Cyclophosphamid

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H301：Giftig bei Verschlucken.

  H340：Kann genetische Defekte verursachen.

  H350：Kann Krebs verursachen.

  H360：Kann die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

• Sicherheit

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P270：Bei Gebrauch nicht essen, trinken oder rauchen.

  P301+P310：BEI VERSCHLUCKEN: Sofort GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

  P321：Besondere Behandlung

  P330：Mund ausspülen.

  P405：Unter Verschluss aufbewahren.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Cyclophosphamide Chemische Eigenschaften,Einsatz,Produktion Methoden

• ERSCHEINUNGSBILD

  FEINES, WEISSES, GERUCHLOSES, KRISTALLINES PULVER (MONOHYDRAT). WIRD FLüSSIG BEI VERLUST DES KRISTALLWASSERS. VERFäRBT SICH DUNKEL BEI KONTAKT MIT LICHT.

• CHEMISCHE GEFAHREN

  Zersetzung beim Verbrennen unter Bildung giftiger Rauche mit Phosphoroxiden und Stickstoffoxiden.

• ARBEITSPLATZGRENZWERTE

  TLV nicht festgelegt (ACGIH 2005).
  MAK nicht festgelegt (DFG 2005).
  

• AUFNAHMEWEGE

  Aufnahme in den Körper durch Inhalation des Aerosols und durch Verschlucken.

• INHALATIONSGEFAHREN

  Verdampfung bei 20°C vernachlässigbar; eine gesundheitsschädliche Partikelkonzentration in der Luft kann jedoch beim Dispergieren schnell erreicht werden, vor allem als Pulver.

• WIRKUNGEN BEI KURZZEITEXPOSITION

  WIRKUNGEN BEI KURZZEITEXPOSITION:
  Die Substanz reizt die Augen, die Haut und die Atemwege. Möglich sind Auswirkungen auf Blut, Blase, Zentralnervensystem und Herz.

• WIRKUNGEN NACH WIEDERHOLTER ODER LANGZEITEXPOSITION

  Möglich sind Auswirkungen auf Blut, Blase, Lunge und Knochenmark mit nachfolgender Leukopenie, Blasenentzündung, Lungenfibrose. Krebserzeugend für den Menschen. Kann zu vererbbaren genetischen Schäden führen. Fruchtbarkeitsschädigend oder entwicklungsschädigend.

• LECKAGE

  Fachmann zu Rate ziehen! Verschüttetes Material in abdichtbaren Behältern sammeln; falls erforderlich durch Anfeuchten Staubentwicklung verhindern. Reste sorgfältig sammeln. An sicheren Ort bringen. Persönliche Schutzausrüstung: Atemschutzgerät, P3-Filter für giftige Partikel.

• S-Sätze Betriebsanweisung:

  S22:Staub nicht einatmen.
  S24/25:Berührung mit den Augen und der Haut vermeiden.

• Chemische Eigenschaften

  Endoxan is a white crystalline powder (monohydrate). It may be used or shipped in solution. Darkens on exposure to light. Odorless

• Originator

  Cytoxan,Mead Johnson,US,1959

• Verwenden

  An anti-proliferative agent that regulates Bax and Bcl-2 expression.

• Verwenden

  Oncology

• Verwenden

  Cyclophosphamide USP is used to treat acute and chronic lymphocytic leukemia; lung cancer; rhabdomyosarcoma; neuroblastoma; ovarian and mammary carcinoma; multiple myeloma; lymphosarcoma; Burkitt’s lymphoma; Hodgkin’s disease; retinoblastoma; mycosis fungoides

• Indications

  Cyclophosphamide (Cytoxan) is the most versatile and useful of the nitrogen mustards. Preclinical testing showed it to have a favorable therapeutic index and to possess the broadest spectrum of antitumor activity of all alkylating agents. As with the other nitrogen mustards, cyclophosphamide administration results in the formation of cross-links within DNA due to a reaction of the two chloroethyl moieties of cyclophosphamide with adjacent nucleotide bases. Cyclophosphamide must be activated metabolically by microsomal enzymes of the cytochrome P450 system before ionization of the chloride atoms and formation of the cyclic ethylenimmonium ion can occur. The metabolites phosphoramide mustard and acrolein are thought to be the ultimate active cytotoxic moiety derived from cyclophosphamide.

