudine is included in the World Health Organization
's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.
s were caused by environmental retrovirus
es gained currency. It had long been known that most avian cancers were caused by retroviruses, but this knowledge was of limited use in clinical settings due to a lack of drugs that were effective against them. The development of the first anti-retroviral drugs in the 1950s and 60s led to increasing efforts to isolate the expected human analogs of these avian viruses, and then develop suitable drugs to kill them and produce a universal cure for cancer. These efforts eventually culminated in the "War on Cancer
" in the 1970s.
Jerome Horwitz
of the 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
. Development was shelved after it proved insufficiently effective against tumors in mice. In 1974, Wolfram Ostertag of the Max Planck Institute in Germany
reported that AZT was active against Friend murine leukaemia virus, a retrovirus
, in a mouse culture system.
The anti-retroviral approach to develop a "silver bullet" cancer cure ultimately failed. Contrary to early belief, today it is estimated that viruses account for only 10 to 20% of human cancers. However, these efforts advanced the knowledge of cancer considerably, and led to rapid development of many anti-retroviral drugs, which would later prove useful. Zidovudine (AZT) was approved for marketing by the U.S. Food and Drug Administration
(FDA) on March 20, 1987.
AZT crystallizes in a monoclinic
structure, forming a hydrogen bond
ed network of base-paired dimers; its crystal structure was reported in 1988.
(now GlaxoSmithKline) began searching for compounds to treat the disease. Burroughs-Wellcome had expertise in viral diseases, led by researchers including Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts focused on the viral enzyme reverse transcriptase
. Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. Scientists at Burroughs-Wellcome 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 mouse viruses.
At the same time, Samuel Broder
, Hiroaki Mitsuya
, and Robert Yarchoan
of the United States National Cancer Institute
(NCI) had initiated an independent program to develop therapies for HIV/AIDS. The Burroughs-Wellcome scientists were not working directly with HIV, so the two groups began a collaboration. In February 1985, the NCI scientists showed that BW A509U, one of 11 compounds sent to them by Burroughs-Wellcome, had potent activity against HIV in the test tube. Several months later, Broder, Mitsuya, and Yarchoan started the initial phase 1 clinical trial
of AZT at the NCI, in collaboration with scientists from Burroughs-Wellcome and Duke University
. This trial suggested that the drug could be safely administered to patients with HIV and that it could increase CD4
counts in HIV-infected patients.
A placebo
-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome. The study found that AZT could prolong the life of patients with AIDS. Burroughs-Wellcome filed for a patent for AZT in 1985. The United States 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. The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months, 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 paucity of alternatives for treating AIDS at that time affected the risk/benefit ratio, with the certain mortality 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) protocols. AZT is combined with other drugs in order to prevent mutation of HIV into an AZT-resistant form.
in combination with other antiretroviral medications, substantially reducing 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 for 6 weeks after birth.
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.
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%.
, neutropenia
, hepatotoxicity
, cardiomyopathy
, and myopathy
. Damage to muscle cells is reversible upon cessation of AZT treatment. It has been attributed to several possible causes including depletion of mitochondrial DNA
, sensitivity of the γ-DNA polymerase in the cell mitochondria, the depletion of thymidine triphosphate
, oxidative stress
, reduction of intracellular L-carnitine
or apoptosis
of the muscle cells. Anemia due to AZT can be treated using erythropoietin
to stimulate red blood cell
production. Drugs that inhibit hepatic
glucuronidation
, such as indomethacin, acetylsalicylic acid (Aspirin) and trimethoprim
, decrease the elimination rate and increase the toxicity of the drug. Minor side effects include nausea and vomiting, headache, changes in the distribution of body fat, sleep disruption and loss of appetite
while less common but potentially serious side effects include discoloration of fingernails and toenails, mood changes, tingling or numbness of the hands or feet, easy bruising or bleeding and seizures. Serious allergic reactions are rare.
of its reverse transcriptase
. 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; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy). 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.
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
).
The azido group increases the lipophilic
nature of AZT, allowing it to cross cell membrane
s 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 inhibits DNA polymerase
used by human cells to undergo cell division
, but has approximately 100-fold greater affinity for viral reverse transcriptase. Because of this selectivity, in vitro studies have shown that AZT inhibits HIV replication without affecting the function of normal T cells. The cellular DNA polymerase used by mitochondria to replicate is more sensitive to the inhibitory effects of AZT, accounting for its toxic effects on cardiac
and skeletal muscle
s, causing myositis
.
