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PubMed1995

Regulatory and research issues related to cholinesterase inhibition.

Assessing the neurotoxic potential of organophosphate and carbamate pesticides should be greatly facilitated by the knowledge that the mechanism of action of these insecticides is presumed to be the inhibition of cholinesterase, the enzyme which controls the levels of neurotransmitter, acetycholine. Although the inhibition of cholinesterase activity is the recognized mechanism of action, many questions remain regarding the use of cholinesterase inhibition data as a critical effect for establishing risk of cholinesterase-inhibiting pesticides. Specifically, questions have arisen regarding whether blood cholinesterase inhibition correlates with inhibition in target tissues (e.g. brain or muscle) and whether cholinesterase inhibition in any tissue correlates with the adverse clinical and behavioral effects produced by exposure to cholinesterase-inhibiting pesticides. Studies in our laboratory indicate that blood cholinesterase inhibition in both acute and subchronic dosing regimens correlates with inhibition in other tissues, if measurements are taken at the appropriate times. Moreover, there is evidence in the literature and from our laboratory that cholinesterase inhibition correlates with the emergence and severity of clinical signs of poisoning by cholinesterase-inhibiting pesticides.

Animals↗
PubMed2004

The concurrent use of anticholinergics and cholinesterase inhibitors: rare event or common practice?

OBJECTIVES: To measure the prevalence of anticholinergic use cross-sectionally in patients receiving cholinesterase inhibitors and to describe change in use of anticholinergics upon inception of cholinesterase inhibitor treatment. DESIGN: Cross-sectional and inception cohort studies. SETTING: State of Iowa. PARTICIPANTS: Iowa Medicaid beneficiaries aged 50 and older with a pharmacy claim for a cholinesterase inhibitor during January 1997 through February 2000. MEASUREMENTS: Anticholinergic use was determined for all patients with a cholinesterase inhibitor pharmacy claim during January and February of 2000. A frequency distribution of all anticholinergics was compiled, with emphasis placed on those considered inappropriate in the elderly. In a separate analysis, anticholinergic use was determined at two points: 90 days before and after cholinesterase inhibitor inception. RESULTS: Of 557 patients receiving a cholinesterase inhibitor, 197 (35.4%) received an anticholinergic concurrently. Of all anticholinergics, 74.5% (178/239) had been identified as inappropriate for use in the elderly, 22.2% (53/239) under any circumstances. At the time of cholinesterase inhibitor inception, 30.2% (143/474) and 33.5% (159/474) of patients received an anticholinergic 90 days before and 90 days after inception, respectively. Increases in anticholinergic prescribing upon cholinesterase inhibitor inception exceeded decreases (Wilcoxon signed-rank test, S=529, P=.020). CONCLUSION: The concurrent use of anticholinergics and cholinesterase inhibitors is common although rarely appropriate. Patients with Alzheimer's disease deserve to receive the optimum benefit from cholinesterase inhibitor treatment, which can only be achieved through diligent and appropriate use of concurrent pharmacotherapy.

Aged↗
PubMed1996

Administration of purified human plasma cholinesterase protects against cocaine toxicity in mice.

BACKGROUND: Cocaine is metabolized in part by plasma cholinesterase to form ecgonine methyl ester. Decreased plasma cholinesterase activity is associated with enhanced cocaine toxicity in both humans and animals. This study was designed to determine whether the administration of exogenous plasma cholinesterase is protective against cocaine toxicity. METHODS: Using a blinded protocol, female Swiss albino mice were randomized to receive an intraperitoneal injection of either 13.7 mg/kg of purified human plasma cholinesterase dissolved in phosphate buffered saline, or an equal volume of phosphate buffered saline as a control. One hour later, all animals received an intraperitoneal injection of either 100 or 125 mg/kg of cocaine, and the incidence of seizures and death was recorded. In a similar fashion, another group of animals was randomized to receive a human plasma cholinesterase dose of either 13.7 or 27.4 mg/kg, followed by 150 mg/kg of cocaine. RESULTS: Administration of 13.7 mg/kg of human plasma cholinesterase increased plasma cholinesterase activity by a mean of 63 +/- 13 fold, with a Tmax of 90 minutes and a Vd of 85 +/- 13 mL/kg. Cocaine's effects on seizures and death were attenuated by human plasma cholinesterase. A cocaine dose of 150 mg/kg represents an ED100 for seizures and an LD100. At this dose, lethality was reduced to 30% (p < 0.001) and seizures were reduced to 40% (p < 0.001) by administration of 27.4 mg/kg of human plasma cholinesterase. CONCLUSIONS: Pretreatment with purified human plasma cholinesterase protects mice against the convulsive and lethal effects of cocaine.

Animals↗
PubMed1998

The effects of nutrition on plasma cholinesterase activity and cocaine toxicity in mice.

BACKGROUND: Low plasma cholinesterase activity is associated with severe cocaine toxicity in human subjects and animal experiments. Exogenously enhanced plasma cholinesterase activity is protective against cocaine toxicity in animals. Cocaine users tend to have lower plasma cholinesterase activity than controls. Yet, when cocaine users are allowed to use cocaine in controlled settings without dietary restriction, their plasma cholinesterase activity increases. This study evaluates the influence of diet on plasma cholinesterase activity and cocaine toxicity. METHODS: Forty-five Swiss albino mice were maintained on a high (30%) protein diet for 3 weeks. They were then randomized into equal groups and given either the high protein diet, an isocaloric low protein diet, or a protein and calorie deficient diet which consisted of reduced intake of the high protein diet. Body weights and plasma cholinesterase activities were measured after a 21-day study period. All animals then received a fixed dose of intraperitoneal cocaine and were observed for seizures and death. RESULTS: Body weights and plasma cholinesterase activities of the high protein animals remained stable. Weights for the low protein and reduced intake animals fell by 5% and 15%, respectively (p < 0.05 for both vs baseline). Similarly, plasma cholinesterase activities for the low protein and reduced intake animals fell by 4% and 10%, respectively (p = 0.06 for low protein and < 0.05 for reduced intake vs baseline). Cocaine caused seizures in 67% of the high protein animals as compared to 93% and 100% of the low protein and reduced intake animals, respectively (p < 0.05 for high protein vs reduced intake). None of the high protein animals died as compared to 20% and 100% of the low protein and reduced intake animals, respectively (p < 0.05 for high protein vs reduced intake). CONCLUSION: Protein and calorie malnutrition is associated with a reduction in plasma cholinesterase activity and enhanced cocaine toxicity in mice. Further study is needed to determine if dietary factors are partially responsible for variations in plasma cholinesterase activity and cocaine susceptibility in humans.

Animals↗
PubMed1989

Plasma and erythrocyte cholinesterase values for the common long-nosed armadillo, Dasypus novemcinctus.

Plasma and erythrocyte cholinesterase activities were determined for 40 free-living and 12 captive common long-nosed armadillos (Dasypus novemcinctus) in order to establish normal values for monitoring pesticide exposure. Plasma cholinesterase activity ranged from 105 to 549 U/liter with no sexual or seasonal differences. Plasma values from captive animals were significantly lower than those from wild armadillos. Erythrocyte cholinesterase activity ranged from 2,915 to 15,126 U/liter with no differences detected between captive and wild animals or between sexes. However, erythrocyte cholinesterase values varied seasonally. Erythrocyte and plasma cholinesterase activities were not significantly correlated. Packed cell volume ranged from 24 to 51% and did not vary significantly between captive and wild samples, between sexes or among seasons. However, both whole blood and erythrocyte cholinesterase activities showed significant negative correlations with packed cell volume. Controlled experiments are needed to find the factors responsible for the statistically significant difference between plasma cholinesterase activities of captive and wild armadillos. The seasonal variation in erythrocyte cholinesterase activity and the negative correlation between erythrocyte cholinesterase activity and packed cell volume can be explained by an hypothesis that relates the variation in erythrocyte cholinesterase activity to variation in erythrocyte turnover rate. Future work should involve experiments to test this hypothesis.

Animals↗
PubMed1994

Inverse relationship between serum cholinesterase activity and the administration of cyclophosphamide: an index of cyclophosphamide therapy.

