Valrubicin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H301：Giftig bei Verschlucken.

  H312：Gesundheitsschädlich bei Hautkontakt.

  H332：Gesundheitsschädlich bei Einatmen.

  H340：Kann genetische Defekte verursachen.

  H351：Kann vermutlich Krebs verursachen.

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

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P261：Einatmen von Staub vermeiden.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P270：Bei Gebrauch nicht essen, trinken oder rauchen.

  P271：Nur im Freien oder in gut belüfteten Räumen verwenden.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P281：Vorgeschriebene persönliche Schutzausrüstung verwenden.

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

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

  P304+P340：BEI EINATMEN: Die Person an die frische Luft bringen und für ungehinderte Atmung sorgen.

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

  P312：Bei Unwohlsein GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

  P321：Besondere Behandlung

  P322：Gezielte Maßnahmen

  P330：Mund ausspülen.

  P363：Kontaminierte Kleidung vor erneutem Tragen waschen.

  P405：Unter Verschluss aufbewahren.

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

Valrubicin Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S37/39:Bei der Arbeit geeignete Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.

• Beschreibung

  Valrubicin was launched as a new 'chemotherapeutic agent for the treatment of bladder cancer, particularly in patients with BCG-refractory carcinoma in situ (CIS) of the bladder for whom immediate cystectomy is unacceptable. It belongs to the class of anthracyclines, the widest used in human cancers, and is a N-trifluoroacetyl 14-valerate derivative of doxorubicin.Valrubicin can be obtained in 3 steps from daunomycin by N-trifluoroacetylation of the sugar moiety then iodination of the 2-acetyl group and introduction of a valerate residue. A proposed mechanism involved in the cytotoxicity of Valrubicin coud be the blockade of SV40 large T antigen helicase; this cellular enzyme is involved in the formation of a ternary complex with DNA to maintain the topographic structure of DNA during transcription. In patients with CIS of bladder refractory to front line and second line therapies, intravesical instillation of Valrubicin resulted in a complete response with a significant rate and allowed a delay in cystectomy. Systemic absorption was minimal and accordingly produced a lower incidence of cardiotoxicity compared with doxorubicin.

• Chemische Eigenschaften

  Red Solid

• Originator

  Anthra Pharm. (US)

• Verwenden

  Chemotherapy drug used to treat cancer of the bladder.

• Definition

  ChEBI: Valrubicin is an anthracycline and a trifluoroacetamide.

• Manufacturing Process

  N-Trifluoroacetyladriamycin-14-valerate The first way. A mixture of 1.65 g of 14-iodo-N-trifluoroacetyldaunomycin, prepared and purified according to the procedure of Arcamone et al., U.S. Pat. No. 3,803,124, and 1.37 g of sodium valerate in 165 ml of anhydrous acetone was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with anhydrous acetone until the washings were no longer colored. The combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was treated with a 1:1 mixture of water and chloroform (total volume 200 ml), and the aqueous layer was separated and discarded. The chloroform extract was washed twice with cold water, once with aqueous pH 7 buffer, and finally with saturated aqueous sodium chloride. The chloroform solution was dried over sodium sulfate and the chloroform solvent was removed by evaporation under reduced pressure. The residue was dissolved in a small volume of chloroform and the product was precipitated by the addition of petroleum ether (b.p. 38°-49°C). Three additional precipitations from chloroform and petroleum ether afforded 1.36 g of N_x0002_trifluoroacetyladriamycin-14-valerate, m.p. 135°-136°C, in analytical purity and homogeneous by thin layer chromatography (silica gel G; chloroform:methanol:water, 120:20:1 by volume) and high pressure liquid chromatography.
  The second way. A suspension of 750 mg of 14-bromodaunomycin hydrochloride, prepared as described in Arcamone et al. U.S. Pat. 3,803,124, and 2.48 g of powdered sodium valerate in 520 ml of anhydrous acetone was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with anhydrous acetone until the washings were free of color. The combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was dissolved in 150 ml of 0.1 N HCl and the aqueous acid solution was extracted with three 50 ml portions of chloroform to remove aglycone by-products. The aqueous layer, after the addition of 3 ml of methanol, was extracted with four 25 ml portions of 1-butanol. The butanol extracts were combined and evaporated under reduced pressure at 35°C until no further distillate appeared. Filtration of the suspension at this point afforded, after thorough washing with ethyl acetate and drying, 347.7 mg of adriamycin-14-valerate hydrochloride, m.p. 176°-177°C. A second crop of 62.2 mg of product was obtained from further concentration of the filtrate at a somewhat higher temperature. Both crops of material were of high purity by thin layer chromatographic analysis (silica gel G plates; solvent system: chloroform:methanol:water, 100:20:1 by volume). A suspension of 300 mg of adriamycin-14-valerate hydrochloride in 20 ml of ethyl acetate was treated with 0.45 ml of trifluoroacetic anhydride in small portions over a few minutes until all solids had dissolved. The solution was mixed immediately with equal portions of water and chloroform (total volume 100 ml). The chloroform layer was separated and washed once with water and twice with pH 7 aqueous buffer. The chloroform solution was dried over sodium sulfate and then was evaporated to dryness under reduced pressure. The residue was dissolved in 25 ml of methanol, and the resulting solution was heated at reflux for 5 minutes, then cooled and evaporated to dryness. The residue was redissolved in 4 ml of chloroform, and the crude product was precipitated by the addition of 20 ml of petroleum ether (b.p. 38°-49°C). The crude material was purified by chromatography on a silicic acid column. Elution with chloroform containing 0.75% ethanol afforded 181 mg of Ntrifluoroacetyladriamycin-14-valerate, identical chromatographically and by spectral comparison with samples of product prepared as described above. The third way. A suspension of 193.4 mg of adriamycin free base in 20 ml of methylene chloride and