• Definition

  ChEBI: Cyclophosphamide is a phosphorodiamide that is 1,3,2-oxazaphosphinan-2-amine 2-oxide substituted by two 2-chloroethyl groups at the amino nitrogen atom. It is an alkylating agent used in the treatment of several forms of cancer including leukemias, lymphomas and breast cancer.

• Manufacturing Process

  A solution of 7.5 g (0.1 mol) of 1,3-propanolamine and 20.2 g of triethylamine in 100 cc of absolute dioxane is added dropwise at 25°C to 30°C while stirring well to a solution of 25.9 g (0.1 mol) of N,N-bis-(β-chloroethyl)- phosphoric acid amide dichloride in 100 cc of absolute dioxane. After the reaction is complete, the product is separated from the precipitated triethylamine hydrochloride and the filtrate is concentrated by evaporation in waterjet vacuum at 35°C. The residue is dissolved in a large amount of ether and mixed to saturation with water. The N,N-bis-(β-chloroethyl)-N,O-propylene phosphoric acid diamide crystallizes out of the ethereal solution, after it has stood for some time in a refrigerator, in the form of colorless water-soluble crystals. MP 48°C to 49°C. Yield: 65% to 70% of the theoretical.

• Trademarks

  Cytoxan (Bristol-Myers Squibb); Neosar (Sicor).

• Therapeutic Function

  Antineoplastic

• Synthesis Reference(s)

  The Journal of Organic Chemistry, 43, p. 1111, 1978 DOI: 10.1021/jo00400a019

• Allgemeine Beschreibung

  Cyclophosphamide is a fine white crystalline powder. Odorless with a slightly bitter taste. Melting point 41-45 °C. A 2% solution has pH of 4 to 6. Used medicinally as an antineoplastic agent.

• Air & Water Reaktionen

  Water soluble.

• Reaktivität anzeigen

  Cyclophosphamide is sensitive to exposure to light (darkens). Also sensitive to oxidation. Aqueous solutions may be kept for a few hours at room temperature, but hydrolysis occurs at temperatures above 86°F. Solutions in DMSO, 95% ethanol or acetone are stable for 24 hours under normal lab conditions. Incompatible with benzyl alcohol. Undergoes both acid and base hydrolysis at extreme pHs

• Brandgefahr

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

• Biologische Aktivität

  cyclophosphamide, an inactive prodrug, is a kind of nitrogen mustard alkylating agent. cyclophosphamide requires enzymatic and chemical activation. as a result, nitrogen mustard is produced. it causes dna cross-linking that accounts for its cytotoxic properties. [1] ic50 of cytotoxicity in mouse embryo balb/c 3t3 cells is 37.6 μm, [2] ic50 of cytotoxicity against human hl60 cells is 8.79 μm measured by mtt assay. [3]cyclophosphamide attaches the alkyl group to the guanine base of dna causing its crosslinking, strand breakage and inducing mutations.[1] emadi a, jones rj, brodsky ra. cyclophosphamide and cancer: golden anniversary. nat rev clin oncol. 2009 nov; 6 (11):638-47.[2] moon ky, kwon ch. n3-methyl-mafosfamide as a chemically stable, alternative prodrug of mafosfamide. bioorg med chem lett. 1998 jul 7; 8 (13):1673-8.[3] patel mm, mali md, patel sk. bernthsen synthesis, antimicrobial activities and cytotoxicity of acridine derivatives. bioorg med chem lett. 2010 nov 1; 20 (21):6324-6.[4] lutsiak me, semnani rt, de pascalis r,et al. inhibition of cd4(+)25+ t regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. blood. 2005 apr 1; 105 (7):2862-8. epub 2004 dec 9.[5] chang tk, yu l, maurel p, waxman dj. enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome p-450 inducers and autoinduction by oxazaphosphorines. cancer res. 1997 may 15; 57 (10):1946-54.[6] anderson d, bishop jb, garner rc, et al. cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risks. mutat res. 1995 aug; 330 (1-2):115-81.

