Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of sarcoplasmic esterases, lipases as well as the lipid content in the myofibers of the diaphragm of rats intoxicated with the organophosphate isofenphos was studied. Lipid accumulation was documented at light, electron microsopic and by morphometric studies. The distribution of these lipid droplets was irregular and abundant in myofibers with numerous mitochondria (predominantly oxidative fibers). Histochemical inhibition of sarcoplasmic esterases and lipases was observed in the intoxicated animals. This sarcoplasmic inhibition of esterases occurs roughly in parallel to the inhibition of plasma cholinesterase activity. The inhibition of sarcoplasmic lipases may explain, at least partially, the accumulation of lipids. This inhibition probably makes difficult the use of lipids as fuel, especially in the oxidative fibers. In contrast to the small amount of muscle necrosis, (1.30+/-0.745), metabolic muscle impairment was intense and extensive, i.e., decreased activities of esterases and lipases in the sarcoplasm, that should contribute to muscle weakness. Therefore, because segmental necrosis was most prominent in oxidative fibers (and these fibers use lipids as the principal fuel and contain the greater amount of lipases in the sarcoplasm), it is possible that inhibition of activity of lipases is responsible for the segmental necrosis. Although the exact role of these metabolic changes is not known, it is possible that they contribute not only to the induction and evolution of muscle cell necrosis but also to the muscle weakness and clinical impairment of animals and humans in the acute intoxication by these compounds.
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PMID:Sarcoplasmic lipase and non-specific esterase inhibition in myofibers of rats intoxicated with the organophosphate isofenphos. 1004 10

This paper investigates the acute effects of carbofuran in workers of two pesticide-formulating plants. Mean airborne carbofuran concentrations ranged from 0.025 to 1.115 mg/m3 in plant A and from 0.018 to 0.067 mg/m3 in plant B, respectively. In workers of plant A the post-shift blood cholinesterase activity was significantly reduced, compared to pre-shift values. No difference in blood cholinesterase activity was found between pre- and post-shift values in workers of plant B. During the investigation, 25 cases of acute carbofuran poisoning were diagnosed by their clinical picture and depressed cholinesterase activity in blood. Usual symptoms included dizziness, weakness, blurred vision, nausea and sweating. Pallor, epigastric pain, vomiting and chest tightness occurred only in a few cases. Myosis was recorded in 24 cases. Fasciculation of muscle gastrocnemius induced by percussion was found in 6 cases, and four of them had also fasciculation of muscle orbicularis oculi. Inhibition of cholinesterase activity in the blood was related with the clinical features; however, the inhibition was rapidly reversible. In most cases, recovery was complete within 2-3 hours, with or without atropine treatment, after the subjects were removed from exposure. Rapid onset, mild illness and quick recovery are typical characteristics of occupational acute carbofuran poisoning.
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PMID:Acute effects of carbofuran in workers of two pesticide plants. 1021 31

Acrylamide intoxication produces peripheral neuropathy characterized by weakness and ataxia in both humans and experimental animals. Previous studies on animals of different ages and species indicate that the longest and largest nerves are affected earlier with the major pathology in the terminal parts of axons, i.e., distal axonopathy. However, several issues have remained elusive; for example, what are the earliest pathological changes? An equally intriguing question is whether younger animals are more susceptible to acrylamide than older animals. To address these issues, we compared the vulnerability to acrylamide of 3- and 8-week-old mice. These mice were intoxicated with acrylamide in drinking water (400 ppm). The sequence of intoxication could be categorized into three stages. In the initial stage, there was no visible weakness or ataxia. The only noticeable changes were poor performance on the rota-rod test and swelling of motor nerve terminals. Obvious weakness and ataxia of hindlimbs developed gradually (here designated as the early stage). The weakness and ataxia progressed at variable speeds in mice of different ages, and eventually the forelimbs (quadriparesis) were affected in the late stage. Each stage appeared earlier in 3-week-old mice than in 8-week-old mice (7.1 +/- 1.1 vs 15.6 +/- 4.0 days, P < 0.01 for the early stage; and 15.3 +/- 2.1 vs 31.7 +/- 6.0 days, P < 0.01 for the late stage). The progression of neurological deficits was also faster in the younger mice (7.2 +/- 1.8 vs 16.3 +/- 4.2 days, P < 0.01). Pathological changes in the distal parts of motor nerves innervating hindfoot muscles were evaluated by combined cholinesterase histochemistry and immunocytochemistry for neuronal markers to demonstrate motor nerve terminals and neuromuscular junctions simultaneously. In the initial stage, there was axonal swelling in motor nerve terminals. As acrylamide intoxication continued, axonal swelling extended into junctional folds and into the intramuscular nerves, which resulted in Wallerian-like degeneration. Our results indicate that younger mice show a much higher susceptibility to acrylamide intoxication, and pathological changes precede neurological symptoms.
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PMID:Age-dependent acrylamide neurotoxicity in mice: morphology, physiology, and function. 1044 16

