Hydroxycarbamid

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H340：Kann genetische Defekte verursachen.

  H361：Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

Hydroxyurea Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R46:Kann vererbbare Schäden verursachen.
  R63:Kann das Kind im Mutterleib möglicherweise schädigen.
  R61:Kann das Kind im Mutterleib schädigen.
  R40:Verdacht auf krebserzeugende Wirkung.

• S-Sätze Betriebsanweisung:

  S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
  S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
  S22:Staub nicht einatmen.

• Beschreibung

  Readily oxidized in vivo to free radical forms, which destroy the stable tyrosyl free radical of the metalloenzyme ribonucleotide reductase, suppressing deoxyribonucleotide production and blocking DNA synthesis and repair.1,2 Reduces cell proliferation, and causes S-phase arrest and death.3 Induces p53-dependent NF-κB target gene expression in U2OS cells expressing HA-RelA.4 Stimulates fetal hemoglobin production in vitro and in vivo.5 Allows for S phase enrichment of CHO cells with maintenance of viability for enhanced site-specific genome engineering.6 Anticancer and antiviral agent.

• Chemische Eigenschaften

  Off-White Crystalline Solid

• Originator

  Hydrea,Squibb,UK,1967

• Verwenden

  antineoplastic, inhibits ribonucleoside diphosphate reductase

• Verwenden

  Hydroxyurea USP is used to treat Chronic granulocytic leukemia; melanoma; cancer of ovary, head, neck.

• Verwenden

  An anti-neoplastic - inhibits ribonucleoside reductase and DNA replication. A potential therapy for sickle cell anemia which involves the nitrosylation of sickle cell hemoglobin. Horseradish peroxidase catalyzes nitric oxide formation from hydroxyurea in the presence of hydrogen peroxide.

• Definition

  ChEBI: Hydroxyurea is a member of the class of ureas that is urea in which one of the hydrogens is replaced by a hydroxy group. An antineoplastic used in the treatment of chronic myeloid leukaemia as well as for sickle-cell disease. It has a role as a DNA synthesis inhibitor, an EC 1.17.4.1 (ribonucleoside-diphosphate reductase) inhibitor, an antineoplastic agent, a genotoxin, an antimetabolite, a teratogenic agent, a radical scavenger, an immunomodulator and an antimitotic. It is a member of ureas and a one-carbon compound.

• Indications

  Hydroxyurea (Hydrea) inhibits the enzyme ribonucleotide reductase and thus depletes intracellular pools of deoxyribonucleotides, resulting in a specific impairment of DNA synthesis. The drug therefore is an Sphase specific agent whose action results in an accumulation of cells in the late G1- and early S-phases of the cell cycle.

• Manufacturing Process

  The procedure may be illustrated by the following equations relating to the preparation of hydroxyurea from hydroxylamine hydrochloride:
  (1) R4N+Cl-+ NaNCO = R4N+NCO-+ NaCl
  (2) R4N+NCO-+ H2NOH HCl = R4N+Cl-+HONH-CO-NH2
  Equation (1) shows the simple conversion of a quaternary ammonium anion exchange resin from the chloride form to the cyanate form. Equation (2) shows the reaction of the resin in the cyanate form with hydroxylamine hydrochloride whereby hydroxyurea is formed and the anion Cl-is retained by the quaternary resin.
  A 90 x 6 cm column was packed with 2 kg of granular Amberlite IRA-410 resin in the chloride form (a vinylpyridine/divinylbenzene copolymer quaternized with dimethyl sulfate and converted to chloride) and washed with 3 kg of a 10% aqueous solution of sodium cyanate. This changed the resin from the chloride to the cyanate form. Sodium chloride and excess sodium cyanate were then washed from the column with distilled water until the effluent failed to give a white precipitate with silver nitrate. The reaction of equation (2) was conducted by elutriating the column with a solution of 105 grams (1.5 mols) of hydroxylamine hydrochloride in 400 ml water at about 15°C.
  A hot (50° to 70°C) reaction zone developed near the top of the column and about 30 minutes was required for this hot zone to descend the full length of the column. The reaction solution was followed in the column by 2.5 liters of distilled water. Collection of the product was begun when hydroxyurea could be detected in the effluent, as indicated by a black precipitate on warming a sample with a silver nitrate test solution. All the effluents were combined and vacuum evaporated at 35°C to give 90 grams of tan residue corresponding to 79% yield of crude product. After recrystallization from 100 ml of water heated to 75°C, the colorless product was dried in a vacuum desiccator over phosphorus pentoxide to give 60.6 grams (53% yield) of hydroxyurea, MP 133° to 136°C.

