Hydroxycarbamide

Source: Wikipedia, the free encyclopedia.
Hydroxycarbamide
Structural formula
Clinical data
Trade namesDroxia, Hydrea, Siklos, others
Other namesHydroxyurea (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa682004
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: WARNING[1]Rx-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
MetabolismLiver (to CO2 and urea)
Elimination half-life2–4 hours
ExcretionKidney and lungs
Identifiers
  • Hydroxyurea
JSmol)
Melting point133 to 136 °C (271 to 277 °F)
  • O=C(N)NO
  • InChI=1S/CH4N2O2/c2-1(4)3-5/h5H,(H3,2,3,4) checkY
  • Key:VSNHCAURESNICA-UHFFFAOYSA-N checkY
  (verify)

Hydroxycarbamide, also known as hydroxyurea, is a medication used in

sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer.[2][3] In sickle-cell disease it increases fetal hemoglobin and decreases the number of attacks.[2] It is taken by mouth.[2]

Common

antineoplastic family of medications. It is believed to work by blocking the making of DNA.[2]

Hydroxycarbamide was approved for medical use in the United States in 1967.

generic medication.[2]

Medical uses

Hydroxycarbamide is used for the following indications:

Side effects

Reported side effects are:

liver enzymes, creatinine and blood urea nitrogen.[10]

Due to its negative effect on the bone marrow, regular monitoring of the

liver enzymes, are commonly checked.[11] Moreover, because of this, its use in people with leukopenia, thrombocytopenia or severe anemia is contraindicated.[12]

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.[13]

Mechanism of action

Hydroxycarbamide decreases the production of deoxyribonucleotides[14] via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction of nucleoside diphosphates (NDPs).[13]

In the treatment of

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.[13][15]

Natural occurrence

Hydroxyurea has been reported as endogenous in human blood plasma at concentrations of approximately 30 to 200 ng/ml.[16]

Chemistry

Hydroxycarbamide
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Mutagen – Reproductive toxicity
GHS labelling:
GHS08: Health hazard
Danger
H340, H361
P201, P202, P281, P308+P313, P405, P501

Hydroxyurea has been prepared in many different ways since its initial synthesis in 1869.

hydroxylamine hydrochloride and potassium cyanate.[17] Hydroxyurea lay dormant for more than fifty years until it was studied as part of an investigation into the toxicity of protein metabolites.[18]
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.[19] 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).[20]

Pharmacology

Hydroxyurea is a monohydroxyl-substituted urea (hydroxycarbamate)

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.[21]

Biochemical research has explored its role as a

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.[23]

Hydroxyurea has many pharmacological applications under the Medical Subject Headings classification system:[21]

  • 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.[citation needed]

References

  1. FDA
    . Retrieved 22 Oct 2023.
  2. ^ a b c d e f g h i "Hydroxyurea". The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
  3. ^ a b "Hydrea 500 mg Hard Capsules – Summary of Product Characteristics (SPC) – (eMC)". www.medicines.org.uk. Archived from the original on 20 December 2016. Retrieved 14 December 2016.
  4. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. PMID 16000354
    .
  6. PMID 18458272
    .
  7. PMID 17642550. Archived
    from the original on 2009-07-03.
  8. PMID 19541349
    .
  9. PMID 15245690
    .
  10. PMID 17712860
    .
  11. ISBN 978-1-4144-0362-5
    .
  12. ^ "HYDREA" (PDF). Accessdata.fda.gov. US Food and Drug Administration.
  13. ^
    PMID 18367739
    .
  14. ^ "hydroxyurea" at Dorland's Medical Dictionary
  15. PMID 12531879
    .
  16. PMID 19144580
    .
  17. ^
    doi:10.1002/jlac.18691500212
    .
  18. PMID 21454878
    .
  19. ^ US 2705727, Graham PJ, "Synthesis of Ureas", assigned to E.I. du Pont de Nemours & Co., Wilmington, DE 
  20. doi:10.13140/RG.2.1.3607.2720
    .
  21. ^ a b "Hydroxyurea". PubChem. U.S. National Library of Medicine. Archived from the original on 2017-05-18.
  22. S2CID 2675195.[permanent dead link
    ]
  23. PMID 1641648
    .
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