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 NCI scientists Samuel Broder
, Hiroaki Mitsuya
, and Robert Yarchoan
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 favor 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. 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.
In November 2009 GlaxoSmithKline
formed a joint venture with Pfizer
which combined the two companies' HIV assets in one company called ViiV Healthcare
. This included the rights to Zidovudine.
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
used for the treatment of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
/AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
. It is an analog
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of thymidine
Thymidine
Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...
.
AZT was the first approved treatment for HIV, sold under the names Retrovir and Retrovis. 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 that HIV/AIDS was a death sentence. AZT slows HIV spread significantly, but does not stop it entirely. This allows HIV to become AZT-resistant over time, and for this reason AZT is usually used in conjunction with other NRTIs and anti-viral drugs. In this form, AZT is used as an ingredient in Combivir
Combivir
Lamivudine/zidovudine is a pharmaceutical treatment for HIV infection. It is a fixed dose combination of two antiretroviral drugs, lamivudine and zidovudine...
and Trizivir
Trizivir
Abacavir/lamivudine/zidovudine is a pharmaceutical treatment for HIV infection. It is a fixed dose combination of three reverse transcriptase inhibitors patented by GlaxoSmithKline and now marketed by its joint venture with Pfizer, ViiV Healthcare:*abacavir *lamivudine *zidovudine It is indicated...
, among others. Zidovudine is included in the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.
Development
In the 1970s the theory that most cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s were caused by environmental retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
es gained currency. It had long been known that most avian cancers were caused by retroviruses, but this knowledge was of limited use in clinical settings due to a lack of drugs that were effective against them. The development of the first anti-retroviral drugs in the 1950s and 60s led to increasing efforts to isolate the expected human analogs of these avian viruses, and then develop suitable drugs to kill them and produce a universal cure for cancer. These efforts eventually culminated in the "War on Cancer
War on Cancer
The War on Cancer refers to the effort to find a cure for cancer by increased research to improve the understanding of cancer biology and the development of more effective cancer treatments, such as targeted drug therapies. The aim of such efforts is to eradicate cancer as a major cause of death....
" in the 1970s.
Jerome Horwitz
Jerome Horwitz
Dr. Jerome P. Horwitz is a globally renowned American scientist; his affiliations included the Barbara Ann Karmanos Cancer Institute, the Wayne State University School of Medicine and the Michigan Cancer Foundation.- Background :Dr...
of the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine
Wayne State University School of Medicine
The Wayne State University School of Medicine is the largest single-campus medical school in the United States with more than 1,000 medical students. In addition to undergraduate medical education, the school offers master’s degree, Ph.D., and M.D.-Ph.D. programs in 14 areas of basic science to...
first synthesized AZT in 1964 under a US
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH) grant
Federal grant
In the United States, federal grants are economic aid issued by the United States government out of the general federal revenue. A federal grant is an award of financial assistance from a federal agency to a recipient to carry out a public purpose of support or stimulation authorized by a law of...
. Development was shelved after it proved insufficiently effective against tumors in mice. In 1974, Wolfram Ostertag of the Max Planck Institute in Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
reported that AZT was active against Friend murine leukaemia virus, a retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
, in a mouse culture system.
The anti-retroviral approach to develop a "silver bullet" cancer cure ultimately failed. Contrary to early belief, today it is estimated that viruses account for only 10 to 20% of human cancers. However, these efforts advanced the knowledge of cancer considerably, and led to rapid development of many anti-retroviral drugs, which would later prove useful. Zidovudine (AZT) was approved for marketing by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) on March 20, 1987.
Chemistry
Monoclinic crystal system
In crystallography, the monoclinic crystal system is one of the 7 lattice point groups. A crystal system is described by three vectors. In the monoclinic system, the crystal is described by vectors of unequal length, as in the orthorhombic system. They form a rectangular prism with a...
structure, forming a hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
ed network of base-paired dimers; its crystal structure was reported in 1988.
HIV Treatment
In 1984, shortly after the human immunodeficiency virus (HIV) had been confirmed as the cause of AIDS, scientists at the Burroughs-Wellcome CompanyGlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
(now GlaxoSmithKline) began searching for compounds to treat the disease. Burroughs-Wellcome had expertise in viral diseases, led by researchers including Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts focused on the viral enzyme reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
. Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. Scientists at Burroughs-Wellcome 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 mouse viruses.
