Galantamine ( Nivalin , Razadyne , Razadyne ER , Reminyl , Lycoremine ) is used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and other memory disorders. It is an alkaloid that has been isolated from tubers and flowers of Galanthus caucasicus (Caucasian snowdrop), Galanthus woronowii (Voronov's snowdrop), and several other family members Amaryllidaceae , such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (red spider lily). It can also be produced synthetically.
The study of the use of modern medicine began in the Soviet Union in the 1950s. Galantamine was isolated for the first time from bulbs of Galanthus nivalis (ordinary snowflakes) by Bulgarian chemist D. Paskov and his team in 1956. The active ingredients were extracted, identified and studied, particularly in relation to the inhibitory properties of acetylcholinesterase ( AChE). The first industrial process was developed in 1959.
In addition to being used in Alzheimer's disease, galantamine has been used to treat myasthenia, myopathy, muscular dystrophy, and sensory and motor dysfunction associated with central nervous system disorders.
Video Galantamine
Use in mythology
In Homer Odyssey, Hermes's god gave Odysseus a concoction with "black roots, but a flower like milk" called "moly," which Hermes claims would make Odysseus immune to Cerce's magicians. It is believed that moly is a snowdrop Galanthus nivalis , which is the source of galantamine. The moly description given by Greek physicians and herbalist Dioscorides supports the identity of moly as Galanthus nivalis . It has been proposed that the drugs Cerce uses are extracts of Datura stramonium (also known as jimsonweed), which causes memory loss and delirium. This will provide the basis for the use of blood drops as an antidote, because Datura stramonium is anticholinergic, while galantamine is an acetylcholinesterase inhibitor.
Maps Galantamine
Medical use
Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimer's. In the United States, it is approved by the Food and Drug Administration as safe and effective for the treatment of mild to moderate dementia. As with other cholinesterase inhibitors, galantamine may not be effective for treating mild cognitive impairment,
Alzheimer's Disease
Alzheimer's disease is characterized by impaired cholinergic function. One hypothesis is that this damage contributes to the cognitive deficits caused by the disease. This hypothesis forms the basis for the use of galantamine as a cholinergic enhancer in the treatment of Alzheimer's. Galantamine inhibits acetylcholinesterase, an enzyme that hydrolyzes acetylcholine. As a result of the inhibition of acetylcholinesterase, galantamine increases the availability of acetylcholine for synaptic transmission. In addition, galantamine binds to the nicotinic nicotinic receptor allosteric site, leading to conformational changes. This allosteric modulation enhances the nicotinic receptor response to acetylcholine. Activation of presinaptic nicotinic receptors increases the release of acetylcholine, further increasing the availability of acetylcholine. Galantamine's competitive resistance to acetylcholinesterase and nicotinic allosteric modulation serves as a multiple action mechanism.
To reduce the prevalence of negative side effects associated with galantamine, such as nausea and vomiting, an escalation-dosing scheme may be used. The use of dose-escalation schemes has been well received in countries where galantamine is used. The dose-escalation scheme for the treatment of Alzheimer's involves the recommended starting dose of 4,, mg of galantamine tablet administered twice daily (8 mg/day). After at least 4 weeks, the dose can then be increased to 8 mg given twice daily (16 mg/day). After at least 4 weeks at 16 mg/day, treatment may be increased to 12 mg administered twice daily (24 mg/day). Increased doses are based on assessing the clinical benefit and tolerability of the previous dose. If treatment is disrupted for more than three days, this process usually restarts, starting at the initial dose, and again increasing to the current dose.
Available form
This product is provided both in the form of recipes and supplements which are sold freely in tablets twice daily, in extended release capsules once daily, and in oral solution.
Side effects
The profile of Galantamine side effects is similar to other cholinesterase inhibitors, with the most prominent and most frequently observed gastrointestinal symptoms. One study reported a higher proportion of patients treated with galantamine experienced nausea and vomiting compared with the placebo group. Other studies using dose escalation therapy have found that the incidence of nausea will decrease to baseline as soon as each dose increase is given. In practice, some other cholinesterase inhibitors may be better tolerated; however, a careful and gradual titrate for more than three months can lead to long-term equivalent tolerance.
The US Food and Drug Administration (FDA) and international health authorities have issued galantamine warnings based on data from two studies during treatment for mild cognitive impairment (MCI); Higher mortality rates were seen in drug-treated patients. On April 27, 2006, the FDA approved label changes on all forms of galantamine preparations (fluid, regular tablets, and extended release tablets) warning of bradycardia (slow-resting heartbeat), and sometimes atrioventricular block, especially in people who have a tendency. At the same time, the risk of syncope (fainting) appears to increase relative to placebo. "In randomized controlled trials, bradycardia was reported more frequently in patients treated with galantamine than in patients treated with placebo, but rarely severe and rarely led to treatment discontinuation." These side effects have not been reported in studies related to Alzheimer's disease.
Pharmacology
The chemical structure of Galantamine contains tertiary amines. At neutral pH, these tertiary amines will often bind to hydrogen, and most appear as ammonium ions.
Galantamine is a potential potenating ligand of human allosteric receptors nicotinic acetylcholine (nAChRs)? 4 ? 2 ,? 3 ? 4 , and? 6 ? 4 , and chicken nAChRs/mouse? 7 /5-HT 3 in a specific area of ​​the brain. By binding to the nAChRs allosteric site, conformational changes increase the receptor response to acetylcholine. The modulation of nicotinic cholinergic receptors in cholinergic neurons in turn leads to an increase in the amount of acetylcholine released. Galantamine also works as a competitive and reversible cholinesterase inhibitor that is weak in all areas of the body. By inhibiting acetylcholinesterase, it increases the concentration and thus acetylcholine action in certain parts of the brain. Galantamine effects on nAChRs and complementary acetylcholinesterase inhibition form a multiple action mechanism. It is hypothesized that this action may relieve some of the symptoms of Alzheimer's.
Galantamine in pure form is white powder. The 3D structure of the atomic resolution of the galantamine complex and its target, acetylcholinesterase, was determined by X-ray crystallography in 1999 (GDP code: 1DX6; see complex). There is no evidence that galantamine alters the underlying demensing process.
Pharmacokinetics
The absorption of galantamine is rapid and complete and shows linear pharmacokinetics. It is well absorbed with absolute oral bioavailability between 80 and 100%. It has the removal of the seven-hour half terminals. The peak effect of acetylcholinesterase inhibition is achieved approximately one hour after a single oral dose of 8 mg in some healthy volunteers.
Food coagulation delays galantamine absorption levels, but does not affect the absorption rate.
The plasma protein binding to galantamine is about 18%, which is relatively low.
Metabolism
About 75% of the doses of galantamine are metabolized in the liver. In vitro studies have shown that CYP2D6 Liver and CYP3A4 are involved in the metabolism of galantamine. Within 24 hours of intravenous or oral administration, approximately 20% of galantamine dose will be excreted without reaction in the urine.
In humans, several metabolic pathways for galantamine exist. These pathways lead to the formation of a number of different metabolites. One of the metabolites that can be produced can be formed through the glucuronidation of galantamine. In addition, galantamine may be oxidized or demetilized on its nitrogen atom, forming two other possible metabolites. Galantamine can undergo demethylation of its oxygen atoms, forming an intermediate which can then undergo a glucuronidation or sulfate conjugation. Finally, galantamine can be oxidized and then subtracted before finally undergoing demethylation or oxidation on its nitrogen atom, or subsequent demethylation and glucuronidation of its oxygen atoms.
For Razadyne ER, a once-daily formulation, CYP2D6 poor metabolism has a drug exposure that is approximately 50% higher than that of extensive metabolites. Approximately 7% of the population has this genetic mutation; However, since the drug is titrated individually for tolerability, no special dose adjustment is required for this population.
Drug interactions
Because galantamine is metabolised by CYP2D6 and CYP3A4, inhibiting one of these isoenzymes will increase the cholinergic effect of galantamine. Inhibiting these enzymes can cause adverse effects. It was found that paroxetine, the CYP2D6 inhibitor, increased the galactamine bioavailability by 40%. The CYP3A4 inhibitor ketoconazole and erythromycin increase the bioavailability of galantamine by 30% and 12%, respectively.
Synthesis
Galantamine is produced from natural resources and a patented total synthesis process. Many other synthetic methods exist but have not yet been implemented on an industrial scale.
Research
Organophosphate poisoning
The toxicity of the organophosphate results primarily from their action as an irreversible acetylcholinesterase inhibitor. Inhibiting acetylcholinesterase causes an increase in acetylcholine, since the enzyme is no longer available to catalyze its solution. In the peripheral nervous system, the accumulation of acetylcholine may lead to overstimulation of muscarinic receptors followed by desensitization of nicotinic receptors. This leads to severe skeletal muscle fasciculation (involuntary contraction). Effects on the central nervous system include anxiety, anxiety, confusion, ataxia, tremor, seizures, cardiorespiratory paralysis, and coma. As reversible acetylcholinesterase inhibitors, galantamine has the potential to function as an effective treatment of organophosphoric poisoning by preventing the inhibition of irreversible acetylcholinesterase. In addition, galantamine has anticonvulsant properties that make it more desirable as an antidote.
Research partially supported by the US Army has led to US patent applications for the use of galantamine and/or its derivatives for the treatment of organophosphorus poisoning. Indications for the use of galantamine in patent applications include poisoning by nerve agents "including but not limited to soman, sarin, and VX, Tabun, and Novichok agents". Galantamine was studied in the study cited in a patent application for use in conjunction with a neurological agent known as the atropine antidote. According to the researchers, an unexpected synergistic interaction occurs between galantamine and atropine in the amount of 6 mg/kg or higher. Increasing doses of galantamine from 5 to 8 mg/kg reduces the dose of atropine required to protect experimental animals from somanic toxicity in doses of 1.5. Dosage is usually required to kill half of experimental animals.
Autism
Galantamine given in addition to risperidone for autistic children has been shown to improve some symptoms of autism such as irritability, lethargy, and social withdrawal. In addition, cholinergic and nicotinic receptors are believed to play a role in the attention process. Several studies have noted that cholinergic and nicotinic treatments have increased attention on autistic children. Thus, it is hypothesized that the double action mechanism of galantamine may have the same effect in treating children with autism and adolescence.
Anesthesia
Galantamine may have some limited use in reducing the side effects of anesthetic reasoning and diazepam. In one study, the patient control group was given ketalar and diazepam and underwent anesthesia and surgery. The experimental group is given ketalar, diazepam, and nivalin (the active ingredient is galantamine). The drowsiness and disorientation levels of the two groups were then assessed 5, 10, 15, 30 and 60 min after surgery. Groups that had taken nivalin were found to be more alert 5, 10, and 15 minutes after surgery.
References
External links
- Razadyne ER (manufacturer website)
- Proteopedia 1dx6
- AChE inhibitor and substrate (Part II)
- Acetylcholinesterase: An article structure GDP gorge-ous article in PDBe
Source of the article : Wikipedia
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