Hydroxyurea
Encyclopedia
Hydroxycarbamide or hydroxyurea (brand names include Hydrea and Droxia) is an antineoplastic drug
, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera
and essential thrombocythemia. It is also used to reduce the rate of painful attacks in sickle-cell disease
and has antiretroviral properties in diseases such as AIDS
.
s via inhibition of the enzyme ribonucleotide reductase
by scavenging tyrosyl free radicals as they are involved in the reduction NDPs.
In the treatment of sickle-cell disease
, hydroxycarbamide increases the concentration of fetal hemoglobin
. The precise mechanism of action is not yet clear, but it appears that hydroxycarbamide increases nitric oxide
levels, causing soluble guanylyl cyclase activation with a resultant rise in cyclic GMP, and the activation of gammaglobin synthesis necessary for fetal hemoglobin (by removing the rapidly dividing cells that preferentially produce sickle hemoglobin).
In sickle-cell disease, the initial daily dose is 15 mg per kilogram body weight (or less in reduced kidney function
); after two weeks, a fall in the hemoglobin
and platelet
count and an increase in MCV (mean corpuscular volume
) (size of the red blood cells) is to be expected. The dose is then increased every two weeks with monitoring of the full blood count until the dose is either 35 mg/kg or cytopenias develop.
, mucositis, anorexia
, stomatitis
, bone marrow toxicity (which may take 7–21 days to recover after the drug has been discontinued), alopecia
(hair loss), skin changes, abnormal liver enzymes, creatinine
and blood urea nitrogen
.
Due to its effect on the bone marrow, regular monitoring of the full blood count is vital, as well as early response to possible infections. In addition, renal function
, uric acid
and electrolytes, as well as liver enzymes, are commonly checked.
Hydroxycarbamide has been used primarily for the treatment of myeloproliferative diseases, which has an inherent risk of transforming to acute myeloid leukemia
. There has been a longstanding concern that hydroxycarbamide itself carries a leukemia risk, but large studies have shown that the risk is either absent or very small. Nevertheless, it has been a barrier for its wider use in patients with sickle-cell disease.
, neutropenia
.
; the industrial process is analogous. Hydroxyurea may also be synthesized by reaction of ethyl carbamate
with hydroxylamine
; hydroxylamine displaces the ester to give the amide.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera
Polycythemia vera
Polycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
and essential thrombocythemia. It is also used to reduce the rate of painful attacks in sickle-cell disease
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
and has antiretroviral properties in diseases such as AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
.
Mechanism of action
One mechanism of action is thought to be based on its reduction of production of deoxyribonucleotideDeoxyribonucleotide
A deoxyribonucleotide is the monomer, or single unit, of DNA, or deoxyribonucleic acid. Each deoxyribonucleotide comprises three parts: a nitrogenous base, a deoxyribose sugar, and one phosphate group. The nitrogenous base is always bonded to the 1' carbon of the deoxyribose, which is distinguished...
s via inhibition of the enzyme ribonucleotide reductase
Ribonucleotide reductase
Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms...
by scavenging tyrosyl free radicals as they are involved in the reduction NDPs.
In the treatment of sickle-cell disease
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
, hydroxycarbamide increases the concentration of fetal hemoglobin
Fetal hemoglobin
Fetal hemoglobin, or foetal haemoglobin, is the main oxygen transport protein in the fetus during the last seven months of development in the uterus and in the newborn until roughly 6 months old...
. The precise mechanism of action is not yet clear, but it appears that hydroxycarbamide increases nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
levels, causing soluble guanylyl cyclase activation with a resultant rise in cyclic GMP, and the activation of gammaglobin synthesis necessary for fetal hemoglobin (by removing the rapidly dividing cells that preferentially produce sickle hemoglobin).
Uses
Hydroxycarbamide is used for the following indications:- Myeloproliferative diseaseMyeloproliferative diseaseThe myeloproliferative diseases are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than...
(primarily polycythemia veraPolycythemia veraPolycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
and essential thrombocytosisEssential thrombocytosisEssential thrombocythemia is a rare chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause. In some cases this disorder may be progressive, and rarely may evolve into acute myeloid leukemia or myelofibrosis...
