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PubMedDate not supplied

Cholinesterase activity is similar in C3H/HeJ and A/J mice and does not account for their different bronchoconstrictor responsiveness.

Significant interstrain variation in airway responsiveness to acetylcholine (ACh) exists in inbred mouse strains. We hypothesized that part of the variation may be due to between-strain differences in cholinesterase activity. We asked if administration of neostigmine (an acetylcholinesterase inhibitor) and/or succinylcholine (an agent which competes for and inhibits butyrylcholinesterase) altered ACh responsiveness in hyporesponsive C3H/HeJ and hyperresponsive A/J mouse strains. Airway responses to ACh were measured by the airway pressure time index in the presence and absence of succinylcholine (10 mg/kg) and/or neostigmine (0.7 mg/kg). In addition, acetylcholinesterase and butyrylcholinesterase activity were directly measured. Acetylcholinesterase and butyrylcholinesterase inhibition increased airway responses to acetylcholine in both strains, but did not eliminate or decrease the differences in airway responsiveness to ACh previously seen in the two strains. Cholinesterase activities in the two strains were not significantly different. We conclude that differences in either acetylcholinesterase or butyrylcholinesterase in the A/J or C3H/HeJ mouse strains are unlikely to contribute to the differences in airway responsiveness to exogenously administered cholinergic agonists.

Acetylcholine↗
PubMed2004

Protective effect of equine butyrylcholinesterase in inhalation intoxication of rats with sarin: determination of blood and brain cholinesterase activities.

The effect of pretreatment with equine butyrylcholinesterase (EqBuChE) on cholinesterase inhibition in the blood and brain of rats following inhalation intoxication with low concentrations (1.25 microg/L for 60 min) of sarin were studied. Animals pretreated with different doses of equine butyrylcholinesterase showed significant increases in plasma butyrylcholinesterase activity. However, erythrocyte acetylcholinesterase activity was unchanged. The decrease in acetylcholinesterase and butyrylcholinesterase activity after inhalation intoxication was dependent on the dose of equine butyrylcholinesterase used for pretreatment and was always greater for erythrocyte acetylcholinesterase. Acetylcholinesterase activity in different brain regions was unchanged following pretreatment with equine butyrylcholinesterase. After inhalation exposure to sarin, acetylcholinesterase activity was diminished markedly in the pontomedullar area (51.5% of normal activity) and frontal cortex (72.0% of normal activity), and slightly in basal ganglia (91.4% of normal activity). Plasma levels of sarin were determined using fluoride-induced reactivation of inhibited enzyme. As expected, the amounts of sarin in plasma were almost identical in rats pretreated with EqBuChE as well as in untreated rats. In pretreated animals, the plasma amount of sarin did not depend on the dose of equine butyrylcholinesterase used for pretreatment. Our results demonstrate that equine butyrylcholinesterase pretreatment can be considered as an effective prophylaxis against nerve agents (at least with sarin) and seems to be an alternative or superior to prophylaxis provided by reversible cholinesterase inhibitors.

Administration, Inhalation↗
PubMed1989

Acute cholinesterase inhibitor poisoning mimicking pulmonary oedema.

In patients poisoned with a cholinesterase inhibitor, the diagnosis may initially be missed especially when no history is available from the patient or his relatives. The predominant respiratory symptoms may suggest pulmonary oedema as illustrated by the two case reports presented here. A high degree of suspicion and a careful clinical examination are necessary to make the correct diagnosis, which eventually can be confirmed by measurement of red cell and serum cholinesterase activity.

Aged↗
PubMed2004

The effects of fresh frozen plasma on cholinesterase levels and outcomes in patients with organophosphate poisoning.

OBJECTIVE: The aim of this study is to determine the effects of fresh frozen plasma, as a source of cholinesterase, on butyrylcholinesterase (BuChE; plasma or pseudo cholinesterase) levels and outcomes in patients with organophosphate poisoning. MATERIALS AND METHODS: This prospective study was performed at the Department of Intensive Care of Erciyes University Medical School. Over 2 yrs, patients admitted to the ICU for OP poisoning were entered into the study. OP poisoning was diagnosed on the basis of history and BuChE levels. All patients received atropine. Fresh frozen plasma was given to 12 patients. The study was approved by the Ethical Committee, and verbal informed consent was obtained. RESULTS: Thirty-three patients were included in the study. BuChE levels measured at admission and the pralidoxime and atropine doses administered were not different between groups (p>0.05). Although intermediate syndrome developed in 28.6% of patients receiving pralidoxime, there were no intermediate syndrome cases in patients receiving plasma prior to developing intermediate syndrome. The mortality rates were 14.3% in the pralidoxime group and 0% in the plasma+atropine+pralidoxime group. Two patients received plasma after developing the intermediate syndrome, and one patient who received only atropine died. BuChE levels of fresh frozen plasma were 4069.5 +/- 565.1 IU/L. Every two bags of plasma provided an increase in BuChE levels of approximately 461.7 +/- 142.1 IU/L. CONCLUSION: Fresh frozen plasma therapy increases BuChE levels in patients with organophosphate poisonings. The administration of plasma may also prevent the development of intermediate syndrome and related mortality. Plasma (fresh frozen or freshly prepared) therapy may be used as an alternative or adjunctive treatment method in patients with organophosphate pesticide poisoning, especially in cases not given pralidoxime. Further randomized controlled and animal studies are required to infer a definitive result.

Atropine↗
PubMed1998

Pharmacology and clinical efficacy of cholinesterase inhibitors.

The pharmacology and clinical efficacy of cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) are discussed. ChEIs can be classified pharmacologically on the basis of the duration of cholinesterase inhibition. The duration of inhibition is short for tacrine and donepezil, intermediate for rivastigmine, and long for metrifonate. Pharmacokinetic differences also distinguish ChEIs. The two instruments that are most accepted for use in evaluating the efficacy of drugs for AD are the Alzheimer's Disease Assessment Scale-Cognitive Portion (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus). In clinical trials, all ChEIs have produced improvements in the cognitive deficits seen in patients with AD, and some have also improved behavioral problems and increased patients' ability to perform activities of daily living. Only donepezil and metrifonate are administered once daily. Except for metrifonate, the dosage of each drug should be adjusted upward over several weeks to minimize adverse effects. Hepatotoxicity, the most important adverse effect of tacrine, has not been observed with other ChEIs. Tacrine and donepezil have the potential to interact with other drugs that depend on the same metabolic pathways. Although ChEIs generally improve cognition in patients with AD, differences among these medications are substantial in some cases and should be thoroughly considered by clinicians.

Alzheimer Disease↗
PubMed1977

Suxamethonium-neostigmine interaction in patients with normal or atypical cholinesterase.

The effect of neostigmine 0.05 mg/kg on the neuromuscular block produced by suxamethonium was investigated in 10 normal patients and in five patients with atypical plasma cholinesterase activity, by recording the twitch response to ulnar nerve stimulation. In the normal patients, neostigmine potentiated the block produced by suxamethonium whether it was of the depolarizing or desensitizing type. On the other hand, in patients with atypical plasma cholinesterase activity, neostigmine potentiated the depolarizing phase of suxamethonium block, while antagonizing the desensitizing phase. The degree of antagonism was not related to the magnitude of neuromuscular block, but was proportional to the degree of desensitization at the time of antagonism.

Adult↗
PubMed1983

Postoperative ileus, pregnancy-related cholinesterase deficiency and suxamethonium after-pains. A case report.

An account is presented of a patient who developed ileus, of greater or lesser severity, after each of seven operations (including two extra-abdominal and three Caesarean sections). During her most recent pregnancy, reviewed here, her plasma cholinesterase activity was found to be decreased and it remained low until at least the 6th day post-partum. However, as the normal activity had been gained by 6 weeks after delivery, the phenomenon had evidently been pregnancy-related. Despite receiving suxamethonium by infusion to completion of her Caesarean section, she did not show an abnormally prolonged response, although she did suffer considerable suxamethonium "after-pains". The question is posed of a possible relationship between the postoperative ileus, muscle pains and the decrease in cholinesterase activity.

Adult↗
PubMed1987

Phenotyping of individuals sensitive to suxamethonium. The Cholinesterase Research Unit at the Royal Postgraduate Medical School.

Four hundred and thirty blood samples from suxamethonium-sensitive individuals have been phenotyped by the Cholinesterase Research Unit following its transfer from Exeter to the Hammersmith Hospital. The distribution of genotypes has been shown to be similar to that found in Exeter. Screening for the Elk and Elj genes has not yielded any major differences in the gene frequencies of sensitive individuals, even during pregnancy. The uneven sex distribution of the patients, as well as other unusual points that have arisen, are discussed. A new gene for the biosynthesis of cholinesterase has probably been identified.

Cholinesterases↗
PubMed1994

Cholinesterase inhibitors do not prolong neuromuscular block produced by mivacurium.

Cholinesterase inhibitors antagonize neuromuscular block produced by mivacurium, but some may also decrease its metabolism by inhibiting pseudocholinesterase. These opposing interactions were examined in rats anaesthetized with pentobarbitone. After spontaneous recovery from an initial bolus dose of 0.03 mg kg-1, mivacurium was infused to produce 80-90% block of gastrocnemius muscle twitch. After 15 min, the infusion was discontinued and saline, edrophonium, pyridostigmine or neostigmine was administered. Fifteen minutes later, a second bolus dose of mivacurium was given. Edrophonium, pyridostigmine and neostigmine reduced the subsequent maximum block, compared with the change in saline control, by 3%, 19% and 35%, respectively. Correspondingly, the time to recovery of T1 to 50% was decreased by 20%, 58% and 62%. In rats, acetylcholinesterase-mediated antagonism of neuromuscular block predominated over decreased pseudocholinesterase-mediated metabolism, such that prior administration of a cholinesterase inhibitor did not prolong the neuromuscular blocking effects of mivacurium.

Animals↗
PubMed1997

The alpha/beta fold family of proteins database and the cholinesterase gene server ESTHER.

ESTHER (for esterases, alpha/betahydrolase enzyme and relatives) is a database of sequences phylogenetically related to cholinesterases. These sequences define a homogeneous group of enzymes (carboxylesterases, lipases and hormone-sensitive lipases) sharing a similar structure of a central beta-sheet surrounded by alpha-helices. Among these proteins a wide range of functions can be found (hydrolases, adhesion molecules, hormone precursors). The purpose of ESTHER is to help comparison of structures and functions of members of the family. Since the last release, new features have been added to the server. A BLAST comparison tool allows sequence homology searches within the database sequences. New sections are available: kinetics and inhibitors of cholinesterases, fasciculin-acetylcholinesterase interaction and a gene structure review. The mutation analysis compilation has been improved with three-dimensional images. A mailing list has been created.

Amino Acid Sequence↗
PubMed1999

Gestational exposure to chlorpyrifos: dose response profiles for cholinesterase and carboxylesterase activity.

This study investigates the in vivo dose response profiles of the target enzyme cholinesterase (ChE) and the detoxifying enzymes carboxylesterase (CaE) in the fetal and maternal compartments of pregnant rats dosed with chlorpyrifos [(O,O'-diethyl O-3,5,6-trichloro-2-pyridyl) phosphorothionate], a commonly used organophosphorus insecticide. Pregnant rats were dosed daily (po) with chlorpyrifos in corn oil (0, 3, 5, 7, or 10 mg/kg) on gestational days (GD) 14-18. Animals were sacrificed 5 h after the last chlorpyrifos dose (time of maximum brain cholinesterase inhibition) for analysis of ChE and CaE activity in maternal blood, liver, brain, placenta, and fetal liver and brain. The in vitro sensitivity (i.e., IC50, 30 min, 26 degrees C) of CaE also was determined by assaying the activity remaining after incubation with a range of chlorpyrifos-oxon concentrations. In vivo exposure to 10 mg/kg chlorpyrifos from GD14-18 caused overt maternal toxicity, with dose-related decreases in ChE activity more notable in maternal brain than fetal brain. Dose-related effects were also seen with chlorpyrifos-induced inhibition of fetal liver ChE and maternal brain CaE activities. Gestational exposure caused no inhibition of placental ChE or CaE, fetal brain CaE, or maternal blood CaE. ChE activities in the maternal blood and liver, as well as fetal and maternal liver CaE, however, were maximally inhibited by even the lowest dosage of chlorpyrifos. The in vitro sensitivity profiles of CaE to chlorpyrifos-oxon inhibition were valuable in predicting and verifying the in vivo CaE response profiles. Both the in vivo and in vitro findings indicated that fetal liver CaE inhibition was an extremely sensitive indicator of fetal chlorpyrifos exposure.

Analysis of Variance↗
PubMed1995

Intrathecal acetyl cholinesterase inhibitors produce analgesia that is synergistic with morphine and clonidine in rats.

Intrathecal (IT) administration of acetyl cholinesterase inhibitors produces analgesia through a muscarinic action. The addition of IT cholinergic agonists to IT opioids or alpha 2-adrenergic agonists results in enhanced analgesic effects, but it is not clear whether these interactions are synergistic, additive, or less than additive. Dose-response curves for hot plate and tail immersion tests were established for IT neostigmine, physostigmine, and echothiophate in rats. Dose-response curves for hot plate testing were established for IT morphine and clonidine. The effect of maximally effective doses of each of the three cholinergic drugs on hot plate testing was plotted over time. Isobolographic analysis was performed for hot plate testing using neostigmine-morphine and neostigmine-clonidine combinations. The three cholinesterase inhibitors produced profound analgesia on hot plate testing but incomplete analgesia using the tail immersion test. Duration of analgesia on hot plate testing ranged from 45 min for physostigmine to more than 24 h for echothiophate. IT administration of combinations of neostigmine plus morphine and neostigmine plus clonidine both produced significantly more profound analgesia than the calculated additive effects and are, therefore, synergistic in their actions.

Analgesia↗
PubMed1995

Cholinesterase inhibitors increase secretion of APPs in rat brain cortex.

We examined whether cholinesterase inhibitors (ChEI) could alter the release of amyloid precursor protein (APP) from superfused brain cortical slices of the rat. Three ChEI, both reversible and irreversible, were tested for their ability to enhance the release of nonamyloidogenic soluble derivatives (APPs). These included: physostigmine (PHY), heptyl-physostigmine (HEP) and 2,2-dichloro-vinyldimethyl phosphate (DDVP), at concentrations producing cholinesterase (ChE) inhibition ranging from 5% to 95%. All three ChEI elevated APPs release significantly above control levels. Electrical field stimulation significantly increased the release of APPs within 50 min. Similar increase was observed after muscarinic receptor stimulation with bethanechol (BETHA). Tetrodotoxin (TTX) completely blocked the effect of electrical stimulation. These findings suggest that administration of ChEI to Alzheimer's disease (AD) patients may have a neuroprotective effect by activating normal APP processing.

Amyloid beta-Protein Precursor↗
PubMed1996

An indirect cholinesterase inhibitor, metrifonate, increases neocortical EEG arousal in rats.

We investigated the ability of a cholinesterase inhibitor, metrifonate, to desynchronize cortical EEG activity. Metrifonate suppressed immobility-related high voltage spindling activity in young and aged rats at doses of 30 and 60 mg kg-1, p.o., and 10, 30 and 60 mg kg-1, p.o., respectively. The increase in EEG 1-20 Hz amplitude induced by scopolamine (0.2 mg kg-1, i.p.) was fully alleviated by metrifonate (30 and 100 mg kg-1, p.o.) and partially alleviated by a reference cholinesterase inhibitor, THA (3 and 6 mg kg-1, i.p.). Nucleus basalis (NB) lesions induced by quisqualic acid decreased frontal cortical choline acetyltransferase activity by 80% and increased cortical EEG slow waves. Metrifonate and THA did not reverse NB lesion-induced EEG abnormality. We conclude that metrifonate enhances cholinergic desynchronization of cortical EEG waves and that a severe defect of presynaptic NB cholinergic fibres limits the therapeutic effects of metrifonate.

Animals↗
PubMed1998

CSF cholinesterase activity in demented and non-demented subjects.

Samples of cerebrospinal fluid (CSF) were examined, looking mainly at total cholinesterase (ChE) and acetyl-cholinesterase (AChE) levels from 139 living subjects. At the completion of the study, 35 of the 139 patients had died and pathological confirmation of the presence of dementia had been obtained. These results, together with results from other laboratories, provide evidence that a low CSF ChE level presenting in demented patients may indicate a depletion of the brain AChE system, and this may confirm a clinical diagnosis of AD as well as other types of dementia which are associated with an alteration of the brain AChE system. The overlap in the levels of CSF biochemical markers between demented and non-demented subjects which has led to many conflicting reports has always disappointed investigators. It is suggested that some 'control' subjects with CSF ChE activity indistinguishable from that in AD patients may have an abnormal ageing process in their brains (brain at risk), although the symptoms of dementia have not yet been detected. Recognition of a pre-clinical or incubation period is very beneficial for explaining discrepancies in biochemistry and pathology in the literature, and must be considered for both the treatment and the prevention of dementia. The long used treatment, which was designed to inhibit AChE, should no longer be used: treatment must be designed to enhance the activity of the neuronal AChE system, or slow its degeneration.

Acetylcholinesterase↗
PubMed1999

Beta-amyloid levels predict cholinesterase activity in human cerebrospinal fluid.

There is increasing evidence suggesting that beta-amyloid (Abeta) has a direct influence on cholinergic activity. In particular, Abeta has been shown to induce the expression of acetylcholinesterase in the brains of CT-100-expressing transgenic mice and in cell culture experiments. These data indicate a link exists between Abeta production and acetylcholinesterase expression in the human CNS. To test this hypothesis, Abeta levels and cholinesterase activity were measured in 110 human CSF samples. Abeta levels were found to have a significant and positive correlation with cholinesterase activity. This correlation was particularly strong in individuals > 50 years of age. These data support the hypothesis that Abeta can effect cholinergic activity and that this effect may be enhanced in the elderly.

Adolescent↗
PubMed2005

Empirical evidence of neuroprotection by dual cholinesterase inhibition in Alzheimer's disease.

Brain grey matter density changes were quantified using voxel based morphometry in 26 patients with minimal to mild Alzheimer's disease (AD) treated with three cholinesterase inhibitors over 20 weeks. Patients whose drug treatment also inhibited butyrylcholinesterase did not show the widespread cortical atrophic changes in parietotemporal regions invariably reported in untreated AD patients, and which were detectable in the subgroups treated with selective acetylcholinesterase inhibition. This finding is the first empirical evidence that dual cholinesterase inhibition may have neuroprotective potential in AD.

Aged↗