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PubMed1998

Cholinesterases in cardiac ganglia and modulation of canine intrinsic cardiac neuronal activity.

Cholinergic neurotransmission plays a significant role in intrinsic cardiac ganglia with the action of acetylcholine being terminated by acetylcholinesterase (AChE, EC 3.1.1.7). Anatomical studies were performed to characterize neurons associated with AChE and a closely related enzyme, butyrylcholinesterase (BuChE, EC 3.1.1.8), in canine intrinsic cardiac ganglia. Histochemical staining for AChE and BuChE in canine right atrial neurons showed that there were four neuronal populations, namely, those that contained AChE only, BuChE only, both AChE and BuChE, and those that did not contain either enzymes. The neuronal activity of intrinsic cardiac neurons in response to substrates and inhibitors of cholinesterases were studied in anesthetized dogs. The activity of intrinsic cardiac neurons, as measured by changes in the number of action potentials, increased by local application of acetylcholine. However, local application of butyrylcholine led to a considerably greater increase in the activity of intrinsic cardiac neurons. In keeping with the neurochemical heterogeneity in intrinsic cardiac ganglia with respect to cholinesterases, the activity generated by most butyrylcholine-sensitive neurons was not influenced by acetylcholine and the activity generated by the most acetylcholine-sensitive neurons was not influenced by butyrylcholine. This suggests that these two agents preferentially influence different populations of intrinsic cardiac neurons. Enzyme kinetic studies demonstrated that canine AChE preferentially catalyzed the hydrolysis of acetylcholine while canine BuChE preferentially catalyzed the hydrolysis of butyrylcholine. Cholinesterase inhibitors Ro 2-1250 and Ro 2-0638 inhibited both canine cholinesterases, while huperzine A preferentially inhibited canine AChE and ethopropazine inhibited canine BuChE. The activity of neurons in the intrinsic cardiac ganglia significantly increased when Ro 2-1250 or Ro 2-0638 was administered locally. The activity of neurons was not affected when huperzine A or ethopropazine was administered, indicating that both cholinesterases must be inhibited to increase neuronal activity. In summary, these data show that in addition to AChE, intrinsic cardiac ganglia also contain distinct populations of neurons that are associated with BuChE, and the activity generated by these neurons is differentially influenced by their substrates. Because simultaneous inhibition of AChE and BuChE leads to increased neuronal activity, it is concluded that AChE- and BuChE-positive intrinsic cardiac neurons may act synergistically to influence the overall tonic activity of intrinsic cardiac ganglia.

Acetylcholine↗
PubMed2002

Successful treatment of behavioural problems in dementia using a cholinesterase inhibitor: the ethical questions.

OBJECTIVE: To review the effect of cholinesterase inhibitors on the behavioural and neuropsychiatric symptoms of dementia and discuss the current clinical guidelines for the prescription of cholinesterase inhibitors in Australia. METHOD: This paper reports the case of a patient with clinical diagnosis of dementia with lewy bodies (DLB) who was referred to an old age psychiatry service for the treatment of severe visual hallucinations and behavioural problems. RESULTS: Pharmacological treatment with olanzapine produced marked parkinsonism, agitation and confusion. A cholinesterase inhibitor, donepezil, was introduced. The introduction of donepezil was associated with cognitive improvement (mini-mental state examination [MMSE] increased from 23 to 27) and complete remission of behavioural symptoms. CONCLUSION: That cholinesterase inhibitors may have a role in the management of behavioural symptoms of dementia and the current Australian PBS guidelines for prescribing cholinesterase inhibitors are clinically restrictive. This has clinical and ethical implications that need to be addressed by consumers, the medical community and regulating authorities.

Aged↗
PubMed1996

[Therapy of myasthenia gravis with cholinesterase inhibitors--principles and pharmacologic monitoring].

Cholinesterase inhibitors are still important in the treatment of myasthenic patients. Therapeutic principles, indications and adverse effects are discussed in detail. Methods of pharmacological monitoring had been searched over many years. Besides determination of pyridostigmine plasma concentration, erythrocyte-bound acetylcholinesterase (AChE) activity could provide a possibility to monitor therapy with cholinesterase inhibitors. 88 patients with myasthenia gravis were investigated. The results demonstrated that after pyridostigmine erythrocyte-bound as well as synaptic AChE is inhibited. Moreover, erythrocyte-bound AChE has proven to be a parameter of cholinesterase inhibitor effect. After injection of edrophonium-chloride (Tensilon) inhibition of AChE activity can be demonstrated as well. During steady pyridostigmine doses stable plasma concentrations and AChE inhibition depend on the respective dosage. Higher daily doses result in greater stability of pharmacologic parameters, whereas low daily doses lead to great interindividual differences of AChE inhibition even after equal pyridostigmine doses. Intraindividually there is no strong correlation, too. Therefore estimation of erythrocyte-bound AChE activity is not useful for routine pharmacological monitoring of cholinesterase inhibitor therapy, but may be helpful in some clinical conditions. The method provides some advantages over pyridostigmine plasma concentration, since it is applicable for other cholinesterase inhibitors, too, and since it requires less technical equipment and time.

Acetylcholinesterase↗
PubMedDate not supplied

[Cholinesterase activity and protein concentration in the serum of premature and newborn infants].

Cholinesterase activity and concentrations of total protein, albumin and globulins were measured in the serum of 94 carefully selected prematures and newborns during the first week of life. Cholinesterase activity was significantly lower in prematures than in newborns. There was a weak correlation between serum concentration of albumin and cholinesterase activity. Total protein, albumin and gamma-globulins were significantly lower in premature babies. With the exception of alpha-1-globulin, all proteins correlated positively with gestational age. There was no difference in total serum protein concentration between small for gestational age infants and appropriate for gestational age infants. Postnatally, serum protein and cholinesterase activity rose by 27 44% within 7 to 10 weeks in prematures of 30-33 weeks of gestational age. A single infusion of 0.5 g/kg b.w. albumin transiently increased the protein concentration of prematures 1.5 fold; 7 to 10 weeks later, protein concentrations of treated and untreated prematures were no longer different. In conclusion, cholinesterase activity and protein concentrations correlated with gestational age. In prematures with disturbed microcirculation, albumin infusions resulted in a transient increase of protein concentration.

Birth Weight↗
PubMed1987

Brain cDNA clone for human cholinesterase.

A cDNA library from human basal ganglia was screened with oligonucleotide probes corresponding to portions of the amino acid sequence of human serum cholinesterase (EC 3.1.1.8). Five overlapping clones, representing 2.4 kilobases, were isolated. The sequenced cDNA contained 207 base pairs of coding sequence 5' to the amino terminus of the mature protein in which there were four ATG translation start sites in the same reading frame as the protein. Only the ATG coding for Met-(-28) lay within a favorable consensus sequence for functional initiators. There were 1722 base pairs of coding sequence corresponding to the protein found circulating in human serum. The amino acid sequence deduced from the cDNA exactly matched the 574 amino acid sequence of human serum cholinesterase, as previously determined by Edman degradation. Therefore, our clones represented cholinesterase (EC 3.1.1.8) rather than acetylcholinesterase (EC 3.1.1.7). It was concluded that the amino acid sequences of cholinesterase from two different tissues, human brain and human serum, were identical. Hybridization of genomic DNA blots suggested that a single gene, or very few genes, coded for cholinesterase.

Amino Acid Sequence↗
PubMed1993

A multiyear study of blood cholinesterase activity in urban pesticide applicators.

This article is a review of blood cholinesterase activity in a cohort of urban pesticide applicators ranging from 1680 to over 3800 workers. During the period 1981-1991, 208, 788 blood samples were taken for measurement of cholinesterase activity with an average of 6 samples per year from each worker. A total of 150 workers or 0.44% of the cohort was removed from exposure to cholinesterase-inhibiting insecticides because of decreased cholinesterase activity. No worker required treatment for signs of cholinesterase inhibition.

Adult↗
PubMed1987

Expression of cholinesterase genes in human oocytes revealed by in-situ hybridization.

Transcriptional activity of the human cholinesterase genes was examined in developing oocytes from mature ovaries by in-situ hybridization combined with biochemical acetylcholine hydrolysis measurements. High levels of cholinesterase mRNA could be detected in oocytes from primordial, pre-antral and antral follicles but not in atretic follicles, with transient enhancement at the pre-antral stage. Biochemical analysis of enzymatic activity identified the ovarian enzyme as 'true' acetylcholinesterase by its sensitivity to selective inhibitors. Our findings suggest that cholinergic responses may function in human oocytes independently of the surrounding follicular cells, and the pronounced synthesis of cholinesterase transcripts in oocytes suggests that the cholinesterase genes in humans are particularly good candidates for the formation and re-insertion of inheritable processed cholinesterase genes.

Acetylcholinesterase↗
PubMed1997

Interactions underlying subunit association in cholinesterases.

