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PubMed1990

Enzyme immunoassay of human cholinesterase (EC 3.1.1.8). Comparison of immunoreactive substance concentration with catalytic activity concentration in randomly selected serum samples from healthy individuals.

We developed an enzyme immunoassay (ELISA) for quantitation of plasma cholinesterase substance concentrations in native plasma or serum samples. The ELISA assay is based on polyclonal (rabbit) antihuman cholinesterase and a highly specific monoclonal (mouse) antibody, with a commercially available peroxidase-conjugated (rabbit) antibody directed against mouse immunoglobulins as the signal carrier. The detected serum cholinesterase substance concentrations (mean: 4.51 mg/l, SD: 0.90 mg/l) in randomly selected serum samples from 33 healthy individuals were closely and linearly related to the corresponding catalytic activity concentrations.

Calibration↗
PubMed2006

Novel cholinesterase inhibitors as future effective drugs for the treatment of Alzheimer's disease.

Current pharmacotherapy for Alzheimer's disease involves compounds that are aimed at increasing the levels of acetylcholine in the brain by facilitating cholinergic neurotransmission through inhibition of cholinesterase. These drugs, known as acetylcholinesterase inhibitors, have been shown to improve cognition and global functions but have little impact on improving the eventual progression of the disease; however, there is evidence that other cholinesterases such as butyrylcholinesterase can play an important role in cholinergic function in the brain, and the long-suspected non-cholinergic actions of acetylcholinesterase, mainly the interference with the beta-amyloid protein cascade, have recently driven a profound revolution in cholinesterase drug research. Several disease-modifying agents are under development that target these enzymes and have hope of becoming the next generation of effective drugs in the treatment of Alzheimer's disease.

Acetylcholinesterase↗
PubMed1994

Screening for insecticide overexposure under field conditions: a reevaluation of the tintometric cholinesterase kit.

A semiquantitative tintometric field kit has been used in the developing world for almost 30 years to measure whole blood cholinesterase levels in persons exposed to organophosphate pesticides. The validity of this screening kit was evaluated among 79 workers heavily exposed to organophosphates by comparison with a reference assay for erythrocyte cholinesterase. Overall correlation between the two methods was good. However, either sensitivity or specificity of the tintometric kit was less than 75% for each of the three tintometric categories commonly used to define the limit of normal. Because baseline erythrocyte cholinesterase levels were not available for this population, the true sensitivity and specificity of the tintometric assay may be even lower.

Agriculture↗
PubMed2000

Cholinesterase inhibitors for the treatment of Alzheimer's disease in the elderly.

The treatment of Alzheimer's disease is of increasing importance as the population ages and the number of people with the disease increases. The aetiology of Alzheimer's disease is complex and therefore treatment strategies rely on generalised pathological findings. Cholinesterase inhibitors enhance a generalised deficit of central nervous system acetylcholine and are the first class of agents specifically approved for the treatment of Alzheimer's disease. The clinical efficacy of the different cholinesterase inhibitors is similar; however, differences in pharmacodynamic and pharmacokinetic parameters can influence tolerability and safety in the elderly population. Concomitant disease states, significant drug interactions and the altered kinetics and dynamics seen in elderly patients can also affect treatment outcome. Although cholinesterase inhibitors are not 'curative' for Alzheimer's disease, clinical evidence indicates that these drugs can significantly delay the progress of cognitive impairment. Consequently, they represent a useful treatment for the symptoms of Alzheimer's disease in the elderly.

Aged↗
PubMed2003

Drug interactions with cholinesterase inhibitors.

Cholinesterase inhibitors are used for the symptomatic treatment of patients with Alzheimer's disease. This population often has numerous comorbidities and receives treatment with multiple medications. The astute clinician should remain mindful of possible drug interactions, both pharmacokinetic and pharmacodynamic, that may occur with concomitant treatment. Although pharmacokinetic interactions have been reported, pharmacodynamic interactions play a far greater role in the significance of drug interactions, with anticholinergic medications being most concerning. Commonly prescribed medications, such as antihistamines and tricyclic antidepressants, often have anticholinergic properties that alone or in combination with one another can antagonise the effects of cholinesterase inhibitors. Other medication classes such as antipsychotics and cholinergic agents may also result in pharmacodynamic interactions. However, for the most part, cholinesterase inhibitors can be used safely in combination with other medications.

