Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Galantamine is a tertiary alkaloid obtained synthetically or extracted from the bulbs and flowers of several Amaryllidaceae species. Galantamine has a significant therapeutic effect in the management of patients with Alzheimer’s disease (Erkinjuntti et al. 2002, 2008; Kaduszkiewicz et al. 2005; Kavirajan and Schneider 2007; Loy and Schneider 2006; Raskind et al. 2000; Tariot et al. 2000; Wilcock et al. 2000). After a single oral dose of 10 mg of galantamine in healthy volunteers, Bachus et al. (1999) have identified three metabolites in urine, namely, the glucuronide of O-desmethylgalantamine, N-desmethylgalantamine, and epigalantamine (Figure 3.46). Approximately 25.1% of the dose is excreted as galantamine, 19.8% as the glucuronide of O-desmethylgalantamine, 5% as N-desmethylgalantamine, and 0.8% as epigalantamine. No glucuronides of galantamine, epigalantamine, galantaminone, and N-desmethylgalantamine are detected. The major route of metabolism for galantamine is through the liver, accounting for approximately 75% of the total metabolism of galantamine (Westra et al. 1986). Approximately 73% of total radioactivity is excreted within the first 24 h after dose administration in humans. Multiple metabolic pathways and renal excretion are involved in the elimination of galantamine.
Cytotoxic Phenanthridone Alkaloid Constituents of the Amaryllidaceae
Spyridon E. Kintzios, Maria G. Barberaki, Evangelia A. Flampouri in Plants That Fight Cancer, 2019
An impressive feature of these alkaloids is their wide array of biological properties including antiviral, antibacterial, antifungal, antiparasitic, anticancer, antioxidant, anti-inflammatory, and insect antifeedant effects, as well as acetylcholinesterase (AChE), ascorbic acid biosynthesis, and RNA inhibitory activities (Viladomat et al. 1997, Bastida et al. 2006, Berkov et al. 2012, De Andrade et al. 2012, Jin 2016). In terms of commercial success, galantamine (2) stands out amongst the Amaryllidaceae as the first FDA approved drug from the family (Heinrich 2010). As a potent and reversible inhibitor of AChE galantamine has gained prominence on the clinical market as an Alzheimer’s drug (Heinrich 2010). The pursuit of galantamine as an Alzheimer’s drug would not have been possible without indigenous knowledge assimilated from the Caucasus region of Eastern Europe, where its original source Galanthus woronowii was shown to be used traditionally for motor-neuron diseases (Heinrich 2010). The success of galantamine as well as the interesting biological activities exhibited by other constituents of the family has rekindled interest in the Amaryllidaceae as a potential source of further chemotherapeutics (Viladomat et al. 1997, Bastida et al. 2006, Berkov et al. 2012, De Andrade et al. 2012, Jin 2016).
Phytochemicals: Some Basics
Scott Mendelson in Herbal Treatment of Major Depression, 2019
Alkaloids are nitrogen containing molecules produced by about a quarter of plants. Many alkaloids are quite toxic to animals. The alkaloid, nicotine, milligram for milligram, may be as toxic as cyanide.22 Thus, it is likely that alkaloids serve to protect the plants from animal predators. The nitrogen groups in alkaloids make them similar to nitrogen-containing neurotransmitters and other molecules active in the brain. Thus, it is not surprising that many well-known hallucinogenic and otherwise mind-altering plant substances are alkaloids. Examples are nicotine from tobacco, morphine from the poppy, psilocybin from mushrooms, lysergic acid from ergot mold, mescaline from cactus, and ephedrine from Ma Huang. Galantamine, a cholinesterase inhibitor that is an FDAapproved medication to treat Alzheimer’s disease, was originally obtained from bulbs of Galanthus caucasicus, the Caucasian snowdrop flower.23
Determination of galantamine in human plasma by LC-MS/MS using carbamazepine as an internal standard: Method validation and application to a pharmacokinetic study of galantamine hydrobromide prolonged-release capsules in healthy Thai volunteers
Published in Cogent Medicine, 2020
Darunee Hongwiset, Songwut Yotsawimonwat, Chokchai Wongsinsup, Saowarunee Sangsrijan, Chuleegone Sornsuvit
Galantamine, a cholinergic agent, is one of the approved drugs for the treatment of mild to moderate Alzheimer’s disease (AD). With a dual mechanism of action, reversible competitive inhibitor of acetylcholinesterase and allosteric modulator of nicotinic receptor, galantamine is an effective drug which was widely used. Various formulations of galantamine are available in forms of oral solutions, tablets and capsules. Since the use of galantamine is increased, new formulations and/or generic formulations are required. Pharmacokinetic and bioequivalence studies are also essential as a tool in drug development. These studied required a sensitive and robust bioanalytical method. In this study, a rapid HPLC-MS/MS method for quantification of galantamine in human plasma with simple solvent-solvent extraction was developed, validated and applied in the pharmacokinetic study of 8 mg galantamine hydrobromide release capsules in healthy Thai volunteers.
Nicotine-like discriminative stimulus effects of acetylcholinesterase inhibitors and a muscarinic receptor agonist in Rhesus monkeys
Published in Drug Development and Industrial Pharmacy, 2019
Megan J. Moerke, Lance R. McMahon
Galantamine is one of the most widely prescribed drugs for Alzheimer’s disease, but it is also being examined for utility as a smoking cessation pharmacotherapy. Galantamine is an acetylcholinesterase (AChE) inhibitor, and there is also evidence to suggest that galantamine is a positive allosteric modulator of nicotinic acetylcholine (ACh) receptors (nAChRs) [2,3]. However, evidence that galantamine is an allosteric nAChR modulator is not unanimous [4]. Galantamine has been shown to attenuate nicotine self-administration in rats [5,6] and to reduce cigarette smoking among alcohol-dependent patients [7]. It is unclear which mechanism of galantamine, AChE inhibition or allosteric modulation, might be responsible for producing this effect. However, if increasing ACh tone can produce nicotine-like effects, then one might predict other AChE inhibitors to produce similar results when applied to smoking cessation. Donepezil, another widely prescribed pharmacotherapy for Alzheimer’s disease, differs from galantamine in that it is an AChE inhibitor that appears to lack activity as an allosteric modulator of nAChRs [8,9]. Furthermore, another compound, PNU-120596, although not currently approved by the FDA had previously been shown to have cognitive-enhancing effects in monkeys [10]. As opposed to donepezil, the only known mechanism of PNU-120596 is as a positive allosteric modulator that is selective for α7 nAChRs [11]. The α7 nAChR subtype has been targeted for the development of analgesics [12], cognitive enhancing drugs [13] and smoking cessation aids [14].
Aconiti lateralis Radix Praeparata inhibits Alzheimer’s disease by regulating the complex regulation network with the core of GRIN1 and MAPK1
Published in Pharmaceutical Biology, 2021
Yutao Wang, Huixiang Zhang, Jing Wang, Ming Yu, Qianqian Zhang, Shan Yan, Dingyun You, Lanlan Shi, Lihuan Zhang, Limei Wang, Hongxiang Wu, Xue Cao
For another, GRIN1 and MAPK1 have been closely related to neurodegeneration, synaptic plasticity, cell survival and AD in previous researches (Coyle et al. 2016; Preciados et al. 2016; Sun and Nan 2017; Lu and Malemud 2019). GRIN1 protein is a critical subunit of NMDA (Kaniakova et al. 2012), which is the target of memantine (Robinson and Keating 2006), and plays a key role in memory and learning by regulating the plasticity of synapses (Mori et al. 2011; Wang et al. 2011). GluN1 receptors and GRIN1 gene expression levels and location are significantly different in AD samples compared to controls (Leuba et al. 2014; Mohamed et al. 2015; Agca et al. 2020). The MAPK1 gene is believed as one age-dependent transcriptional changing gene that involves in the abnormal hyperphosphorylation of the tau-protein, causing aggregated neurofibrillary tangles (Kálmán et al. 2009). Moreover, galantamine could treat Alzheimer’s disease by attenuating the activation of MAPK1 (Noda et al. 2010). Taken these results together, we hypothesise that the complex regulation network with the core of GRIN1 and MAPK1 may play a key role in the process of Fuzi anti-AD.
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