Galantamine

Galantamine HBr was marketed under the brand name Remi-nyl. The name was changed in 2005 to Razadyne to avoid confusion with the diabetes drug Amaryl (glimeperide). 

Galantamine, like other cholinesterase inhibitors, is currently approved by the FDA only for the treatment of mild to moderate 

Alzheimer s disease however, studies have investigated its potential utility in vascular dementia (Erkinjuntti et al. 2002a) and advanced moderate Alzheimer s disease (Blesa et al. 2003). 

Common side effects reported in clinical trials include nausea, vomiting, diarrhea, anorexia, weight loss, dizziness, abdominal pain, and tremor. Most side effects tend to be dose related and may be decreased with a slow titration schedule of 4 mg twice daily every 4 weeks. Dosing should be done cautiously in patients with moderate renal or hepatic impairment, and galantamine should be avoided in those with severe impairment. 

Galantamine is metabolized primarily by CYP 2D6 and 3A4, and levels may be altered by inducers or inhibitors of these enzymes. Galantamine has not been shown to inhibit major cytochrome P450 enzymes. However, the pharmacodynamic interactions associated with other cholinesterase inhibitors may occur. 

Molecular formula C17H21NO3 Molecular weight 287.35 CAS Registry No 357-70-0 Merck Index 13,4361 

Sample preparation Mix 1 mT, plasma with 100 pL 10 pg/mL IS in MeOH, 1 mL saturated KCl solution, and 100 pL 1 M NaOH, vortex, extract twice with 2.5 mL portions of toluene. Combine the organic layers and evaporate to dryness under a stream of nitrogen at 65°, reconstitute the residue with 100 pL MeOH 10 mM ammonium acetateidiethylamine 90 10 1, inject an aliquot. 

Internal standard codeine phosphate Limit of quantitation 2-lOng/mL 

MonbaUu, J. Verhaeghe, T. Willems, B. Bode, W. Lavrijsen, K. Meuldermans, W. Pharmacokinetics of galantamine, a cholinestrase inhibitor, in several animal species, Arzneimittelforschung, 2003, 53, 486 495. 

Sample preparation Mix 200 pL plasma with 100 pL 50 ng/mL IS in 2% bovine serum albumin in 50 mM pH 7.5 phosphate buffer, add 1 mL 100 mM NaOH, add 500 pL saturated KCl, add 5 mL toluene, extract by over-the-top mixing at 15 rpm for 10 min, centrifuge at 2000 g for 10 min. Evaporate the organic layer to dryness under a stream of nitrogen at 65°, reconstitute the residue with 200 pL mobile phase, inject a 20 pL aliquot. 

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Donepezil has the advantage of once-daily administration and appears to be better tolerated than tacrine. Tacrine is particularly harmful to the liver. The new dragp rivastigmine and galantamine, like the other two, are effective in treating mild-to-moderate dementia of AD. 

Donepezil is administered orally once daily at bedtime. It can be taken with or without food. Galantamine is administered orally twice daily, preferably with morning and evening meals. 

NICE] National Institute for Clinical Effectiveness (2001). Guidanee on the Use of Donepezil, Rivastigmine and Galantamine far the Treatment of Alzheimer s Disease. Technology Assessment Guidance No. 19. London ... 

Galantamine is a ChE inhibitor, which elevates acetylcholine in the cerebral cortex by slowing the degradation of acetylcholine.37 It also modulates the nicotinic acetylcholine receptors to increase acetylcholine from surviving presynaptic nerve terminals. In addition, it may increase glutamate and serotonin levels. The clinical benefit of action of these additional neurotransmitters is unknown. 

Galantamine is approved for the treatment of mild to moderate dementia of Alzheimer s disease. It can be dosed once or twice daily (if using the immediate-release tablet or extended-release capsule). The initial dose is 8 mg daily (or 4 mg twice daily) for 4 weeks. If tolerated the dose can be increased if needed to 16 mg daily (or 8 mg twice daily) for at... 

Data from product Information for tacrine, donepezil, rivastigmine, galantamine, and memantine.34-38... 

The adverse reactions associated with galantamine are similar to that observed with the ChE inhibitors (e.g., nausea, vomiting, and diarrhea). 

CYP3A4 and 2D6 are the major enzymes involved in the metabolism of galantamine. Pharmacokinetic studies with inhibitors of this system have resulted in increased galantamine concentrations or reductions in clearance. Similarly to donepezil, if inhibitors are given concurrently with galantamine, monitoring for increased cholinergic side effects should be done. Studies with inducers of these enzymes have not been completed.37... 

Data from Product Information tacrine, donepezil, galantamine, memantine, and rivastigmine.34-38... 

The courts, however, are not bound by the decision of the Patent Office to issue the patent. In considering whether the application had utility, the Federal Circuit approvingly quoted the district court s determination that the application "did not provide analysis or insight connecting the [summaries of the six references]. .. to galantamine s potential to treat Alzheimer s disease [4]." In conjunction with this analysis, witness testimony given at trial was also considered. For example, the sole inventor testified that "when I submitted this patent, I certainly wasn t sure, and a lot of other people weren t sure, that cholinesterase inhibitors [such as galantamine] would ever work [to treat Alzheimer s disease] [5]." (Emphasis added). 

No direct comparative trials have assessed the effectiveness of one agent over another. Donepezil, rivastigmine, and galantamine are indicated in mild to moderate AD, while donepezil is also indicated in severe AD. 

Galantamine is a cholinesterase inhibitor that also has activity as a nicotinic receptor agonist. 

Wilcock, G.K., et al., "Efficacy and Safety of Galantamine in Patients with Mild to Moderate Alzheimer s Disease Multicentre Randomised Controlled Trial," BMJ, 321,1445-1449 (2000). 

FIGURE 13 Structural formula of the main compound galantamine hydrobromide. 

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