Aged↗
PubMed2004

Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents.

Alzheimer's disease (AD) is characterized by progressive dementia caused by the loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning and brain deposits of amyloid beta peptide (A beta) and neurofibrillary tangles (NFT). A small fraction of early onset familial AD (FAD) is caused by mutations in genes, such as the beta-amyloid precursor protein (APP) and presenilins that increase the load of A beta in the brain. These studies together with findings that A beta is neurotoxic in vitro, provide evidence that some aggregates of this peptide are the key to the pathogenesis of AD. The yield of A beta and the processing and turnover of APP are regulated by a number of pathways including apolipoprotein E, cholesterol and cholinergic agonists. Early studies showed that muscarinic agonists increased APP processing within the A beta sequence (sAPP alpha). More recently, we have presented evidence showing that some, but not all, anticholinesterases reduce secretion of sAPP alpha as well as A beta into the media suggesting that cholinergic agonists modulate A beta levels by multiple mechanisms. Herein we review the recent advances in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. We propose and support the position that the influence of cholinergic stimulation on amyloid formation is critical in light of the early targeting of the cholinergic basal forebrain in AD and the possibility that maintenance of this cholinergic tone might slow amyloid deposition. In this context, the dual action of certain cholinesterase inhibitors on their ability to increase acetylcholine levels and decrease amyloid burden assumes significance as it may identify a single drug to both arrest the progression of the disease as well as treat its symptoms. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. We critically discuss recent trends in AD research, from molecular and genetic to clinical areas, as it relates to the effects of cholinergic agents and their secondary effects on A beta. Finally, we examine different neurobiological mechanisms that provide the basis of new targets for AD drug development.

Alzheimer Disease↗
PubMed1984

Innervation of syngeneic vein grafts in the rat. The regeneration of cholinesterase positive nerves.

The regeneration of cholinesterase positive nerves into segments of the supradiaphragmatic inferior vena cava transplanted from one rat into the abdominal aorta of another rat of the same inbred strain and sex were studied, using a histochemical thiocholine method for the demonstration of cholinesterase. Iso-OMPA and BW-284 C 51 were used as inhibitors for nonspecific cholinesterase (nsChE) and acetylcholinesterase (AChE), respectively. A total of 12 grafts were examined 3, 5, 8, 16, 27 and 32 weeks after transplantation. One single regenerating nsChE reactive nerve was seen near the suture line in a 3-week-old graft. Some solitary regenerating nerves were regularly seen in the grafts at 5 weeks. Eight weeks after grafting some solitary sparsely distributed nerves were found in the outer layers of the graft. In the 16-, 27-, and 32-week-old grafts, nsChE reactive nerves and small nerve bundles were running either solitary or forming nerve plexa in addition to nerves in the vicinity of vasa vasorum. These regenerated nsChE reactive nerves are probably vasomotor in nature. The AChE reaction showed a clear activity in the intimal layer of the grafted veins. No AChE reactive nerves were seen in the 3-, 5-, and 8-week-old grafts. Only occasional AChE positive nerves were observed 16, 28 and 32 weeks after transplantation. These nerves are probably sympathetic cholinergic nerves.

Acetylcholinesterase↗
PubMed1976

[Study of hydrolysis of aminoalcohol ethers, phenol and choline under the action of horse blood serum cholinesterase].

Hydrolysis of ethers of saturated and unsaturated alcohols and ethers, e.g. phenol and choline, under the action of horse blood serum cholinesterase, was studied. The reactivity towards enzymatic hydrolysis is decreased due to a greater length of the chain in the alcohol residue of the benzoic acid aminoethers; at nCH2 = 4 the compound is a poor substrate. An increase in nydrophobicity of the acyl residue of the ether molecule also leads to a decrease in the Vmax and Km values. In case of cholinesterase substrates, an increase in the molecule hydrophobicity results in an increase of its non-productive absorption on the active surface of the enzyme, which decreases its hydrolysis. Aminobutynol benzoates are hydrolyzed by cholinesterase more rapidly as compared to the ethers of corresponding aminobutanols and their homologs.

