Hydroxycarbamide


Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, chronic myelogenous leukemia, cervical cancer, and essential thrombocythemia. In sickle-cell disease it increases fetal hemoglobin and decreases the number of attacks. It is taken by mouth.
Common side effects include bone marrow suppression, fevers, loss of appetite, psychiatric problems, shortness of breath, and headaches. There is also concern that it increases the risk of later cancers. Use during pregnancy is typically harmful to the baby. Hydroxycarbamide is in the antineoplastic family of medications. It is believed to work by blocking the making of DNA.
Hydroxycarbamide was approved for medical use in the United States in 1967. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system. Hydroxycarbamide is available as a generic medication.

Medical uses

Hydroxycarbamide is used for the following indications:
Reported side-effects are: neurological reactions, nausea, vomiting, diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity, megaloblastic anemia, thrombocytopenia, bleeding, hemorrhage, gastrointestinal ulceration and perforation, immunosuppression, leukopenia, alopecia, skin rashes, erythema, pruritus, vesication or irritation of the skin and mucous membranes, pulmonary edema, abnormal liver enzymes, creatinine and blood urea nitrogen.
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. Moreover, because of this, severe anemia and neutropenia are contraindicated.
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.

Mechanism of action

Hydroxycarbamide decreases the production of deoxyribonucleotides via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction of nucleoside diphosphates.
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 production. 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 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.

Names

Brand names include: Hydrea, Litalir, Droxia, and Siklos.

Natural occurrence

Hydroxyurea has been reported as endogenous in human blood plasma at concentrations of approximately 30 to 200 ng/ml.

Chemistry

Hydroxyurea has been prepared in many different ways since its initial synthesis in 1869. Medical chemists, Dresler and Stein created Hydroxyurea from hydroxylamine, hydrochloric acid and potassium cyanide as a technical exercise in organic chemistry, as part of a series of experiments generating derivatives of urea. Hydroxyurea lay dormant for more than fifty years until it was studied as part of an investigation into the toxicity of protein metabolites. 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 salt cyanates and hydroxylamine hydrochloride in aqueous solution. 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..

Pharmacology

Hydroxyurea is a monohydroxyl-substituted urea 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.
Biochemical research has explored its role as a DNA replication inhibitor which causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents.
Hydroxyurea has many pharmacological applications under the Medical Subject Headings classification system: