Penicillamin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

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

  P405：Unter Verschluss aufbewahren.

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

D-Penicillamine Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
  R40:Verdacht auf krebserzeugende Wirkung.
  R20/21/22:Gesundheitsschädlich beim Einatmen,Verschlucken und Berührung mit der Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
  S24/25:Berührung mit den Augen und der Haut vermeiden.
  S22:Staub nicht einatmen.

• Beschreibung

  Penicillamine is an orally bioavailable copper chelator and penicillin degradation product. It increases urinary and fecal copper excretion and decreases liver copper concentration in a rat model of copper overload when administered at 0.67 mmol/kg per day, but does not affect kidney, spleen, or brain copper levels. Penicillamine (100 mg/kg per day) dissolves copper-rich granules in hepatic lysosomes of Long-Evans cinnamon (LEC) rats, which spontaneously develop hepatic injury and acute hepatitis and have a mutation homologous to that of the human Wilson disease gene. Penicillamine has anticonvulsant and proconvulsant effects in mice when administered at 0.5 and 250 mg/kg, respectively, which are blocked by the nitric oxide synthase (NOS) inhibitors L-NAME and 7-nitroindazole . Formulations containing penicillamine have been used to treat Wilson disease, cystinuria, and active rheumatoid arthritis.

• Chemische Eigenschaften

  White to off-white crystalline powder

• Originator

  Cuprimine,MSD,US,1963

• Verwenden

  chelating agent (Cu), antirheumatic

• Verwenden

  D-(-)-Penicillamin is used as an antirheumatic and as a chelating agent in Wilson′s disease. It is used as a copper chelator to form mixed disulfides with cysteine or other sulfide media components. It is used to inactivate protein-1 DNA binding and to inhibit the growth of asynchronous cultures of rabbit articular chondrocytes.

• Verwenden

  As a Penicillin metabolite, D-(-)-Penicillamin can be used in the treatment of Wilson’s disease, Cystinuria, Scleroderma and arsenic poisoning.

• Definition

  ChEBI: An optically active form of penicillamine having D-configuration. Pharmaceutical form (L-form is toxic) of chelating agent used to treat heavy metal poisoning.

• Manufacturing Process

  (a) Preparation of mercuric chloride complex of penicillamine: To a solution of 372 g (1 mol) of potassium benzyl-penicillin in 940 ml of distilled water at room temperature is added a solution of 40 g (1 mol) of sodium hydroxide in 180 ml of distilled water over a period of one-half hour. The solution is then stirred for two hours at room temperature. While maintaining room temperature, 67 ml of concentrated hydrochloric acid is added at a slow rate. This solution is then added, over a period of time of one-half hour, to a solution of 271 g (1 mol) of HgCl2 in 3.52 liters of distilled water in the presence of 50 g of Hyflo and 5 ml of octyl alcohol. After one hour of agitation, the resulting mixture is treated with 185 ml of concentrated hydrochloric acid and filtered.
  (b) Removal of benzylpenilloaldehyde: To the filtrate obtained in step (a), warmed to 50°C is slowly added 108 g (1 mol) of phenyl hydrazine. The mixture is cooled to room temperature and 84 ml of concentrated hydrochloric acid are added. The mixture is agitated briefly and the precipitated benzylpenilloaldehyde phenyl hydrazone is filtered off.
  (c) Preparation of isopropylidene penicillamine hydrochloride: To the filtrate obtained in step (b) is added at 20°C to 25°C a total of 85 g of hydrogen sulfide. The precipitated HgS is filtered off and the filtrate is concentrated under reduced pressure to a volume of 200 to 500 ml. Following a polish filtration, the product-rich concentrate is mixed with 1.5 liters of isobutyl acetate. The mixture is refluxed at about 40°C under reduced pressure in equipment fitted with a water separation device. When no further water separates, the batch is cooled to 30°C and filtered. The reactor is washed with 1 liter of acetone, which is used also to wash the cake. The cake is further washed with 200 ml of acetone. The acetone washes are added to the isobutyl acetate filtrate and the mixture is refluxed for 20 to 30 minutes. After a holding period of one hour at 5°C. the crystals of isopropylidene penicillamine hydrochloride are filtered and washed with 200 ml of acetone. On drying for twelve hours at 25°C this product, containing 1 mol of water, weighs about 178 g (73%).
  (d) Preparation of penicillamine hydrochloride: The 178 g of isopropylidene penicillamine hydrochloride obtained in step (c) is dissolved in 350 ml of distilled water. The solution is heated at 90°C to 95°C for one to one and onehalf hours, removing acetone by distillation through an efficient column. There is then added 2.6 liters of isobutyl acetate. The mixture is refluxed at a temperature of about 40°C under reduced pressure in equipment fitted with a water separation device. When no further water separates, the pressure is adjusted so that the mixture distills at a vapor temperature of 83°C to 88°C. A total of 650 ml of distillate is collected. The batch is allowed to cool to 50°C and then filtered. The crystals are washed with isobutyl acetate and then dried at 35°C for 24 hours. The virtually anhydrous penicillamine hydrochloride obtained weighs about 128 g (69% from potassium benzyl-penicillin).

• Trademarks

  Cuprimine(Merck); Depen (Medpointe), Artamin (Sanabo, Austria), Atamir (Sandoz, Denmark), Dimetylcystein (Lilly, Denmark), Metalcaptase (Knoll, South Africa), Reumacillin (Leiras, Finland), Trisorcin (Merckle, Germany), Trolovol (Asta Medica, Germany).

• Therapeutic Function

  Antiarthritic

• Allgemeine Beschreibung

  D-Penicillamine contains a β-lactam chemical structure.

• Biochem/physiol Actions

  Penicillamine is a characteristic degradation product of penicillin type antibiotics. One atom of copper combines with two molecules of penicillamine. Penicillamine reduces excess cystine excretion in cystinuria. This is by disulfide interchange between penicillamine and cystine, which results in formation of a readily excreted penicillamine-cysteine disulfide. Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed. Penicillamine lowers IgM rheumatoid factor and depresses T-cell activity.

• Clinical Use

  Rheumatoid arthritis, Wilson’s disease, cystinuria, lead poisoning, chronic active hepatitis

• Sicherheitsprofil

  Poison by intraperitoneal route. Moderately toxic by subcutaneous and intravenous routes. Mildly toxic by ingestion. An experimental teratogen. Human systemic effects by ingestion: agranulocytosis, dermatitis, fever, hemorrhage, increased body temperature, dermatitis, leukopenia, proteinuria, thrombocytopenia. Human teratogenic effects by an unspecified route: developmental abnormalities of the craniofacial areas, skin, and skin appendages, and body wall. Experimental reproductive effects. Questionable human carcinogen producing leukemia. Mutation data reported. Used in the treatment of rheumatoid arthritis, metal poisonings, and cystinuria. When heated to decomposition it emits very toxic fumes of NOx and SOx. See also MERCAPTANS.

• Synthese

  d-penicillamine can be synthesized in a multistep process that begins with heating isobutyraldehyde, pyridine, sulfur, and ammonia in benzene to form 5,5-dimethyl-2- isopropyl-?3-thiazoline. Treatment with hydrogen cyanide gives 4-cyano-5,5-dimethyl- 2-isopropylthiazolidine, which on acid hydrolysis gives d,l-penicillamine hydrochloride. Resolution is accomplished by conversion of the racemate to d,l-3-formyl- 2,2,5,5-tetramethylthiazolidine-4-carboxylic acid by treatment first with acetone, then with acetic formic anhydride. The enantiomers are separated in the usual manner, using, for example, l-lysine or d-(?)- threo-1-(4-nitrophenyl)-2-aminopropane-1,3- diol. Acidification liberates d-3-formyl- 2,2,5,5-tetramethylthiazolidine-4-carboxylic acid, which is hydrolyzed with hydrochloric acid to yield d-penicillamine hydrochloride. Neutralization with ethanolic triethylamine affords d-penicillamine.
  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
  Sodium aurothiomalate: increased risk of haematological toxicity

• Stoffwechsel

  Penicillamine undergoes limited metabolism in the liver, to S-methyl penicillamine.
  It is mainly excreted in the urine as disulfides, along with some S-methyl penicillamine and unchanged drug; a small amount may be excreted in the faeces

• läuterung methode

  The melting point of D-(-)-penicillamine depends on the rate of heating (m 202-206o is obtained by starting at 195o and heating at 2o/minute). It is soluble in H2O and alcohols but insoluble in Et2O, CHCl3, CCl4 and hydrocarbon solvents. Purify it by dissolving it in MeOH and adding Et2O slowly. Dry it in vacuo and store it under N2. [Weight et al. Angew Chem, Int Ed (English) 14 330 1975, Cornforth in The Chemistry of Penicillin (Clarke, Johnson and Robinson eds) Princeton Univ Press, 455 1949, Review: Chain et al. Antibiotics (Oxford University Press) 2 1949, Polymorphism: Vidler J Pharm Pharmacol 28 663 1976]. The D-S-benzyl derivative has m 197-198o (from H2O), [] D 17 -20o (c 1, N NaOH), -70o (N HCl). [Beilstein 4 IV 3228.]

D-Penicillamine Upstream-Materialien And Downstream Produkte

Penicillamin Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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