Hydroxycarbamide

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Structural formula
Structural formula of hydroxycarbamide
General
Non-proprietary name Hydroxycarbamide
other names
  • N -hydroxycarbamide
  • Hydroxyurea
  • Hydroxyurea
Molecular formula CH 4 N 2 O 2
Brief description

white solid

External identifiers / databases
CAS number 127-07-1
EC number 204-821-7
ECHA InfoCard 100.004.384
PubChem 3657
DrugBank DB01005
Wikidata Q212272
Drug information
ATC code

L01 XX05

Drug class

Cytostatic

Mechanism of action

Ribonucleotide reductase inhibitors

properties
Molar mass 76.05 g · mol -1
Physical state

firmly

Melting point

144-146 ° C

solubility

soluble in water

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
08 - Dangerous to health

danger

H and P phrases H: 340-360
P: 201-202-280-308 + 313-405-501
Toxicological data

5760 mg kg −1 ( LD 50ratoral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Hydroxycarbamide ( INN ), also known as hydroxyurea or hydroxyurea , is a cytostatic agent that is used in particular to treat malignant blood diseases ( leukemia , myeloproliferative neoplasias ). It is also approved for the treatment of sickle cell anemia . It has been tested in experimental studies for antiretroviral treatment in HIV infection.

Mechanism of action

The effect of the substance is based on the inhibition of the enzyme ribonucleotide reductase , which reduces ribose to deoxyribose. This takes place via a radical mechanism that requires the formation of a tyrosine radical in the active center of the enzyme. The stable tyrosine radical is created by a nearby iron center, which consists of two Fe 3+ . Hydroxyurea complexes the iron and causes the iron to be reduced to Fe 2+ , which significantly limits the DNA synthesis capacity of the respective cell.

Pharmacokinetics

After oral administration, hydroxycarbamide is rapidly absorbed from the gastrointestinal tract . The exact bioavailability is not known, but appears to be high (no significant difference in the levels with oral versus iv administration). The maximum serum concentration is reached about 2 hours after ingestion. Since the molecule is relatively small, hydroxycarbamide diffuses well into different body compartments. At higher blood levels, the blood-brain barrier is crossed and there is a transfer into the liquor . The substance also penetrates into ascites , pleural effusions, and into breast milk . The mechanism of biotransformation or metabolism is not exactly known. There is no metabolism via the cytochrome P450 system. The substance is mainly excreted in unchanged form via the kidneys .

Medical application

For myeloproliferative diseases

Hydroxycarbamide is used for cytoreductive therapy in myeloproliferative diseases ( chronic myeloid leukemia (CML), polycythemia vera , essential thrombocythemia , osteomyelofibrosis ). Its use in CML has declined sharply after the introduction of Imatinib (Glivec ® ), but in certain situations the use of hydroxycarbamide can still be useful. In the case of polycythemia vera, regular bloodletting is usually the treatment method of choice, but in the case of significantly increased leukocyte counts or platelet counts , the use of hydroxycarbamide can be useful. A classic area of ​​application is also essential thrombocythemia, here the substance competes with the drug anagrelide . Osteomyelofibrosis is also a typical field of application.

Sickle cell disease

The substance has also been approved by the European Medicines Agency ( EMA) for the treatment of sickle cell anemia. On June 29, 2007, Addmedica (Paris) received the marketing authorization for hydroxycarbamide (Siklos ® ) for this indication. Occasionally, patients with sickle cell anemia may develop U. life-threatening or painful vaso-occlusive crises, d. H. Vascular occlusions due to the agglomeration of sickle cells. Hydroxycarbamide increases fetal hemoglobin synthesis (Hb F) in the blood. A higher percentage of Hb F in the blood has a protective effect against the polymerisation of sickle cells. Its effectiveness in vaso-occlusive crises has been demonstrated in several clinical studies.

Antiretroviral therapy for HIV infection

A number of clinical studies have examined the combination of hydroxycarbamide with antiretroviral agents for the treatment of HIV infection. The results were inconsistent. It should therefore only be used within controlled clinical studies. The substance has not been approved for the treatment of HIV infection.

