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PubMed2003

The cost-benefit of cholinesterase inhibitors in mild to moderate dementia: a willingness-to-pay approach.

OBJECTIVE: This study aimed to measure the economic value of cholinesterase inhibitors when used to treat Alzheimer's disease using the willingness-to-pay (WTP) approach and the framework of cost-benefit analysis. METHODS AND STUDY DESIGN: A cost-benefit analysis using the WTP approach was employed. The study sample consisted of 28 nonprofessional caregivers of outpatients with mild to moderate dementia from Toronto, ON, Canada. The caregivers were presented with four scenarios. In the first scenario, scenario A, a hypothetical patient with mild dementia was stabilised with a cholinesterase inhibitor. In the second scenario, scenario A with adverse effects, the above patient (A) experienced adverse effects caused by the drug. In the third scenario, scenario B, the patient exhibited behavioural symptoms in addition to mild dementia, and both were stabilised with the drug. In the fourth scenario, scenario B with adverse effects, the above patient (B) experienced adverse effects caused by the drug. The caregivers were then asked what amount they would pay, in Canadian dollars, each year to buy the medication, assuming that they were the caregivers of the patient described. A multivariate regression analysis was performed to assess the relationship between the demographic data (including the caregiver's yearly income) and the WTP. The average WTP was also predicted for the general population and the elderly population of Canada using data from Statistics Canada, and these values were compared with the cost of the medication. STUDY PERSPECTIVE: Nonprofessional caregiver perspective. All monetary values are 1999 values unless otherwise specified. RESULTS: The mean yearly WTP was $Can4540 (95% CI 2334-6746) for scenario A, $Can3686 (95% CI 1530-5842) for scenario A with adverse effects, $Can5003 (95% CI 2661-7345) for scenario B and $Can4486 (95% CI 2222-6750) for scenario B with adverse effects. The WTP decreased when drug adverse effects were present (significantly in scenario A; p = 0.04), but did not significantly increase when behavioural symptoms were present and stabilised. In all scenarios, caregiver yearly income was the only significant predictor of WTP, in the direction expected. For all scenarios, the calculated WTPs from the regression analysis using our sample mean, the average Canadian population data and the elderly population data were all higher than the yearly cost of the cholinesterase inhibitors, with the net benefit ranging from $Can1723 to $Can4508. CONCLUSIONS: The results of the study, from a small sample of nonprofessional caregivers, revealed that the caregivers are willing to pay more for cholinesterase inhibitors than the drugs cost, even when the adverse effects of the drugs are taken into consideration. This indicates a net benefit for cholinesterase inhibitors in the treatment of mild to moderate dementia from a consumer's point of view.

Adult↗

PubMed1982

Effect of exposure to organophosphorus compounds on S-cholinesterase in workers removing poisonous depots.

Biological monitoring and the control of safety precautions against organophosphorus compounds (parathion, malathion, and methylparathion) was performed through the measurement of S-cholinesterase (E.C.3.1.1.8) in personnel removing poisonous depots. Depressions in S-cholinesterase activity where found in a majority of 62 workers in comparison to their preexposure values. After the last exposure the S-cholinesterase activity of the workers returned to the individual preexposure values; a few individuals needed about half a year for their S-cholinesterase activity to reach the preexposure level. As no workers showed either pathological values for the enzyme or poisoning symptoms, it was concluded that the measurement of S-cholinesterase activity is an adequate and sensitive method for monitoring and controlling exposure to organophosphorus compounds.

Adolescent↗

PubMed1979

Cholinesterase activity in Japanese quail dusted with carbaryl.

Japanese quail (Coturnix coturnix japonica) were dusted with 5% carbaryl to determine if this topical treatment would alter plasma and brain cholinesterase activities. Within 6 hours after dusting, plasma cholinesterase activity was depressed compared with controls, the depression averaging 20% for females and 27% for males. By 24 hours the cholinesterase activity of females had returned to normal, but the cholinesterase activity of males remained depressed. Brain cholinesterase activity was not affected by the treatment, and there were no overt toxic signs.

Animals↗

PubMed2001

New thiocholine ester substrates for the assay of human serum cholinesterase.

BACKGROUND: Several thiocholine alkanoyl esters were newly synthesized and explored as substrates for the assay of human serum cholinesterase after being subjected to the Ellman reaction (Arch Biochem Biophys 1958;74:443-50 and Arch Biochem Biophys 1959;82:70-7). METHODS: We synthesized thiocholine ester iodides by the method of Renshow et al. (J Am Chem Soc 1938;60:1765-70). We examined solubility in H(2)O, substrate specificity serum for cholinesterase, (spontaneous) self-hydrolysis, storage stability, and reaction conditions for measurement of the activity of the enzyme. RESULTS: Isobutyryl and cyclohexane-carboxyl esters showed the best efficiency for the specific and stable assay of human serum cholinesterase. Aqueous solubility of each was >10 mmol/L, and the reactivity with acetylcholinesterase was negligible. For isobutyryl and cyclohexane-carboxyl esters, respectively, spontaneous hydrolysis in the aqueous phase was approximately 1/25 and approximately 1/175 slower than the enzymatic hydrolysis, and assays with these substrates were linear to 1800 and 3000 U/L, respectively. The K(m) values of these acylthiocholines with human cholinesterase were almost equivalent (6.9 x 10(-3) mmol/L). The substrates were stable in aqueous solution and in the solid state as the iodides for at least 5 years at 5 degrees C. CONCLUSIONS: The isobutyrate and cyclohexane-carboxylate of thiocholine are suitable for the specific assay of human serum cholinesterase.

Cholinesterases↗

PubMed2001

[Relationship between cholinesterase, prothrombin activity and albumin and the pathology of the liver].

BACKGROUND: To investigate the relationship between serum cholinesterase, albumin and plasma prothrombin activity and the pathology of the liver in patients with viral hepatitis. METHODS: Totally 135 patients diagnosed as chronic hepatitis, cirrhosis and/or severe hepatitis with needle biopsy of liver were enrolled in this study. Serum cholinesterase and albumin of the patients were detected with enzyme rate method; meanwhile, their plasma prothrombin activity was detected with turbidimetry test. RESULTS: The percentage of decrease of the level of serum cholinesterase was higher than that of albumin and plasma prothrombin activity in chronic mild and moderate hepatitis; the level of serum cholinesterase, albumin and plasma prothrombin activity decreased gradually followed by the exacerbation of inflammatory reaction (P<0.001) and by the elevation of degree of fibrosis of the liver (P <0.001) their correlation coefficient was 0.720 to 0.778 (P<0.001). CONCLUSION: The level of serum cholinesterase could better a nd more sensitively reflect the synthetic function and the damage of the pathology of the liver than that of albumin and plasma prothrombin activity could do, they all negatively correlated with the pathology of the liver.

Adolescent↗

PubMed2002

Evidence that the clinical effects of cholinesterase inhibitors are related to potency and targeting of action.

Since degenerative alterations associated with cholinergic changes in the brains of demented patients occur in specific regions, optimal efficacy may be achieved by targeting the actions of potent cholinesterase inhibitors in relevant regions. When evaluating the activities of these agents, only cerebrospinal fluid (CSF)-based studies in demented patients provide reliable data. Preclinical or healthy volunteer studies of cholinesterase inhibitory activity using plasma or erythrocytes as an enzyme source are inconclusive due to differences between enzymes, their relative activities, and the profiles of their isoforms from different sources, with additional changes during disease progression. Tacrine and rivastigmine inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the CSF of Alzheimer's disease patients. Both enzymes are involved in the breakdown of acetylcholine (ACh) in the brain and dual inhibition may lead to greater, broader efficacy, as well as a greater potential for disease modification. However, potent and rapid elevation in levels of ACh may also induce more acute tolerability problems, such as nausea and vomiting. Only rivastigmine appears to show brain region-selectivity, particularly for regions involved in attention and behaviour and that are known to degenerate during the progression of various dementia types. This selectivity is due to preferential inhibition of the G1 form of AChE and, probably, also BuChE. Cholinesterase inhibitors that lack preferential selectivity for particular isoforms may provide less targeted actions. This may explain the relatively higher incidences of certain peripheral side effects observed during maintenance treatment with some of these drugs. All cholinesterase inhibitors interact via ACh, additionally available due to enzyme inhibition, with nicotinic and muscarinic receptors (nAChRs and mAChRs). Allosteric modulation of a presynaptic nAChR has been shown in vitro with many of these agents, and it has been proposed, but not demonstrated, that this may result in an increased release and potentiation of ACh in the brain. The clinical relevance of this mechanism is unknown. The rapidly reversible actions of donepezil, tacrine and galantamine may lead to tolerance due to their ability to upregulate target enzyme activities; however upregulation is not seen with the slowly reversible (pseudo-irreversible) inhibitor rivastigmine. Available clinical data support the hypothesis that potent, slowly reversible inhibitors of AChE and BuChE targeted to the G1 isoforms may lead to greater, broader and more sustained benefits. However, further investigation of the cholinesterase inhibitors to elucidate more definitely the clinical consequences of their differing pharmacological properties is required.

Cholinesterase Inhibitors↗

PubMed2005

Cholinesterase inhibitors in the treatment of dementia.

Dementia associated with probable Alzheimer's disease (AD) is one of the most common types of dementia. Patients with AD often have cholinergic deficits in association with the disease. The cholinesterase inhibitors donepezil hydrochloride, galantamine hydrobromide, and rivastigmine tartrate are the current mainstays of symptomatic treatment for patients with AD. In clinical trials for all three agents, beneficial effects on standard measures of cognitive and global function have been observed in patients with mild to moderate AD. Although none of the cholinesterase inhibitors has been approved for treatment of patients in advanced stages of AD, all three agents have had beneficial cognitive effects among patients with less severe forms of the disease. The author provides information on recommended dosing for all three medications, noting that cholinesterase inhibitors must be titrated carefully. When administered with caution, galantamine, rivastigmine, and donepezil are generally well-tolerated pharmacologic treatment options. The author notes that, after patients and their caregivers understand that no change in status is considered an "improvement" and a desirable clinical outcome for patients with AD, if no benefits are achieved with the use of one cholinesterase inhibitor, switching to another medication in this class might be beneficial. The author further suggests that the benefits found in cholinesterase inhibitors for patients with AD might also be applicable to patients with other types of dementia such as vascular dementia and dementia with Lewy bodies as cholinergic deficits have been reported in association with these types of dementia as well.

Acetylcholine↗

PubMed2005

Serum cholinesterase activity and proteosynthetic function of liver in patients with diabetes mellitus.

INTRODUCTION: Diabetes mellitus is associated with a lot of changes in intermediary metabolism and several authors reported on higher frequency of liver diseases in patients with diabetes. AIM OF THE STUDY: Was to establish the changes of blood serum cholinesterase, prealbumin and albumin, parameters which are accepted as an index of liver proteosynthetic function, in patients with diabetes mellitus. PATIENTS AND METHODS: The study group consisted of 207 patients with diabetes mellitus (83 patients with type I and 124 patients with type II diabetes mellitus). Control group consisted of 179 healthy subjects. The activity of cholinesterase was assayed by the kinetic method, concentrations of prealbumin and albumin were determined immunochemically. RESULTS: Activity of serum cholinesterase was significantly higher in group of patients with diabetes mellitus than in control group (65.05 vs 73.33 microkat/l). The concentration of prealbumin was lower in blood serum of patients with diabetes than in controls (308.10 vs 285.85 mg/l). Serum levels of albumin were not different in both studied groups. After dividing of patients according to the type of diabetes, 80 % of abnormal values of cholinesterase and prealbumin were present in patients with type II diabetes. CONCLUSIONS: The results of our study showed abnormal values of determined liver tests approximately in 22 % of patients with diabetes mellitus. The character of laboratory changes--increased activity of cholinesterase, decreased concentration of prealbumin and normal levels of albumin, suggests development of liver steatosis in these patients. The most of pathological findings were in patients with diabetes type II (Tab. 3, Ref. 20).

Adolescent↗

PubMed1991

[A case of serum cholinesterase anenzymia].

A report is given on a 66-year-old man suffering from serum cholinesterase anenzymia. The following tests were performed to characterize the genetic pseudo-cholinesterase variants: plasma cholinesterase activity using benzoyldicholine as substrate (according to Kalow) and dibucaine and sodium fluoride as inhibiting substances. In addition, polyacrylamide density gradient gel electrophoresis followed by esterase staining technique (Mascall) was used for the electrophoretic separation of cholinesterase isoenzymes. Similarly, the only daughter's and the granddaughter's sera were analyzed. Determination of activity and inhibitor numbers indicated that the propositus had the homozygote "silent gene" genotype (A = 2, DN = 0, FN = 0). The granddaughter showed an isoenzyme constellation within normal ranges (A = 128, DN = 80, FN = 58); for the daughter apparently normal values were also found for activity and inhibitor numbers (A = 73, DN = 82, FN = 58). Figure 1 shows the results of electrophoretic separation from the sera tested and Fig. 2 results obtained by densitometric assessment. Electrophoretic separation and the zymogram obtained from the propositus' serum show only sample peak and albumin fractions. In contrast, the granddaughter's serum turned out to be absolutely normal. In the daughter's sample, however, three cholinesterase components normally found in serum were missing, as also shown by densitometry. Despite apparently normal activity and rather insignificant inhibitor numbers, gradient gel electrophoresis clearly revealed her to be a heterozygote carrier of the silent gene Es variant. As our data are in accordance with results obtained by other investigators, this observation cannot be regarded as exceptional.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

[Cholinesterase activity in the human striatum with special consideration of the terminal islands].

The distribution pattern of cholinesterase activity in the basal forebrain region was examined in five human brains without any history of neurologic or psychiatric disorders. Complete sets of serial sections allowed a three-dimensional reconstruction of this region. The intensity grading and the distribution pattern of the specific and non-specific cholinesterase activity was depicted diagramatically. The distribution pattern of cholinesterase activity in the supracommissural striatum demonstrated the well-known striosomal configuration, particularly in the head of the caudate nucleus. Within this nucleus caudatus the striosomes appeared connected with a subventricular zone of low acetylcholinesterase-activity. Bands of very high activity could be demonstrated from the dorsolateral and ventral areas of the caudate nucleus to the lateral border of the putamen and the commissural and subcommissural division of the ventral striatum. The distribution pattern of cholinesterase activity in the subcommissural region showed very close correlation to the cytomorphological subdivisions of the striatum as defined by Brockhaus (1942). In addition to his topographic description it was possible to define the tuberculum olfactorium and several subdivisions of the interstitial nucleus of the stria terminalis. The inhibition of non-specific esterase activity by ISO-OMPA in the globus pallidus allowed distinction between striatal and pallidal components. Three-dimensional reconstructions of the terminal islands revealed several types, which were named according to their topography as insulae substriatales, -subventriculares, -olfactoriae, -magnae, and -interstitiales. Characteristically, the core of these islands consisted of clusters of tightly packed, extremely high acetylcholinesterase-positive cells. Cholinesterase activity of the surrounding rim region ranged from negative to strongly positive depending on the position and type of the island. The findings suggest that the islands represent derivatives of the fundus striati region as defined by Brockhaus and are connected to the dorsal striatum by means of cellular bridges.

Acetylcholinesterase↗

PubMedDate not supplied

Paradoxical elevation of plasma cholinesterase.

Biological monitoring of workers exposed to hazardous or toxic substances is common in industry. Plasma and red blood cell (RBC) cholinesterase activity level monitoring is used to detect early toxic effects of exposure to organophosphate and carbamate insecticides. However, the validity of plasma cholinesterase level monitoring alone in such exposures is of questionable value since depressed, normal, and elevated levels of activity in test results lead to risk assessment dilemmas. The finding of an elevated plasma cholinesterase level in an exposed plant pathologist led to referral for evaluation of test results. We reviewed the prevalence and significance of elevated plasma cholinesterase levels. The prevalence of elevated plasma cholinesterase values ranges from 1.0 percent to 12.9 percent, depending on the kind of testing and populations surveyed. The benefits and/or risks of elevated levels over time remain to be elucidated.

Adult↗

PubMed1986

Is succinyldicholine the substrate of choice for the measurement of cholinesterase activity?

We have developed a succinyldicholine-based assay for serum cholinesterase (EC 3.1.1.8) to help establish whether patients with suspected sensitivity to drugs of this type have enzyme abnormalities that cannot be detected by conventional laboratory techniques. Although the method discriminates between cholinesterase activities of drug-sensitive and nonsensitive people as well as an assay involving propionylthiocholine does, it has not revealed cholinesterase abnormalities in patients who experienced prolonged apnea after succinyldicholine, in whom no enzyme defect could be demonstrated by other procedures. Of 50 individuals who were apneic for between 20 and 180 min, only one had a cholinesterase activity less than the mean for E1u homozygotes by more than 2.5 SD. We conclude that the number of patients who experience clinical problems due to enzyme abnormalities that at present go unrecognized is small. Consequently, although succinyldicholine might eventually become the substrate of choice for cholinesterase, its advantages over propionylthiocholine are not yet sufficient to encourage its use.

Adult↗

PubMed1977

[Cholinesterase activity and expression of axial teratogenesis in quail embryo exposed to organophosphates].

The expression of the axial terotogenesis and the cholinesterasic activities have been studied simultaneously in the Quail embryo. High concentration of malathion (1 000 microgram) slightly reduces the cholinesterasic activities and does not produce morphogenetic disturbance. Bidrin (250 microgram) and parathion (100 microgram), strongly inhibit the cholinesterasic activities producing drastic axial deformities. The use of graduated concentrations of parathion shows that these axial abnormalities take place with a high level of cholinesterase inhibition. With organophosphorus, there is a good correlation between the axial teratogenesis and the cholinesterase inactivation.

Abnormalities, Drug-Induced↗

PubMed1979

[Role of the acetylcholine--cholinesterase system in the development of epilepsy].

The report pertains to some data on the cholinesterase activity in the blood serum and CSF of 62 patients with epilepsy, in correlation with different clinical characteristics (the severity of the disease, the character of the EEG, frequency of seizures, treatment efficacy, etc). In 86,8% of the cases there was a significant increase in the activity of serum cholinesterase. Increased cholinesterase activity correlated only with pronounced pathological changes in the EEG (reverse correlation) and the efficacy of treatment (direct correlation). After surgical treatment of 9 cases there was a drop in the cholinesterase activity of the blood serum and CSF, which correlated with an improvement in the general state of the patients. On the basis of personal experience, as well as literary data, it is assumed that an increase in the cholinesterase activity in epileptic patients is not related to the main etiological factors of this disease but is rather a secondary change, a peculiar "symptom" of the disease.

Adolescent↗

PubMed1982

[Cholinesterase activity in the Pacinian corpuscles in denervation and the application of colchicine to the nerve].

In the Pacinian corpuscles, cholinesterase activity was predominantly revealed along the plasma membrane and in the cytoplasm of the inner core cells. A faint quantity of histochemical end product was detected in the axis cylinder. An increased cholinesterase activity was found after the nerve transection. This change coincides in time with phagocytosis of degenerated axis cylinder by the inner core cells. A decrease in cholinesterase activity was observed in the Pacinian corpuscles after colchicine application to the nerve. This effect may be due to either the blockade of axoplasmic transport of cholinesterase in afferent nerve or/and to the elimination of the trophic influence exerted by the nerve on the cholinesterase activity in the inner care cells.

Animals↗

PubMedDate not supplied

[Interaction between various cholinesterases and reversible inhibitors of polymethylene-bis-(trimethylammonium) diiodide series].

It is established that derivatives of polymethylene bistrimethylammonium (CH3)3N+(CH2)nN+(CH3)3 (n = 4-10) are reversible competitive and mixed action inhibitors with respect to acetylcholinesterase of human erythrocytes, butyryl cholinesterase of horse blood serum, cholinesterase of frog brain and Todarodes pacificus optical ganglion. In case of mammals and frog cholinesterase the inhibitors efficiency rises with n, but the activity of the Todarodes pacificus cholinesterase less sensitive of the inhibitors is characterized by a "step" dependence on the length of the polymethylene chain of the inhibitor molecule. Studies in sensitivity of cholinesterases to this type of inhibitors revealed differences between enzymes of the same type in different animals.

Acetylcholinesterase↗

PubMed1982

[Inhibitory effect of antineoplastic agents on human cholinesterases].

Human motor endplate acetylcholinesterase was inhibited in vitro by alkylating antineoplastic agents, most strongly by mechlorethamine, followed by DTIC, ACNU, cyclophosphamide and ifosfamide. Eleven other antineoplastic agents did not inhibit the enzyme substantially nor interfered with cholinesterase measurement. Cyclophosphamide and mechlorethamine inhibited human plasma pseudocholinesterase most strongly, followed by thiotepa, ACNU, DTIC, ifosfamide and BCNU. Mechlorethamine, ACNU and ifosfamide inhibited the motor endplate and plasma cholinesterase practically equally, DTIC inhibited motor endplate cholinesterase more strongly, while cyclophosphamide was a more selective inhibitor of plasma cholinesterase. Inhibition of human red blood cell acetylcholinesterase was identical to that of motor endplate acetylcholinesterase; therefore, red cells would be a preferable indicator in monitoring cholinesterase inhibition by antineoplastic agents.

Acetylcholinesterase↗

PubMed1982

Plasma cholinesterase activity and tachyphylaxis during prolonged succinylcholine infusion.

Fifteen patients were studied during general anesthesia (nitrous oxide-fentanyl, N = 7 or nitrous oxide-isoflurane, N = 8) to determine the relationship between plasma cholinesterase activity and succinylcholine requirements during prolonged infusion. Using train-of-four stimulation, neuromuscular block was maintained at 90% for at least 1 hour, and plasma cholinesterase was measured at 30-minute intervals. During the infusion, succinylcholine requirements increased in every patient (tachyphylaxis), but there was no significant change in plasma cholinesterase activity. Succinylcholine requirements during the 1st hour of infusion in patients given fentanyl were correlated with preinfusion cholinesterase activity. It is concluded that tachyphylaxis to succinylcholine is not the result of increased metabolism from enzyme induction and that succinylcholine requirement is related to plasma cholinesterase activity.

Cholinesterases↗