Hydroxycarbamide

Hydroxycarbamide
Structural formula
Clinical data
Trade names Apo-Hydroxyurea, Droxia, Hydrea, others
AHFS/Drugs.com International Drug Names
MedlinePlus a682004
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration
Oral
ATC code L01XX05 (WHO)
Legal status
Legal status
Pharmacokinetic data
Metabolism Hepatic (to CO2 and urea)
Biological half-life 2-4 hours
Excretion Renal and lungs
Identifiers
CAS Number 127-07-1 YesY
PubChem (CID) 3657
IUPHAR/BPS 6822
DrugBank DB01005 YesY
ChemSpider 3530 YesY
UNII X6Q56QN5QC YesY
KEGG D00341 YesY
ChEBI CHEBI:44423 YesY
ChEMBL CHEMBL467 YesY
NIAID ChemDB 006310
ECHA InfoCard 100.004.384
Chemical and physical data
Formula CH4N2O2
Molar mass 76.0547 g/mol
3D model (Jmol) Interactive image
  (verify)

Hydroxycarbamide (INN, BAN) or hydroxyurea (USAN, AAN) is an antineoplastic drug 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 HIV/AIDS.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[1]

Medical uses

Hydroxycarbamide is used for the following indications:

Side effects

Reported side-effects are: drowsiness, nausea, vomiting and diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity (dose-limiting toxicity; 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.[10]

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.[11] 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.[12]

Mechanism of action

Hydroxycarbamide decreases the production of deoxyribonucleotides[13] via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction NDPs.[12]

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 chain synthesis necessary for fetal hemoglobin production (which inhibits the formation of sickle hemoglobin aggregates). A few red cell clones called F cells are progeny of a small pool of immature committed erythroid precursors (BFU-e) that retain the ability to produce HbF.[12][14]

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.[15]

References

  1. "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  2. 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.
  3. 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. doi:10.7326/0003-4819-148-12-200806170-00221. PMC 3256736Freely accessible. PMID 18458272.
  4. 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.
  5. 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.
  6. Rustin, MH (November 2012). "Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data". Br J Dermatol. 167 (Suppl 3): 3–11. doi:10.1111/j.1365-2133.2012.11208.x. PMID 23082810.
  7. Escribano, L.; Álvarez-Twose, I. N.; Sánchez-Muñoz, L.; Garcia-Montero, A.; Núñez, R.; Almeida, J.; Jara-Acevedo, M.; Teodósio, C.; et al. (2009). "Prognosis in adult indolent systemic mastocytosis: A long-term study of the Spanish Network on Mastocytosis in a series of 145 patients". Journal of Allergy and Clinical Immunology. 124 (3): 514–521. doi:10.1016/j.jaci.2009.05.003. PMID 19541349.
  8. Dalziel, K.; Round, A.; Stein, K.; Garside, R.; Price, A. (2004). "Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: A systematic review and economic analysis". Health technology assessment (Winchester, England). 8 (28): iii, ii1–120. PMID 15245690.
  9. 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.
  10. Liebelt, E.; Balk, S.; Faber, W.; Fisher, J.; Hughes, C.; Lanzkron, S.; Lewis, K.; Marchetti, F.; Mehendale, H.; Rogers, J. M.; Shad, A. T.; Skalko, R. G.; Stanek, E. J. (2007). "NTP-CERHR expert panel report on the reproductive and developmental toxicity of hydroxyurea". Birth defects research. Part B, Developmental and reproductive toxicology. 80 (4): 259–366. doi:10.1002/bdrb.20123. PMID 17712860.
  11. Longe, Jacqueline L. (2002). Gale Encyclopedia Of Cancer: A Guide To Cancer And Its Treatments. Detroit: Thomson Gale. pp. 514–516. ISBN 978-1-4144-0362-5.
  12. 1 2 3 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.
  13. "hydroxyurea" at Dorland's Medical Dictionary
  14. 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. PMC 151872Freely accessible. PMID 12531879.
  15. Kettani, T; Gulbis, B; Ferster, A; Kumps, A (2009). "Plasma hydroxyurea determined by gas chromatography-mass spectrometry". Journal of Chromatography B. 877 (4): 446–450. doi:10.1016/j.jchromb.2008.12.048.
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