At the same time, Samuel Broder
Samuel Broder
Samuel Broder is an American oncologist and medical researcher. He was a co-developer of some of the first effective drugs for the treatment of AIDS and was Director of the National Cancer Institute from 1989 to 1995....
, Hiroaki Mitsuya
Hiroaki Mitsuya
is a Japanese virologist famous for his role in discovery of the anti-HIV drug zidovudine as well as other anti-AIDS drugs including didanosine and zalcitabine . Mitsuya obtained his M.D. and Ph.D. at Kumamoto University in Japan...
, and Robert Yarchoan
Robert Yarchoan
Robert Yarchoan is a medical researcher who played an important role in the development of the first effective drugs for AIDS. He is the Chief of the HIV and AIDS Malignancy Branch in the NCI and also coordinates AIDS and AIDS malignancy research throughout the NCI as Director of the Office of HIV...
of the United States National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
(NCI) had initiated an independent program to develop therapies for HIV/AIDS. The Burroughs-Wellcome scientists were not working directly with HIV, so the two groups began a collaboration. In February 1985, the NCI scientists showed that BW A509U, one of 11 compounds sent to them by Burroughs-Wellcome, had potent activity against HIV in the test tube. Several months later, Broder, Mitsuya, and Yarchoan started the initial phase 1 clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
of AZT at the NCI, in collaboration with scientists from Burroughs-Wellcome and Duke University
Duke University
Duke University is a private research university located in Durham, North Carolina, United States. Founded by Methodists and Quakers in the present day town of Trinity in 1838, the school moved to Durham in 1892. In 1924, tobacco industrialist James B...
. This trial suggested that the drug could be safely administered to patients with HIV and that it could increase CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
counts in HIV-infected patients.
A placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome. The study found that AZT could prolong the life of patients with AIDS. Burroughs-Wellcome filed for a patent for AZT in 1985. The United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approved the drug (via the then-new FDA accelerated approval system
FDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...
) for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-defunct medical term for pre-AIDS illness) on March 20, 1987. The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months, 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 paucity of alternatives for treating AIDS at that time affected the risk/benefit ratio, with the certain mortality of HIV infection outweighing the risk of drug toxicity. One of AZT's side effects is anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, 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) protocols. AZT is combined with other drugs in order to prevent mutation of HIV into an AZT-resistant form.
HIV Prophylaxis
AZT may be used as post-exposure prophylaxisPost-exposure prophylaxis
Post-exposure prophylaxis is any prophylactic treatment started immediately after exposure to a pathogen , in order to prevent infection by the pathogen and the development of disease.-Rabies:...
in combination with other antiretroviral medications, substantially reducing 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
Vertical transmission
Vertical transmission, also known as mother-to-child transmission, is the transmission of an infection or other disease from mother to child immediately before and after birth during the perinatal period. A pathogen's transmissibility refers to its capacity for vertical 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 for 6 weeks after birth.
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.
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%.
Side effects
Chronic, high-dose therapy with AZT is associated with significant side effects, including anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
, cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
, and myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
. Damage to muscle cells is reversible upon cessation of AZT treatment. It has been attributed to several possible causes including depletion of mitochondrial DNA
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
, sensitivity of the γ-DNA polymerase in the cell mitochondria, the depletion of thymidine triphosphate
Thymidine triphosphate
5-Methyluridine triphosphate or m5UTP is one of five nucleoside triphosphates. It is the ribonucleoside triphosphate of thymidine, but the 5-methyluridine nomenclature is used because the term thymidine triphosphate is used for the deoxyribonucleoside by convention.-References:...
, oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, reduction of intracellular L-carnitine
Carnitine
Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is widely...
or apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
of the muscle cells. Anemia due to AZT can be treated using erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
to stimulate red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
production. Drugs that inhibit hepatic
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
, such as indomethacin, acetylsalicylic acid (Aspirin) and trimethoprim
Trimethoprim
Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...
, decrease the elimination rate and increase the toxicity of the drug. Minor side effects include nausea and vomiting, headache, changes in the distribution of body fat, sleep disruption and loss of appetite
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
while less common but potentially serious side effects include discoloration of fingernails and toenails, mood changes, tingling or numbness of the hands or feet, easy bruising or bleeding and seizures. Serious allergic reactions are rare.
