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At least 91 records · Page 5Linked to original sources
PubMed1992

Ambenonium is a rapidly reversible noncovalent inhibitor of acetylcholinesterase, with one of the highest known affinities.

Steady state patterns of inhibition of purified human erythrocyte acetylcholinesterase by three inhibitors were analyzed. Edrophonium acted essentially as a competitive inhibitor, whereas tacrine and ambenonium gave mixed competitive and uncompetitive inhibition with acetylthiocholine as substrate. Inhibition constants for the competitive components were 470 microM for edrophonium, 65 microM for tacrine, and 0.12 nM for ambenonium. The extremely high affinity of ambenonium permitted analysis of the rates of approach to steady state inhibition. These rates were characterized by a single exponential time course with rate constants, kexp, that showed a linear dependence when plotted against ambenonium concentration, at fixed substrate concentration. The intercepts of these plots were independent of the substrate concentration and indicated an ambenonium dissociation rate constant of 0.013 +/- 0.002 sec-1. The slope of the plot at the lowest substrate concentration approximated the ambenonium bimolecular or association rate constant and gave a value of 5.2 +/- 0.6 x 10(7) M-1 sec-1. Three models were examined to account for the nearly linear dependence of the slopes of these plots on the substrate concentration. These models indicated that ambenonium and acetylthiocholine competed for a peripheral anionic site in the acetyl-enzyme intermediate formed during substrate hydrolysis. The apparent equilibrium dissociation constant of acetylthiocholine for this peripheral site (1.2-1.4 mM) was significantly different from that calculated from substrate inhibition data (20.1 +/- 2.8 mM). We propose that acetylthiocholine can interact with the acetyl-enzyme both at the peripheral site and at the active site but that only the latter interaction inhibits substrate hydrolysis.

Acetylcholinesterase↗
PubMedDate not supplied

[The effect of pH and reversible inhibitors on decarbamylation of acetylcholinesterase].

Decarbamylation rate of membrane-bound methyl- and dimethyl-carbamylated acetylcholinesterase of human erythrocytes and bovine brain is reliably 1.1-1.6 times lower than that of the soluble enzyme. Such reversible inhibitors as tacrine (of non-competition action), ambenonium (mixed action) and galanthamine (competitive type of action) decelerate the decarbamylation rate of acetylcholinesterase. At pH 6 tacrine inhibits the reduction rate of soluble acetylcholinesterase activity of human erythrocytes more intensively than that of membrane-bound acetylcholinesterase. No differences in decarbamylation rate were found for the both forms of the enzyme at pH 8. Tacrine, a non-competitive inhibitor in concentrations below the inhibition constant (Ki = 1.4 x 10(-7) M) exerts the most intensive effect on the decarbamylation rate of methyl- and dimethylcarbamylated acetylcholinesterase of the mouse brain, while ambenonium and galanthamine in concentrations much (tens times) exceeding their Ki (3.1 x 10(-10) M and 4.4 x 10(-7) M, respectively) provide a decrease of the decarbamylation rate.

Acetylcholine↗
PubMed1985

Self-cancellation of drug properties as a mode of organ selectivity: the antimuscarinic effects of ambenonium.

Ambenonium is known to be an inhibitor of acetylcholinesterase, and recent data have shown this drug to antagonize muscarinic receptors as well. This latter property was confirmed by Schild analyses of ambenonium-induced blockade of responses to bethanechol in guinea-pig ileal longitudinal smooth muscle, taenia caeci, trachea and rat anococcygeus muscle. Statistical analysis showed ambenonium to be a simple competitive antagonist of responses to bethanechol in these tissues with pKB values in each tissue not significantly different from each other (mean pKB = 6.0). However, considerable variability in pKB estimates was encountered when ambenonium was utilized to block responses to acetylcholine. Ambenonium was a less potent antagonist of tissue responses to acetylcholine, and the underestimation in the pKB (as compared to that obtained with bethanechol) could be eliminated by prior treatment of tissues with the acetylcholinesterase inhibitor neostigmine. These data suggested that ambenonium had a dual effect on tissue responses to acetylcholine-producing potentiation by blockade of acetylcholinesterase and concomitant antagonism by blockade of muscarinic receptors. The Schild regressions obtained for ambenonium antagonism of acetylcholine responses formally satisfied criteria for simple competitive antagonism of a homogenous population of receptors (linear regression, slope equal to unity). The fact that these regressions yielded erroneous apparent pKB values suggests how two properties of a drug in one molecule could provide misleading information about drug receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

[Cholinergic crisis in a patient with myasthenia treated by plasma exchange and anticholinesterase agents].

A patient with myasthenia receiving treatment with anticholinesterase agents and plasma exchanges for an acute episode, developed three successive periods of neurological deterioration during which plasma cholinesterase levels were determined. The risk of onset of a cholinergic crisis under these circumstances has been reported in the literature but not documented. The accidents in the present case were related to cumulative overdose effects of anticholinesterase agents and depletion of cholinesterase, suggesting caution in the use of anticholinesterase agents when frequent plasma exchanges are being carried out in a patient with myasthenia.

Ambenonium Chloride↗
PubMed1973

Thymoma, myasthenia gravis, erythroblastopenic anemia and systemic lupus erythematosus in one patient.

A 50-year-old woman who initially had myasthenia gravis subsequently presented with thymoma, erythroblastopenic anemia and systemic lupus erythematosus during 17 years of follow-up. In a review of the literature no similar documented cases were found, although 14 patients were reported with three of the above diseases, two also having positive LE cell tests. An association of several autoimmune disorders in one patient may be more frequent than was previously believed.

Ambenonium Chloride↗