Stavudine
Encyclopedia
Stavudine is a nucleoside analog reverse transcriptase inhibitor
(NARTI) active against HIV
.
. It was subsequently reconsidered as an anti-HIV agent by the Rega Institute for Medical Research
in Belgium
. Stavudine was approved by the U.S. Food and Drug Administration
(FDA) on June 24, 1994 for adults and on September 6, 1996 for pediatric use and again as an extended-release version for once-a-day dosing in 2001. The fourth antiretroviral drug
on the market, its patent expired in the United States on 2008-06-25.
of thymidine
. It is phosphorylated by cellular kinase
s into active triphosphate. Stavudine triphosphate inhibits the HIV reverse transcriptase
by competing with natural substrate, thymidine triphosphate. It also causes termination of DNA synthesis
by incorporating into it.
Simultaneous use of zidovudine
is not recommended, as it can inhibit the intracellular phosphorylation
of stavudine. Other anti-HIV drugs do not possess this property.
, but with clinical doses its carcinogen
ic effects are non-existent. It is also one of the most likely antiviral drugs to cause lipodystrophy
, and for this reason it is no longer considered an appropriate treatment for most patients in developed countries.
It is still used as first choice in first line therapy in resource poor settings such as in India. Only in case of development of peripheral neuropathy or pregnancy is it changed to the next choice - Zidovudine
.
On Monday 30 November 2009, the World Health Organisation stated that "[The WHO] recommends that countries phase out the use of Stavudine, or d4T, because of its long-term, irreversible side-effects. Stavudine is still widely used in first-line therapy in developing countries due to its low cost and widespread availability. Zidovudine
(AZT) or Tenofovir (TDF) are recommended as less toxic and equally effective alternatives."
Reverse transcriptase inhibitor
Reverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
(NARTI) active against 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...
.
History
Stavudine was first synthetized in the sixties by Jerome HorwitzJerome 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...
. It was subsequently reconsidered as an anti-HIV agent by the Rega Institute for Medical Research
Rega Institute for Medical Research
The Rega Institute for Medical Research is a Belgian scientific establishment that is part of the Catholic University of Leuven in central Belgium...
in Belgium
Belgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
. Stavudine was approved 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 June 24, 1994 for adults and on September 6, 1996 for pediatric use and again as an extended-release version for once-a-day dosing in 2001. The fourth antiretroviral drug
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...
on the market, its patent expired in the United States on 2008-06-25.
Mechanism of action
Stavudine is an analogAnalog (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...
. It is phosphorylated by cellular kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s into active triphosphate. Stavudine triphosphate inhibits the HIV 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...
by competing with natural substrate, thymidine triphosphate. It also causes termination of DNA synthesis
DNA synthesis
DNA synthesis commonly refers to:*DNA replication - DNA biosynthesis *Polymerase chain reaction - enzymatic DNA synthesis *Oligonucleotide synthesis - chemical synthesis of nucleic acids...
by incorporating into it.
Simultaneous use of zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
is not recommended, as it can inhibit the intracellular phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of stavudine. Other anti-HIV drugs do not possess this property.
Pharmacokinetics
The oral absorption rate of stavudine is over 80%. Approximately half of stavudine is actively secreted unchanged into the urine and the other half is eliminated through endogenic pathways.Adverse events
The main severe adverse effect is peripheral neuropathy, which can be corrected by reducing dosage. Stavudine has been shown in laboratory test to be genotoxicGenotoxic
In genetics, genotoxicity describes a deleterious action on a cell's genetic material affecting its integrity. This includes both certain chemical compounds and certain types of radiation....
, but with clinical doses its carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic effects are non-existent. It is also one of the most likely antiviral drugs to cause lipodystrophy
Lipodystrophy
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...
, and for this reason it is no longer considered an appropriate treatment for most patients in developed countries.
It is still used as first choice in first line therapy in resource poor settings such as in India. Only in case of development of peripheral neuropathy or pregnancy is it changed to the next choice - Zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
.
On Monday 30 November 2009, the World Health Organisation stated that "[The WHO] recommends that countries phase out the use of Stavudine, or d4T, because of its long-term, irreversible side-effects. Stavudine is still widely used in first-line therapy in developing countries due to its low cost and widespread availability. Zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
(AZT) or Tenofovir (TDF) are recommended as less toxic and equally effective alternatives."