Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease*

Asthana, Sanjay; Greig, Nigel H.; Hegedũs, Lajos; Holloway, Harold W.; Raffaele, Kathleen C.; Schapiro, Mark B.; Soncrant, Timothy T.

doi:10.1016/0009-9236(95)90246-5

Cited by 58 publications

(32 citation statements)

References 42 publications

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“…In neuronal cultures, (-)-phenserine and posiphen are reported neuroprotective against glutamate excitotoxicity and oxidative stress and augment the survival of neural stem cells [29]. These actions appear to translate to animal studies, in which increased brain-derived neurotrophic factor (BDNF) levels [29] as well as elevated neurogenesis within the dentate gyrus, increased synaptogenesis and reduced inflammatory markers have been described [29], [79], [72]–[74].…”

Section: Discussionmentioning

confidence: 98%

(-)-Phenserine Attenuates Soman-Induced Neuropathology

Pan

Chen

et al. 2014

PLoS ONE

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Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.

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Section: Discussionmentioning

confidence: 98%

(-)-Phenserine Attenuates Soman-Induced Neuropathology

Pan

Chen

et al. 2014

PLoS ONE

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“…Physostigmine, a centrally active reversible cholinesterase inhibitor, and tacrine, a longer acting cholinesterase inhibitor, have been used in earlier stages of Alzheimer's disease to improve memory (Asthana et al, 1995;Gustafson et al, 1987). Results have been inconsistent, although some investigators have employed dosage schedules that appeared to cause transient improvement (Thal et al, 1983).…”

Section: Introductionmentioning

confidence: 97%

Effects of physostigmine on scopolamine-induced changes in quantitative electroencephalogram and cognitive performance

Ebert

Oertel

Wesnes³

et al. 1998

Hum. Psychopharmacol. Clin. Exp.

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The eects of physostigmine on scopolamine-induced changes were investigated in a randomized, double-blind crossover study utilizing quantitative electroencephalogram (qEEG) and cognitive tasks. Ten healthy male volunteers received scopolamine 0 . 6 mg subcutaneously. After 90 min, single doses of either 0 . 5, 1 . 0 and 2 . 0 mg physostigmine salicylate or placebo were administered subcutaneously in randomized order. qEEG, cognitive function and the visual analogue scale were recorded before and at 1, 2, 3, 4, 6, and 8 h after scopolamine administration; that was 0 . 5, 1 . 5, 2 . 5, 4 . 5, and 6 . 5 h after physostigmine administration. Scopolamine produced an increase in delta (1 . 25±4 . 50 Hz) and theta power (4 . 75±6 . 75 Hz) in qEEG 1 h after administration compared to baseline, while physostigmine decreased the spectral delta power density in qEEG compared to placebo. The maximal eect of physostigmine was seen up to 1 . 5 h after injection. A dose-dependent reversal of the scopolamine induced decrements in cognitive performance was found 0 . 5 h after administration of physostigmine. Psychometric tests sensitively discriminated between the doses of physostigmine, and showed dose-and time-dependent eects. The results suggest that physostigmine may reverse the scopolamine-induced changes in both qEEG and cognitive function. This reversal was temporary and of short duration. #

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“…Distinguishing changes caused by flow from those caused by enzyme activity in regions with higher AChE levels may be more problem atic because the net incorporation of e l C]PMP in the high-activity regions is partially flow limited. The phy sostigmine challenge study (subj ect group 3) demon strates that [ l l C]PMP does provide a sensitive index to AChE activity, since estimates were shown to drop 40% to 50% after a dose of the AChE inhibitor physostigmine selected to inhibit approximately 50% of the enzyme activity (Somani et aI., 1987;Asthana et a! ., 1995).…”

Section: Kinetic Analysis Of R II C]pmpmentioning

confidence: 99%

Kinetic Modeling of N-[¹¹C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain

Koeppe

Frey

Snyder

et al. 1999

J Cereb Blood Flow Metab

102

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Summary: N-[IIC]Methylpiperidin-4-yl propionate(C I ClPMP) is a substrate for hydrolysis by acetylcholinester ase (AChE) . This work evaluates kinetic analysis alternatives for estimation of relative AChE activity using dynamic positron emission tomography (PET) studies of rIIC]PMP. The PET studies were performed on three groups of subjects: (I) 12 normal volunteer subjects, aged 20 to 45 years, who received a single intravenbus injection of 16 to 32 mCi of C I ClPMP; (2) six subjects, aged 21 to 44 years, who received two 16-mCi injections of C IC]PMP (baseline and visual stimulation, re spectively); and (3) five subjects, aged 24 to 40 years, who received two 16-mCi injections separated by 200 minutes (baseline and after a I-hour constant infusion of 1.5 mg of physostigmine, respectively) . Dynamic acquisition consisted of a 17-frame sequence over 80 minutes. All analysis methods were based on a first-order kinetic model consisting of two tissue compartments with the parameter k3' representing PMP hydrolysis, being the index of AChE activity. Four different schemes were used to estimate k3: (1) an unconstrained non linear least-squares fit estimating blood-brain barrier transport Positron emission tomography (PET) offers the ability to quantify biochemical features in living humans through the use of radiolabeled tracers and the applica tion of tracer kinetics and compartmental analysis. This study evaluates kinetic analysis alternatives for charac- 1150parameters, K I and k2' in addition to the hydrolysis rate con stant k3; (2) and (3) , two methods of constraining the fit by fixing the volume of distribution of free tracer (DVfree); and (4), a direct estimation of k3 without use of an arterial input function based on the shape of the tissue time-activity curve alone. Results showed that k3 values from the unconstrained fitting and no input methods were estimated with similar ac curacy, whereas the two methods using DVfrce constraints yielded similar results. The authors conclude that the optimal analysis method for C iClPMP differs as a function of AChE activity. All four methods gave precise measures of k3 in re gions with low AChE activity (-10% coefficient of variation in cortex), but surprisingly, with unconstrained methods yielding estimates with lower variability than constrained methods. In regions with moderate to high AChE activity, constrained methods were required to yield meaningful estimates and were superior to the unconstrained methods. Key Words:N-C I Clmethylpiperidin-4-yl propionate-Tracer kinetics Acetylcholinesterase-Positron emission tomography.terizing the in vivo behavior of N-e l C]methylpiperidin-4-yl propionate (C l C]PMP) to yield quantitative esti mates of the model parameter k3 as an index of regional acetylcholinesterase (AChE) activity in the human brain. Acetylcholine, the acetic acid ester of choline, is a neu rotransmitter present in cholinergic synapses of the CNS. Acetylcholinesterase is an enzyme of the CNS (as well as muscles and red cells) that catalyzes the hydrolysis...

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Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease*

Cited by 58 publications

References 42 publications

(-)-Phenserine Attenuates Soman-Induced Neuropathology

(-)-Phenserine Attenuates Soman-Induced Neuropathology

Effects of physostigmine on scopolamine-induced changes in quantitative electroencephalogram and cognitive performance

Kinetic Modeling of N-[¹¹C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain

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Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease*

Cited by 58 publications

References 42 publications

(-)-Phenserine Attenuates Soman-Induced Neuropathology

(-)-Phenserine Attenuates Soman-Induced Neuropathology

Effects of physostigmine on scopolamine-induced changes in quantitative electroencephalogram and cognitive performance

Kinetic Modeling of N-[11C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain

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Kinetic Modeling of N-[¹¹C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain