AChE and BChE are inhibited by galantamine, having IC50 values of 0.5 and 8.5 μM, respectively[1]. In permanently transfected HEK 293 cells, galantamine functions as a positive allosteric modulator (PAM) of human α4β2 AChR expression. At very low concentrations (EC50=0.25 nM), galantamine boosts the response of (α4β2)2α5 AChR to 1 μM ACh by up to 220%. Using the FLEXstation assay, only a minor increase (20%) of α4β2 or (α4β2)2β3 AChR was found. At concentrations greater than 1 μM, galantamine inhibits each of the three AChR subtypes [2].

In the hippocampus, but not in the prefrontal cortex, acute galantamine administration (0.3–3 mg/kg, i.p.) raises IGF2 mRNA levels in a dose- and time-dependent manner. In the hippocampus, galantamine (3 mg/kg, i.p.) temporarily raises the mRNA levels of fibroblast growth factor 2 and decreases the mRNA levels of brain-derived neurotrophic factor, but has no effect on other neurotrophic/growth factors. mRNA concentrations. Mecamylamine, a nonselective nicotinic acetylcholine receptor (nAChR) antagonist, and methylaconitine, a selective α7 nAChR antagonist, can both suppress galantamine-induced increases in hippocampal IGF2 mRNA levels, but tirenzepine, a preferential M1 muscarinic ACh receptor antagonist, cannot. Additionally, IGF2 mRNA levels were elevated by the selective α7 nAChR agonist PHA-543613, but not by the acetylcholinesterase inhibitor donepezil. Additionally, methylaconitine can inhibit the rise of hippocampus IGF2 protein caused by galantamine [2].

Absorption, Distribution and Excretion
Galantamine exhibits dose-linear pharmacokinetics within a dose range of 8–32 mg/day. Oral bioavailability of galantamine is 90–100%. The time to peak concentration (Tmax) after oral administration is approximately 1 hour. Ten hours after administration, the mean plasma galantamine concentration was 82–97 µg/L in the 24 mg/day dose group and 114–126 µg/L in the 32 mg/day dose group. In healthy individuals, renal clearance accounts for approximately 20–25% of the total plasma clearance; galantamine clearance is reduced in patients with renal impairment. Approximately 20% of the dose is excreted unchanged in the urine within 24 hours after oral or intravenous administration. In a study of radiolabeled drugs, approximately 95% of the total radioactive material was recovered in the urine and 5% in the feces. Of the dose recovered in urine, approximately 32% is the unmetabolized parent compound and 12% is in glucuronide form. The mean volume of distribution is 175 liters. Approximately 52.7% of galantamine is distributed in blood cells, with a plasma concentration-to-dose ratio of 1.2. Galantamine can cross the blood-brain barrier. Renal clearance is 65 mL/min, and total plasma clearance is approximately 300 mL/min. Protein binding is low (18%). The mean volume of distribution is 175 liters. In healthy male subjects, approximately 1 hour after a single oral dose of 8 mg galantamine, the maximum inhibition of acetylcholinesterase activity was approximately 40%. Galantamine is rapidly and completely absorbed. The absolute oral bioavailability of galantamine is approximately 90%. The pharmacokinetics of galantamine are linear, with a dose range of 8 to 32 mg/day. For more complete data on the absorption, distribution, and excretion of galantamine (6 items in total), please visit the HSDB record page. Metabolism/Metabolites In vitro studies have shown that approximately 75% of the drug is metabolized via CYP2D6 and CYP3A4. CYP2D6 promotes O-demethylation of the drug to O-demethylgalantamine; the CYP3A4-mediated pathway generates galantamine-N-oxide. Important metabolic pathways also include N-demethylation, epimerization, and sulfate conjugation. Other metabolites include norgalantamine, O-demethylgalantamine, O-demethylnorgalantamine, epigalantamine, and galantamineone; these metabolites do not have clinically significant pharmacological activity. Galantamine can also undergo glucuronidation: In an oral radiolabeled drug study in subjects with poor and high CYP2D6 metabolism, approximately 14-24% of the total radioactivity was identified as galantamine glucuronide 8 hours after administration. O-demethylation of CYP2D6 is particularly pronounced in patients with high CYP2D6 metabolism, but in a radiolabeled drug study, both poor and high CYP2D6 metabolism in subjects' plasma, unchanged galantamine (39-77%) and its glucuronide metabolites (14-24%) were dominant. Total plasma clearance, or non-renal clearance, accounts for 20-25% of drug elimination. In oral 3(H)-galantamine studies, unmetabolized galantamine and its glucuronide accounted for the majority of plasma radioactivity in individuals with poor and high CYP2D6 metabolism. Within 8 hours of administration, 39-77% of the total plasma radioactivity of galantamine and 14-24% of galantamine glucuronide are unmetabolized. After 7 days, 93-99% of the radioactivity is recovered, with approximately 95% excreted in urine and approximately 5% in feces. The average total recovery of unchanged galantamine in urine is 32% of the administered dose, and the average total recovery of galantamine glucuronide is 12% of the administered dose. Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in urine. In vitro studies have shown that cytochrome P450 2D6 and CYP3A4 are the main isoenzymes involved in galantamine metabolism, and inhibitors of both pathways can moderately improve the oral bioavailability of galantamine. CYP2D6-mediated O-demethylation is more pronounced in rapid CYP2D6 metabolizers than in slow metabolizers. However, in the plasma of individuals with both poor and high metabolic capacity, unmetabolized galantamine and its glucuronide account for the majority of the sample radioactivity. Galantamine is metabolized by hepatic cytochrome P450 enzymes. Known metabolites of galantamine include galantamine N-oxide, O-demethylgalantamine, N-demethylgalantamine, and [(1S,12S,14R)-14-hydroxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadec-6(17),7,9,15-tetraen-9-yl] hydrogen sulfate. Biological half-life: The terminal half-life of galantamine is approximately 7 hours. Elimination half-life: 7 hours

