HYDROXYUREA

Hydroxycarbamide (INN) 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.

Mechanism of action

One mechanism of action is thought to be based on its reduction of production of deoxyribonucleotides[1] via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction NDPs.[2]

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 gammaglobulin synthesis necessary for fetal hemoglobin (by removing the rapidly dividing cells that preferentially produce sickle hemoglobin).[2][3]

[edit]Uses

Hydroxycarbamide is used for the following indications:

Myeloproliferative disease (primarily polycythemia vera and essential thrombocytosis[4])

Sickle-cell disease[5] (breaks down cells that are prone to sickle, as well as increasing fetal hemoglobin content)

AIDS as an adjunct to ddI in combination antiretroviral therapies[6]

Second line treatment for psoriasis[7] (slows down the rapid division of skin cells)

Biochemical research as a DNA replication inhibitor[8] that causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks (see DNA repair)

Treatment for systemic mastocytosis[citation needed]

[edit]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.[citation needed]

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.[2]

[edit]Side effects

Reported side-effects are: drowsiness, nausea, vomiting and diarrhea, constipation, 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.[9]

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.[citation needed]

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.[2]

[edit]Contraindications

Contraindications are: severe anemia, neutropenia.[citation needed]

[edit]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.[9]

[edit]Synthesis

Hydroxyurea was first synthesized in 1869 by Dresler and Stein from hydroxylamine and hydrogen cyanide; the industrial process is analogous.[10] Hydroxyurea may also be synthesized by reaction of ethyl carbamate with hydroxylamine; hydroxylamine displaces the ester to give the amide.[11]