We reported a 63-year-old woman, suffered from myasthenia gravis with thymoma who later developed subacute motor neuronopathy after thymectomy. She noticed distally dominant muscle weakness and atrophy of bilateral upper extremities without sensory loss 4 month after thymomectomy. Her muscle weakness did not improve by intravenous administration of anti-cholinesterase (Tensilon test). Electrophysiological examinations showed no decremental response of examined muscles during repetitive nerve stimulation, nor motor nerve conduction block nor demyelination of affected peripheral nerves. Laboratory study demonstrated positive anti-acetylcholine receptor, anti-nuclear and SS-A antibodies. On immunohistochemistry, the patient's sera positively stained human and rat anterior horn cell cytoplasm as well as axoplasm of spinal white matter and root nerve axon, suggesting the presence of anti-axon antibody, possibly against neurofilament or tubulin components. The biopsied muscle specimen showed neurogenic muscle changes, but with no evidence of vasculitis nor cellular infiltration. Therapeutic trial of plasmapheresis was effective for her muscle weakness. Further recovery of weakness and muscle atrophy of hand muscles was obtained by combined therapy of intravenous and oral corticosteroid administration and plasmapheresis. These clinical, electrophysiological and histological findings suggested that antibodies against neuronal component might be responsible for her motor neuronopathy associated with myasthenia gravis. The findings of our case study may support the idea that some cases of motor neuron disease are caused by auto-immune mechanism.
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PMID:[Subacute motor neuronopathy associated with myasthenia gravis and thymoma]. 1054 13

Forty years ago, a patient with MG probably had a fifty-fifty chance of surviving a myasthenic crisis, defined as the need for mechanical ventilatory support. Approximately 16% of all patients experience a crisis, a figure that has not changed appreciably since then. Progressive weakness, oropharyngeal symptoms, refractoriness to anticholinesterase medication, intercurrent infection, and invasive procedures including needle biopsies of thymic gland masses, and reactions to contrast agents used in the performance of CT of the chest have been implicated in the development of crisis. It is now standard practice to treat severe crisis in an intensive care unit. The ready availability of intensive care in most hospitals belies the fall in the mortality of myasthenic crisis to 6% over the past several decades. Crisis is a temporary exacerbation, regardless of the proximate cause, and the goal is to keep the patient alive until it subsides, usually in 2 weeks. In the past, edrophonium was used to differentiate myasthenic crisis from cholinergic crisis, but that is now moot because withdrawal of cholinesterase medication is necessary for improvement in both situations. The underlying immunologic derangements in myasthenic crisis are not well understood, but there is a rapidly fatal antibody-mediated syndrome that bears resemblance to crisis and is associated with inflammation and necrosis of the end-plate region.
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PMID:Medical therapies in myasthenia gravis. 1141 59

A patient was a fifty-year-old man, who had a 35 year-history of facioscapulohumeral muscular dystrophy (FSHD). He was admitted to our hospital because of acute progressive weakness involving his lower extremities without any fluctuation in the recent 3 weeks. We clinically followed him for 30 years and he was able to do all daily activities, walked alone, drove a car and climbed stairs with a handrail. His 76-year-old mother had about 60 year-history of FSHD and could walk with support. On admission, neurological examination revealed moderate to marked muscle weakness and atrophy of the face, limb-girdle and all extremities, predominantly in the upper proximal limbs. He could hardly stand and needed a stick for walking. He had no blepharoptosis or ocular movement disturbance, and did not complain of difficulties in swallowing and chewing. CK values and other laboratory data were normal, and serum anti-Jo-1 antibody, anti-SSA/Ro antibody and anticardiolipin IgG antibody were negative. Because EMG examination revealed myopathic changes and an X-ray examination of the lumbar spine was normal. Thus, polymyositis and neurologenic disorders were ruled out. Disturbance in chewing and swallowing, that were uncommon in FSHD, appeared about a month after admission. Repetitive stimulation test revealed typical waning pattern. Edrophonium chloride injection was effective for decreased waning and the clinical symptoms. The titer of serum anti-ACh receptor antibody was 97 nmol/l, confirming the diagnosis of myasthenia gravis. Because of fluctuated dyspnea, thymectomy was done and his condition gradually relieved after administration of corticosteroid and choline esterase inhibitor. From this experience, we learned that we have to consider other neuromuscular disorders, even rare ones, if there existed unusual weakness of underlying muscular dystrophy.
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PMID:[A patient with facioscapulohumeral muscular dystrophy accompanied by myasthenia gravis]. 1167 58