Amino Alcohols↗
PubMed2000

Cholinesterase inhibitors and Gingko extracts--are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration.

The efficacy of four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) and Ginkgo special extract EGb 761 in Alzheimer's disease were compared. The differences in the effects of the active substance and placebo on cognition were measured on the ADAS-Cog scale, taking into account the different degrees of dementia in the various studies and the dropout rate due to adverse drug reactions. Efficacy, expressed as the delay in symptom progression or the difference in response rate between active substance and placebo, showed no major differences between the four cholinesterase inhibitors and the Ginkgo special extract. Only tacrine exhibited a high dropout rate due to adverse drug reactions. In view of this, the subject of new prescriptions should be critically reviewed. Second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) and Ginkgo special extract EGb 761 should be considered equally effective in the treatment of mild to moderate Alzheimer's dementia.

Alzheimer Disease↗
PubMed2000

Prolonged neuromuscular block with mivacurium in a patient with cholinesterase deficiency.

Mivacurium is a short-acting, nondepolarizing neuromuscular blocking agent hydrolyzed by plasma cholinesterase. Because it allows fast recovery, it is a commonly used muscle relaxant for patients undergoing short surgical procedures. We report the case of a 5-year-old boy who underwent outpatient inguinal herniorraphy and developed unexpected prolonged neuromuscular block after the use of mivacurium. He required mechanical ventilation support in the intensive care unit because he could not attain adequate muscle power 1 hour after termination of anesthesia; the muscular paralysis persisted for 5 hours after the bolus dose of 0.3 mg/kg mivacurium. Subsequent investigation revealed an extremely low plasma cholinesterase concentration (115 U/L), and this was later determined to be a congenital condition. This is the first reported case of cholinesterase deficiency diagnosed as a result of general anesthesia in Taiwan.

Child, Preschool↗
PubMed2001

Galantamine: new preparation. The fourth cholinesterase inhibitor for Alzheimer's disease.

(1) The reference symptomatic treatment for mild to moderate Alzheimer's disease is a cholinesterase inhibitor such as donepezil, but efficacy is only moderate and only about 10% of those patients treated actually benefit. (2) Galantamine is the fourth cholinesterase inhibitor to be marketed in France for Alzheimer's disease. The clinical file contains data from five double-blind placebo-controlled trials lasting 3-6 months, but no data comparing galantamine with other drugs. (3) These trials show that about 5-13% of patients treated with galantamine may be improved. (4) Adverse effects are very frequent, and are similar to those of other cholinesterase inhibitors, i.e. nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, etc. (5) For patients who are eligible for drug therapy, the reference treatment is still donepezil, for want of anything better.

Alzheimer Disease↗
PubMed2002

Species differences in normal brain cholinesterase activities of animals and birds.

The normal cholinesterase activity in brain tissue was measured in 15 mammalian and 44 avian species using the Ellman method. Enzyme activity exhibited considerable interspecies variability. In mammals, the enzyme activities ranged from approximately 2 to 10 micromole/min/g of wet tissue. With the exception of the carnivores (dog, fox, coyote), no consistency of the enzyme activity could be identified in related mammalian species. The range of interspecies differences associated with avian cholinesterase activity were approximately double when compared to the mammalian species tested. Enzyme activities in avian species ranged from approximately 10 to 30 micromole/min/g. Comparisons for uniformity of enzyme activity between closely related avian species were poor in most instances. The considerable variability of the brain cholinesterase activities in avian and mammalian species illustrates the need for reliable normal values for individual species to improve ability to monitor environmental exposure or to confirm acute poisonings associated with organophosphate or carbamate insecticides.

Animals↗
PubMed2002

The tolerability and safety of cholinesterase inhibitors in the treatment of dementia.