To determine whether serum cholinesterase activity can be a monitoring index of cyclophosphamide therapy in patients with steroid-resistant glomerulopathy, we compared the cholinesterase activity of 37 patients who received a combined therapy that included the use of cyclophosphamide, prednisolone, antiplatelet drugs, and anticoagulant drugs, with the cholinesterase activity of 25 patients who received prednisolone therapy that excluded cyclophosphamide from the combined therapy. In the prednisolone and the combined groups, cholinesterase activity declined as shown in the following formula: Y = 371-26.4 x log(X): (r2 = 0.28), Y = 444-147.7 x log(X): (r2 = 0.95), respectively. (Y: cholinesterase activity, X: the day after treatment). In the combined therapy group, the prevalence of adverse reactions following treatment in the subgroup below 200 U/l of cholinesterase activity was significantly greater (P < 0.01) than that in the subgroup above 200 U/l of cholinesterase activity. However, there was no significant difference (P < 0.25) in the prevalence of adverse reactions between the subgroups with more or less than 184 U/l of cholinesterase activity following treatment. These results suggest the importance of not going below 200 U/l of cholinesterase activity after treatment when the normal cholinesterase activity range is between 300 and 760 U/l (e.g. less than 65% of the lowest value of the normal range of other hospitals) in order to eliminate the hazards of cyclophosphamide to the patients with steroid-resistant glomerulopathy.

Adolescent↗
PubMed1993

Rapid potentiometric determination of cholinesterases in plasma and red cells: application to eptastigmine monitoring.

Eptastigmine (MF 201) is a new physostigmine derivative with potent inhibitory activity on cholinesterases. Here we present a new potentiometric cholinesterase activity assay suitable for MF 201 monitoring. The analysis is performed on a differential pH system and has the following characteristics: (a) within-run precision: C.V. 2.0% (plasma cholinesterase), 1.8% (red cell cholinesterase); (b) between-run precision: C.V. 4.0% (plasma cholinesterase); (c) linearity: 1-10 kU/l (plasma cholinesterase), 6-70 U/g Hb (red cell cholinesterase); (d) comparison with a reference method (x, HITACHI 737 Boerhinger Mannheim, Italy): y = 0.785x - 0.07; n = 37; r = 0.998. The assay has been applied to the determination of plasma and red cell cholinesterase activity in volunteers over 60 years of age treated with a single oral dose of 30 mg eptastigmine. We found that red cell cholinesterase is selectively inhibited after MF 201 administration with the following kinetics (time, % of inhibition, mean +/- S.E., n = 6): 0 h, 0; 1 h, 17 +/- 4.6; 2 h, 24 +/- 4; 4 h, 23 +/- 4.4; 12 h, 14 +/- 3. Eptastigmine plasma levels were also determined by a HPLC method: maximum concentration was found one hour after drug administration.

Administration, Oral↗
PubMed1987

The effects of blood flow and detoxification on in vivo cholinesterase inhibition by soman in rats.

The in vivo time course of cholinesterase inhibition was measured in brain, lung, spleen, hind limb skeletal muscle, diaphragm, intestine, kidney, heart, liver, and plasma of rats receiving 90 micrograms/kg soman, im. This dose of soman produced severe respiratory depression and transient hypertension, but no significant changes in the cardiac output or heart rate of anesthetized rats. The rate and maximal extent of in vivo cholinesterase inhibition by soman varied widely among the tissues. Although cardiac output was unchanged by soman administration, the blood flow in heart, brain, and lung (bronchial arterial flow and arteriovenous shunts) was increased, whereas blood flow in spleen, kidney, and skeletal muscle was decreased. The relative importance of tissue blood flow, tissue levels of cholinesterase and acetylcholinesterase, and tissue levels of soman-detoxifying enzymes (diisopropyl-fluorophosphatase and carboxylesterase) in determining the in vivo rate and maximal extent of cholinesterase inhibition was examined by multiple regression analysis. The best multiple regression model for the maximal extent of cholinesterase inhibition could explain only 63% of the observed variation. The best multiple regression model for the in vivo rate of cholinesterase inhibition contained three independent variables (blood flow, carboxylesterase, and cholinesterase) and could account for 94% of the observed variation. Of these three variables blood flow was the most important, accounting for 79% of the variation in the in vivo rate of cholinesterase inhibition. This suggests that it may be possible to use a flow-limited physiological pharmacokinetic model to describe the kinetics of in vivo cholinesterase inhibition by soman.

Acetylcholinesterase↗
PubMed2001

Determination of whole blood cholinesterase in different animal species using specific substrates.

Whole blood cholinesterase was measured using acetyl-, butyryl- and propionylthiocholine as substrates in 10 healthy adult dogs, cats, horses, pigs, goats, sheep and cows, in order to determine and characterise the cholinesterase activity in whole blood of the main domestic animals. An in vitro exposure test with two anticholinesterase compounds, the organophosphate insecticide coumaphos and the carbamate insecticide imidocarb, was also performed. In whole blood of ruminants and pigs, acetylthiocholine yielded the highest cholinesterase activity and other substrates were poorly hydrolysed; in dogs and cats, although acetylthiocholine showed the highest cholinesterase activity, butyryl- and propionylthiocholine also produced high cholinesterase values; in horses, propionylthiocholine was the substrate that yielded the highest cholinesterase activity, closely followed by butyrylthiocholine. All within- and between-run coefficients of variation observed in whole blood samples were less than 5 and 7 per cent, respectively, except when butyrylthiocholine was used as substrate in ruminant blood samples. Butyryl- and propionylthiocholine were the substrates that yielded higher inhibitions after coumaphos exposure, whereas the use of acetylthiocholine showed the highest cholinesterase inhibition after imidocarb exposure. The use of at least two substrates (acetyl and butyrylthiocholine) is recommended for whole blood cholinesterase analyses in domestic animals since it will allow monitoring of both acetyl- and butyrylcholinesterase activities, respectively, and a more accurate detection of exposure to anticholinesterase compounds. However, acetylthiocholine could be used as a unique substrate for whole blood cholinesterase determination in porcine and ruminant samples since butyrylcholinesterase activity is very low in these species. Additionally, propionylthiocholine could be used as an alternative substrate to butyrylthiocholine in horse whole blood samples.

2,2'-Dipyridyl↗
PubMed1979

Sensitivity of the canine pancreatic intraductal pressure to subclinical reduction in cholinesterase acitivity.

As a continuation of work from this laboratory on anticholinesterase induced pancreatitis, a study of the relationship between reduced serum cholinesterase activity and changes in pancreatic intraductal pressure was undertaken. Pharmakokinetic studies in three dogs revealed rapid reduction in serum cholinesterase activity following an IV bolus dose of the cholinesterase inhibitor 0,0-diethyl-0-(2-isopropyl-6-methyl-4-pyrimidinyl)phosphorothioate. Following each dose of cholinesterase inhibitor, stable levels of cholinesterase inhibition were reached in 30 minutes. In four dogs the pancreatic duct was perfused from the tail of the ventral pancreas and intraductal pressures measured. A total of 25 mg/kg of the cholinesterase inhibitor was given in 5 mg/kg doses 30 minutes apart, and serum cholinesterase measured 30 minutes after each dose. Mean pressures were established over a 15 minute interval. Linear regression analysis of 23 data points revealed a significant (p < 0.001) cumulative dose-related increase in pancreatic intraductal pressure [Pressure (cm saline) = 14.2 + 1.03 x Cumulative Dose (mg/kg)] and significant (p< 0.001) negative correlation between serum cholinesterase activity and intraductal pressure [Pressure (cm saline) = 48.0 - 0.057 x Esterase Activity (mU/ml)]. These data suggest that, in dogs, reduced cholinesterase activity is directly related to increased pancreatic intraductal pressure, and it may be a factor in the pathogenesis of pancreatitis.

Animals↗
PubMed2004

Histochemical localization of cholinesterase activity in the dental epithelium of guinea pig teeth.

Cholinesterase is known for its remarkable diversity in distribution and function. An association of this enzyme with proliferative and morpho-differentiating tissues has been reported in several species. Here we report on the first evidence of the presence of cholinesterase in the enamel organ of continuously erupting incisors and molars of the guinea pig. Frozen sections of the incisors and molars of the guinea pig were incubated for histochemical demonstration of cholinesterase activity by means of the thiocholine method as described by Karnovsky and Root. The cholinesterase activity was observed in several types of cells of the dental epithelium; cells forming the basal portion of the enamel organ, outer enamel epithelium and maturation stage ameloblasts of both the incisors and molars. In the crown analogue side, the outer enamel epithelial cells gained strong reactions for cholinesterase and maintained the reaction throughout the secretory and maturation stages of amelogenesis. In contrast, cholinesterase reactions were lacking in the inner enamel epithelium, pre-ameloblasts, and secretory ameloblasts. In the early stage of enamel maturation, ameloblasts began to show positive reactions for cholinesterase, which was upregulated in the incisal direction. Although both tooth types showed similar reactive patterns for cholinesterase at the growing ends, maturation ameloblasts depicted a different pattern of staining displaying the reactions only sporadically in molars. These data indicate the role of cholinesterase in the enamel organ in tooth morphogenesis and function of guinea pig teeth.

Ameloblasts↗
PubMed1995

Clinical and analytical considerations in the utilization of cholinesterase measurements.

Many theories have been advanced but the true physiological function for serum cholinesterase has still not been identified. Evidence has been presented for the abnormal expression of cholinesterase genes in many types of human tumors. Cholinesterase measurements are still used to monitor exposure to organophosphate insecticides and their clinical application requires a good understanding of the inter and intra-individual variation, as well as some knowledge of the time sequence between exposure and measurement of the cholinesterase activity. The use of serum cholinesterase measurement in liver disease varies in different countries. A case has not been made for the cost-effectiveness of adding serum cholinesterase as part of a screening procedure for the diagnosis of liver disease. During the last 10 years much information has been obtained on the molecular biology and genetics of acetylcholinesterase and butyrylcholinesterase, distinct enzymes encoded by two different, but related genes. It has been established that BChE is included by a single gene which corresponds to the E1 locus. The complete amino acid sequence of human serum cholinesterase and the location of disulfide bonds within the sequence have been described. The molecular basis of many variants of human serum cholinesterase has been described in detail. It is not rare for multiple mutations to occur within a single butyrylcholinesterase gene or there may be combination of mutations. At least 11 silent variants of human butyrylcholinesterase have been identified. There still exists a wide variety of substrates and analytical conditions for butyrylcholinesterase measurement in a number of clinical situations. No real evidence has been provided for clinical value for their use in the diagnosis of Alzheimer disease or monitoring the use of cholinesterase inhibitors in the treatment of pre-senile dementia of Alzheimer type. However, the insights from molecular biology technology may well open up more challenges in a variety of clinical situations.

Cholinesterases↗
PubMed1987

A comparison of the effects of two inhibitors on brain cholinesterase.

In the present paper various routes of administration (i.m., i.v. and i.c.v.) of physostigmine are compared and the effect of two drugs producing inhibition of cholinesterase, physostigmine and metrifonate, on the activity of cholinesterase in the brain of the rat and on levels of acetylcholine (ACh) and choline (Ch). After intramuscular administration of physostigmine (500 micrograms/kg), the activity of cholinesterase in brain was maximally inhibited (76%) at 5 min and recovered to 50% at 40 min. At 5 min, areas of the brain such as the striatum and medulla oblongata showed 49 and 67% inhibition, respectively. Levels of physostigmine in brain peaked at 5 min (1.28 nmol/g). With the exception of the cerebellum, there was a direct correlation between the concentration of physostigmine and inhibition of cholinesterase in a given area. With the intravenous route of administration (100 micrograms/kg), the activity of cholinesterase in brain was maximally inhibited (67%) at 3 min and recovered to 50% at 12 min. At 60 min, the activity of cholinesterase was 90% of control. Levels of physostigmine in brain peaked at 2 min (0.47 nmol/g). At 15 min, with intraventricular administration (4 micrograms), the activity of cholinesterase was 73% and 31% inhibited in the hippocampus and striatum, respectively. Other areas of brain showed intermediate values of inhibition. Levels of acetylcholine were increased 18 and 22% above control in the striatum and hippocampus, respectively and did not change in the medulla. After intramuscular administration of metrifonate (80 mg/kg), the activity of cholinesterase decreased to 26% at 30 min, recovered to 50% at 180 min and returned to 74% at 360 min. Levels of acetylcholine increased by 45% at 45 min, then returned to normal by 120 min. When metrifonate (2.5 mg) was given intraventricularly the activity of cholinesterase decreased in the left side injected at 30 min to 20% in hippocampus; 22% in the medulla; 50% in the cerebellum; 58% in the striatum and 72% in cortex. Levels of acetylcholine increased maximally at 45 min in hippocampus and cortex and peaked in the striatum at 60 min. The greatest increases were seen in the hippocampus and cortex with 60 and 55%, respectively. The results of this study reveal some major differences between the effects of the two substances in brain. Four major conclusions are apparent from this study. First, based on these results, it is concluded that metrifonate is more likely to produce a therapeutic effect in humans.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1997

Mipafox differential inhibition assay for heart muscle cholinesterases: substrate specificity and inhibition of three isoenzymes by physostigmine and quinidine.

1. A differential inhibition assay was developed for the quantitative determination of cholinesterase isoenzymes acetylcholinesterase (AChE; EC 3.1.1.7), cholinesterase (BChE; EC 3.1.1.8), and atypical cholinesterase in small samples of left ventricular porcine heart muscle. 2. The assay is based on kinetic analysis of irreversible cholinesterase inhibition by the organophosphorus compound N,N'-di-isopropylphosphorodiamidic fluoride (mipafox). With acetylthiocholine (ASCh) as substrate (1.25 mM), hydrolytic activities (A) of cholinesterase isoenzymes were determined after preincubation (60 min, 25 degrees C) of heart muscle samples with either saline (total activity, A tau), 7 microM mipafox (AM1), or 0.8 mM mipafox (AM2): (BChE) = A tau-AM1, (AChE) = AM1-AM2, (Atypical ChE) = AM2. 3. The mipafox differential inhibition assay was used to determine the substrate hydrolysis patterns of myocardial cholinesterases with ASCh, acetyl-beta-methylthiocholine (A beta MSCh), propionylthiocholine (PSCh), and butyrylthiocholine (BSCh). The substrate specificities of myocardial AChE and BChE resemble those of erythrocyte AChE and serum BChE, respectively. Michaelis constants KM with ASCh were determined to be 0.15 mM for AChE and 1.4 mM for BChE. 4. Atypical cholinesterase, in respect to both substrate specificity and inhibition kinetics, differs from cholinesterase activities of vertebrate tissue and, up to now, could be identified exclusively in heart muscle. The enzyme's Michaelis constant with ASCh was determined to be 4.0 mM. 5. The reversible inhibitory effects of physostigmine (eserine) and quinidine on heart muscle cholinesterases were investigated using the differential inhibition assay. With all three isoenzymes, the inhibition kinetics of both substances were strictly competitive. The physostigmine inhibition of AChE was most pronounced (Ki = 0.22 microM). Quinidine most potently inhibited myocardial BChE (Ki = 35 microM).

Animals↗
PubMed1998

Role of oligosaccharides in the pharmacokinetics of tissue-derived and genetically engineered cholinesterases.

