In acute severe anticholinesterase poisoning by organophosphate compounds, pralidoxime (P-2-AM, pyridine-2-aldoxime methiodide) used in the recommended doses, intravenously, has not been shown to reactivate the inhibited cholinesterase, as evidenced both clinically and biochemically. In vitro studies using pralidoxime iodide up to ten times the recommended concentrations, produced insignificant reactivation of cholinesterases inhibited by the organophosphate insecticide Bidrin (di-methyl-3-hydroxyl-N, N-dimethyl-crotonamide phosphate). This was even so despite prolonged exposure of the inhibited cholinesterases to the oxime. The value of pralidoxime as a reactivator of phosphorylated cholinesterases is therefore in doubt, and should not be used in preference to large doses of atropine and other supportive treatment in poisoning by organophosphate insecticides.
Five patients were bitten by the Malayan krait Bungarus candidus (Linnaeus) in eastern Thailand or north western Malaya. Two patients were not envenomed but the other three developed generalised paralysis which progressed to respiratory paralysis in two cases, one of which ended fatally. One patient showed parasympathetic abnormalities. Anticholinesterase produced a dramatic improvement in one patient. Another patient probably benefited from paraspecific antivenom. The efficacy of antivenoms and adjuvants such as anticholinesterases in patients with neurotoxic envenoming requires further study.
Trimeresurus purpureomaculatus venom acetylcholinesterase has been partially purified by Sephadex G-200 gel filtration chromatography and DEAE Sephacel ion exchange chromatography. The enzyme has a mol. wt of 58,600. It was strongly inhibited by physostigmine salicylate and edrophonium chloride and exhibited substrate inhibition at high substrate concentration. The content of acetylcholinesterase in Trimeresurus purpureomaculatus venom was estimated to be much less than 0.3%.
Alzheimer's disease (AD) has become recognised as a major cause of morbidity and mortality in the ageing population worldwide. Over 20 million people worldwide are affected by AD, which ensures that the disease imposes a major economic burden. Alzheimer's disease is a progressive neurodegenerative disorder with characteristic clinical and neuropathological features. Neurofibrillary tangles, neuritic plaques and amyloid angiopathy occur in varying severity in brains of patient's with Alzheimer's disease. Biological markers of AD allowing an early definitive premorbid diagnoses are currently not available. Memory loss for recent events is invariable and often the earliest prominent symptom. Language disorders, difficulties with complex tasks, depression, psychotic symptoms and behavioral changes are other common manifestations of AD. Diagnosis involves the early detection of cognitive decline and ruling out other causes of dementia like vascular dementia, Lewy body dementia, fronto-temporal degeneration or reversible causes like hypothyroidism. Acetylcholinesterase inhibitors have shown to be effective in mild to moderate AD in improving the cognitive function of patients in clinical trials. Caregiver intervention programs have considerable potential to improve both the caregiver and patient quality of life.
Matched MeSH terms: Cholinesterase Inhibitors/therapeutic use
We describe a patient with myasthenia gravis and thymoma who developed recurrent severe myasthenic crises associated with the use of combination chemotherapy.
Poisoning is one of the most important causes of morbidity and mortality in developing countries like India. Anticholinesterase compounds like organophosphates (OP) and carbamates account for the majority of these poisoning cases because of their easy availability and agricultural use. Carbamates are as popular as OPs as insecticides that often go undiagnosed. A fatal case of carbofuran poisoning is presented where serial cholinesterase estimation played a major role in the diagnosis of the same. The pertinent medical literature on carbofuran poisoning is reviewed. The establishment of poison information center in each state is needed for proper diagnosis and management of poisoning cases.
A cross-sectional study was conducted to investigate the effects of acute and chronic pesticide exposure on the plasma beta-glucuronidase enzyme activity among five patients of acute pesticide poisoning in Tengku Ampuan Rahimah Hospital, Klang, 230 farmers in the MADA area, Kedah and 49 fishermen in Setiu, Terengganu. The duration of pesticide exposure among the patients was unknown, but the plasma samples from patients were collected on day one in the hospital. The duration of pesticide exposure among the farmers was between 1 and 45 years. The beta-glucuronidase activity was compared with plasma cholinesterase activity in the same individual. The plasma cholinesterase activity was measured using Cholinesterase (PTC) Reagent set kit (Teco Diagnostics, UK) based on colorimetric method, while the plasma beta-glucuronidase activity was measured fluorometrically based on beta-glucuronidase assay. The plasma cholinesterase activity was significantly reduced (p<0.05) among the patients (1386.786+/-791.291 U/L/min) but the inhibition in plasma cholinesterase activity among the farmers (7346.5+/-1860.786 U/L/min) was not significant (p>0.05). The plasma beta-glucuronidase activity among the farmers was significantly elevated (p<0.05) (0.737+/-0.425 microM/h) but not significant among the patients (p>0.05). The plasma cholinesterase activity was positively correlated with the plasma beta-glucuronidase activity among the farmers (r=0.205, p<0.01) but not among the patients (r=0.79, p>0.05). Thus, plasma beta-glucuronidase enzyme activity can be measured as a biomarker for the chronic exposure of pesticide. However, further studies need to be performed to confirm whether plasma beta-glucuronidase can be a sensitive biomarker for anticholinesterase pesticide poisoning.
