Acute and chronic effects of oral physostigmine and lecithin in Alzheimer's disease

Thal, Leon J.; Masur, David; Sharpless, Nansie S.; Fuld, Paula Altman; Davies, Peter

doi:10.1016/0278-5846(86)90032-1

Cited by 61 publications

(23 citation statements)

References 22 publications

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“…There are minor differences between the two reports, i. e. they found tacrine to be 1.5 times more and physostigmine 2 times less potent than we did. Both cholinesterase inhibitors have been widely used in vivo, but relatively few studies have reported plasma/serum concentrations of physostigmine (15)(16)(17) or tacrine (18)(19)(20). The doses were increased until adverse peripheral effects in the majority of the respective patients or volunteers indicated the upper tolerance level.…”

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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“…Second, intravenous administration is impractical as a meaningful long-term treatment of memory loss in MS. Future trials may wish to evaluate the effectiveness of oral cholinesterase inhibitors. Oral physostigmine has been studied extensively in patients with SDAT (26)(27)(28)(29)(30)(31)(32)(33) and amnesic patients (34,35). Third, it is unclear from this study if the positive effects observed on the SRT can be extrapolated to the memory demands of everyday living.…”

Section: Discussionmentioning

confidence: 90%

Effects of Intravenous Physostigmine and Lecithin on Memory Loss in Multiple Sclerosis: Report of a Pilot Study

Leo

Rao

1988

Neurorehabilitation and Neural Repair

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This paper reports the results of a pilot study designed to assess the efficacy of intravenous physostigmine and dietary lecithin for treating memory loss in patients with multiple sclerosis (MS). Four patients with definite MS participated in a twophase (dose-finding and crossover), double-blind clinical trial. In the dose-finding phase, all patients exhibited an improvement in verbal memory (as assessed by the Selective Reminding Test) at the highest of four doses (1.0 mg). In the double-blind, crossover phase, patients were administered placebo or physostigmine (1.0 mg). A significant improvement in verbal memory was observed in three of four patients during the drug condition. None of the patients reported significant medication side effects. This study provides preliminary evidence that cholinergic pharmacotherapy may be useful in treating memory disturbance in MS. Key Words: Multiple sclerosis—Memory loss—Physostigmine—Lecithin.In his 1877 description of patients with multiple sclerosis (MS), Charcot (1) listed &dquo;enfeeblement of memory&dquo; as a cardinal feature of the disease. This astute clinical observation was virtually ignored until the past decade, when controlled neuropsychological investigations of memory began to appear in the scientific literature. These neuropsychological investigations have consistently shown that learning and memory functions are impaired in at least 50% of patients with MS (for reviews of the literature, see references 2 and 3). In a previous study, we (4) demonstrated a relationship between the degree of ventricular dilatation on computed tomography (CT) and severity of memory loss in patients with chronic progressive MS, suggesting that memory loss appears to be directly related to the degree of cerebral disease involvement. Although memory loss in MS is now well studied, attempts to treat this symptom have not appeared in the literature.Pharmacological studies during the past three decades have increasingly supported the hypothesis that cholinergic neurons are involved in memory and learning processes (5,6). Interference with cholinergic transmission by scopolamine, a cholinergic blocking agent capable of crossing the blood-brain barrier, results in marked impairment in the normal human's ability to acquire information into long-term storage (7-10). This effect is minimized if physostigmine, a cholinesterase inhibitor, is administered simultaneously (5,8). Scopolamine does not appear to affect attention/vigilance (9,10) or short-term memory functions (i.e., span memory) (7, 11), arguing against a more diffuse sedative effect. Furthermore, if scopolamine is administered with amphetamine, a stimulant, no improvement is observed in long-term memory functions (5). These findings suggest that interference with the normal cholinergic system can interfere with long-term memory.Recent attention has focused on the role of neurotransmitter disruption as an explanation for the memory and cognitive deficits of carious brain-damaged

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“…Physostigmine has been studied in AD (Jotkowitz, 1983;Thal et al, 1983Thal et al, , 1986Thal et al, , 1989Wettstein, 1983;Levin and Peters, 1984;Mohs et al, 1985a,b;Beller, Overall and Swann, 1985;Mayeux, 1987, 1988;Becker et al, 1988;Beller et al, 1988;Harrell et al, 1990;Jenike, Albert and Baer, 1990). It has a minor positive but highly variable effect and a low therapeutic ratio with a short duration of action.…”

Section: Acetylcholinesterase Inhibitionmentioning

confidence: 96%

The treatment of Alzheimer's disease

Allen

Burns

1995

J Psychopharmacol

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Acute and chronic effects of oral physostigmine and lecithin in Alzheimer's disease

Cited by 61 publications

References 22 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

Effects of Intravenous Physostigmine and Lecithin on Memory Loss in Multiple Sclerosis: Report of a Pilot Study

The treatment of Alzheimer's disease

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