Hepatotoxicity
In several large placebo-controlled clinical trials, no increase in serum enzyme elevations or hepatotoxicity was reported in patients treated with galantamine compared to the placebo group. While the sponsor has received reports of cases of elevated liver enzymes and hepatitis associated with galantamine, no clinically significant cases of hepatotoxicity have been published. Acetylcholinesterase inhibitors used to treat Alzheimer's disease, except for tacrine, are rarely associated with clinically significant acute liver injury. Probability score: E (unlikely to be a cause of clinically significant liver injury). Protein Binding At treatment-related concentrations, galantamine has a plasma protein binding rate of 18%. Interactions
/ Concomitant use of cimetidine or paroxetine with galantamine / May increase the bioavailability of galantamine. / Concomitant use of anticholinergic drugs with galantamine / May reduce the efficacy of these drugs. During anesthesia, galantamine may enhance the neuromuscular blocking effects of succinylcholine and similar neuromuscular blocking agents. Galantamine/concomitant use with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase gastric acid secretion and potentially cause gastrointestinal irritation; patients should be monitored for occult gastrointestinal bleeding. For more complete data on interactions of galantamines (6 in total), please visit the HSDB record page.

[1]. Acetylcholinesterase inhibitors of natural origin. International Journal of Research in Pharmaceutical and Biomedical Sciences 3(SI 1):67-86.

[2]. Roles of accessory subunits in alpha4beta2(*) nicotinic receptors. Mol Pharmacol. 2008 Jul;74(1):132-43.

[3]. Galantamine increases hippocampal insulin-like growth factor 2 expression via α7 nicotinic acetylcholine receptors in mice. Psychopharmacology (Berl). 2013 Feb;225(3):543-51.

Therapeutic Uses
Cholinesterase Inhibitor
Galanamin is indicated for the treatment of mild to moderate Alzheimer's disease-related dementia. / Included in US Product Label/

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Drug Warnings In two two-year randomized, placebo-controlled trials involving patients with mild cognitive impairment (MCI), there were 13 deaths in the larzadamine group (n=1026) and 1 death in the placebo group (n=1022). The causes of death were varied and expected in older adults; approximately half of the deaths in the larzadamine group appeared to be due to various vascular causes (myocardial infarction, stroke, and sudden death). Although the difference in mortality between the larzadamine and placebo groups was significant in these two studies, the results differ considerably from those of other larzadamine studies. Specifically, in both studies of mild cognitive impairment (MCI), the mortality rate in the placebo group was significantly lower than that in trials of rezadaline treatment for Alzheimer's disease or other dementia (0.7 vs. 22-61 per 1000 person-years, respectively). While the mortality rate in MCI patients treated with rezadaline was also lower than that observed in trials of rezadaline treatment for Alzheimer's disease and other dementia (10.2 vs. 23-31 per 1000 person-years, respectively), the relative difference was much smaller. When data from studies of Alzheimer's disease and other dementia were pooled (n=6000), the mortality rate in the placebo group numerically exceeded that in the rezadaline group. Furthermore, in the MCI studies, no participants in the placebo group died after 6 months, a highly unexpected finding in this population. Patients with mild cognitive impairment experience memory decline exceeding expectations for their age and education level, but not meeting the current diagnostic criteria for Alzheimer's disease.
FDA Pregnancy Risk Classification: B / No evidence of risk to humans. Although adverse reactions have been observed in animal studies, adequately controlled studies in pregnant women have not shown an increased risk of fetal malformations; or, in the absence of adequate human studies, animal studies have shown no fetal risk. The possibility of fetal harm is small but still exists. /
Cholinergic activity may lead to an increased risk of seizures (seizures may also be a manifestation of Alzheimer's disease).
Adverse reactions occurring in patients receiving galantamine hydrobromide at a rate ≥5% and at least twice that in the placebo group include nausea, vomiting, diarrhea, anorexia, and weight loss. Most adverse reactions occur during dose escalation. Taking the medication with food, using antiemetics, and ensuring adequate fluid intake may help mitigate the effects of these adverse events.
For more complete data on drug warnings for galantamine (14 in total), please visit the HSDB record page.

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Pharmacodynamics
Galantamine is a competitive, reversible acetylcholinesterase inhibitor that works by increasing acetylcholine levels. Galantamine enhances cholinergic tone by inhibiting acetylcholinesterase in muscles and the brain via central and peripheral pathways. Galantamine is also a positive allosteric modulator of nicotinic acetylcholine receptors in neurons. Because dementia is a progressive neurodegenerative disease, galantamine has little effect on altering the underlying course of dementia, and its therapeutic effect may only be short-term. However, in clinical studies of Alzheimer's disease, galantamine has improved cognitive function, overall function, activities of daily living, and behavioral symptoms. Galantamine has also shown therapeutic effects in studies of vascular dementia and Alzheimer's disease with cerebrovascular disease. In one study, galantamine reversed scopolamine-induced acute anticholinergic syndrome, characterized by somnolence, disorientation, and delirium.

C17H21NO3

287.3535

287.152

357-70-0

Galanthamine hydrobromide;1953-04-4;Galanthamine-d6;1128109-00-1;Galanthamine-O-methyl-d3;1279031-09-2

9651

White to off-white solid powder

1.3±0.1 g/cm3

439.3±45.0 °C at 760 mmHg

119-121ºC

219.5±28.7 °C

0.0±1.1 mmHg at 25°C

1.636

1.75

1

4

1

21

440

3

CN1CC[C@@]23C=C[C@@H](C[C@@H]2OC4=C(C=CC(=C34)C1)OC)O

ASUTZQLVASHGKV-JDFRZJQESA-N

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

(1S,12S,14R)-9-methoxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6(17),7,9,15-tetraen-14-ol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 59 mg/mL (~205.32 mM)
1M HCl : 50 mg/mL (~174.00 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)