Haematology Watch

HYDROXYUREA


Hydroxyurea or hydroxycarbamide (the latter being the recommended International Nonproprietary Name) is an antineoplastic drug used in hematological malignancies, specifically polycythemia vera and essential thrombocytosis. 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 believed 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, hydroxyurea increases the concentration of fetal haemoglobin. The precise mechanism of action is not yet clear, but it appears that hydroxyurea 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]

Uses

Hydroxyurea is used for the following indications:

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]

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.[citation needed]

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]

Hydroxyurea 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 hydroxyurea 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]

Contraindications

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

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.[citation needed]

References

  1. ^ hydroxyurea at Dorland's Medical Dictionary
  2. ^ a b c d Platt OS (2008). "Hydroxyurea for the treatment of sickle cell anemia". N. Engl. J. Med. 358 (13): 1362–9. doi:10.1056/NEJMct0708272. PMID 18367739. 
  3. ^ Cokic VP, Smith RD, Beleslin-Cokic BB, et al. (2003). "Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase". J Clin Invest 111 (2): 231–9. doi:10.1172/JCI16672. PMID 12531879. http://www.jci.org/articles/view/16672.  Full text at PMC: 151872
  4. ^ Harrison CN, Campbell PJ, Buck G, et al. (July 2005). "Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia". N. Engl. J. Med. 353 (1): 33–45. doi:10.1056/NEJMoa043800. PMID 16000354. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=16000354&promo=ONFLNS19. 
  5. ^ Lanzkron S, Strouse JJ, Wilson R, et al. (June 2008). "Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease". Ann. Intern. Med. 148 (12): 939–55. PMID 18458272. 
  6. ^ Frank I, Bosch RJ, Fiscus S, et al. (September 2004). "Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307". AIDS Res. Hum. Retroviruses 20 (9): 916–26. doi:10.1089/aid.2004.20.916. PMID 15597521. 
  7. ^ Sharma VK, Dutta B, Ramam M (2004). "Hydroxyurea as an alternative therapy for psoriasis". Indian J Dermatol Venereol Leprol 70 (1): 13–7. PMID 17642550. http://www.ijdvl.com/article.asp?issn=0378-6323;year=2004;volume=70;issue=1;spage=13;epage=17;aulast=Sharma. 
  8. ^ Koç A, Wheeler LJ, Mathews CK, Merrill GF (January 2004). "Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools". J. Biol. Chem. 279 (1): 223–30. doi:10.1074/jbc.M303952200. PMID 14573610. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=14573610.