• Therapeutic Function

  Cancer chemotherapy

• Allgemeine Beschreibung

  HONH-CO-NH₂. The drug is available in a 500-mg capsulefor oral use. Hydroxyurea is often considered an antimetabolitedrug, and it is used to treat myelogenousleukemia, ovarian cancer, and essential thrombocytosis. Themechanism of action of hydroxyurea involves inhibition ofDNA biosynthesis by inhibition of the enzyme ribonucleotidereductase). Resistance can occur viaincreased expression of ribonucleotide reductase. The oralbioavailability is quite high approaching 100% and the drugis distributed to all tissues. Hydroxyurea readily enters theCNS and distributes to human breast milk. A major portionof the total dose is excreted unchanged in the urine. Thedrug has been shown to increase the toxicity of 5-FU, andhydroxyurea may increase the effectiveness of some antimetaboliteHIV drugs. The toxicity profile includes myelosuppression,leucopenia, nausea, vomiting, pruritus hyperpigmentation,headache, drowsiness, and confusion.

• Allgemeine Beschreibung

  Odorless or almost odorless white to off-white crystalline solid. Tasteless.

• Air & Water Reaktionen

  Water soluble.

• Reaktivität anzeigen

  An amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

• Brandgefahr

  Flash point data for Hydroxyurea are not available; however, Hydroxyurea is probably combustible.

• Biochem/physiol Actions

  Anti-neoplastic. Inactivates ribonucleoside reductase by forming a free radical nitroxide that binds a tyrosyl free radical in the active site of the enzyme. This blocks the synthesis of deoxynucleotides, which inhibits DNA synthesis and induces synchronization or cell death in S-phase.

• Mechanism of action

  Hydroxyurea is rapidly absorbed after oral administration, with peak plasma levels achieved approximately 1 to 2 hours after drug administration; its elimination half-life is 2 to 3 hours. The primary route of excretion is renal, with 30 to 40% of a dose excreted unchanged.

• Clinical Use

  Hydroxyurea is used for the rapid lowering of blood granulocyte counts in patients with chronic granulocytic leukemia. The drug also can be used as maintenance therapy for patients with the disease who have become resistant to busulfan. Only a small percentage of patients with other malignancies have had even brief remissions induced by hydroxyurea administration.

• Nebenwirkungen

  Hematological toxicity, with white blood cells affected more than platelets, may occur. Megaloblastosis of the bone marrow also may be observed. Recovery is rapid, generally within 10 to 14 days after discontinuation of the drug. Some skin reactions, including hyperpigmentation and hyperkeratosis, have been reported with chronic treatment.

• Synthese

  Hydroxyurea (30.6.1) is made by reacting sodium cyanate with hydroxylamine. In this reaction, hydroxylamine hydrochloride and a basic ion-exchange resin are used.

  

• Veterinary Drugs and Treatments

  Hydroxyurea may be useful in the treatment of polycythemia vera, mastocytomas, and leukemias in dogs and cats. It is often used to treat dogs with chronic myelogenous leukemia no longer responsive to busulfan. Hydroxyurea, potentially, may be of benefit in the treatment of feline hypereosinophilic syndrome and in the adjunctive treatment of canine meningiomas. It can also be used in dogs for the adjunctive medical treatment (to reduce hematocrit) of right to left shunting patent ductus arteriosis or tetralogy of Fallot.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
  Antivirals: increased toxicity with didanosine and stavudine - avoid.
  Vaccines: risk of generalised infections - avoid.

• Stoffwechsel

  Hydroxyurea has excellent oral bioavailability (80–100%), and serum levels peak within 2 hours of consuming the capsules. If a positive response is noted within 6 weeks, toxicities generally are mild enough to permit long-term or indefinite therapy on either a daily or every-3-day basis. Leukopenia and, less commonly, thrombocytopenia and/or anemia are the most serious adverse effects. Excretion of the unchanged drug and the urea metabolite is via the kidneys. The carbon dioxide produced as a by-product of hydroxyurea metabolism is excreted in the expired air.

• läuterung methode

  Recrystallise hydroxyurea from absolute EtOH (10g in 150mL). Note that the rate of solution in boiling EtOH is slow (15-30minutes). It should be stored in a cool dry place, but some decomposition could occur after several weeks. [Deghenghi Org Synth Coll Vol V 645 1973.] It is very soluble in H2O and can be crystallised from Et2O. [Kfod Acta Chem Scand 10 256 1956, Beilstein 3 IV 170.]

• Einzelnachweise

  Gr?sland et al. (1985), The tyrosyl free radical in ribonucleotide reductase; Health Perspect., 64 139 Yarbro (1992), Mechanism of action of hydroxyurea; Oncol., 3 (Suppl 9) 1 Singh and Xu (2016), The Cell Killing Mechanisms of Hydroxyurea; Genes (Basel), 7 99 Campbell et al. (2021), Temporal modulation of the NF-kB Re1A network in response to different types of DNA damage; J., 478 533 Baliga et al. (2000), Mechanism for fetal hemoglobin induction by hydroxyurea in sickle cell erythroid progenitors; J. Hematol., 65 227 Kwak et al. (2021), Hydroxyurea selection for enhancement of homology-directed targets integration of transgenes in CHO cells; Biotechnol, 62 26

Hydroxyurea Upstream-Materialien And Downstream Produkte

Hydroxycarbamid Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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