Clinical data | |
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Trade names | Droxia, Hydrea, Siklos, others |
Other names | Hydroxyurea (USAN US) |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682004 |
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Routes of administration | By mouth |
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Pharmacokinetic data | |
Metabolism | Liver (to CO2 and urea) |
Elimination half-life | 2–4 hours |
Excretion | Kidney and lungs |
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CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.004.384 |
Chemical and physical data | |
Formula | CH4N2O2 |
Molar mass | 76.055 g·mol−1 |
3D model (JSmol) | |
Melting point | 133 to 136 °C (271 to 277 °F) |
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Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. [4] [5] In sickle-cell disease it increases fetal hemoglobin and decreases the number of attacks. [4] It is taken by mouth. [4]
Common side effects include bone marrow suppression, fevers, loss of appetite, psychiatric problems, shortness of breath, and headaches. [4] [5] There is also concern that it increases the risk of later cancers. [4] Use during pregnancy is typically harmful to the fetus. [4] Hydroxycarbamide is in the antineoplastic family of medications. It is believed to work by blocking the making of DNA. [4]
Hydroxycarbamide was approved for medical use in the United States in 1967. [4] It is on the World Health Organization's List of Essential Medicines. [6] Hydroxycarbamide is available as a generic medication. [4]
Hydroxycarbamide is used for the following indications:
Reported side effects are: neurological reactions (e.g., headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions), nausea, vomiting, diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity (dose-limiting toxicity; may take 7–21 days to recover after the drug has been discontinued), megaloblastic anemia, thrombocytopenia, bleeding, hemorrhage, gastrointestinal ulceration and perforation, immunosuppression, leukopenia, alopecia (hair loss), skin rashes (e.g., maculopapular rash), erythema, pruritus, vesication or irritation of the skin and mucous membranes, pulmonary edema, abnormal liver enzymes, creatinine and blood urea nitrogen. [12]
Due to its negative 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. [13] Moreover, because of this, its use in people with leukopenia, thrombocytopenia or severe anemia is contraindicated. [14]
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. [15]
Hydroxycarbamide decreases the production of deoxyribonucleotides [16] via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction of nucleoside diphosphates (NDPs). [15]
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 gamma globin gene expression and subsequent gamma chain synthesis necessary for fetal hemoglobin (HbF) production (which does not polymerize and deform red blood cells like the mutated HbS, responsible for sickle cell disease). Adult red cells containing more than 1% HbF are termed F cells. These cells are progeny of a small pool of immature committed erythroid precursors (BFU-e) that retain the ability to produce HbF. Hydroxyurea also suppresses the production of granulocytes in the bone marrow which has a mild immunosuppressive effect particularly at vascular sites where sickle cells have occluded blood flow. [15] [17]
Hydroxyurea has been reported as endogenous in human blood plasma at concentrations of approximately 30 to 200 ng/ml. [18]
Hazards | |
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Occupational safety and health (OHS/OSH): | |
Main hazards | Mutagen – Reproductive toxicity |
GHS labelling: | |
Danger | |
H340, H361 | |
P201, P202, P281, P308+P313, P405, P501 |
Hydroxyurea has been prepared in many different ways since its initial synthesis in 1869. [19] The original synthesis by Dresler and Stein was based around the reaction of hydroxylamine hydrochloride and potassium cyanate. [19] Hydroxyurea lay dormant for more than fifty years until it was studied as part of an investigation into the toxicity of protein metabolites. [20] Due to its chemical properties hydroxyurea was explored as an antisickling agent in the treatment of hematological conditions.
One common mechanism for synthesizing hydroxyurea is by the reaction of calcium cyanate with hydroxylamine nitrate in absolute ethanol and by the reaction of a cyanate salt and hydroxylamine hydrochloride in aqueous solution. [21] Hydroxyurea has also been prepared by converting a quaternary ammonium anion exchange resin from the chloride form to the cyanate form with sodium cyanate and reacting the resin in the cyanate form with hydroxylamine hydrochloride. This method of hydroxyurea synthesis was patented by Hussain et al. (2015). [22]
Hydroxyurea is a monohydroxyl-substituted urea (hydroxycarbamate) antimetabolite. Similar to other antimetabolite anti-cancer drugs, it acts by disrupting the DNA replication process of dividing cancer cells in the body. Hydroxyurea selectively inhibits ribonucleoside diphosphate reductase, an enzyme required to convert ribonucleoside diphosphates into deoxyribonucleoside diphosphates, thereby preventing cells from leaving the G1/S phase of the cell cycle. This agent also exhibits radiosensitizing activity by maintaining cells in the radiation-sensitive G1 phase and interfering with DNA repair. [23]
Biochemical research has explored its role as a DNA replication inhibitor [24] which causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks (see DNA repair). Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. [25]
Hydroxyurea has many pharmacological applications under the Medical Subject Headings classification system: [23]
Brand names include: Hydrea, Litalir, Droxia, and Siklos.[ citation needed ]
Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time. Older terms included Cooley's anemia and Mediterranean anemia for beta-thalassemia. These have been superseded by the terms Transfusion-Dependent Thalassemia (TDT) and non-Transfusion-Dependent Thalassemia (NTDT). Patients with TDT require regular transfusions, typically every two to five weeks. TDTs include Beta-thalassemia major, nondeletional HbH disease, survived Hb Bart's disease, and severe HbE/beta-thalassemia.
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Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.
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Fetal hemoglobin, or foetal haemoglobin is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream to organs and tissues in the fetus. It is produced at around 6 weeks of pregnancy and the levels remain high after birth until the baby is roughly 2–4 months old. Hemoglobin F has a different composition than adult forms of hemoglobin, allowing it to bind oxygen more strongly; this in turn enables the developing fetus to retrieve oxygen from the mother's bloodstream, which occurs through the placenta found in the mother's uterus.
In hematology, thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150×109 to 450×109 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 750×109/L.
In hematology, essential thrombocythemia (ET) is a rare chronic blood cancer characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leukemia or myelofibrosis. It is one of the blood cancers wherein the bone marrow produces too many white or red blood cells, or platelets.
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.
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