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| Trade names | Droxia, Hydrea, Siklos, others |
| Other names | Hydroxyurea (USANUS) |
| 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) |
| Eliminationhalf-life | 2–4 hours |
| Excretion | Kidney and lungs |
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| 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 ashydroxyurea, is anantimetabolite medication used insickle-cell disease,essential thrombocythemia,chronic myelogenous leukemia,polycythemia vera, andcervical cancer.[3][4] In sickle-cell disease it increasesfetal hemoglobin and decreases the number of attacks.[3] It is taken by mouth.[3]
Commonside effects includebone marrow suppression, fevers, loss of appetite,psychiatric problems,shortness of breath, andheadaches.[3][4] There is also concern that it increases the risk of latercancers.[3] Use duringpregnancy is typically harmful to the fetus.[3] Hydroxycarbamide is in theantineoplastic family of medications. It is believed to work by blocking the making ofDNA.[3]
Hydroxycarbamide was approved for medical use in the United States in 1967.[3] It is on theWorld Health Organization's List of Essential Medicines.[5] Hydroxycarbamide is available as ageneric medication.[3]
Hydroxycarbamide is used for the followingindications:
Reported side effects are:neurological reactions (e.g.,headache,dizziness,drowsiness,disorientation,hallucinations, andconvulsions),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 andperforation,immunosuppression,leukopenia,alopecia (hair loss),skin rashes (e.g.,maculopapular rash),erythema,pruritus,vesication orirritation of theskin andmucous membranes,pulmonary edema, abnormalliver enzymes,creatinine andblood urea nitrogen.[11]
Due to its negative effect on the bone marrow, regular monitoring of thefull blood count is vital, as well as early response to possible infections. In addition,renal function,uric acid andelectrolytes, as well asliver enzymes, are commonly checked.[12] Moreover, because of this, its use in people with leukopenia, thrombocytopenia or severeanemia is contraindicated.[13]
Hydroxycarbamide has been used primarily for the treatment of myeloproliferative diseases, which has an inherent risk of transforming toacute 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.[14]
Hydroxycarbamide decreases the production ofdeoxyribonucleotides[15] via inhibition of the enzymeribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction of nucleoside diphosphates (NDPs).[14] Additionally, hydroxycarbamide causes production of reactive oxygen species in cells, leading to disassembly of replicative DNA polymerase enzymes and arresting DNA replication.[16]
In the treatment ofsickle-cell disease, hydroxycarbamide increases the concentration offetal hemoglobin. The precise mechanism of action is not yet clear, but it appears that hydroxycarbamide increasesnitric oxide levels, causing solubleguanylyl cyclase activation with a resultant rise incyclic 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.[14][17]
Hydroxyurea has been reported as endogenous in human blood plasma at concentrations of approximately 30 to 200 ng/ml.[18]
| Hazards | |
|---|---|
| Occupational safety and health (OHS/OSH): | |
Main hazards | Mutagen –Reproductive toxicity |
| GHS labelling: | |
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| 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 ofhydroxylamine hydrochloride andpotassium 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 inhibitsribonucleoside diphosphate reductase, an enzyme required to convert ribonucleoside diphosphates into deoxyribonucleoside diphosphates, thereby preventing cells from leaving theG1/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 aDNA replication inhibitor[24] which causes deoxyribonucleotide depletion and results in DNA double strand breaks nearreplication forks (seeDNA 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 theMedical Subject Headings classification system:[23]
Brand names include: Hydrea, Litalir, Droxia, and Siklos.[citation needed]