Cholinesterase inhibitors (ChEIs) are dosed in two phases for the treatment of dementia, an initial dose-escalation phase to achieve a therapeutic dose and a maintenance phase where the therapeutic dose is given for long-term therapy. ChEIs are associated with a range of side effects as a result of cholinergic stimulation in different areas of the brain and the periphery Acute, centrally-mediated gastrointestinal events (mostly nausea and vomiting) are class effects of all ChEIs, and are reported mostly during the dose-escalation phase of therapy. These events have been associated more with the dual acetylcholinesterase/butyrylcholinesterase (AChE/BuChE) inhibitor rivastigmine than with the AChE-selective inhibitors donepezil and galantamine, probably due to rivastigmine's higher potency. However, these events can be minimised using slow dose escalation with small dose graduations and administration with food. Other side effects associated with ChEIs include central nervous system events, extrapyramidal symptoms, sleep disturbances and cardiorespiratory events, associated with cholinergic activity in the cortex, caudate nucleus, brainstem and medulla, respectively, and muscle cramps and weakness, cardiorespiratory events and urinary incontinence, associated with peripheral cholinergic activity. These symptoms are mostly reported during the maintenance phase of therapy. They are more frequently reported with donepezil, but are rarely reported with rivastigmine, and galantamine may not have been marketed long enough to make an adequate assessment. These differences are due to the drugs' respective pharmacology. For example, donepezil and rivastigmine are active centrally, in contrast to galantamine, which is more active peripherally. Furthermore, rivastigmine preferentially inhibits the G1 isoform of cholinesterase, predominantly located in the cortex, hippocampus and in neuritic plaques, while donepezil and galantamine are not selective for any cholinesterase isoforms and have wide cholinergic activity both centrally and peripherally The cholinergic activity of rivastigmine, in contrast to donepezil and galantamine, is apparently more targeted at clinically relevant brain sites. The pharmacological profile of rivastigmine results in it having a low potential to interact with other drugs and it may be used with a high margin of safety in patients having a wide variety of concomitant diseases. Donepezil and galantamine may have significant interactions with other drugs that are metabolised by the hepatic cytochrome system and therefore need to be used with caution in patients with many concomitant illnesses. When dosed with care, ChEIs are well tolerated and patient compliance and patient and caregiver acceptability are good. The favourable tolerability and safety profiles of these agents make them suitable first-line therapy for dementia. In addition, patients who have tolerability and/or safety problems in maintenance treatment that limit the use of donepezil or galantamine may benefit from switching to rivastigmine.

Carbamates↗
PubMed1975

[Comparative study of the changes in the EEG and cholinesterase activity in experimental Dipterex poisoning].

A systematic study is conducted on cats, poisoned with the organophosphorus insecticide Dipterex. The changes in spontaneous and induced cortical activity along with those in serum and erythrocyte cholinesterase after intraperitoneal and intramuscular injection of Dipterex are investigated. Against the background of lowered cholinesterase activity, recorded in all the experiments , the changes in EEG appear to be discrete and inconstant. Uron single treatment with Dipterex, desynchronization prevails in the spontaneous EEG, whereas in the responses induced by light stimulants an increase of delayed negative potentiale prevails. Upon repeated Dipterex introduction, theta-like waves appear, associated with activation of paroxysmal manifestations existing in advance. Finally, the correlation between changes in cholinesterase activity and EEG is discussed.

Animals↗
PubMed1992

Decreased plasma cholinesterase activity enhances cocaine toxicity in mice.

The illicit use of cocaine continues in epidemic proportions. Despite the incidence of life-threatening complications from cocaine use, little is known of the individual determinants of cocaine toxicity. In vitro analysis demonstrating that cocaine is poorly metabolized by the serum of patients with low plasma cholinesterase (PCh) activity (succinylcholine sensitivity) led to the hypothesis that altered PCh activity might modulate cocaine toxicity. An in vivo mouse model was created to test this theory. Mice were pretreated s.c. with either parathion [a mixed plasma and red blood cell cholinesterase (RBCCh) inhibitor], tetraisopropyl pyrophosphoramide (a selective PCh inhibitor) or placebo, and cholinesterase activity was determined at 24 hr. Incremental doses of i.p. cocaine were administered in a controlled and blinded fashion, and lethality was observed. Ten mg/kg s.c. parathion produced a mean suppression of 68 +/- 9 and 61 +/- 8% of PCh and RBCCh activity, respectively. One mg/kg s.c. tetraisopropyl pyrophosphoramide produced a mean suppression of 78 +/- 3 and 9 +/- 8% of PCh and RBCCh activity, respectively. Each pretreatment produced a statistically significant increase in cocaine lethality throughout the dose-response curve. Our results suggest that PCh activity is an important determinant of cocaine toxicity. This effect appears to be independent of either RBCCh activity or manifestations of organophosphate intoxication.

Animals↗
PubMedDate not supplied

[Use of 1- and 2-thionaphthylacetates as cholinesterase substrates].

1- and 2-thionaphthylacetates were tested as cholinesterase substrates. It was shown that the butyrilcholinesterase from horse serum can hydrolize these compounds. The hydrolysis velocity of 1-thionaphthylacetate was comparable with hydrolysis velocity of acetylthiocholine (the well known cholinesterase substrate), but 2-thionaphthylacetate was hydrolysed more slowly. The values of the kinetic parameters V and K(m) for butyrylcholinesterase hydrolysis of 1- and 2-thionaphthylacetates were determined. It was offered to use 1-thionaphthylacetates as the substrate for cholinesterases.

Acetylthiocholine↗
PubMed1992

The effects of inhibition of plasma cholinesterase and hepatic microsomal enzyme activity on cocaine, benzoylecgonine, ecgonine methyl ester, and norcocaine blood levels in pigs.

We measured the blood levels of cocaine and its three major metabolites, benzoylecgonine, ecgonine methyl ester, and norcocaine, in three groups of male pigs weighing about 26 kg (25.75 +/- 0.25 kg) to determine the effects of inhibition of plasma cholinesterase and hepatic microsomal enzyme activity on cocaine metabolism. In addition, systemic elimination half-life, volume of distribution, and clearance of cocaine were calculated for the three groups. Group 1 pigs (n = 4) were pretreated with normal saline solution, group 2 pigs (n = 4) were pretreated with tetraisopropyl pyrophosphoramide, a specific plasma cholinesterase inhibitor, and group 3 pigs (n = 4) were pretreated with cimetidine, a hepatic microsomal enzyme inhibitor, all administered intramuscularly. Pigs were anesthetized with intravenous sodium thiopental; a carotid arterial cannula and an external jugular catheter were then inserted for the administration of cocaine and for blood sampling. Forty-five minutes later, when pigs were again completely awake, cocaine 3 mg/kg was given intravenously. Arterial blood samples were collected for the analysis of cocaine and cocaine metabolite levels just before and at 5, 10, 15, 30, 45, 60, 120, 180, and 1440 minutes after the administration of cocaine. Cocaine and cocaine metabolite blood levels were analyzed with high-pressure liquid chromatography methods and plasma cholinesterase activity was measured with a colorimetric method. The blood levels of cocaine and cocaine metabolites were significantly different among the three groups (p less than 0.05, analysis of variance). Statistically significant differences in half-life, volume of distribution and clearance were also seen among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Cholinesterase activity in the chondrocranium of normal and exencephalic mouse fetus with trisomy 12.

Cholinesterase (ChE) activity in the chondrocranium of normal and exencephalic trisomy 12 mouse fetuses was studied. Non-specific cholinesterase activity was found strongly in the developing bone cells at the central zone and weakly in the more maturely developed bone cells at the peripheral zone of the chondrocranium of both normal and exencephalic trisomy 12 mouse fetuses. In exencephalic mouse fetuses, the ChE-activity was lesser than in the normal ones which corresponded to hypoplastic chondrocranium. The centrifugal direction of the maturity of individual bone cells could be demonstrated by the activity of cholinesterase. The young bone cells showed strong ChE-activity while the more matured cells showed weak ChE-activity. The enzyme activity disappeared when the definite tissue structure was well developed. From this study, it may be concluded that ChE plays a role in chondrocranium development which is different from its known function in the adult tissue.

Anencephaly↗