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PubMed1977

The use of serum cholinesterase in succinylcholine apnoea.

Fifteen patients demonstrating unexpected prolonged apnoea lasting several hours after succinylcholine have been treated by a new preparation of human serum cholinesterase. Adequate spontaneous respiration was re-established in an average period of ten minutes after the injection. In 12 patients biochemical genetic examinations confirmed the presence of an atypical serum cholinesterase. In three patients none of the usual variants were found. It is therefore supposed that other unknown variants of serum cholinesterase exist which cannot hydrolyze succinylcholine. The use of serum cholinesterase in succinylcholine apnoea provided considerable relief to both patient and anaesthetist.

Adolescent↗

PubMed2002

[Plasma cholinesterase variations as a result of prolonged neuromuscular blockade. Review and problems encountered in two cases of prolonged neuromuscular blockade after muscle relaxation with succinylcholine as compared to mivacurium].

Succinylcholine and mivacurium are degraded more slowly in patients with a qualitatively or quantitatively reduced plasma cholinesterase and are therefore known for inducing a prolonged postoperative apnea. Perioperative laboratory screening even including plasma cholinesterase activity testing will not prevent this due to a possible aberration only in the qualitative cholinesterase activity. This is illustrated by introducing two cases reports of prolonged apnea after administration of mivacurium or succinylcholine. The pathophysiology of plasma cholinesterase is reviewed including genetically determined variants and the degradation pathways of mivacurium and succinylcholine. Only extensive laboratory chemical tests are sufficient to prevent this possible complication. Due to the rare incidence there is no evidence for recommending these laboratory investigations in all patients. Once prolonged apnea occurs following the administration of mivacurium or succinylcholine the best choice is ongoing ventilation combined with a sufficient sedation.

Apnea↗

PubMed1980

Prenatal diagnosis of neural tube defects. V. The value of amniotic fluid cholinesterase studies.

Total cholinesterase activity in amniotic fluid obtained from 150 fetuses was measured. Elevated values were found in 94% of samples from fetuses known to have neural tube defects (spina bifida, anencephaly) when compared to nonbloody samples from normal fetuses. Contamination of amniotic fluid with blood was observed to elevate total cholinesterase activity in some, but not all, such specimens. Total cholinesterase activity did not vary with gestational age between 15 and 24 weeks. These data were compared to our large alpha-fetoprotein (AFP) assay experience used for the prenatal detection of neural tube defects. We concluded that the assay of total cholinesterase activity in amniotic fluid could be a useful adjunct to the AFP assay, especially in those samples contaminated with blood.

Amniotic Fluid↗

PubMed1983

A microfluorometric assay for cholinesterases, suitable for multiple kinetic determinations of picomoles of released thiocholine.

A highly sensitive microfluorometric assay for cholinesterases has been developed. Enzymatic activity is measured by monitoring the thiocholine produced by specific hydrolysis of acetylthiocholine. This is carried out by reacting the thiocholine formed with the fluorogenic compound N-(4(7 diethylamino-4-methylcoumarin-3-yl)phenyl)maleimide to yield an intensely fluorescent product. The assay is linear over a range extending from a few picomoles to nanomoles of thiocholine. The specificity and accuracy of this microfluorometric assay were examined using microgram quantities of rat brain tissue as a source for cholinesterases. The specific activities and the Km values determined by this new method for both cholinesterase activities present in the brain (acetylcholine hydrolase, EC 3.1.1.7, and "nonspecific" cholinesterase-acylcholine acylhydrolase, EC 3.1.1.8) were identical to those reported earlier using the less sensitive spectrophotometric and radiometric methods. The background emission caused by nonenzymatic hydrolysis of the substrate is relatively low, and does not exceed background values encountered in other methods. The assay may be used for monitoring the kinetics of enzymatic activities in microscale reaction mixtures, providing a linear determination of the thiocholine produced over a period of at least 30 h at room temperature. The method can also be adapted for use in other enzymatic assays where reagents containing thiol groups can be produced or consumed.

Acetylthiocholine↗

PubMed1980

Purification and characterization of anti-cholinesterase factor from the venom of Naja naja atra.

The anti-cholinesterase factor from Naja naja atra venom was purified by means of successive column chromatography on Sephadex G-75, carboxymethyl-cellulose and hydroxyapatite. The purified anti-cholinesterase factor was homogeneous by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The molecular weight was estimated to be approx. 50 000. The isoelectric point was determined to be 6.8. This factor was found to be the first cholinesterase inhibitor protein. We have called this anti-cholinesterase factor atramine.

Amino Acids↗

PubMed1987

Inhibition of human serum and rabbit muscle cholinesterase by local anesthetics.

The effects of tertiary amine local anesthetics (procaine, mepivacaine, lidocaine, tetracaine, dibucaine, and bupivacaine) and chlorpromazine were investigated for rabbit muscle acetylcholinesterase and human serum cholinesterase. The muscle enzyme was poorly inhibited by local anesthetics containing an amide linkage. The serum cholinesterase was inhibited by all those compounds, their relative potencies being proportional to their octanol/water partition coefficients. The dissociation constants of tetracaine and procaine, ester anesthetics, were 1000-fold and 100-fold, respectively, that which would be expected from their partition coefficient basis respective to the other amide anesthetics. Procaine showed competitive inhibition of serum cholinesterase, whereas for most anesthetics a mixed type of inhibition was observed. Procaine probably binds at the main anionic site, while the other positively charged anesthetics bind to either the catalytic centre or to the peripheral or modulator anionic site, modifying the kinetic behaviour of cholinesterase as has been demonstrated by the appearance of negative cooperativity for binding to the substrate.

Acetylcholinesterase↗

PubMedDate not supplied

Phosphonylation of purified human, canine and porcine cholinesterase by soman. Stereoselective aspects.

Cholinesterases (EC 3.1.1.8, acylcholine acylhydrolase) from the sera of man, dog and pig were purified 400-600-fold using a combination of ion-exchange and affinity chromatography. In a first approach, phosphonylation by soman was studied by using the half-resolved epimers C(+)P(+/-)-soman and C(-)P(+/-)-soman. The degradation of soman at the nanomolar level was followed in time by determining the remaining soman by capillary gas chromatography with NP detection. In the three sera investigated the P-(-)-epimer phosphonylates at a higher rate than its corresponding P(+)-counterpart and the stereoselectivity is greater for the C(+)-epimers than for the C(-)-epimers. Individual soman isomers were isolated from C(+)- and C(-)-epimers and quantified by gas chromatography. Second-order rate constants were determined for the phosphonylation of purified cholinesterase by isolated soman isomers. The C(+)P(-)-isomer has the highest phosphonylation rate for the three species; the other toxic isomer, C(-)P(-), has a five to ten-fold lower rate. The overall stereoselectivity is more marked in human cholinesterase than in canine. Porcine serum cholinesterase is phosphonylated by the P(-)-isomers at a slightly higher rate than the human enzyme.

Animals↗

PubMed1980

o-Toluoylcholine as substrate for measurement of serum pseudo-cholinesterase activity.

New synthetic substrates for serum pseudo-cholinesterase activity were compared with the common substrates for the routine assays, with regard to reactivity, specificity and stability; o- and m-toluoylcholine as well as o- and m-toluoyldimethylaminoethanol esters had selective specificities for pseudo-cholinesterase. The last three substrates, however, were unstable in solution at 4 degrees C. On the other hand, o-toluoylcholine could be stored in solution for several days with no appreciable degradation, and it was extremely stable with regard to pH and temperature. No or little hydrolysis of o-toluoylcholine was observed by various enzymes other than pseudo-cholinesterase. The enzymatic method using o-toluoylcholine as substrate was reproducible, and the results correlated well with those obtained using butylthiocholine as substrate and 5,5'-dithiobis-(2-nitrobenzoic acid) as color reagent. In conclusion, o-toluoylcholine is a favorable substrate for the determination of serum pseudo-cholinesterase activity.

Butyrylcholinesterase↗

PubMed1982

Gel electrophoresis of maternal and fetal serum cholinesterases from normal pregnancies and of those affected by neural tube defects.

The cholinesterase isozymes of maternal and fetal sera from normal pregnancies and those in which the fetus had a neural tube defect were studied using flat-bed vertical polyacrylamide gel electrophoresis. Normal maternal and fetal sera had multiple bands of cholinesterase activity, including the two bands in the position of those found in amniotic fluid from NTD pregnancies. The one difference between maternal and fetal sera was that the faster of these two "amniotic fluid bands" was acetylcholinesterase in fetal serum, as in the neural tube defect amniotic fluids, but non-specific cholinesterase in maternal serum. In artificial mixtures this difference could be used to differentiate between maternal and fetal blood-contamination of amniotic fluids, but in samples naturally contaminated at amniocentesis this test did not always agree with the Kleihauer findings. Both maternal and fetal sera had additional weak acetylcholinesterase activity in the most anodally migrating enzyme bands, but all other enzyme activity was non-specific cholinesterase. No difference was observed in the isozymes of fetal serum from normal fetuses and those with neural tube defects, or of maternal serum from normal and neural tube defect pregnancies.

Amniotic Fluid↗

PubMed1978

Effects of cholinesterase inhibitors on the spasmogenic action of acetate esters on rat uterus.

Acetate esters, such as phenyl acetate and aspirin, induced atropine-sensitive contractions of isolated uterus only when choline was present. These contractions were selectively and reversibly inhibited by carbamate-type cholinesterase inhibitors, such as neostigmine and eserine, and quaternary ammonium compounds, such as tetraethylammonium and decamethonium. After treatment with organophosphorus cholinesterase inhibitors, such as di-isopropyl fluorophosphate and tetraethyl pyrophosphate, the uterus failed to respond to the acetate esters, even when high concentrations of choline were present. The inhibition of the response of the uterus by organophosphates was effectively removed by pyridine-2-aldoxime methiodide. Pretreatment of the uterus with neostigmine or simultaneous addition of high concentrations of quaternary ammonium compounds prevented the inhibition by organophosphates. The inhibition produced by neostigmine was also reduced by simultaneous addition of quaternary ammonium compounds. These findings suggest that some esterase having an anionic site and an esteratic site, probably cholinesterase, may mediate in the uterine contractions induced by acetate esters in the presence of choline, and that inhibition by organophosphates, carbamates and quaternary ammonium compounds of cholinesterase activity in the preparation may impede the initiation of contractions by the acetate esters in the presence of choline.

Acetates↗

PubMed1993

Cholinesterase inhibitor effects on extracellular acetylcholine in rat striatum.

The effects of inhibition of cholinesterase on levels of extracellular acetylcholine in the striatum of freely moving rats, were investigated with a microdialysis technique. Acetylcholine could not be detected under basal conditions. However, local administration of the cholinesterase inhibitors neostigmine, physostigmine or heptyl-physostigmine through the dialysis probe elevated acetylcholine above the detection limit. Complex interactions between the effects of local and systemic cholinesterase inhibitors were observed. Whereas systemic administration of physostigmine or heptylphysostigmine alone increased the extracellular concentration of acetylcholine, they also caused acetylcholine to fall below baseline levels, which had been established by perfusing physostigmine through the microdialysis probe. These studies demonstrate the ability of local inhibition of cholinesterase to affect the observation of effects of systemically-administered drugs.

Acetylcholine↗

PubMed1993

The effects of novel cholinesterase inhibitors and selective muscarinic receptor agonists in tests of reference and working memory.

In recent years muscarinic receptor agonists and cholinesterase inhibitors have been developed for the treatment of Alzheimer's disease. We have evaluated examples from both classes of compounds in rodent tests of reference and working memory, as well as tests that are sensitive to the side-effects of these compounds. Thus, three selective muscarinic receptor partial agonists L-689,660, (M1/M3), AF102B (M1/M3) and L-687,306 (M1) and two cholinesterase inhibitors, E2020 and eptastigmine, were compared in a mouse tail-flick (TF) test, a rat response sensitivity (RS) test, in rat tests of reference memory, passive avoidance (PA) or conditioned suppression of drinking (CSD), and working memory (delayed-matching-to-position, DMTP). In the TF test, all of the compounds tested, with the exception of L-687,306, (1.0-30.0 mg/kg) dose-dependently induced antinociception of which L-689,660 was the most potent (minimum effective dose (MED) = 0.03 mg/kg). In the RS test, all of the compounds, but again with the exception of L-687,306, (1.0-30.0 mg/kg), dose-dependently reduced response rates, of which L-689,660 was again the most potent (MED = 0.1 mg/kg). In the reference memory test, all the compounds reversed the effects of a scopolamine-induced deficit with L-687,306 being the most potent (MED = 0.01 mg/kg). By contrast, in the DMTP test, although both the cholinesterase inhibitors and L-687,306 reversed the effects of scopolamine-induced deficit, L-689,660 and AF102B were without effects. These results suggest that cholinesterase inhibitors and low efficacy M1 selective muscarinic receptor agonists can reverse the effects of a scopolamine-induced deficit in animal tests of reference and working memory at doses that do not induce the side-effects usually associated with cholinomimetics.

Animals↗

PubMed1993

Structure-function relationship studies in human cholinesterases reveal genomic origins for individual variations in cholinergic drug responses.

1. Due to their involvement in the termination of neurotransmission at cholinergic synapses and neuromuscular junctions, cholinesterases are the target proteins for numerous drugs of neuro-psychopharmacology importance. 2. In order to perform structure-function relationship studies on human cholinesterases with respect to such drugs, a set of expression vectors was engineered, all of which include cloned cDNA inserts encoding various forms of human acetyl- and butyrylcholinesterase. These vectors were designed to be transcribed in vitro into their corresponding mRNA products which, when microinjected into Xenopus oocytes, are efficiently translated to yield their catalytically active enzymes, each with its distinct substrate specificity and sensitivity to selective inhibitors. 3. A fully automated microtiter plate assay for evaluating the inhibition of said enzymes by tested cholinergic drugs and/or poisons has been developed, in conjunction with computerized data analysis, which offers prediction of such inhibition data on the authentic human enzymes and their natural or mutagenized variants. 4. Thus, it was found that asp70-->gly substitution renders butyrylcholinesterase succinylcholine insensitive and resistant to oxime reactivation while ser 425-->Pro with gly70 gives rise to the "atypical" butyrylcholinesterase phenotype, abolishing dibucaine binding. 5. Furthermore, differences in cholinesterase affinities to physostigmine, ecothiophate and bambuterol were shown in these natural variants. 6. Definition of key residues important for drug interactions may initiate rational design of more specific cholinesterase inhibitors, with fewer side effects. This, in turn, offers therapeutic potential in the treatment of clinical syndromes such as Alzheimer's and Parkinson's disease, glaucoma and myasthenia gravis.

Animals↗

PubMed1975

Dietary fat alteration of plasma cholinesterase response to malathion.

This study revealed the influence of organophosphate pesticides on cholinesterase levels of male Sprague-Dawley rats. Subjects were fed fat-free, normal-fat, and high-fat test diets. Sub-acute doses of malathion were given subcutaneously and cholinesterase levels were determined. Malathion was chosen because it is the least toxic of the organophosphate cholinesterase-inhibiting pesticides. Stastical analysis of the data showed that malathion does inhibit blood cholinesterase to the greatest degree in normal-fat diet animals, with the least effect on high-fat groups and fat-free subjects fall in between the two groups.

Animals↗

PubMed1991

The binding of cholinesterase inhibitors tacrine (tetrahydroaminoacridine) and 7-methoxytacrine to muscarinic acetylcholine receptors in rat brain in the presence of eserine.

Cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-aminoacridine) is known to interfere with the binding of specific ligands to muscarinic receptors with unusually steep binding inhibition curves. We investigated whether the concentration dependence of the inhibition of binding is associated with the inhibitory effect of tacrine on the activity of cholinesterases, and compared the effect of tacrine with that of 7-methoxytacrine. Tacrine was found to inhibit the specific binding of [3H]quinuclidinyl benzilate (QNB) in rat brain cortex with IC50 values of 11 microM both in the absence and in the presence of 100 microM eserine, which had been added to ensure complete inhibition of cholinesterases at all concentrations of tacrine; in the cerebellum, the IC50 value was 10 microM in the absence and 14 microM in the presence of eserine; Hill slope factors (nH) were in the range of 1.55-1.79 and were not significantly affected by the presence of eserine. 7-Methoxytacrine inhibited the binding of [3H]QNB with an IC50 value of 2.3 microM in the cortex and of 2.6 microM in the cerebellum. The results indicate that the degree and the steep course of the inhibition of [3H]QNB binding to M1 and M2 muscarinic receptors by tacrine do not depend on its inhibitory effect on cholinesterases, and that 7-methoxytacrine is likely to interfere with the function of muscarinic receptors 4-5 times more strongly than tacrine.

Animals↗

PubMed1996

[Decrease in plasmatic cholinesterase activity in severe bacterial infections: comparison with the decrease observed in severe liver cirrhosis].

As the influence of sepsis on plasma cholinesterase activity is not clearly established, plasma cholinesterase activity was measured in 30 healthy surgical orthopaedic patients, 11 patients with severe postoperative infections and 18 patients with patent cirrhosis (Child-Pugh C). Plasma cholinesterase activities were significantly decreased (P < 0.001) in patients with postoperative infections (1,706 +/- 535 Ul.L-1) and in those with patent cirrhosis (1,318 +/- 538 Ul.L-1) in comparaison to healthy surgical patients (4,716 +/- 1,232 Ul.L-1). The decrease in patients with postoperative infections and in those with patent cirrhosis was similar. It remains to be assessed whether the activity of anaesthetic agents biotransformed by plasma cholinesterase is modified during severe infections.

Anesthetics↗

PubMedDate not supplied

Comparisons of the acute effects of cholinesterase inhibitors using a neurobehavioral screening battery in rats.

The clinical signs of intoxication produced by cholinesterase inhibitors, many of which are used as pesticides, are considered important information for regulatory purposes. We conducted acute studies of cholinesterase inhibitors to compare their effects as determined by a functional observational battery (FOB) and motor activity. The acute effects of two carbamates (carbaryl, aldicarb) and five organophosphates (OP) (chlorpyrifos, diazinon, parathion, fenthion, and diisopropyl fluorophosphate, or DFP) were evaluated on the day of dosing at the time of peak effect, at 1 and 3 days, and 1 week after dosing (oral gavage, in corn oil). A high dose was selected that produced clear cholinergic signs, and lower doses were chosen to produce a range of effects. Generally all cholinesterase inhibitors produced autonomic signs of cholinergic overstimulation (salivation, lacrimation, and miosis), hypothermia, mild tremors and mouth-smacking (chewing motions), lowered motor activity, decreased tail-pinch response, and altered neuromuscular function (gait changes and increased foot splay). The measures generally found to be most sensitive on the day of dosing were body temperature, motor activity, gait, and the presence of mouth-smacking and fine tremors. However, no single measure was the most sensitive across all compounds; for example, the lowest dose of fenthion decreased motor activity by 86% but did not alter the tail-pinch response, whereas the lowest dose of parathion did not lower activity but did decrease the tail-pinch response. For some measures, differences in the slopes of the dose-response curves were evident. Many effects were still observed at 24 h, but recovery was apparent for all compounds. Interestingly, residual effects at 72 h were obtained with the carbamates (carbaryl, aldicarb) as well as with the Op fenthion, but not with the other compounds. Thus, the overall clinical picture of toxicity was similar for these cholinesterase inhibitors, but compound-specific differences emerged in terms of the individual measures, dose-response, and time course.

Aldicarb↗

PubMed2006

Prognostic value of human erythrocyte acetyl cholinesterase in acute organophosphate poisoning.

Acute organophosphate poisoning (OPP) such as dichlorvos may be monitored by the measurement of the erythrocyte acetyl cholinesterase (EAChE) and the serum cholinesterase (SChE) activities. The aim of this study was to look at correlation between the severity of the OPP judged by certain parameters such as coma, hemodynamic disturbances, respiratory failure, and the decrease of cholinesterases enzymes including EAChE and SChE at admission. Cholinesterase activity was determined upon admission and then on days 3 and 15 in the morning. Clinical effects, EAChE, and SChE activities data were investigated in 42 patients with OPP aged of 29.6 +/- 11.8 years with acute cholinergic crisis in all cases. They were comatose in 29% of cases, presenting both hypotension or shock and hypoxemia in 17% of cases. Fifteen of them (36%) required mechanical ventilation. The mean EAChE activity at admission was 24.3 +/- 11.6 micromol/mL per hour at 37 degrees C; it was 1260 +/- 2204 IU/L for SChE. There were no correlations between the EAChE and the SChE activities. The EAChE was decreased only in comatose patients and those presenting hypotension, hypoxemia, and bradycardia with a cutoff of 23.5 micromol/mL per hour at 37 degrees C. Death was observed in 2 patients with a deep decrease of the EAChE at 5 micromol/mL per hour at 37 degrees C in 1 case and 9 micromol/mL per hour at 37 degrees C in another. The kinetics of improvement of the EAChE activity below the cutoff showed the absence of statistical improvement of the EAChE activity on day 3 (16.6 +/- 9 vs 19.5 +/- 5.7 micromol/mL per hour at 37 degrees C); this improvement was remarkable on day 15 (16.6 +/- 9 vs 27.5 +/- 6.5micromol/mL per hour at 37 degrees C, P = .0004). In summary, the marked decrease of EAChE activity appears in this study as prognostic factor in acute OPP, and coma, respiratory failure, hemodynamic disturbances, and death are associated with a decrease of the EAChE of less than 23.5 micromol/mL per hour at 37 degrees C.

Acetylcholinesterase↗