Off-label use

Information on the use of hydroxycarbamide in chronic myelomonocytic leukemia (CMML) according to Section 30 (2) AM-RL.

dosage

The substance comes in tablets of 500 or 1000 milligrams (mg). The usual dosage is between 250 mg daily (e.g. one 500 mg tablet every 2 days) to about 2 g daily.

Side effects

Possible side effects are, for example: drowsiness, nausea, vomiting (rare), diarrhea, constipation, inflammation of the oral mucosa (rare), loss of appetite, hair loss, skin rash, increased liver values ​​(usually temporary). The medically most significant side effect is the dampening effect not only on the blood disease, but also on healthy blood formation ( myelosuppression ). This effect usually limits the dose that can be given. Another important side effect is an increase in the level of uric acid in the blood. In correspondingly predisposed patients, this can lead to a deterioration in kidney function or even a gout attack . The question of whether hydroxycarbamide has a leukemogenic potential , i.e. H. Whether there is an increased risk of later developing leukemia with treatment is a matter of controversy. The risk is likely to be low. There have also been isolated reports of patients with spinaliomas ( squamous cell carcinoma of the skin) after hydroxycarbamide therapy.

Use in pregnancy

In animal experiments, hydroxycarbamide is clearly genotoxic and embryotoxic . Women planning a pregnancy should discontinue hydroxycarbamide after consulting their doctor.

Trade names

Monopreparations

Litalir (D, A, CH), Siklos (A), Syrea (D),

Individual evidence

  1. a b c d e data sheet Hydroxyurea at AlfaAesar, accessed on April 28, 2017 ( PDF )(JavaScript required) .
  2. Entry on hydroxycarbamide in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  3. Schubert-Zsilavecz, Manfred., Roth, Hermann J .: Medicinal Chemistry: Targets - Drugs - Chemical Biology; 191 tables . 2., completely reworked. and exp. Ed. Dt. Apotheker-Verl, Stuttgart 2010, ISBN 978-3-7692-5002-2 .
  4. Approval information (PDF; 66 kB).
  5. ^ European Medicines Agency - Find medicine - Siklos. Retrieved September 7, 2012 .
  6. ^ MH Steinberg, F. Barton, O. Castro, CH Ebeneow, SK Ballas, A. Kutlar, E. Orringer, R. Bellevue, N. Olivieri, J. Eckman, M. Varma, G. Ramirez, B. Adler, W. Smith, T. Carlos, K. Ataga, L. DeCastro, C. Bigelow, Y. Saunthararajah, M. Telfer, E. Vichinsky, S. Claster, S. Shurin, K. Bridges, M. Waclawiw, D. Bonds, M. Terrin: Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. In: JAMA. 289 (13), 2003, pp. 1645-1651. PMID 12672732 .
  7. ^ I. Frank, RJ Bosch, S. Fiscus, F. Valentine, C. Flexner, Y. Segal, P. Ruan, R. Gulick, K. Wood, S. Estep, L. Fox, T. Nevin, M. Stevens, JJ Eron Jr; ACTG 307 Protocol Team: 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. In: AIDS Res Hum Retroviruses. 20 (9), 2004, pp. 916-926. PMID 15597521 .
  8. S. Swindells, CJ Cohen, DS Berger, KT Tashima, Q. Liao, BF Pobiner, JW Snidow, GE Pakes, JE Hernandez; NZTA4008 Study Team: Abacavir, efavirenz, didanosine, with or without hydroxyurea, in HIV-infected adults failing initial nucleoside / protease inhibitor-containing regimens. In: BMC Infect Dis. 5 (1), 2005, p. 23. PMID 15819974 .
  9. F. Lori, A. Foli, A. Groff, L. Lova, L. Whitman, N. Bakare, RB Pollard, J. Lisziewicz: Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ( 'virostatic') mechanisms. In: AIDS. 19 (11), 2005, pp. 1173-1181. PMID 15990570 .
  10. Initiation of a commenting procedure on the amendment of the Drugs Directive (AM-RL) (PDF; 68 kB). G-BA decision of February 12, 2013.
  11. Essential thrombocythemia (ET): leukemogenic risk after treatment with hydroxycarbamide. In: The medicament letter. 5, 1998, p. 39 weblink .
  12. Spinalioma under hydroxycarbamide ("From the UAW database"). In: Deutsches Ärzteblatt . Vol. 99, issue 19, May 10, 2002. weblink .