Consensus Conference on the Methodology of Clinical Trials of "Nootropics", Munich, June 1989

Amaducci, Laura; Angst, J.; Bech, Per; Benkert, Otto; Bruinvels, J.; Engel, Rolf R.; Cg, Gottfries; Hippius, Hanns; R, Levy; Lingjaerde, O

doi:10.1055/s-2007-1014502

Cited by 46 publications

(27 citation statements)

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“…Clinical studies on the efficacy of reversible cholinesterase inhibitors should employ an individual dose finding phase according to the report of a consensus Conference on the methodology of clinical trials of "nootropics" (31) and, in addition, include the concomitant degree of ex vivo enzyme Inhibition. The lower doses of galanthamine, physostigmine and tacrine used so far in many clinical studies possibly did not cause the anticipated degrees of Inhibition of brain acetylcholinesterase activity, and this would explain in part the limited effect.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Acetylcholinesterase Activity in Human Brain Tissue and Erythrocytes by Galanthamine, Physostigmine and Tacrine

Thomsen¹,

Kaden²,

Fischer³

et al. 1991

Clinical Chemistry and Laboratory Medicine

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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.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Acetylcholinesterase Activity in Human Brain Tissue and Erythrocytes by Galanthamine, Physostigmine and Tacrine

Thomsen¹,

Kaden²,

Fischer³

et al. 1991

Clinical Chemistry and Laboratory Medicine

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“…A purely symptom-oriented selection of patients or diagnoses such as 'dementia syndrome' or 'organic brain syn drome' is not sufficient. This differs from other guide lines [1,2] which do not consider definition of the study population as an etiologically homogenous group as an essential step. The DSM-III-R-criteria currently offer a good diagnostic standard for a specific diagnosis.…”

Section: Selection Of Patientsmentioning

confidence: 63%

“…In line with new European recommendations [1,2] on the selection of outcome measures, different levels of assessment should be con sidered. We suggest a global clinical evaluation (e.g.…”

Section: Trial Design and Target Variablesmentioning

confidence: 99%

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Recommendations for Clinical Drug Trials in Dementia

Zetzsche¹,

Baimbridge²,

Möhler³

et al. 1990

Dement Geriatr Cogn Disord

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“…In various attempts to develop recommendations or guidelines for the evaluation of this class of substances this fact is pretty well reflected [Amaducci et al, 1990: Clinical Research Working Group 1990Delini-Stula. 1990;CPMP Efficacy Working Party, unpubl.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Efficacy of Pyritinol in Patients with Senile Dementia of the Alzheimer Type (SDAT) and Multi-infarct Dementia (MID)

Fischhof

Saletu

Rüther³

et al. 1992

Neuropsychobiology

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This trial was performed to investigate the efficacy of pyritinol in the treatment of senile dementia. Initially, a total of 183 inpatients were screened for eligibility. Of 164 patients who met the inclusion criteria, 156 completed the trial. Allocation of the patients to the Senile Dementia of the Alzheimer Type group or the Multi-infarct Dementia group was based on the Hachinski Ischemic Score, computed tomography scans and electroencephalographic (EEG) findings. In a 12-week double-blind treatment phase either 200 mg pyritinol dihydrochloride-monohydrate or placebo was given 3 times daily. Confirmatory statistics included item 2 of the Clinical Global Impression, the total score of the Short Cognitive Performance Test (Syndrom Kurz Test) and the factor ‘cognitive disturbances’ of the Sandoz Clinical Assessment Geriatric scale. In addition, data on tolerance, of EEG brain mapping and of a responder analysis were evaluated based on descriptive statistics. The therapeutic efficacy of pyritinol was clearly demonstrated by confirmatory analysis as the drug was statistically significantly superior to placebo in all 3 target variables. The clinical relevance of the outcome was underlined by the analysis of the descriptive variables and by the convergence found at the different observation levels. The EEG mapping demonstrated significant differences between placebo and pyritinol, with the latter decreasing slow and increasing fast alpha and beta activity, which reflects improvement of vigilance. Based on the results of this trial, it can be accepted that the therapeutic effect of pyritinol is superior to placebo in patients with mild to moderate dementia of both degenerative and vascular etiology.

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Consensus Conference on the Methodology of Clinical Trials of "Nootropics", Munich, June 1989

Cited by 46 publications

References 0 publications

Inhibition of Acetylcholinesterase Activity in Human Brain Tissue and Erythrocytes by Galanthamine, Physostigmine and Tacrine

Inhibition of Acetylcholinesterase Activity in Human Brain Tissue and Erythrocytes by Galanthamine, Physostigmine and Tacrine

Recommendations for Clinical Drug Trials in Dementia

Therapeutic Efficacy of Pyritinol in Patients with Senile Dementia of the Alzheimer Type (SDAT) and Multi-infarct Dementia (MID)

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