Galanthamine

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H315：Verursacht Hautreizungen.

  H317：Kann allergische Hautreaktionen verursachen.

  H319：Verursacht schwere Augenreizung.

  H373：Kann die Organe schädigen bei längerer oder wiederholter Exposition.

  H410：Sehr giftig für Wasserorganismen mit langfristiger Wirkung.

• Sicherheit

  P260：Dampf/Aerosol/Nebel nicht einatmen.

  P261：Einatmen von Staub vermeiden.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P272：Kontaminierte Arbeitskleidung nicht außerhalb des Arbeitsplatzes tragen.

  P273：Freisetzung in die Umwelt vermeiden.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  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.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

  P314：Bei Unwohlsein ärztlichen Rat einholen / ärztliche Hilfe hinzuziehen.

  P321：Besondere Behandlung

  P332+P313：Bei Hautreizung: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P333+P313：Bei Hautreizung oder -ausschlag: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P362：Kontaminierte Kleidung ausziehen und vor erneutem Tragen waschen.

  P363：Kontaminierte Kleidung vor erneutem Tragen waschen.

  P391：Verschüttete Mengen aufnehmen.

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

Galanthamine Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Galantamine is an Amaryllidaceae alkaloid which is first obtained from the plant of snowdrop (Galanthus nivalis), and nowadays, it’s extracted from the plants of Narcissus and Galanthus species or obtained from chemosynthesis. In many areas in Europe such as Bulgaria, eastern Turkey, and the Caucasus, the plants of Galanthus are native species. But its earliest pharmaceutical applications are seldom known. Plaitakis and Duvoisin hypothesized that “moly” in ancient Homer’s epic might be snowdrops. In Homer’s epic Odyssey, “moly” was used as an antidote by Odysseus against Circe’s poisonous drugs. To be used as an antidote may be the plants of Galanthus’ oldest medicinal records. But there is not much evidence for that. There is little evidence of the traditional application of the plants of Galanthus, and it is certain that until the Second World War, the plants of Galanthus and other genera of Amaryllidaceae were not frequently used in European drugs
  Italian scholar Iannello studied Pancratium illyricum L., an Amaryllidaceae species endemic to Sardinia, and isolated a new galantamine-type alkaloid in its leaves. This new galantamine-type compound exhibited a pronounced in?vitro AChE inhibitory activity (IC50? =? 3.5±1.1? μM) in comparison with the reference standard galantamine hydrobromide (IC50?=?1.5±0.2?μM)

• Chemische Eigenschaften

  Off-White Solid

• Physikalische Eigenschaften

  Hydrobromide of galantamine can be used as drug although galantamine can’t be used as drugs
  Appearance: an almost white powder. Solubility: soluble in water; slightly soluble in alcohol; and insoluble in acetone, trichloromethane, and diethyl ether. Melting point: 269–270?°C. Specific optical rotation: ?90 to ?100°.

• Originator

  Reminyl,Janssen Pharmaceutica Inc.

• Occurrence

  Galanthamine is a bulb plant found throughout the world.

• History

  In the early 1950s, Soviet Union’s scientists started modern medicine research of galantamine. In 1951, the Soviet Union’s pharmacologist Mashkovsky and Kruglikova-Lvova firstly proved its AChE-inhibiting properties, which was published in the paper. In 1957, the Bulgarian pharmacologist Paskov et?al. found that the plants of Galanthus were the richest sources of galantamine, which opened a way for its commercial development by the company Sopharma in Bulgaria. Galantamine hydrobromide was launched into market under the trade name Nivalin. Initially, Nivalin was used in anesthesia to antagonize the effects of non-depolarizing muscle relaxants, and since then, it was rapidly introduced in other areas of medicine
  Galantamine hydrobromide was launched into market for the indication of mild to moderate Alzheimer’s disease firstly in 1995, developed by Sanochemia Pharmaceuticals. In the United States, galantamine hydrobromide was developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, and was listed under the trade name Razadyne in 2001. So far, galantamine hydrobromide has been marketed in more than 20 countries and regions, such as the United States, Europe, and Japan.

• Verwenden

  Galantamine is approved for the treatment of mild-to-moderate AD.It is a reversible specific inhibitor of AChE,and in addition it modulates central nicotinic receptors toincrease cholinergic neurotransmission.

• Verwenden

  A selective acetylcholinesterase inhibitor. Useful for the treatment of Alzheimer's disease.

• Verwenden

  synthetic fluoroquinolone antibiotic agent

• Indications

  Its formulation includes capsule, tablet, and oral solution. It is used in the symptomatic treatment of mild to moderately severe dementia in Alzheimer’s disease.

• Definition

  ChEBI: A natural product found in Crinum asiaticum var. sinicum.

• Manufacturing Process

  2 Methods of isolation of galantamine from Narcissus pseudonarcissus bulbs 1. 10 kg air-dried, comminuted bulbs of Narcissus pseudonarcissus "Carlton" is carefully mixed with 400 g sodium carbonate. 23 L dichloroethane is added. The mixture is allowed to stand for 10 h; then the solvent is decanted. The bulbs are once again doused with 23 L dichloroethane which is decanted after 2 to 3 hs. After that, 17 L dichloroethane is added to the bulbs for the third time; however, this is decanted immediately. The mixed dichloroethane extracts are extracted by means of 10% sulfuric acid (2 times 600 ml each; 2 times 300 ml each).
  The acidic extracts are mixed and purified from traces of dichloroethane by means of shaking out with diethyl ether. Under stirring and cooling to 15° to 20°C, about 200 ml of a 25% aqueous ammonia solution is then added up to alkaline litmus reaction (the pH is in the range of 7 to 8). Different from the indications in the art, the companion alkaloids do not precipitate. The alkaline solution is saturated with salt and extracted with diethyl ether.
  After evaporation of the ether, a negligible residue remains, which is also different from the indications in the art. The pH-value of the aqueous phase is set to about 14 by saturating it with potash. The aqueous phase is repeatedly extracted with diethyl ether. The mixed ether extracts are evaporated to dryness, the remaining galanthamine-containing residue is dissolved in acetone (50 ml). In contrast to the art, there is no precipitate. 350 ml acetone is replenished, 200 g aluminum oxide is added, and stirring is effected for 45 min. The aluminum oxide is filtered off and washed twice with 100 ml acetone each time. The mixed acetone solutions are evaporated to dryness. 1.3 g of an oily residue is obtained which is examined by means of HPLC.
  2. 100 kg air-dried, comminuted bulbs of Narcissus pseudonarcissus "Carlton" is carefully mixed with 4 kg of sodium carbonate. The mixture is divided into three equal parts, and each is doused with 15 L special boiling-point gasoline 80/110. The mixtures are allowed to stand for 24 hs. The solvents are each renewed twice, collected, and evaporated to dryness in low vacuum. The extracts are placed in 2% aqueous sulfuric acid and adjusted to a pH of 4 with concentrated aqueous ammonia solution. Five extractions with diethyl ether follow. The aqueous phase is set to a pH of 9 with concentrated ammonia and extracted five times with diethyl ether. These ether fractions are collected, dried with sodium sulfate, and evaporated. 20 g of a slightly yellow, oily residue is obtained, which is recrystallized from hot isopropanol. 10 g of white galanthamine base having a melting point of 129°-130°C is obtained.
  Galantamine may be isolated from Galanthus nivalis or G. woronowi bulbs too.

• Therapeutic Function

  Cholinesterase inhibitor

• Allgemeine Beschreibung

  Galantamine, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro-[3a,3,2,ef][2]-benzazepin-6-ol (Nivalin, Reminyl), is an alkaloid extractedfrom the tuberous plant Leucojum aestivum (L.) belongingto the Amaryllidaceae family and from the bulbs of thedaffodil, Narcissus pseudonarcissus. It is a reversiblecholinesterase inhibitor that appears to have no effect on butyrylcholinesterase.In addition, it acts at allosteric nicotinicsites, further enhancing its cholinergic activity. Galantamineundergoes slow and minor biotransformation with approximately5% to 6% undergoing demethylation. It is primarilyexcreted in the urine.

• Pharmakologie

  hydrolyzed and metabolized by AChE.?When AD occurs, neurons in the basal forebrain region of the brain are lost, resulting in the reduction of synthesis, storage and release of ACh, which leads to a variety of clinical manifestations especially memory and recognition dysfunction. Galantamine is a reversible AChE inhibitor, which is highly selective and competitive. It competitively binds to AChE in a synaptic gap with Ach, blocks the degradation of Ach by AChE, and thus achieves efficacy. Besides, it has the activity as an allosteric modulator of nicotinic acetylcholine receptor (nAChR). nAChR is mainly located in the muscarinic choline receptor’s presynaptic structure. It can promote the release of Ach, which is critical to maintain the survival and function of cholinergic neurons. The study found that in cerebral cortex of the patients of AD, nAChR was significantly reduced. Galantamine binds to AChR’s allosteric site to increase the transmission of acetylcholine signaling.
  Galantamine has a 53-fold greater inhibitory activity in?vitro for AChE than for butyrylcholinesterase (BChE). The low affinity of galantamine for BChE may be responsible for a tolerability advantage. BChE, which is primarily found in plasma, is not thought to be directly involved in the cholinergic disruption seen in early AD, and its inhibition may contribute to peripheral side effects.
  It was recorded in Martindale: The Complete Drug Reference that an initial oral dose of 4?mg is given twice daily with food for 4?weeks and then increased to 8?mg twice daily. This dose should be maintained for at least 4?weeks; thereafter, the dose may be further increased to 12?mg twice daily according to response and tolerance. The clinical benefit of galantamine should be reassessed, preferably within the first 3?months and thereafter on a regular basis
  Galantamine is metabolized by hepatic cytochrome P450 enzymes CYP3A4 and CYP2D6, glucuronidated, and excreted unchanged in the urine. After intravenous injection or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine, and the other was metabolized by the hepar.

• Clinical Use

  Before the 1990s, galantamine was mainly used to treat poliomyelitis sequelae, muscle atrophy, postoperative intestinal muscle paralysis, urinary retention, and myasthenia gravis. In the 1990s, it was found that galantamine had improved memory impairment in mice, suggesting that it might be effective for central cholinergic disorders in Alzheimer’s disease
  In a 3–6?months’ well-designed clinical trial, recipients of galantamine achieved significant improvements in cognitive symptoms compared to placebo recipients. Galantamine also improved activities of daily living in these patients and significantly reduced the requirement for caregiver assistance with activities of daily living. Clinical development of new indications of galanthamine is currently underway, such as smoking cessation and improving cognitive impairment in schizophrenia and mania.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antibacterials: erythromycin increases concentration of galantamine.

• Stoffwechsel

  Galantamine is partially (up to 75%) metabolised by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4; a number of active metabolites are formed.
  After 7 days, 90-97% of a single oral dose is recovered in the urine with up to about 6% detected in the faeces; about 20-30% of the dose is excreted in the urine as unchanged galantamine. Clearance is reported to be 20% lower in females than in males and 25% lower in poor metabolisers than in extensive metabolisers.

Galanthamine Upstream-Materialien And Downstream Produkte

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