Hydroxycarbamide

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Hydroxycarbamide, also known as hydroxyurea, is an antimetabolite medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer.<ref name=AHFS2016/><ref name=UK2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In sickle-cell disease it increases fetal hemoglobin and decreases the number of attacks.<ref name=AHFS2016/> It is taken by mouth.<ref name=AHFS2016/>

Common side effects include bone marrow suppression, fevers, loss of appetite, psychiatric problems, shortness of breath, and headaches.<ref name=AHFS2016/><ref name=UK2016/> There is also concern that it increases the risk of later cancers.<ref name=AHFS2016/> Use during pregnancy is typically harmful to the fetus.<ref name=AHFS2016/> Hydroxycarbamide is in the antineoplastic family of medications. It is believed to work by blocking the making of DNA.<ref name=AHFS2016/>

Hydroxycarbamide was approved for medical use in the United States in 1967.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> Hydroxycarbamide is available as a generic medication.<ref name=AHFS2016/>

Medical uses

Hydroxycarbamide is used for the following indications:

• Myeloproliferative disease (primarily essential thrombocythemia and polycythemia vera). It has been found to be superior to anagrelide for the control of ET.<ref name="pmid16000354">Template:Cite journal</ref>
• Sickle-cell disease<ref name="pmid18458272">Template:Cite journal</ref> (increases production of fetal hemoglobin that then interferes with the hemoglobin polymerisation as well as by reducing white blood cells that contribute to the general inflammatory state in sickle cell patients.)
• Second line treatment for psoriasis<ref name="pmid17642550">Template:Cite journal</ref> (slows down the rapid division of skin cells)
• Systemic mastocytosis with associated hematological neoplasm(SM-AHN) <ref>Template:Cite journal</ref> (The utility in treating SM-AHN with hydroxycarbamide stems from its myelosuppressive activity, it does not however exhibit any selective anti-mast cell activity)
• Chronic myelogenous leukemia (largely replaced by imatinib, but still in use for its cost-effectiveness)<ref>Template:Cite journal</ref>

Side effects

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.<ref name=Liebelt2007>Template:Cite journal</ref>

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.<ref name="gale">Template:Cite book</ref> Moreover, because of this, its use in people with leukopenia, thrombocytopenia or severe anemia is contraindicated.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name=Platt2008/>

Mechanism of action

Hydroxycarbamide decreases the production of deoxyribonucleotides<ref>Template:DorlandsDict</ref> via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction of nucleoside diphosphates (NDPs).<ref name=Platt2008>Template:Cite journal</ref> Additionally, hydroxycarbamide causes production of reactive oxygen species in cells, leading to disassembly of replicative DNA polymerase enzymes and arresting DNA replication.<ref>Template:Cite journal</ref>

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.<ref name=Platt2008/><ref name="pmid12531879">Template:Cite journal</ref>

Natural occurrence

Hydroxyurea has been reported as endogenous in human blood plasma at concentrations of approximately 30 to 200 ng/ml.<ref>Template:Cite journal</ref>

Chemistry

Template:Chembox Hydroxyurea has been prepared in many different ways since its initial synthesis in 1869.<ref name="Dresler and Stein et al 1869">Template:Cite journal</ref> The original synthesis by Dresler and Stein was based around the reaction of hydroxylamine hydrochloride and potassium cyanate.<ref name="Dresler and Stein et al 1869" /> Hydroxyurea lay dormant for more than fifty years until it was studied as part of an investigation into the toxicity of protein metabolites.<ref name="PMC3069221">Template:Cite journal</ref> 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.<ref name = "Hydroxyurea synthesis">Template:Cite patent</ref> 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).<ref name="Hussain et al 2016">Template:Cite journal</ref>

Pharmacology

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.<ref name=pubchem>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Biochemical research has explored its role as a DNA replication inhibitor<ref name="pmid14573610">Template:Cite journalTemplate:Dead link</ref> 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.<ref name=pmid1641648>Template:Cite journal</ref>

Hydroxyurea has many pharmacological applications under the Medical Subject Headings classification system:<ref name="pubchem"/>

• Antineoplastic agents – Substances that inhibit or prevent the proliferation of neoplasms.
• Antisickling agents – Agents used to prevent or reverse the pathological events leading to sickling of erythrocytes in sickle cell conditions.
• Nucleic acid synthesis inhibitors – Compounds that inhibit cell production of DNA or RNA.
• Enzyme inhibitors – Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
• Cytochrome P-450 CYP2D6 inhibitors – Agents that inhibit one of the most important enzymes involved in the metabolism of xenobiotics in the body, CYP2D6, a member of the cytochrome P450 mixed oxidase system.

Society and culture

Brand names

Brand names include: Hydrea, Litalir, Droxia, and Siklos.Template:Citation needed

References

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