• Mechanism of action

  Cyclophosphamide can be given orally, intramuscularly, or intravenously. The plasma half-life of intact cyclophosphamide is 6.5 hours.Only 10 to 15% of the circulating parent drug is protein bound, whereas 50% of the alkylating metabolites are bound to plasma proteins. Since cyclophosphamide and its metabolites are eliminated primarily by the kidneys, renal failure will greatly prolong their retention.
  Cyclophosphamide has a wide spectrum of antitumor activity. In lymphomas, it is frequently used in combination with vincristine and prednisone (CVP [or COP] regimen) or as a substitute for mechlorethamine in the MOPP regimen (C-MOPP). High dosages of intravenously administered cyclophosphamide are often curative in Burkitt’s lymphoma, a childhood malignancy with a very fast growth rate.Oral daily dosages are useful for less aggressive tumors, such as nodular lymphomas, myeloma, and chronic leukemias.

• Pharmakologie

  Besides being used as an alkylating agent in cancer chemotherapy, cyclophosphamide is a unique drug when used as an immunosuppressant. First, it is the most powerful of all such drugs. Second, it kills proliferating cells, and evidently alkylates a certain region of remaining cells. Finally, its action on T-cells is such that despite its overall suppressive effect, it can, in certain environments, suppress the response of these cells to antigens.
  Cyclophosphamide is successfully used for bone transplants. In small doses, it is effective for autoimmune disorders.

• Pharmakokinetik

  The drug is metabolized in the liver and is eliminated via the kidney, with approximately 15% of a given dose being excreted unchanged. Doses should be reduced in patients with levels of creatinine clearance less than 30 mL/min. Interestingly, hepatic dysfunction does not seem to alter metabolism of this drug, but caution should be exercised in patients with inhibited cytochrome P450 (CYP450) enzymes or with a combination of factors that could negatively impact drug activation/inactivation pathways.

• Clinical Use

  Cyclophosphamide is a component of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and other drug combinations used in the treatment of breast cancer. Cyclophosphamide in combination may produce complete remissions in some patients with ovarian cancer and oat cell (small cell) lung cancer. Other tumors in which beneficial results have been reported include non–oat cell lung cancers, various sarcomas, neuroblastoma, and carcinomas of the testes, cervix, and bladder. Cyclophosphamide also can be employed as an alternative to azathioprine in suppressing immunological rejection of transplant organs.

• Nebenwirkungen

  Chloroacetaldehyde toxicity is accompanied by glutathione depletion, indicating that, as expected, this electrophilic by-product alkylates Cys residues of critical cell proteins. Alkylation of Lys, adenosine, and cytidine residues also is possible. The CYP-generated carbinolamine undergoes nonenzymatic hydrolysis to provide the aldophosphamide either in the bloodstream or inside the cell. If this hydrolysis occurs extracellularly, the aldophosphamide is still able to penetrate cell membranes to reach the intracellular space. Once inside the cell, acrolein (a highly reactive α,β-unsaturated aldehyde) splits off, generating phosphoramide mustard. With a pKa of 4.75, the mustard will be persistently anionic at intracellular pH and trapped inside the cell.

• Sicherheitsprofil

  Confirmed human carcinogen producing leukemia, Hodgkin's dsease, gastrointestinal and bladder tumors. Experimental carcinogenic, neoplas tigenic, and teratogenic data. A human poison by ingestion and many other routes. Human systemic effects: hdney changes (hepatic dysfunction), leukopenia (reduced white blood cell count), nausea and alopecia (loss of hair), liver changes, agranulocytosis. Human reproductive and teratogenic effects by multiple routes: spermatogenesis, testicular changes, epiddymis and sperm duct changes, menstrual cycle changes, fetal developmental abnormahties of the craniofacial area, musculoskeletal and cardiovascular systems. Experimental reproductive effects. Human mutation data reported. A powerful skin irritant. Used as an immunosuppressive agent in nonmalignant diseases. When heated to decomposition it emits hghly toxic fumes of PO,, NOx, and Cl-.

• Synthese

  Cyclophosphamide, 2-[bis-(2-chloroethyl)amino]tetrahydro- 2H-1,3,2-oxazaphosphorin-2-oxide (30.2.1.15), is made by reacting bis(2-chloroethyl)amine with phosphorous oxychloride, giving N,N-bis-(2-chloroethyl)dichlorophosphoramide (30.2.1.14), which upon subsequent reaction with 3-aminopropanol is transformed into cyclophosphamide (30.2.1.15).

  

• mögliche Exposition

  Exodan is used as an immunosuppressive agent in nonmalignant diseases; treatment of malignant lymphoma, multiple meyloma; leukemias, and other malignant diseases. Exodan has been tested as an insect chemosterilant and for use in the chemical shearing of sheep. Exodan is not produced in the United States.; manufactured in Germany and imported into the United States since1959. The FDA estimates that 200,000
  300,000 patients per year are treated with exodan. It is administered orally and through injection. The adult dosage is usually 1
  5 mg/kg of body weight daily or 10
  15 mg/kg administered intravenous every 7
  10 days

• Veterinary Drugs and Treatments

  In veterinary medicine, cyclophosphamide is used primarily in small animals (dogs and cats) in combination with other agents both as an antineoplastic agent (lymphomas, leukemias, carcinomas, and sarcomas) and as an immunosuppressant (SLE, ITP, IMHA, pemphigus, rheumatoid arthritis, proliferative urethritis, etc.). Its use in treating acute immune-mediated hemolytic anemia is controversial;there is some evidence that it does not add beneficial effects when used with prednisone.
  Cyclophosphamide has been used as a chemical shearing agent in sheep.

• in vitro

  cyclophosphamide has a dose-dependent, bimodal effect on the immune system. low-dose cyclophosphamide not only decreases cell number but leads to decreased functionality of regulatory t cells (tregs). cyclophosphamide treatment enhances apoptosis and decreases homeostatic proliferation of these cells. expression of gitr and foxp3, which are involved in the suppressive activity of tregs, is down-regulated after cyclophosphamide administration.[4] in primary human hepatocyte cultures, cyclophosphamide increases cyp3a4, cyp2c8, and cyp2c9 protein levels, causing its 4-hydroxylation rate enhance.[5] in somatic cells, cyclophosphamide produces gene mutations, chromosome aberrations, micronuclei and sister chromatid exchanges in a variety of cultured cells in the presence of metabolic activation as well as sister chromatid exchanges without metabolic activation. [6]

• in vivo

  it has produced chromosome damage and micronuclei in rats, mice and chinese hamsters, and gene mutations in the mouse spot test and in the transgenic lacz construct of muta™mouse. [6]

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
  Cytotoxics: increased toxicity with high-dose cyclophosphamide and pentostatin - avoid.

• Erste Hilfe

  If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seekmedical attention immediately. If this chemical contactsthe skin, remove contaminated clothing and wash immediately with soap and water. Seek medical attention immediately. If this chemical has been inhaled, remove fromexposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing hasstopped and CPR if heart action has stopped. Transferpromptly to a medical facility. When this chemical hasbeen swallowed, get medical attention. Give large quantities of water and induce vomiting. Do not make an unconscious person vomit.

• Carcinogenicity

  Cyclophosphamide is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

• Stoffwechsel

  The initial metabolic step is mediated primarily by CYP2B6 (and, to a much lower extent, by CYP3A4) and involves hydroxylation of the oxazaphosphorine ring to generate a carbinolamine. This hydroxylation reaction must occur before the molecule will be transported into cells. CYP3A4 (but not CYP2B6) also catalyzes an inactivating N-dechloroethylation reaction, which yields highly nephrotoxic and neurotoxic chloroacetaldehyde.

• Lager

  Store at -20°C

• Versand/Shipping

  UN3464 Organophosphorus compound, solid, toxic, n.o.s, Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN1851 Medicine, liquid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials

• Inkompatibilitäten

  Should be protected from exposure to temperatures above 30°C/86°F.

• Waste disposal

  Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform with EPA regulations governing storage, transportation, treatment, and waste disposal

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