• Trademarks

  Valstar (Valera).

• Therapeutic Function

  Antineoplastic

• Allgemeine Beschreibung

  Valrubicin is available in 200-mg vials for intravesicular administrationin the treatment of bladder cancer (orphan drugstatus). The increased lipophilicity associated with the valericacid ester and trifluoro acetate functionalities increasestissue penetration and remains intact because, in large measure,of the lack of exposure to hydrolyzing enzymes causedby direct delivery into the bladder followed by voiding ofthe instilled solution. This local action also minimizes cardiotoxicityand other adverse effects seen with other anthracyclines.The major adverse effects that are seen are bladderirritation and reddening of the urine.

• Mechanism of action

  Valrubicin is an anthracycline that affects a variety of interrelated biological functions, most of which involve nucleic acid metabolism. In cells, it inhibits the incorporation of nucleosides into nucleic acids, causes chromosomal damage, and arrests the cell cycle in G2. Although valrubicin does not bind strongly to DNA, valrubicin metabolites interfere with the normal DNA breaking-resealing action of DNA topoisomerase II.

• Clinical Use

  Valrubicin currently has orphan drug status in the treatment of bacille Calmette-Guérin (BCG)–refractory bladder cancer (the total patient population is ~1,000 individuals) and is used with patients for whom surgical intervention would result in high morbidity or death.

• Nebenwirkungen

  The most commonly reported adverse reactions are abdominal pain, urinary tract infection, hematuria, and dysuria. Systemic exposure to the drug and its metabolites would, of course, be greater in patients whose bladder wall integrity has been compromised by disease, and these patients should not receive valrubicin.

• Sicherheitsprofil

  Poison by intraperitoneal route.Human mutation data reported. When heated todecomposition it emits toxic fumes of Fí and NOx.

• Stoffwechsel

  It is administered directly into the bladder through a catheter (intravesically). The lipophilic drug is water insoluble, but it dissolves in an aqueous vehicle that includes polyoxyethylene glycol and ethanol. The patient retains the drug in the bladder for 2 hours, then voids the solution in the normal fashion. Valrubicin is active as administered, and despite the fact that hydrolysis of the ester and trifluoroacetamide can be envisioned, it is excreted essentially unchanged. Less than 1% of an administered dose is absorbed systemically, so there is essentially no exposure to metabolizing enzymes. The reduced C13-alcoholic metabolite does not form to any appreciable extent during the 2-hour treatment period. Therapy is considered to be almost exclusively local, and there is little risk for cardiac toxicity, bone marrow suppression, drug–drug interactions, or other side effects.

Valrubicin Upstream-Materialien And Downstream Produkte

Valrubicin Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

Global(187)Suppliers

56124-62-0, Valrubicin Verwandte Suche: