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| Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of Galanthus nivalis (common snowdrop), Galanthus caucasicus (Caucasian snowdrop), Galanthus woronowii (Voronov's snowdrop), and other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (red spider lily). It can also be produced synthetically.
Galantamine is primarily known for its potential to slow cognitive decline. It is used clinically for treating early-stage Alzheimer's disease and memory impairments, although it has had limited success with the more advanced condition of dementia.
It works by increasing the amount of a type of neurotransmitter named acetylcholine by the inhibiting activity of an enzyme called acetylcholinesterase known for breaking down acetylcholine. This elevates and prolongs acetylcholine levels boosting acetylcholine's neuromodulatory functionality, subsequently enhancing functionality of the various cognitions that acetylcholine is involved in, such as memory processing, reasoning, and thinking. Galantamine may cause serious adverse effects, such as stomach bleeding, liver injury or chest pain.
Galantamine was isolated for the first time from bulbs of Galanthus nivalis (common snowdrop) in the Soviet Union in the 1940s. The active ingredient was extracted, identified, and studied, in particular in relation to acetylcholinesterase (AChE)-inhibiting properties. The first industrial process was developed in 1959. However, it was not until the 1990s when full-scale synthesis was upscaled and optimized. |
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Read full article at Wikipedia
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InChI=1S/C17H21NO3/c1- 18-8-7-17-6-5-12(19)9-14(17)21-16-13(20-2)4-3-11(10-18)15(16)17/h3-6,12,14,19H,7-10H2,1-2H3/t12-,14-,17-/m0/s1 |
| ASUTZQLVASHGKV-JDFRZJQESA-N |
| [H][C@]12C[C@@H](O)C=C[C@]11CCN(C)Cc3ccc(OC)c(O2)c13 |
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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plant metabolite
Any eukaryotic metabolite produced during a metabolic reaction in plants, the kingdom that include flowering plants, conifers and other gymnosperms.
cholinergic drug
Any drug used for its actions on cholinergic systems. Included here are agonists and antagonists, drugs that affect the life cycle of acetylcholine, and drugs that affect the survival of cholinergic neurons.
EC 3.1.1.7 (acetylcholinesterase) inhibitor
An EC 3.1.1.* (carboxylic ester hydrolase) inhibitor that interferes with the action of enzyme acetylcholinesterase (EC 3.1.1.7), which helps breaking down of acetylcholine into choline and acetic acid.
EC 3.1.1.8 (cholinesterase) inhibitor
An EC 3.1.1.* (carboxylic ester hydrolase) inhibitor that interferes with the action of cholinesterase (EC 3.1.1.8).
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
(via alkaloid )
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antidote to curare poisoning
A role borne by a molecule that acts to counteract or neutralize the deleterious effects of curare.
cholinergic drug
Any drug used for its actions on cholinergic systems. Included here are agonists and antagonists, drugs that affect the life cycle of acetylcholine, and drugs that affect the survival of cholinergic neurons.
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View more via ChEBI Ontology
galantamina
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WHO MedNet
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galantamine
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WHO MedNet
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galantamine
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WHO MedNet
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galanthaminum
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WHO MedNet
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(−)-galantamine
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DrugCentral
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(−)-galanthamine
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PDBeChem
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(4aS,6R,8aS)-3-methoxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol
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IUPAC
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Galanthamine
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KEGG COMPOUND
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1272
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DrugCentral
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9272
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ChemSpider
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C00001570
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KNApSAcK
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C08526
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KEGG COMPOUND
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CPD-19430
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MetaCyc
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D04292
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KEGG DRUG
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DB00674
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DrugBank
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Galantamine
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Wikipedia
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GNT
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PDBeChem
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HMDB0014812
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HMDB
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LSM-5604
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LINCS
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357-70-0
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CAS Registry Number
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ChemIDplus
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357-70-0
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CAS Registry Number
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NIST Chemistry WebBook
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93736
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Beilstein Registry Number
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Beilstein
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93736
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Reaxys Registry Number
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Reaxys
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Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, Franklin MC, Height JJ (2012)
Structures of human acetylcholinesterase in complex with pharmacologically important ligands.
Journal of medicinal chemistry 55, 10282-10286 [PubMed:23035744]
[show Abstract]
Human acetylcholinesterase (AChE) is a significant target for therapeutic drugs. Here we present high resolution crystal structures of human AChE, alone and in complexes with drug ligands; donepezil, an Alzheimer's disease drug, binds differently to human AChE than it does to Torpedo AChE. These crystals of human AChE provide a more accurate platform for further drug development than previously available. | Gullapalli RP, Aracava Y, Zhuo J, Helal Neto E, Wang J, Makris G, Merchenthaler I, Pereira EF, Albuquerque EX (2010)
Magnetic resonance imaging reveals that galantamine prevents structural brain damage induced by an acute exposure of guinea pigs to soman.
Neurotoxicology 31, 67-76 [PubMed:19782102]
[show Abstract]
Galantamine, a drug used to treat Alzheimer's disease, has recently emerged as a potential medical countermeasure against the toxicity of organophosphorus (OP) compounds, including the nerve agent soman. Here, magnetic resonance imaging (MRI) was used to characterize the neurotoxic effects of soman and the ability of galantamine to prevent these effects in guinea pigs, the best non-primate model to predict the effectiveness of antidotes against OP toxicity in humans. The brains of treated and untreated guinea pigs were imaged using a clinical 3.0 Tesla MRI scanner at 48 h before and 6-7 h, 48 h and 7 days after their challenge with 1.0xLD50 soman (26.6 microg/kg, sc). Significant brain atrophy was observed among all untreated animals at 7 days after their challenge with soman. In mildly intoxicated animals, significant shortening of spin-spin relaxation times (T2) was observed in the thalamus and amygdala at 7h after the challenge. In severely intoxicated animals, T2 values and T2-weighted signal intensities increased significantly in the piriform cortex, hippocampus, thalamus and amygdala; in most regions, changes were long-lasting. Voxel-based morphometric analysis of the images revealed that other brain regions were also damaged in these animals. Neuronal loss was confirmed histopathologically. In animals that were treated with galantamine (8 mg/kg, im) 30 min prior to the exposure to soman, T2, T2-weighted signal intensities, and CSF volumes were largely unaffected. It is, therefore, concluded that galantamine can effectively prevent the structural brain damage induced by an acute exposure to soman. | Moriguchi S, Shioda N, Han F, Yeh JZ, Narahashi T, Fukunaga K (2009)
Galantamine enhancement of long-term potentiation is mediated by calcium/calmodulin-dependent protein kinase II and protein kinase C activation.
Hippocampus 19, 844-854 [PubMed:19253410]
[show Abstract]
Galantamine, a novel Alzheimer's drug, is known to inhibit acetylcholinesterase activity and potentiate nicotinic acetylcholine receptor (nAChR) in the brain. We previously reported that galantamine potentiates the NMDA-induced currents in primary cultured rat cortical neurons. We now studied the effects of galantamine on long-term potentiation (LTP) in the rat hippocampal CA1 regions. The field excitatory postsynaptic potentials (fEPSPs) were induced by stimulation of the Schaffer collateral/commissural pathways in the hippocampal CA1 region. Treatment with 0.01-10 microM galantamine did not affect the slope of fEPSPs in the CA1 region. Galantamine treatment increased calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase Calpha (PKCalpha) activities with a bell-shaped dose-response curve peaked at 1 microM, thereby increasing the phosphorylation of AMPA receptor, myristoylated alanine-rich protein kinase C, and NMDA receptor as downstream substrates of CaMKII and/or PKCalpha. By contrast, galatamine treatment did not affect protein kinase A activity. Consistent with the bell-shaped CaMKII and PKCalpha activation, galantamine treatment enhanced LTP in the hippocampal CA1 regions with the same bell-shaped dose-response curve. Furthermore, LTP potentiation induced by galantamine treatment at 1 microM was closely associated with both CaMKII and PKC activation with concomitant increase in phosphorylation of their downstream substrates except for synapsin I. In addition, the enhancement of LTP by galantamine was accompanied with alpha7-type nAChR activation. These results suggest that galantamine potentiates NMDA receptor-dependent LTP through alpha7-type nAChR activation, by which the postsynaptic CaMKII and PKC are activated. | Hansen SB, Taylor P (2007)
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors.
Journal of molecular biology 369, 895-901 [PubMed:17481657]
[show Abstract]
Rapid neurotransmission is mediated through a superfamily of Cys-loop receptors that includes the nicotinic acetylcholine (nAChR), gamma-aminobutyric acid (GABA(A)), serotonin (5-HT(3)) and glycine receptors. A class of ligands, including galanthamine, local anesthetics and certain toxins, interact with nAChRs non-competitively. Suggested modes of action include blockade of the ion channel, modulation from undefined extracellular sites, stabilization of desensitized states, and association with annular or boundary lipid. Alignment of mammalian Cys-loop receptors shows aromatic residues, found in the acetylcholine or ligand-binding pocket of nAChRs, are conserved in all subunit interfaces of neuronal nAChRs, including those that are not formed by alpha subunits on the principal side of the transmitter binding site. The amino-terminal domain containing the ligand recognition site is homologous to the soluble acetylcholine-binding protein (AChBP) from mollusks, an established structural and functional surrogate. We assess ligand specificity and employ X-ray crystallography with AChBP to demonstrate ligand interactions at subunit interfaces lacking vicinal cysteines (i.e. the non-alpha subunit interfaces in nAChRs). Non-competitive nicotinic ligands bind AChBP with high affinity (K(d) 0.015-6 microM). We mutated the vicinal cysteine residues in loop C of AChBP to mimic the non-alpha subunit interfaces of neuronal nAChRs and other Cys loop receptors. Classical nicotinic agonists show a 10-40-fold reduction in binding affinity, whereas binding of ligands known to be non-competitive are not affected. X-ray structures of cocaine and galanthamine bound to AChBP (1.8 A and 2.9 A resolution, respectively) reveal interactions deep within the subunit interface and the absence of a contact surface with the tip of loop C. Hence, in addition to channel blocking, non-competitive interactions with heteromeric neuronal nAChR appear to occur at the non-alpha subunit interface, a site presumed to be similar to that of modulating benzodiazepines on GABA(A) receptors. | Loy C, Schneider L (2006)
Galantamine for Alzheimer's disease and mild cognitive impairment.
The Cochrane database of systematic reviewsCD001747 [PubMed:16437436]
[show Abstract]
BackgroundGalantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor.ObjectivesTo assess the clinical effects of galantamine in patients with mild cognitive impairment (MCI), probable or possible Alzheimer's disease (AD), and potential moderators of effect.Search strategyThe trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, last updated on 25 April 2005 using the terms galanthamin*, galantamin* and Reminyl. Published reviews were inspected for further sources. Additional information was collected from unpublished clinical research reports for galantamine obtained from Janssen and from http://www.clinicalstudyresults.org/.Selection criteriaTrials selected were randomised, double-blind, parallel-group comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in subjects with MCI or AD.Data collection and analysisData were extracted independently by the reviewers and pooled where appropriate and possible. Outcomes of interest include the clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Assessment Scale-cognitive sub scale (ADAS-cog), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). Potential moderating variables of treatment effect assessed included trial duration, dose, and diagnosis of possible versus probable Alzheimer's disease.Main resultsTen trials with a total 6805 subjects were included in the analysis. Treatment with galantamine led to a significantly greater proportion of subjects with improved or unchanged global rating scale rating (k = 8 studies), at all dosing levels except for 8 mg/d . Confidence intervals for the ORs overlapped across the dose range of 16 mg to 36 mg per day, with point estimates of 1.6 - 1.8 when analysed with the intention-to-treat sample. Treatment with galantamine also led to significantly greater reduction in ADAS-cog score at all dosing levels (k = 8), with greater effect over six months compared to three months. Confidence intervals again overlapped. Point estimate of effect was lower for 8 mg/d but similar for 16 mg to 36 mg per day. For example, treatment effect for 24 mg/d over six months was 3.1 point reduction in ADAS-cog (95%CI 2.6-3.7, k = 4, ITT).ADCS-ADL, DAD and NPI were reported only in a small proportion of trials: all showed significant treatment effect in some individual trials at least. Confidence interval of treatment effect for the one trial recruiting patients with possible AD overlapped with the other seven recruiting patients with probable AD. Galantamine's adverse effects appeared similar to those of other cholinesterase inhibitors and to be dose related. Prolong release / once daily formulation of galantamine at 16 - 24mg/d was found to have similar efficacy and side-effect profile as the equivalent twice-daily regime. Data from the two MCI trials suggest marginal clinical benefit, but a yet unexplained excess in death rate.Authors' conclusionsSubjects in these trials were similar to those seen in earlier anti dementia AD trials, consisting primarily of mildly to moderately impaired outpatients. Galantamine's effect on more severely impaired subjects has not yet been assessed.Nevertheless, this review shows consistent positive effects for galantamine for trials of three to six months' duration. Although there was not a statistically significant dose-response effect, doses above 8 mg/d were, for the most part, consistently statistically significant. Galantamine's safety profile in AD is similar to that of other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over a four week period, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably most preferable initially. Longer term use of galantamine has not been assessed in a controlled fashion. Galantamine use in MCI is not recommended due to its association with an excess death rate. | Orgogozo JM, Small GW, Hammond G, Van Baelen B, Schwalen S (2004)
Effects of galantamine in patients with mild Alzheimer's disease.
Current medical research and opinion 20, 1815-1820 [PubMed:15537482]
[show Abstract]
BackgroundGalantamine is an acetylcholinesterase inhibitor that modulates nicotinic receptors. It is effective in mild to moderate Alzheimer's disease (AD) but no trial has focused exclusively on mild AD. We performed a post-hoc sub-set analysis using data from four randomised trials to explore the efficacy of galantamine versus placebo in mild AD.MethodsParticipants in all studies met NINCDS-ADRDA criteria for probable AD. We examined data from patients with baseline Mini Mental State Examination (MMSE) 21-24 who received galantamine 24 mg/day (GAL) or placebo (PLAC). Scores for the Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog), Clinician's Interview-Based Impression of Change (CIBIC), Disability Assessment for Dementia (DAD), and ACDS-ADL scales were compared.ResultsOf the 694 patients (362 GAL, 332 PLAC, mean baseline MMSE 22.4 +/- 1.1, mean age 74 +/- 7.9 years), 65% completed 6 months treatment (223 GAL, 229 PLAC). Mean change in ADAS-cog at 6 months was -1.5 (95% confidence interval -2.2, -0.8, p < 0.001) for GAL and +0.2 (-0.6, 0.9, p = 0.72) for PLAC. This difference was statistically significant (p = 0.001). Significantly more patients receiving galantamine were classified as 'improved' using the CIBIC (26.9% GAL vs 14.3% PLAC, p < 0.001). Galantamine was generally well tolerated; most common adverse events were nausea, vomiting and diarrhoea.ConclusionsPooled data from four randomised trials of patients with mild AD indicate that patients who received galantamine 24 mg/day for 6 months improved cognition more often than those who received placebo and that a higher proportion receiving galantamine were globally improved. This suggests that patients with mild AD benefit from galantamine treatment. | Greenblatt HM, Guillou C, Guénard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL (2004)
The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design.
Journal of the American Chemical Society 126, 15405-15411 [PubMed:15563167]
[show Abstract]
Bifunctional derivatives of the alkaloid galanthamine, designed to interact with both the active site of the enzyme acetylcholinesterase (AChE) and its peripheral cation binding site, have been assayed with Torpedo californica AChE (TcAChE), and the three-dimensional structures of their complexes with the enzyme have been solved by X-ray crystallography. Differences were noted between the IC(50) values obtained for TcAChE and those for Electrophorus electricus AChE. These differences are ascribed to sequence differences in one or two residues lining the active-site gorge of the enzyme. The binding of one of the inhibitors disrupts the native conformation of one wall of the gorge, formed by the loop Trp279-Phe290. It is proposed that flexibility of this loop may permit the binding of inhibitors such as galanthamine, which are too bulky to penetrate the narrow neck of the gorge formed by Tyr121 and Phe330 as seen in the crystal structure. | Loy C, Schneider L (2004)
Galantamine for Alzheimer's disease.
The Cochrane database of systematic reviewsCD001747 [PubMed:15495017]
[show Abstract]
BackgroundGalantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor.ObjectivesTo assess the clinical effects of galantamine in patients with probable or possible Alzheimer's disease (AD), and potential moderators of effect.Search strategyThe trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, last updated on 25 August 2005 using the terms galanthamin*, galantamin* and Reminyl. Published reviews were inspected for further sources. Additional information was collected from unpublished clinical research reports for galantamine obtained from Janssen.Selection criteriaTrials selected were randomised, double-blind, parallel-group comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in subjects with AD.Data collection and analysisData were extracted independently by the reviewers and pooled where appropriate and possible. Outcomes of interest include the clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Assessment Scale-cognitive sub scale (ADAS-cog), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). Potential moderating variables of treatment effect assessed included trial duration, dose, and diagnosis of possible vs. probable Alzheimer's disease.Main resultsSeven trials with a total 3777 subjects were included in the analysis. Treatment with galantamine led to a significantly greater proportion of subjects with improved or unchanged global rating scale rating (k=7), at all dosing levels except for 8mg/d . Confidence intervals for the ORs overlapped across the dose range of 16mg to 36mg per day, with point estimates of 1.6-2.1 when analysed with the intention-to-treat sample. Treatment with galantamine also led to significantly greater reduction in ADAS-cog score at all dosing levels (k=7), with greater effect over 6 months compared to 3 months. Confidence intervals again overlapped. Point estimate of effect was lower for 8mg/d but similar for 16mg to 36mg per day. For example, treatment effect for 24mg/d over 6 months was 3.1point reduction in ADAS-cog (95%CI 2.6-3.7, k=4, ITT).ADCS-ADL, DAD and NPI were reported only in a small proportion of trials: all showed significant treatment effect in some individual trials at least. Confidence interval of treatment effect for the one trial recruiting patients with possible AD overlapped with the other six recruiting patients with probable AD. Galantamine's adverse effects appeared similar to those of other cholinesterase inhibitors and to be dose related.Reviewers' conclusionsSubjects in these trials were similar to those seen in earlier anti dementia AD trials, consisting primarily of mildly to moderately impaired outpatients. Galantamine's effect on more severely impaired subjects has not yet been assessed.Nevertheless, this review shows consistent positive effects for galantamine for trials of 3 to 6 months duration. Although there was not a statistically significant dose-response effect, doses above 8mg/d were, for the most part, consistently statistically significant. Galantamine's safety profile is similar to that of other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over a 4 week period, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably most preferable initially. Longer term use of galantamine has not been assessed in a controlled fashion. | Farlow MR (2003)
Clinical pharmacokinetics of galantamine.
Clinical pharmacokinetics 42, 1383-1392 [PubMed:14674789]
[show Abstract]
Galantamine is the most recently approved cholinergic drug for the treatment of Alzheimer's disease, the most common type of dementia. Vascular dementia and Alzheimer's disease with cerebrovascular disease are also common in older patients. Dementia affects cognition, causes losses in ability to perform activities of daily living and often results in the emergence of psychiatric and abnormal behavioural symptoms. Dementia also results in an ever-increasing burden and a decreased quality of life for caregivers. Treatments for dementia, particularly Alzheimer's disease, have focused on improving function in the cholinergic system. Vascular dementia and diffuse Lewy body dementia are also associated with significant defects in cholinergic function. Galantamine works by inhibiting acetylcholinesterase and by allosterically modulating nicotinic receptors. In clinical trials, galantamine has shown benefits in the domains of cognition, function in activities of daily living, and behaviour. Galantamine is about 90% bioavailable and displays linear pharmacokinetics. It has a relatively large volume of distribution and low protein binding. Metabolism is primarily through the cytochrome P450 system, specifically the CYP2D6 and CYP3A4 isoenzymes. Population pharmacokinetic modelling with galantamine has shown that the variables affecting clearance are age, sex, and bodyweight. Model simulations demonstrate the importance of a slower dose-escalation schedule in patients with moderate hepatic impairment. In several large trials, galantamine has been shown to be well tolerated, with most adverse events being mild-to-moderate and gastrointestinal in nature. Based on the literature and clinical trial experience, galantamine appears to be an excellent treatment option for patients with Alzheimer's disease, vascular dementia or Alzheimer's disease with cerebrovascular disease. | Lilienfeld S (2002)
Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease.
CNS drug reviews 8, 159-176 [PubMed:12177686]
[show Abstract]
Galantamine hydrobromide is a tertiary alkaloid drug that has been developed and approved in a number of countries including the USA and several countries in Europe as a treatment for mild-to-moderate Alzheimer's disease (AD). Galantamine has a unique, dual mode of action. It is a reversible, competitive inhibitor of acetylcholinesterase (AChE), and is the only drug actively marketed for the treatment of AD with proven activity as an allosteric modulator of nicotinic acetylcholine receptors (nAChRs). This latter activity is thought to be particularly important since decreases in the expression and activity of nAChRs make a large contribution to the reduction in central cholinergic neurotransmission in patients with AD. Galantamine exhibits favorable pharmacokinetic characteristics including predictable linear elimination kinetics at the recommended maintenance doses (16 and 24 mg/day), a relatively short half-life (approximately 7 h) and high bioavailability. It is extensively metabolized in numerous pathways, mainly in the liver via cytochrome P450 enzymes CYP2D6 and CYP3A4, and has a low potential for clinically significant drug-drug interactions. During four large randomized, double-blind, placebo-controlled trials of up to 6 months duration, galantamine 16 and 24 mg/day significantly benefited cognitive and global function, ability to perform activities of daily living (ADL) and behavior, relative to placebo and baseline, for up to 6 months. Caregiver burden (time spent by caregivers supervising patients or assisting them with ADL), and caregiver distress (related to patients' behavioral symptoms) were also reduced. Cognitive and functional abilities were preserved at or near baseline for at least 12 months in patients who received galantamine 24 mg/day for 12 months in a long-term US study. These benefits were maximized by early and continued galantamine treatment and, again, were associated with significant reductions in caregiver burden. Trials of the efficacy of galantamine in dementia related to cerebrovascular disease have also yielded positive results. There are no safety concerns associated with the use of galantamine. The incidence of adverse events, particularly cholinergically mediated events affecting the gastrointestinal system, is generally low and can be minimized using the recommended slow dose-escalation scheme. Galantamine may, therefore, help to reduce the overall burden and cost involved in caring for dementia patients. Taking all evidence into account, galantamine has the potential to become a first-line therapy for dementia. | Mannens GS, Snel CA, Hendrickx J, Verhaeghe T, Le Jeune L, Bode W, van Beijsterveldt L, Lavrijsen K, Leempoels J, Van Osselaer N, Van Peer A, Meuldermans W (2002)
The metabolism and excretion of galantamine in rats, dogs, and humans.
Drug metabolism and disposition: the biological fate of chemicals 30, 553-563 [PubMed:11950787]
[show Abstract]
Galantamine is a competitive acetylcholine esterase inhibitor with a beneficial therapeutic effect in patients with Alzheimer's disease. The metabolism and excretion of orally administered (3)H-labeled galantamine was investigated in rats and dogs at a dose of 2.5 mg base-Eq/kg body weight and in humans at a dose of 4 mg base-Eq. Both poor and extensive metabolizers of CYP2D6 were included in the human study. Urine, feces, and plasma samples were collected for up to 96 h (rats) or 168 h (dogs and humans) after dosing. The radioactivity of the samples and the concentrations of galantamine and its major metabolites were analyzed. In all species, galantamine and its metabolites were predominantly excreted in the urine (from 60% in male rats to 93% in humans). Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Major metabolic pathways were glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization. All metabolic pathways observed in humans occurred in at least one animal species. In extensive metabolizers for CYP2D6, urinary metabolites resulting from O-demethylation represented 33.2% of the dose compared with 5.2% in poor metabolizers, which showed correspondingly higher urinary excretion of unchanged galantamine and its N-oxide. The glucuronide of O-desmethyl-galantamine represented up to 19% of the plasma radioactivity in extensive metabolizers but could not be detected in poor metabolizers. Nonvolatile radioactivity and unchanged galantamine plasma kinetics were similar for poor and extensive metabolizers. Genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of galantamine. | Bartolucci C, Perola E, Pilger C, Fels G, Lamba D (2001)
Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs.
Proteins 42, 182-191 [PubMed:11119642]
[show Abstract]
The 3D structure of a complex of the anti-Alzheimer drug galanthamine with Torpedo californica acetylcholinesterase is reported. Galanthamine, a tertiary alkaloid extracted from several species of Amarylidacae, is so far the only drug that shows a dual activity, being both an acetylcholinesterase inhibitor and an allosteric potentiator of the nicotinic response induced by acetylcholine and competitive agonists. The X-ray structure, at 2.5A resolution, shows an unexpected orientation of the ligand within the active site, as well as unusual protein-ligand interactions. The inhibitor binds at the base of the active site gorge, interacting with both the acyl-binding pocket and the principal quaternary ammonium-binding site. However, the tertiary amine group of galanthamine does not directly interact with Trp84. A docking study using the program AUTODOCK correctly predicts the orientation of galanthamine in the active site. The docked lowest-energy structure has a root mean square deviation of 0.5A with respect to the corresponding crystal structure of the complex. The observed binding mode explains the affinities of a series of structural analogs of galanthamine and provides a rational basis for structure-based drug design of synthetic derivatives with improved pharmacological properties. Proteins 2001;42:182-191. | Sramek JJ, Frackiewicz EJ, Cutler NR (2000)
Review of the acetylcholinesterase inhibitor galanthamine.
Expert opinion on investigational drugs 9, 2393-2402 [PubMed:11060814]
[show Abstract]
Galanthamine (or galantamine, Reminyl) is a tertiary alkaloid acetylcholinesterase inhibitor (AChEI) which has been approved in several countries for the symptomatic treatment of senile dementia of the Alzheimer's type. Derived from bulbs of the common snowdrop and several Amaryllidaceae plants, (-)-galanthamine (GAL) has long been used in anaesthetics to reverse neuromuscular paralysis induced by turbocurarine-like muscle relaxants and more recently, has been shown to attenuate drug- and lesion-induced cognitive deficits in animal models of learning and memory. GAL directly inhibits acetylcholinesterase activity, while demonstrating much weaker activity on butyrylcholinesterase (BuChE). GAL also stimulates pre- and postsynaptic nicotinic receptors, although the clinical significance of this finding is yet unclear. Numerous variants and analogues of GAL have also been developed, with varying potency in inhibiting AChE activity. GAL is readily absorbed after oral administration, with a t(max) of 52 min and a plasma elimination t(1/2) of 5.7 h. The efficacy of GAL administered to Alzheimer's disease (AD) patients has been well demonstrated by large-scale clinical trials. Typical of AChEIs, the most common adverse events associated with GAL are nausea and vomiting. In conclusion, evidence to date suggests galanthamine to be similar to other AChEIs in improving cognitive function in AD patients. | Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL (1999)
Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution.
FEBS letters 463, 321-326 [PubMed:10606746]
[show Abstract]
(-)-Galanthamine (GAL), an alkaloid from the flower, the common snowdrop (Galanthus nivalis), shows anticholinesterase activity. This property has made GAL the target of research as to its effectiveness in the treatment of Alzheimer's disease. We have solved the X-ray crystal structure of GAL bound in the active site of Torpedo californica acetylcholinesterase (TcAChE) to 2.3 A resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp-84) and the acyl-binding pocket (Phe-288, Phe-290). The tertiary amine group of GAL does not interact closely with Trp-84; rather, the double bond of its cyclohexene ring stacks against the indole ring. The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp-72, near the top of the gorge. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 A) with Glu-199. The relatively tight binding of GAL to TcAChE appears to arise from a number of moderate to weak interactions with the protein, coupled to a low entropy cost for binding due to the rigid nature of the inhibitor. | Mayrhofer O (1966)
Clinical experiences with diallyl-nor-toxiferine and the curare antidote galanthamine.
Southern medical journal 59, 1364-1368 [PubMed:5333582] |
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