) - Sickle-cell diseaseSickle-cell diseaseSickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
(breaks down cells that are prone to sickle, as well as increasing fetal hemoglobinFetal hemoglobinFetal hemoglobin, or foetal haemoglobin, is the main oxygen transport protein in the fetus during the last seven months of development in the uterus and in the newborn until roughly 6 months old...
content) - AIDSAIDSAcquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
as an adjunct to ddI in combination antiretroviral therapies - Second line treatment for psoriasisPsoriasisPsoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
(slows down the rapid division of skin cells) - Biochemical research as a DNA replicationDNA replicationDNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
inhibitor that causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks (see DNA repairDNA repairDNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
) - Treatment for systemic mastocytosis
Dose
The dose depends on the indication, but tends to be 500 milligrams once a day when treatment is initiated. In myeloproliferative disease, further increases are determined by the response of the cell count and whether myelosuppression (decreased production of other blood cells) develops.In sickle-cell disease, the initial daily dose is 15 mg per kilogram body weight (or less in reduced kidney function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
); after two weeks, a fall in the hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
and platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count and an increase in MCV (mean corpuscular volume
Mean corpuscular volume
The mean corpuscular volume, or "mean cell volume" , is a measure of the average red blood cell size that is reported as part of a standard complete blood count....
) (size of the red blood cells) is to be expected. The dose is then increased every two weeks with monitoring of the full blood count until the dose is either 35 mg/kg or cytopenias develop.
Side effects
Reported side-effects are: drowsiness, nausea, vomiting and diarrhea, constipationConstipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, mucositis, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, stomatitis
Stomatitis
Stomatitis is an inflammation of the mucous lining of any of the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth...
, bone marrow toxicity (which may take 7–21 days to recover after the drug has been discontinued), alopecia
Alopecia
Alopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...
(hair loss), skin changes, abnormal liver enzymes, creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
and blood urea nitrogen
Blood urea nitrogen
The blood urea nitrogen test is a measure of the amount of nitrogen in the blood in the form of urea, and a measurement of renal function. Urea is a by- product from metabolism of proteins by the liver and is removed from the blood by the kidneys.-Physiology:The liver produces urea in the urea...
.
Due to its effect on the bone marrow, regular monitoring of the full blood count is vital, as well as early response to possible infections. In addition, renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
, uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
and electrolytes, as well as liver enzymes, are commonly checked.
Hydroxycarbamide has been used primarily for the treatment of myeloproliferative diseases, which has an inherent risk of transforming to acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
. There has been a longstanding concern that hydroxycarbamide itself carries a leukemia risk, but large studies have shown that the risk is either absent or very small. Nevertheless, it has been a barrier for its wider use in patients with sickle-cell disease.
Contraindications
Contraindications are: severe 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...
.
Use in pregnancy
Category D - investigational or post-marketing data show risk to the fetus. However, potential benefits may outweigh the potential risk. Generally this rating is reserved for drugs with no safer alternatives.Synthesis
Hydroxyurea was first synthesized in 1869 by Dresler and Stein from hydroxylamine and hydrogen cyanateCyanate
The cyanate ion is an anion with the chemical formula written as [OCN]− or [NCO]−. In aqueous solution it acts as a base, forming isocyanic acid, HNCO. The cyanate ion is an ambidentate ligand, forming complexes with a metal ion in which either the nitrogen or oxygen atom may be the electron-pair...
; the industrial process is analogous. Hydroxyurea may also be synthesized by reaction of ethyl carbamate
Ethyl carbamate
Ethyl carbamate is a chemical compound with the molecular formula C3H7NO2 first prepared in the nineteenth century. Structurally, it is an ester of carbamic acid...
with hydroxylamine
Hydroxylamine
Hydroxylamine is an inorganic compound with the formula NH2OH. The pure material is a white, unstable crystalline, hygroscopic compound. However, hydroxylamine is almost always provided and used as an aqueous solution. It is used to prepare oximes, an important functional group. It is also an...
; hydroxylamine displaces the ester to give the amide.