Dermal absorption of chlorpyrifos, an organophosphate insecticide is important because of its use in agriculture and control of household pests. The objectives of this study are to investigate firstly, the biochemical changes in the blood and secondly, histomorphometric changes in the hippocampus of adult mice following dermal application of chlorpyrifos in sub-toxic doses. Male Swiss albino mice (60 days) were segregated into one control and two treated groups (n=10). Chlorpyrifos, diluted with xylene, was applied in doses of 1/2 of LD(50) (E1) and 1/5 of LD(50) (E2) over the tail of mice of the two treated groups, 6 hours daily for 3 weeks. AChE levels in the serum and brain were estimated using a spectrophotometric method (Amplex Red reagent). Coronal serial sections were stained with 0.2 % thionin in acetate buffer and pyramidal neurons of Cornu Ammonis of hippocampus were counted at 400x magnification using Image Pro Express software. At the end of 3 weeks, body weights were reduced significantly in E1 group. Serum AChE concentrations were reduced by 97 % in E1 and 74 % in E2 groups compared to controls. The neurons of CA 3 and CA 1 in the hippocampus showed evidences of morphological damage in both treated groups. Furthermore, the neuronal count was significantly reduced in CA 3 layer of hippocampus in E1 group.
An inhibitive assay of insecticides using Acetylcholinesterase (AChE) from the local fish Clarias batrachus is reported. AChE was assayed according to the modified method of Ellman. Screening of insecticide and heavy metals showed that carbofuran and carbaryl strongly inhibited C. batrachus AChE. The inhibition concentration (IC) IC50 values (and the 95% confidence interval) for both carbofuran and carbaryl inhibition on C. batrachus AChE at 6.66 (5.97-7.52) and 130.00 (119.3-142.5) microg l(-1), respectively was within the IC50 range of Electrophorus electricus at 6.20 (6.03-6.39) and 133.01 (122.40-145.50) microg l(-1), respectively and were much lower than bovine AChE at 20.94 (19.53-22.58) and 418.80 (390.60-451.60) microg l(-1), respectively. The results showed that C. batrachus have the potential to be used as a cheaper and more readily available source of AChE than other more commercially available sources.
Normal platelet functions are critical for achieving primary haemostasis. Numerous medications have been shown to affect platelet functions. Pyridostigmine (Mestinon), an orally active cholinesterase inhibitor that is commonly used to treat myasthenia gravis has been documented to cause epistaxis and prolonged bleeding after a cut in anectodal reports. This study was initiated after a patient diagnosed to have myasthenia gravis, developed multiple bruises a week after being started on Mestinon. The objective of this study was to investigate the effect of Mestinon on platelet aggregation stimulated with various agonists in vitro.
A significant acetylcholinesterase (AChE) inhibitory activity was observed for the hexane extract from the bark of Mesua elegans (Clusiaceae). Thus, the hexane extract was subjected to chemical investigation, which led to the isolation of nine 4-phenylcoumarins, in which three are new; mesuagenin A (1), mesuagenin C (3), mesuagenin D (4) and one new natural product; mesuagenin B (2). The structures of the isolated compounds were characterized by spectroscopic data interpretation, especially 1D and 2D NMR. Four compounds showed significant AChE inhibitory activity, with mesuagenin B (2) being the most potent (IC(50)=0.7μM).
Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors. Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. Compound 4k, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.10 μmol/L. Pyrolidine analogues might be potential acetyl cholinesterase agents for AD.