To understand the role of glycosylation in the circulation of cholinesterases, we compared the mean residence time of five tissue-derived and two recombinant cholinesterases (injected intravenously in mice) with their oligosaccharide profiles. Monosaccharide composition analysis revealed differences in the total carbohydrate, galactose, and sialic acid contents. The molar ratio of sialic acid to galactose residues on tetrameric human serum butyrylcholinesterase, recombinant human butyrylcholinesterase, and recombinant mouse acetylcholinesterase was found to be approximately 1.0. For Torpedo californica acetylcholinesterase, monomeric and tetrameric fetal bovine serum acetylcholinesterase, and equine serum butyrylcholinesterase, this ratio was approximately 0.5. However, the circulatory stability of cholinesterases could not be correlated with the sialic acid-to-galactose ratio. Fractionation of the total pool of oligosaccharides obtained after neuraminidase digestion revealed one major oligosaccharide for human serum butyrylcholinesterase and three or four major oligosaccharides in other cholinesterases. The glycans of tetrameric forms of plasma cholinesterases (human serum butyrylcholinesterase, fetal bovine serum acetylcholinesterase, and equine serum butyrylcholinesterase) clearly demonstrated a reduced heterogeneity and higher maturity compared with glycans of monomeric fetal bovine serum acetylcholinesterase, dimeric tissue-derived T. californica acetylcholinesterase, and recombinant cholinesterases. T. californica acetylcholinesterase, recombinant cholinesterases, and monomeric fetal bovine serum acetylcholinesterase showed a distinctive shorter mean residence time (44-304 min) compared with tetrameric forms of plasma cholinesterases (1902-3206 min). Differences in the pharmacokinetic parameters of cholinesterases seem to be due to the combined effect of the molecular weight and charge- and size-based heterogeneity in glycans.

Acetylcholinesterase↗
PubMed1998

Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology.

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.

Alzheimer Disease↗
PubMed1994

Cholinesterase activity in pregnant women and newborns.

Plasma and red blood cell cholinesterase activity in blood samples from 259 pregnant women and cord blood from some of their newborn were compared with samples from 25 nonpregnant female volunteers and with laboratory norms (Ellman method). Plasma cholinesterase was significantly lower (p < 0.05) and red blood cell cholinesterase higher (p < 0.05) in pregnant women than in nonpregnant controls in a repeated measures analysis. By the sixth post-partum week, both plasma and red blood cell cholinesterase were similar to nonpregnant control activity. Fetal cord red blood cell cholinesterase activity was also lower than in nonpregnant women, but plasma levels were not significantly different. When compared with standard laboratory normal ranges, most (98-100%) plasma cholinesterase values in pregnant women and newborn were within range, whereas the majority (59-87%, depending on trimester) of red blood cell levels were above range in pregnancy and below range in 53% of newborns. A low red blood cell cholinesterase in pregnant women is more consistent with a possible overexposure to anticholinesterases than a low plasma cholinesterase. Periods of altered sensitivity to specific cholinesterase inhibiting drugs and environmental agents are suggested by these findings.

Adolescent↗
PubMed2000

[Alteration of banked blood cholinesterase level and its significance in emergency treatment of acute organophosphorus pesticide poisoning].

OBJECTIVE: To observe the relationship between the preservation days of banked blood and the alteration level of plasma cholinesterase with the aim of making proper selection of banked blood in emergency treatment of acute organophosphorus pesticide poisoning (AOPP). METHODS: We selected at random the banked blood that has been stored for different length of time before blood transfusion so as to determine the plasma cholinesterase value. The normal plasma cholinesterase value was determined on blood samples in the Blood Center which served as a control group. The cholinesterase value was determined with a kit of the BM Company and the Cobes-Fara II automatic analysor of the Roch Company. RESULTS: It was found that there was no significant difference of plasma cholinesterase value between the one-day banked blood and the normal control group (P > 0.05), but the plasma cholinesterase values of the other experiment groups were all significantly lower than that of the control group (P < 0.05). As compared with the normal control group, the relative ratio with fixed base was about from 80 percent to 16 percent. It seems that the preservation days are in negative correlation with the cholinesterase value (r = -0.7929, P < 0.01). The curvilinear regression equation is Y = -1,823.3 Ln(X) +/- 6,229.4. CONCLUSION: With the increase of the banked blood preservation days after blood sampling, the plasma cholinesterase value decreased gradually. So in the emergency treatment of severe AOPP, it is essential to use the fresh blood collected within one day, so as to avoid missing the chance of first-aid treatment. This study provides the experimental basis for emphasizing transfusion of fresh blood and ensuring transfusion of highly active cholinesterase in treating AOPP.

Adolescent↗