A 50-year-old man swallowed 200 ml of an insecticide containing the organophosphates dimethoate and phenitrotion in an attempted suicide. On admission, signs of a cholinergic syndrome were observed: miosis, rhinorrhoea, and fasciculations. This was followed by bradycardia with hypotension and vomiting. The patient was treated with the antidotes atropine and obidoxime. Decreasing consciousness necessitated intubation, mechanical ventilation and other supportive measures. Although the serum concentrations of both organophosphate compounds rapidly decreased, the activity of cholinesterase showed a prolonged inhibition. The clinical course was complicated by hypotension, acute respiratory distress syndrome, nosocomial pneumonia, and an epileptic seizure. A period with muscle weakness and a persisting depressive disorder then followed. This case is characteristic for acute intoxications with irreversible acetylcholinesterase inhibitors, such as organophosphate compounds. The treatment of these potentially severe intoxications includes rapid decontamination and the administration of high doses of atropine followed by obidoxime. Mechanical ventilation and circulatory support are also indicated.
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PMID:[Poisoning with organophosphate compounds]. 1180 37

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.
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PMID:The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. 1213 67

Ten to twenty percent of the offspring of mothers suffering from myasthenia gravis (MG) also develop transient neonatal MG, since maternal antibodies are able to cross the placenta. We report the course of two newborns of a mother with MG and a healthy father. The first pregnancy was complicated during the 3rd trimester by a hydramnion. The newborn presented with generalized muscle weakness, respiratory distress, weak sounding, anaemia, and poor sucking. Mechanical ventilation was necessary. Confirmation of the diagnosis was achieved by the result of repetitive muscle stimulation, showing a typical decrement in the EMG, and measurement of serum antiacetylcholin receptor antibodies. For 3 months, the infant was treated with neostigmin (cholinesterase inhibitor). After 26 days of hospitalization, the patient was released and followed up regularly. Myasthenic symptoms completely resolved. Side effects of the treatment were not observed. The course of the second pregnancy was normal. This second newborn was healthy. Our case report is remarkable for the very different presentation of two children of the same mother with MG during pregnancy and after delivery, with one child developing severe transient neonatal MG, initially requiring intensive care unit (ICU) treatment followed by quick recovery, and one child being healthy. We also present a score for monitoring the clinical course and adjusting anticholinesterase therapy accordingly.
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PMID:[Transient neonatal myasthenia gravis]. 1224 67

Pesticides, such as parathion, are metabolized by cytochrome p-450 system to paraoxon, which is a potent cholinesterase inhibitor. Paraoxonase (PON) catalyzes the hydrolysis of these toxic metabolites and protects against pesticide toxicity. A glutamine/arginine (Gln/Arg) polymorphism at amino acid position 192 of PON has been described. The Arg/Arg genotype is associated with higher serum paraoxonase activity compared to Gln/Gln. The Arg/Gln genotype is associated with intermediate serum PON activity. The potential association between PON genotype and symptoms of chronic pesticide toxicity was examined among 100 farm workers. As part of a cross-sectional study of pesticide toxicity among mixed-race farm workers in the Western Cape. South Africa, 100 farm workers were genotyped for polymorphism of the paraoxonase gene at amino acid position 192. Subjects with two or more of the following symptoms were considered to have evidence of chronic toxicity: abdominal pain, nausea, rhinorrhea, dizziness, headache, somnolence, fatigue, gait disturbance, limb numbness, paresthesias, limb pain, or limb weakness. In multivariable logistic regression analysis, the independent predictors of chronic toxicity were previous history of head trauma resulting in loss of consciousness (OR 2.8, 95% CI = 1.7-6.7), having worked as a pesticide applicator (OR 5.4, 95% CI = 3.2-8.9), and having one of the two "slow metabolism" (Gln/Gln or Gln/Arg) genotypes (OR 2.9, 95% CI = 1.7-6.9). Furthermore, the prevalence of chronic toxicity increased in a stepwise fashion from 15% among pesticide nonapplicators with a "fast metabolism" (Arg/Arg) genotype, to 42.9% among pesticide nonapplicators with "slow metabolism" (Gln/Gln or Gln/Arg) genotypes, to 58.8% among pesticide applicators with "fast metabolism" genotype, and 75.0% among pesticide applicators with "slow metabolism" genotypes (P = 0.001). Age, number of years on the job, smoking history, alcohol history, education level, plasma or red blood cell cholinesterase level, or previous history of acute organophosphate poisoning were not statistically significant predictors of chronic toxicity. The PON genotype is an important determinant of a farmworker's susceptibility to chronic pesticide poisoning.
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PMID:Association between human paraoxonase gene polymorphism and chronic symptoms in pesticide-exposed workers. 1262 27


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