Coriandrum sativum L., commonly known as coriander and belonging to the family Apiaceae (Umbelliferae), is cultivated throughout the world for its nutritional value. The present study was undertaken to investigate the effects of fresh Coriandrum sativum leaves (CSL) on cognitive functions, total serum cholesterol levels and brain cholinesterase activity in mice. In this study, CSL (5, 10 and 15% w/w of diet) was fed orally with a specially prepared diet for 45 days consecutively to experimental animals. Elevated plus-maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam, scopolamine and ageing-induced amnesia served as the interoceptive behavioral models.
Matched MeSH terms: Cholinesterase Inhibitors/pharmacology; Cholinesterase Inhibitors/therapeutic use
Hexacyclic derivatives share vital pharmacological properties, considered useful in Alzheimer's disease. The aim of this study was synthesis and its evaluation for acetyl cholinesterase inhibitory activity of novel hexacyclic analogues. Compound 4f, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.72 μmol/L.
Bioassay-guided extraction of the stem bark of Knema laurina showed the acetylcholinesterase (AChE) inhibitory activity of DCM and hexane fractions. Further repeated column chromatography of hexane and DCM fractions resulted in the isolation and purification of five alkenyl phenol and salicylic acid derivatives. New compounds, (+)-2-hydroxy-6-(10'-hydroxypentadec-8'(E)-enyl)benzoic acid (1) and 3-pentadec-10'(Z)-enylphenol (2), along with known 3-heptadec-10'(Z)-enylphenol (3), 2-hydroxy-6-(pentadec-10'(Z)-enyl)benzoic acid (4), and 2-hydroxy-6-(10'(Z)-heptadecenyl)benzoic acid (5) were isolated from the stem bark of this plant. Compounds (1-5) were tested for their acetylcholinesterase inhibitory activity. The structures of these compounds were elucidated by the 1D and 2D NMR spectroscopy, mass spectrometry and chemical derivatizations. Compound 5 showed strong acetylcholinesterase inhibitory activity with IC(50) of 0.573 ± 0.0260 μM. Docking studies of compound 5 indicated that the phenolic compound with an elongated side chain could possibly penetrate deep into the active site of the enzyme and arrange itself through π-π interaction, H-bonding, and hydrophobic contacts with some critical residues along the complex geometry of the active gorge.
Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer's disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC(50) 0.11μmol/L.
The asiatic acid, a triterpenoids isolated from Centella asiatica was used to delineate its inhibitory effect on acetylcholinesterase (AChE) properties, excitatory post synaptic potential (EPSP) and locomotor activity. This study is consistent with asiatic acid having an effect on AChE, a selective GABA(B) receptor agonist and no sedative effect on locomotor.
Alzheimer's disease (AD) is the most common form of dementia among older people and the pathogenesis of this disease is associated with oxidative stress. Acetylcholinesterase inhibitors with antioxidant activities are considered potential treatments for AD. Some novel ketone derivatives of gallic hydrazide-derived Schiff bases were synthesized and examined for their antioxidant activities and in vitro and in silico acetyl cholinesterase inhibition. The compounds were characterized using spectroscopy and X-ray crystallography. The ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays revealed that all the compounds have strong antioxidant activities. N-(1-(5-bromo-2-hydroxyphenyl)-ethylidene)-3,4,5-trihydroxybenzohydrazide (2) was the most potent inhibitor of human acetyl cholinesterase, giving an inhibition rate of 77% at 100 μM. Molecular docking simulation of the ligand-enzyme complex suggested that the ligand may be positioned in the enzyme's active-site gorge, interacting with residues in the peripheral anionic subsite (PAS) and acyl binding pocket (ABP). The current work warrants further preclinical studies to assess the potential for these novel compounds for the treatment of AD.
Chlorpyrifos (CPF), an organophosphate pesticide inhibits acetylcholinesterase (AChE) and causes neuromuscular incoordination among children and elderly. The objectives of the present study were to compare the neurotoxic effects of dermal application of CPF on the cerebellum in the parameters of glial fibrillary acidic protein (GFAP) expression in young and adult mice and to correlate with the changes in acetylcholinesterase levels. Male Balb/c mice, 150 days old (adult) and 18 days old (young) were dermally applied with ½ LD(50) of CPF over the tails for 14 days. Serum AChE concentration was estimated and GFAP immunostaining was performed on sagittal paraffin sections through the vermis of cerebellum. Although reduced in both age-groups exposed to CPF, percentage of reduction in serum AChE was more in adult compared to the young. Under GFAP immunostaining, brown colour fibres and glial cells were observed in cerebellar cortex and medulla in both the experimental groups. The mean GFAP-positive glial cell count in cerebellar medulla per mm(2) of section was significantly (p