Determination of blood acetylcholinesterase inhibition caused by reversible inhibitors in vivo

Smith, M.H.

doi:10.1016/0006-2944(74)90027-1

Cited by 8 publications

(9 citation statements)

References 5 publications

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“…Such methods are therefore rather inapplicable to in vivo experiments with reversible inhibitors of acetylcholinesterase as they would cause significant dissociation of the inhibited complex and hence reduce the measured inhibition below that actually occurring in vivo (O'Brien, 1967). The advantage of the radiometric assay used in these experiments has been discussed previously (Smith, 1974;Barber et al 1976) and the results obtained indicate both edrophonium and 3-OH PTMA to be far more effective in inhibiting this enzyme than was originally suggested.…”

Section: Discussionmentioning

confidence: 73%

The Relationship Between the Pharmacokinetics, Cholinesterase Inhibition and Facilitation of Twitch Tension of the Quaternary Ammonium Anticholinesterase Drugs, Neostigmine, Pyridostigmine, Edrophonium and 3‐hydroxyphenyltrimethylammonium

Barber

Calvey

Muir

1979

British J Pharmacology

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1 The relationship between the concentration of drug in plasma, the inhibition of erythrocyte acetylcholinesterase and the facilitation of neuromuscular transmission has been studied in the rat after the administration of neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethylammonium (3-OH PTMA). 2 After the administration of neostigmine or pyridostigmine, acetylcholinesterase activity recovered only slowly due to the covalent nature of the inhibition. In contrast, recovery from the reversible inhibition caused by edrophonium or 3-OH PTMA was rapid and showed a direct relationship to the plasma concentration of these drugs. 3 There was a statistically significant linear correlation between the logarithm of the plasma concentration of the drugs and the increase in the tibialis twitch tension. 4 The relationship between the inhibition of acetylcholinesterase and the facilitation of neuromuscular transmission was complex. When the enzyme was less than 85% inhibited no facilitation occurred.Between 85% and 98% inhibition, facilitation was linearly related to enzyme inhibition. Above 98% inhibition, facilitation was unrelated to inhibition of the enzyme.

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Section: Discussionmentioning

confidence: 73%

The Relationship Between the Pharmacokinetics, Cholinesterase Inhibition and Facilitation of Twitch Tension of the Quaternary Ammonium Anticholinesterase Drugs, Neostigmine, Pyridostigmine, Edrophonium and 3‐hydroxyphenyltrimethylammonium

Barber

Calvey

Muir

1979

British J Pharmacology

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“…Biochemistry Blood samples (10 ml) were withdrawn from an indwelling cannula and placed in heparinized bottles (Evans Medical Ltd) in order to determine the degree of acetylcholinesterase inhibition achieved in whole blood by the anticholinesterase drug. Enzyme activity was determined as described by Smith (1974) and the activity was expressed as percentage of control values. The blood samples were stored on dry ice until assayed, because previous animal experiments had shown that, in the case of neostigmine, blood samples recovered their acetylcholinesterase activity on standing at 40 C due to decarbamylation of the inhibited enzyme.…”

Section: Methodsmentioning

confidence: 99%

“…Enzyme activity was determined as described by Smith (1974) (b) Simultaneous measurements of gastrointestinal activity were made by one of us (G.B.G.) by auscultation of the abdomen.…”

Section: Biochemistrymentioning

confidence: 99%

Preliminary Assessment of Rx 72601, a New Anticholinesterase in Man: Reversal of Competitive Neuromuscular Blockade

Dettmar

Metcalf

Smith

et al. 1974

Brit J Clinical Pharma

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The effect of RX 72601, neostigmine plus atropine, or saline on neuromuscular blockade with (+)-tubocurarine was studied in a double blind trial in four healthy male volunteers. 2 The methods used to assess neuromuscular function were voluntary grip strength and indirectly evoked muscle twitches. The muscarinic action was assessed by measuring intestinal motility with a pressure sensitive radio pill, and auscultation of the abdomen. Blood pressure and pulse rate were also recorded. The degree of acetylcholinesterase inhibition achieved in whole blood was determined before and at intervals after the administration of the anticholinesterases. 3 Both RX 72601 (0.66-0.83 mg) and neostigmine (2.5 mg) completely reversed the neuromuscular blockade produced by tubocurarine, but the time course of reversal differed. RX 72601 (0.66-0.83 mg) produced similar inhibition of acetylcholinesterase in whole blood to neostigmine (2.5 mg). The doses of RX 72601 used caused minimal stimulation at muscarinic sites as evidenced by the limited effect on pulse rate and intestinal activity. 4 It was concluded that RX 72601 could be safely used to reverse the effects of neuromuscular blockade without the need for premedication with atropine.

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“…Unfortunately, many of the available methods used to determine cholinesterase activity (for instance, techniques involving dilution or significant concentrations of high affinity substrates) cannot be reliably applied to the assay of reversible enzyme inhibitors. Radiometric determinations of acetylcholinesterase activity (Smith, 1974) are less subject to these limitations, since they depend on the use of relatively small concentrations of lyophilized, low affinity substrate. These methods have been used in the present experiments; although some reversal of enzyme inhibition must occur on addition of the substrate, measurements of acetylcholinesterase activity should be closely related to the concentration of edrophonium in both in vivo and in vitro conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Blood (50 4) was added to freeze-dried [14C]-acetyl-p-methylcholine; after 1 min, the reaction was stopped by the addition of HCI (100 jI; 200mmollitre). [1-'4C]-acetic acid was extracted from the mixture as described by Smith (1974), and radioactivity was counted by liquid scintillation spectrometry.…”

Section: Measurement Of Acetylcholinesterase Activity In Blood Cellsmentioning

confidence: 99%

The Effect of Edrophonium on Erythrocyte Acetylcholinesterase and Neuromuscular Function in the Rat

Barber

Calvey

Muir

et al. 1976

British J Pharmacology

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I The relation between the concentration of edrophonium in plasma, inhibition of red cell acetylcholinesterase, and neuromuscular transmission was studied in the rat. 2 In both in vivo and in vitro conditions, red cell acetylcholinesterase activity was predictably related to the concentration of the quaternary amine.3 After low doses of edrophonium (1.0 gmol/kg) there was a significant correlation between the monophasic potentiation of twitch tension and the plasma concentration of the drug. In contrast, with higher doses of edrophonium (4.0 or 10.0 imol/kg) a biphasic potentiation of twitch tension was observed; this was only correlated with the plasma concentration of the drug during the secondary decline in neuromuscular facilitation. Subsequent recovery of normal neuromuscular transmission invariably occurred at a constant plasma concentration of edrophonium.

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Determination of blood acetylcholinesterase inhibition caused by reversible inhibitors in vivo

Cited by 8 publications

References 5 publications

The Relationship Between the Pharmacokinetics, Cholinesterase Inhibition and Facilitation of Twitch Tension of the Quaternary Ammonium Anticholinesterase Drugs, Neostigmine, Pyridostigmine, Edrophonium and 3‐hydroxyphenyltrimethylammonium

The Relationship Between the Pharmacokinetics, Cholinesterase Inhibition and Facilitation of Twitch Tension of the Quaternary Ammonium Anticholinesterase Drugs, Neostigmine, Pyridostigmine, Edrophonium and 3‐hydroxyphenyltrimethylammonium

Preliminary Assessment of Rx 72601, a New Anticholinesterase in Man: Reversal of Competitive Neuromuscular Blockade

The Effect of Edrophonium on Erythrocyte Acetylcholinesterase and Neuromuscular Function in the Rat

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