Cholinesterases occur in a family of molecular forms, both as homo-oligomers of catalytic subunits, which can be either soluble, amphiphilic or lipid-anchored to the membrane; and hetero-oligomers of catalytic subunits and structural subunits. The structural subunits afford a method for precise localization of cholinesterases for specific function. A number of mutagenesis studies suggest that the C-terminal region of one alternatively spliced form of cholinesterase is involved in association of catalytic subunits into tetramers and in the association of these tetramers with structural subunits, however, there is currently no structural information about this region. In addition, none of the mutagenesis studies have clearly defined the residues important in these interactions. Here, multiple sequence alignment, structure prediction techniques and analysis of three-dimensional structural data are combined with a re-examination of mutagenesis and biochemical data. Three-dimensional models for the C-terminal region and for soluble tetrameric cholinesterase are proposed, and a set of rules governing subunit association are formulated. The simple model for association of catalytic and structural subunits presented is consistent with data for all known cholinesterases from species as divergent as nematode and man.

Amino Acid Sequence↗
PubMed1981

The aryl acylamidases and their relationship to cholinesterases in human serum, erythrocyte and liver.

Human serum aryl acylamidase associated with serum cholinesterase was purified to homogeneity. Evidence for the identity of the two enzymes was based on co-elution profiles, co-purification in the different steps including affinity chromatography with constant ratios of specific activity and percentage recoveries, co-migration on gel electrophoresis, parallel inhibition by typical cholinesterase inhibitors and co-precipitation by antibody raised against the purified enzyme. Human liver aryl acylamidase was partially purified. Based on the elution profiles, purification data, inhibitory characteristics and gel electrophoresis it was concluded that aryl acrylamidase of liver was not associated with liver cholinesterase. More conclusive evidence for the non-association of the liver aryl acylamidase and cholinesterase came from their clear-cut separation on procainamide-Sepharose affinity chromatography. Both the serum and liver aryl acylamidase were compared with the purified erythrocyte aryl acylamidase associated with acetylcholinesterase. While the erythrocyte and serum aryl acylamidases showed some similarities in their sensitivities to amines like serotonin or tryptamine and choline derivatives, the liver enzyme was unaffected by any of these compounds. A notable observation was the activation by tyramine of the serum aryl acylamidase but not the erythrocyte and liver aryl acylamidases. The liver aryl acylamidase also differed from the other two in its relative insensitivity to inhibition by eserine, neostygmine and other cholinesterase inhibitors. Immunodiffusion and immunoprecipitation studies showed that the aryl acylamidases from the liver and erythrocytes were immunologically non-identical with the serum enzyme.

Amidohydrolases↗
PubMed2005

Neonatal cholinesterase inhibitor poisoning: materno-fetal exchange of pesticide.

This is a case report of a neonatal cholinesterase inhibitor poisoning after non-accidental ingestion of a carbamate containing pesticide by the mother prior to delivery. The mother presented with symptoms of cholinesterase inhibitor poisoning at 40 weeks of gestation. A fetal bradycardia was present. The mother improved after administration of intravenous atropine. Spontaneous labour ensued and a term female infant weighing 3200 g was delivered. The infant had signs of cholinergic stimulation and decreased levels of serum cholinesterase. The neonate presented with a marked tachycardia. The heart rate normalized after administration of atropine. Therefore, we concluded that the tachycardia was due to the cholinesterase inhibitor substance, causing catecholamine release by stimulation of nicotinic receptors. Another potential contributing factor to the tachycardia, although unlikely in our patient, was the atropine administered to the mother prior to delivery. Mother and infant recovered well. We conclude that infants can present with tachycardia associated with cholinesterase inhibitor toxicity. Despite the side-effects intravenous atropine should not be withheld in the treatment of mother and infant.

Adult↗
PubMed1993

Protease inhibitors and indolamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer's disease.

Neurofibrillary tangles and amyloid plaques express acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in Alzheimer's disease. We had found that traditional AChE inhibitors such as BW284C51, tacrine and physostigmine were more potent inhibitors of the AChE in normal axons and cell bodies than of the AChE in plaques and tangles. We now report that the reverse pattern is seen with indolamines, carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal neurons and axons. This shift in enzymatic affinity may lead to the abnormal protein processing which is thought to play a major role in the pathogenesis of AD. The availability of pharmacological and dietary means for altering brain indolamines raises novel therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer's disease.

Acetylcholinesterase↗
PubMed1986

Growth hormone modulates serum cholinesterase.

Adult male rats have lower serum cholinesterase activity levels than adult female rats and hypophysectomized male rats have higher activity levels than sham-operated males (similar to control females). GH administered to hypophysectomized male rats abolishes the effect of hypophysectomy on serum cholinesterase. Adult male rats treated neonatally with monosodium L-glutamate to induce arcuate nucleus lesions of the hypothalamus have higher serum cholinesterase activities and decreased serum GH concentrations. GH administered to these male rats results in decreased serum cholinesterase activities. These experiments demonstrate that GH is a negative modulator of serum cholinesterase in the male rat.

Animals↗
PubMed1999

Behavioral changes and cholinesterase activity of rats acutely treated with propoxur.

Early assessment of neurological and behavioral effects is extremely valuable for early identification of intoxications because preventive measures can be taken against more severe or chronic toxic consequences. The time course of the effects of an oral dose of the anticholinesterase agent propoxur (8.3 mg/kg) was determined on behaviors displayed in the open-field and during an active avoidance task by rats and on blood and brain cholinesterase activity. Maximum inhibition of blood cholinesterase was observed within 30 min after administration of propoxur. The half-life of enzyme-activity recovery was estimated to be 208.6 min. Peak brain cholinesterase inhibition was also detected between 5 and 30 min of the pesticide administration, but the half-life for enzyme activity recovery was much shorter, in the range of 85 min. Within this same time interval of the enzyme effects, diminished motor and exploratory activities and decreased performance of animals in the active avoidance task were observed. Likewise, behavioral normalization after propoxur followed a time frame similar to that of brain cholinesterase. These data indicate that behavioral changes that occur during intoxication with low oral doses of propoxur may be dissociated from signs characteristic of cholinergic over-stimulation but accompany brain cholinesterase activity inhibition.

Animals↗
PubMed2005

Chronic neuropsychological sequelae of cholinesterase inhibitors in the absence of structural brain damage: two cases of acute poisoning.

Here we describe two cases of carbamate poisoning. Patients AMF and PVM were accidentally poisoned by cholinesterase inhibitors. The medical diagnosis in both cases was overcholinergic syndrome, as demonstrated by exposure to cholinesterase inhibitors. The widespread use of cholinesterase inhibitors, especially as pesticides, produces a great number of human poisoning events annually. The main known neurotoxic effect of these substances is cholinesterase inhibition, which causes cholinergic overstimulation. Once AMF and PVM had recovered from acute intoxication, they were subjected to extensive neuropsychological evaluation 3 and 12 months after the poisoning event. These assessments point to a cognitive deficit in attention, memory, perceptual, and motor domains 3 months after intoxication. One year later these sequelae remained, even though the brain magnetic resonance imaging (MRI) and computed tomography (CT) scans were interpreted as being within normal limits. We present these cases as examples of neuropsychological profiles of long-term sequelae related to acute poisoning by cholinesterase inhibitor pesticides and show the usefulness of neuropsychological assessment in detecting central nervous system dysfunction in the absence of biochemical or structural markers.

Adult↗
PubMed1994

Prognostic value of serum cholinesterase in organophosphate poisoning.

OBJECTIVE: To determine whether serum cholinesterase level has a prognostic value in human acute organophosphorus poisoning. DESIGN: Cohort (prospective) prognosis study. SETTING: Medical ICU at University Hospital. PATIENTS: Thirty consecutive patients admitted to the ICU for acute organophosphate poisoning. MEASUREMENTS: Serum cholinesterase level was measured in all patients at the time of hospital admission. Severity of intoxication was assessed by the total dose of atropine required to relieve poisoning manifestations, the Simplified Acute Physiology Score, the need for assisted ventilation, and by a specific grading system previously validated that identified two groups of patients: group 1 (low severity, n = 18) and group 2 (high severity, n = 12). RESULTS: Serum cholinesterase level did not correlate with the total dose of atropine or with the Simplified Acute Physiology Score. Mean serum cholinesterase level was not significantly different between group 1 and group 2 patients (448 +/- 409 U/L in group 1 compared with 611 +/- 575 U/L in group 2 (p = NS); it was also not significantly different between patients with and without mechanical ventilation support (567 +/- 571 vs 470 +/- 409, respectively). CONCLUSION: Serum cholinesterase levels have no prognostic value in acute organophosphate poisoning. Thus, a grading system to identify high-risk patients based on this measurement is most likely unreliable.

Acute Disease↗
PubMed2002

Serum cholinesterase activity in patients with burns.

Serum cholinesterase activities were measured in 300 patients with thermal injuries. The samples were drawn immediately upon admission and thereafter daily until the time of the patients' discharge or death. According to the burn severity a characteristic decrease was noted during the first days. The decline during the first 24 hours as well as its value (measured 24 hours after admission) was found to be correlated with the total body surface area burned. In all patients the decrease in cholinesterase activity persisted for days, but in patients with inhalation trauma this decrease was significantly greater than in patients without lung injury. It seems that serum cholinesterase activity reflects not only the presence of an inhalation trauma. The cholinesterase measurement seems to be also a good method to observe the course of illness after a burn injury. Our data suggest a correlation between cholinesterase activity and morbidity. The inhalation trauma aggravates the thermal trauma.

Adult↗
PubMed2004

Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy.

The deficiency in cholinergic neurotransmission in Alzheimer's disease has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease. The clinical benefits of these agents include improvements, stabilisation or less than expected decline in cognition, function and behaviour. The common mechanism of action underlying this class of agents is an increase in available acetylcholine through inhibition of the catabolic enzyme, acetylcholinesterase. There is substantial evidence that the cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, decrease acetylcholinesterase activity in a number of brain regions in patients with Alzheimer's disease. There is also a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement. However, the cholinesterase inhibitors are reported to have additional pharmacological actions. Rivastigmine inhibits butyrylcholinesterase with a similar affinity to acetylcholinesterase, although it is not clear whether the inhibition of butyrylcholinesterase contributes to the therapeutic effect of rivastigmine. Based on data from preclinical studies, it has been proposed that galantamine also potentiates the action of acetylcholine on nicotinic receptors via allosteric modulation; however, the effects appear to be highly dependent on the concentrations of agonist and galantamine. It is not yet clear whether these concentrations are related to those achieved in the brain of patients with Alzheimer's disease within therapeutic dose ranges. Preclinical studies have shown that donepezil and galantamine also significantly increase nicotinic receptor density, and increased receptor density may be associated with enhanced synaptic strengthening through long-term potentiation, which is related to cognitive function. Despite these differences in pharmacology, a review of clinical data, including head-to-head studies, has not demonstrated differences in efficacy, although they may have an impact on tolerability. It seems clear that whatever the subsidiary modes of action, clinical evidence supporting acetylcholinesterase inhibition as the mechanism by which cholinesterase inhibitors treat the symptoms of Alzheimer's disease is accumulating. Certainly, as a class, the currently approved cholinesterase inhibitors (donepezil, galantamine, rivastigmine and tacrine) provide important benefits in patients with Alzheimer's disease and these drugs offer a significant advance in the management of dementia.

Acetylcholinesterase↗
PubMed2005

Drug persistency of two cholinesterase inhibitors: rivastigmine versus donepezil in elderly patients with Alzheimer's disease.

OBJECTIVES: To compare persistency rates and persistency days in patients with Alzheimer's disease (AD) who initiated therapy with either rivastigmine or donepezil, and to identify factors influencing persistency in a real-world setting. DESIGN AND METHODS: This study used data collected by MarketScan from 1 January 1999 to 31 December 2002. Patients were included if they were newly diagnosed with AD and filled at least one prescription for rivastigmine or donepezil between 1 July 2000 and 30 June 2001, were > or =65 years of age on the index prescription date, and had continuous health and prescription insurance during the entire study period. Patients were excluded if they filled a prescription for any cholinesterase inhibitor during the 18 months prior to initiation of the study drugs. Patients who refilled their initial cholinesterase inhibitor prescription within a permissible gap of 60 days after depleting the drug supply from the prior prescription were considered to be persistent. Sensitivity analysis was performed to test the robustness of the persistency definition. The Kaplan-Meier method was used to determine persistency rates across time and Cox proportional hazards models were used to estimate relative risks of discontinuation or switch with adjustment for other covariates, and to identify factors significantly influencing persistency of the study drugs. RESULTS: Of the newly treated AD patients, the proportion of rivastigmine and donepezil patients who continued their medication was the same (47%; p = 0.5). On average, rivastigmine users continuously used their medication for 234 days (median 312 days) while those taking donepezil used their medication for 235 days (median 315 days) [p = 0.91]. Patients were more likely to discontinue or switch their initial cholinesterase inhibitor if they used a central nervous system (CNS) medication before initiation of therapy (relative risk [RR] = 1.23; 95% CI 1.01, 1.51 without adjustment for study variables; RR = 1.30; 95% CI 1.05, 1.60 with adjustment for study variables). On the other hand, patients were less likely to discontinue their cholinesterase inhibitor if they visited their physician office frequently (RR = 0.24; 95% CI 0.18, 0.32 without adjustment; RR = 0.23; 95% CI 0.17, 0.30 with adjustment) or if they were hospitalised after initiation of their cholinesterase inhibitor therapy (RR = 0.60; 95% CI 0.39, 0.91 without adjustment; RR = 0.65; 95% CI 0.42, 0.99 with adjustment). CONCLUSION: Patients who were newly diagnosed with AD and initiated therapy with either rivastigmine or donepezil had similar levels of persistency with their initial AD therapy in a real-world setting.

Aged↗