No abstract

Measurements were done to determine the plasma concentrations of galanthamine and two of its metabolites, as well as the corresponding inhibition of acetylcholinesterase activity in erythrocytes after applying 5 and 10 mg galanthamine hydrobromide as a constant-rate intravenous infusion for 30 minutes and single oral doses of 10 mg in eight healthy male volunteers. The data obtained revealed first-order pharmacokinetics, complete oral bioavailability, and a mean terminal half-life of 5.68 hours (95% confidence interval, 5.17 to 6.25 hours). Renal clearance accounted for only 25% of the total plasma clearance (CL = 0.34 L.kg-1.hr-1). Only negligible quantities of the putative metabolites, epigalanthamine and galanthaminone, were detected in blood and urine. The inhibition of acetylcholinesterase activity was closely correlated with the pharmacokinetics of galanthamine, a median maximal value of 53% being achieved by applying 10 mg galanthamine intravenously. Analysis of in vitro and ex vivo concentration responses revealed no differences, indicating that no metabolites of galanthamine exert additional inhibition of acetylcholinesterase activity.

Summary:Galanthamine, physostigmine and 9-amino-l,2,3,4-tetrahydroacridine (tacrine) were evaluated s inhibitors of human acetylcholinesterase activity from samples of postmortem human brain, fresh brain cortex biopsies and human erythrocytes. Acetylcholinesterase activity was most effectively inhibited in all tissues by physostigmine, followed by tacrine and galanthamine. The respective inhibitor concentrations exerting a half maximal effect (IC 50 ) on acetylcholinesterase in postmortem human brain frontal cortex were 14nmol/l, 1.0 μιηοΐ/ΐ and 3.2 μηιόΐ/ΐ versus 15 nmol/1, 1.1 μτηοΐ/ΐ and 2.8 μιηοΐ/ΐ in the hippocampus region. In addition, the Inhibition of acetylcholinesterase by galanthamine was similar in postmortem brain and brain cortical biopsies from patients submitted to brain-tumour removal, indicating that postmortem changes up to 28 h after death probably did not influence the measurement of acetylcholinesterase Inhibition. While physostigmine and tacrine acted equally on acetylcholinesterase from different sources, galanthamine was 10-fold less potent in inhibiting the enzyme activity from human brain than from human erythrocytes. Comparison with issues from mice revealed that galanthamine was selectively more potent in suppressing acetylcholinesterase in human erythrocytes. The results are discussed in the light of pharmacokinetic data, and conclusions are drawn for further clinical studies.in Alzheimer's disease were determined: the frontal Reversible cholinesterase inhibitors are currently used cortex and the hippocampus. Since measurement of for symptomatic treatment of cognitive deficits and red-cell acetylcholinesterase Inhibition ex vivo may memory impairment in Alzheimer's disease. One pos-predict enzyme Inhibition in the brain (6, 7), it seemed tulated mechanism is restoration of the cholinergic useful to perform additional in vitro experiments with deficit at synaptic sites in the brain by inhibition of erythrocytes. Postmortem acetylcholinesterase activacetylcholine metabolisipti (1), b t severalother mech^ ity has been shown to be stable (8) for at least 31 h. anisms have also been discussed (2 -5). It was the It has also been reported, however, that the 4S and purpose of this study to measure the inhibition of 10S molecular forms in the brain are extremely labile acetylcholinesterase 1 ) from various sources by galan-and that freezing of either subcellular or intact tissue thamine, physostigmine and tacrine. A series of con-causes dramatic shifts in the level of the molecular centration response trials was performed using human forms (9), although the molecular shift was not asbrain tissue; and, prior to further specified analysis soeiated with any change of total acetylcholinesterase currently in progress, two separate regions of interest activity. To identify possible alterations in postmortem tissue, the inhibition of acetylcholinesterase by 1 ) Enzymes: Acetyl holinesterase, EC 3.1.1.7 galanthamine in fresh human brain cortex samplesEur.

A comparative study of adverse drug reactions (ADR) leading to hostpial admission showed that 103 (4.1%) out of 2499 medical admissions in Jerusalem and 167 (5.7%) out of 2933 admissions in Berlin were due to such reactions. Sex distribution in the two patient--populations was almost equal but the Jerusalem patients were younger. The most frequent ADRs were digitalis intoxication (in Berlin) and reactions to antibiotics (in Jerusalem). Other important differences were noted in the relative frequencies of ADRs associated anticoagulants, hypoglycemic agents and oral contraceptives. They were probably related to differences in drug usage in the two countries. The most common major side effects were arrhythmias, allergic reactions, bleeding, congestive heart failure, bronchospasm and hypoglycemia. The following risk factors were identified in both cities: old age, female sex, impaired renal function, previous history of ADR and polypragmasia.

No abstract