Drug Galanthamine Research Articles

The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6

Galanthamine proved effective in symptomatic treatment of senile dementia of Alzheimer's type. The aim of this study was to elucidate the metabolism of galanthamine. Two novel metabolites of galanthamine have been isolated from the urine of eight young men after single doses of 10–15 mg. Some 19.8% of the doses were excreted as O-demethylgalanthamine glucuronide, 5% as N-demethylgalanthamine, 25.1% as galanthamine, and 0.8% as epigalanthamine. After coadministration of quinidine hydrogen sulfate, which inhibits cytochrome P450 2D6 (CYP2D6) selectively, O-demethylgalanthamine glucuronide was highly diminished in urine. In vitro, human liver microsomes metabolized galanthamine to O-demethylgalanthamine with Vmax 5.2 nmol/mg protein/h and Km 187 μM. K1 of quinidine to inhibit O-demethylation was 28 nM. To inhibit cholinesterases, O-demethylgalanthamine was 10-fold more selective for acetylcholinesterase (AChE) versus butyrylcholinesterase (BuChE) than galanthamine. After glucuronidation, O-demethylgalanthamine failed to inhibit AChE and BuChE. N-Demethylgalanthamine inhibited cholinesterases less potently than galanthamine.

Comparative effects of the anticholinesterase drug galanthamine on the mechanical activity of isolated rat jejunum and ileum

1. The effects of cumulatively applied galanthamine hydrobromide (0.1–300 μM) on the mechanical activity of isolated proximal jejunum and distal ileum were studied. 2. Galanthamine was found to increase the spontaneous mechanical activity and exert by itself an enhancement of the smooth muscle tone in the two segments, both effects being more pronounced in ileum than in jejunum. 3. The galanthamine-induced augmentation of the spontaneous mechanical activity was tetrodotoxin (TTX)-sensitive, whereas the contractile effect of the drug on the tone was TTX-insensitive in both segments. 4. The present results showed not only quantitative differences in the tonic effects of galanthamine in both intestinal segments but they suggest some qualitative differences in cholinergic neuronal control along the gastro-intestinal tract.

High-performance liquid chromatographic determination of galanthamine, a long-acting anticholinesterase drug, in serum, urine and bile

The anticholinesterase drug galanthamine is obtained from alkalinized serum by repeated liquid—liquid extraction. The resulting extract is approximately 100 times concentrated with respect to the original sample. Quantitative determination of galanthamine is performed with normal-phase liquid chromatography using a mixture of dichloromethane— n-hexane and ethanolamine as an eluent. Phenacetin is used as internal standard. The absorption of the column effluent is monitored at 235 nm. No endogenous sources of interference have been observed. A galanthamine serum level of 5 ng/ml is found as the minimum detectable concentration; the coefficient of variation at this level is 37.8% ( n = 4). For the assay of galanthamine in the concentration range 10–100 ng/ml, standard deviations vary between 18.9 and 2.5% ( n = 32).

Treatment of respiratory depression with the anticholinesterase drug galanthamine hydrobromide.

Treatment of respiratory depression with the anticholinesterase drug galanthamine hydrobromide.

Some toxicologic properties of the alkaloids galanthamine and securinine

The two drugs galanthamine hydrobromide (I) and securinine nitrate (II) have been briefly investigated with respect to their toxicologic actions in intact mice and cats, as inhibitors of the in vitro acetylcholinesterase-acetylcholine system and as blocking agents on the action current from the single node of Ranvier in frog sciatic nerve. Compound I closely mimics the classic anticholinesterase physostigmine in its actions on all these systems. In terms of toxicity indexes, compound I was found to be about half as powerful as physostigmine in blockade of the isolated esterase system, and to display an intravenous LD 50 value of 5.2 mg/kg in mice. Compound II is a comparatively weak anticholinesterase and nodal blocking agent, but a very powerful convulsant and paralyzant in mice and cats, with actions reminiscent of those displayed by strychnine. The intravenous LD 50 value for compound II in mice is 3.5 mg/kg.