Viral resistance
Even at very high doses, AZT does not destroy the HIV infection, but only delays the replication of the virus and the progression of the disease. During prolonged AZT treatment, HIV has the ability to gain an increased resistance to AZT by mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of its reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
. 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
Protease inhibitor
Protease inhibitor can refer to:* Protease inhibitor : a class of medication that inhibits viral protease* Protease inhibitor : molecules that inhibit proteases...
or a non-nucleoside reverse transcriptase inhibitor; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy). AZT has been shown to work additively or synergistically with many antiviral agents such as acyclovir and interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
; however, ribavirin
Ribavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...
decreases the antiviral effect of AZT.
Mechanism of action
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
, the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that HIV uses to make a DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
copy of its RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
. Reverse transcription is necessary for production of the viral double-stranded DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, which is subsequently integrated into the genetic material of the infected cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
(where it is called a provirus
Provirus
A provirus is a virus genome that is integrated into the DNA of a host cell.This state can be a stage of virus replication, or a state that persists over longer periods of time as either inactive viral infections or an endogenous retrovirus. In inactive viral infections the virus will not replicate...
).
The azido group increases the lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
nature of AZT, allowing it to cross cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s easily by diffusion
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
and thereby also to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. 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 inhibits DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
used by human cells to undergo cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, but has approximately 100-fold greater affinity for viral reverse transcriptase. Because of this selectivity, in vitro studies have shown that AZT inhibits HIV replication without affecting the function of normal T cells. The cellular DNA polymerase used by mitochondria to replicate is more sensitive to the inhibitory effects of AZT, accounting for its toxic effects on cardiac
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
and skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
s, causing myositis
Myositis
Myositis is a general term for inflammation of the muscles. Many such conditions are considered likely to be caused by autoimmune conditions, rather than directly due to infection It is also a documented side effect of the lipid-lowering drugs statins and fibrates.Elevation of creatine kinase in...
.
Patent issues
The patents on AZT have been the target of some controversy. In 1991, Public CitizenPublic Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts: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 NCI scientists Samuel Broder
Samuel Broder
Samuel Broder is an American oncologist and medical researcher. He was a co-developer of some of the first effective drugs for the treatment of AIDS and was Director of the National Cancer Institute from 1989 to 1995....
, Hiroaki Mitsuya
Hiroaki Mitsuya
is a Japanese virologist famous for his role in discovery of the anti-HIV drug zidovudine as well as other anti-AIDS drugs including didanosine and zalcitabine . Mitsuya obtained his M.D. and Ph.D. at Kumamoto University in Japan...
, and Robert Yarchoan
Robert Yarchoan
Robert Yarchoan is a medical researcher who played an important role in the development of the first effective drugs for AIDS. He is the Chief of the HIV and AIDS Malignancy Branch in the NCI and also coordinates AIDS and AIDS malignancy research throughout the NCI as Director of the Office of HIV...
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
United States Court of Appeals for the Federal Circuit
-Vacancies and pending nominations:-List of former judges:-Chief judges:Notwithstanding the foregoing, when the court was initially created, Congress had to resolve which chief judge of the predecessor courts would become the first chief judge...
ruled in 1992 in favor 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. In 2002, another lawsuit was filed over the patent by the AIDS Healthcare Foundation
AIDS Healthcare Foundation
AIDS Healthcare Foundation , the largest global AIDS organization, currently provides medical care and/or services to more than 152,000 individuals in 26 countries worldwide in the US, Africa, Latin America/Caribbean, the Asia-Pacific Region and Eastern Europe...
.
However, the patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
expired in 2005 (placing AZT in the public domain
Public domain
Works are in the public domain if the intellectual property rights have expired, if the intellectual property rights are forfeited, or if they are not covered by intellectual property rights at all...
), allowing other drug companies to manufacture and market generic AZT without having to pay GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
any royalties. The U.S. FDA has since approved four generic
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
forms of AZT for sale in the U.S.
In November 2009 GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
formed a joint venture with Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
which combined the two companies' HIV assets in one company called ViiV Healthcare
ViiV Healthcare
ViiV Healthcare is a pharmaceutical company specializing in the development of therapies for HIV that was created as a joint venture by Pfizer and GlaxoSmithKline in November 2009 with both companies transferring their HIV assets to the new company. 85% of the company is owned by GlaxoSmithKline...
. This included the rights to Zidovudine.