Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyridostigmine bromide (Pyr), a reversible cholinesterase inhibitor, is currently suggested to be the most effective pretreatment drug against intoxication with potent organophosphates (OP). This investigation was conducted to determine if oral low doses of Pyr would affect performance of a simple visual discrimination task, and further to assess the alterations of motor or motivational function that might underlie the performance deficits in the water-deprived rats. Rats were trained extensively on a successive light-intensity discrimination implemented with the use of a multiple schedule. The multiple schedule consisted of one fixed-ratio (FR-10) and one differential reinforcement of low rates (DRL-10 s) component, which were signalled by the 10-s discriminative stimuli of bright (S+) and dim (S-) houselights, respectively, in simple alternation. The light intensity difference (S-/S+) was about 0.6. Pyr, at doses (3-12 mg/kg), which did not cause overt symptoms, moderately decreased S+ respondings but did not affect S- respondings. The ratio of S+/S- respondings, an index of discrimination performance, was moderately decreased. Over the range of doses evaluated, Pyr also attenuated the corresponding water intake in a dose-dependent manner, but it did not significantly affect locomotor activity. The lowest effective doses of the above affected behaviors were virtually identical (6 mg/kg). These results suggest that the disruptive effects of a single oral low dose of Pyr on the rat operant performance involve motivational dysfunction rather than motor impairment.
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PMID:Acute effects of oral low doses of pyridostigmine on simple visual discrimination and unconditioned consummatory acts in rats. 153 77

Pyridostigmine bromide, a reversible inhibitor of acetylcholinesterase (AChE), is effectively used as a pre-treatment to organophosphate intoxication. Previous studies have shown that an oral dose of 30 mg twice a day produces a sufficient inhibition of the enzyme activity (20-40%) without causing any significant adverse effect. During the Persian Gulf war pyridostigmine was taken for the first time under a chemical warfare threat. We searched for symptoms and complaints that may be related to the medication. Our survey included 213 soldiers who completed a questionnaire regarding possible symptoms and their severity. AChE inhibition level was compared between groups of soldiers with and without complaints. The most frequent symptoms were nonspecific and included dry mouth, general malaise, fatigue and weakness. Typical effects, such as nausea, abdominal pain, frequent urination and rhinorrhea, were infrequent. The severity of the symptoms was generally mild. The symptoms appeared around 1.6 h after taking the medication and recurred after each intake. No correlation was found between levels of cholinesterase and type or severity of complaints. Anxiety, which accompanies wartime, may have contributed to the appearance of significant symptoms. Further investigations concerning the effects of pyridostigmine ingestion under stressful conditions are warranted.
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PMID:Survey of symptoms following intake of pyridostigmine during the Persian Gulf war. 175 41

Pyridostigmine bromide (Pyr), the current drug of choice in the management of myasthenia gravis, has been suggested for use in Alzheimer's dementia, and as a prophylactic treatment for intoxication with organophosphate cholinesterase inhibitors. The present study was undertaken to evaluate the dose-response and time-course effects of acute oral administration of Pyr over a broad dose range (3-40 mg/kg) on the lever pressing of rats maintained under a multiple fixed-ratio (FR-20) time-out schedule of reinforcement for water reward. The drug produced a dose-dependent biphasic response depression in the overall rate of FR responding. Low doses of Pyr (less than or equal to 12 mg/kg) that caused no gross signs of toxicity only moderately decreased rates of responding, primarily due to a decrease in response rates. Whereas high doses of Pyr (greater than 24 mg/kg) which produced overt signs of peripheral cholinergic intoxication markedly suppressed overall responding, primarily due to cessation of responding. The lowest effective dose of performance disruption was 6 mg/kg, and the ED50 was calculated as 23.3 (17.9-28.7) mg/kg. The time-course data of performance disruption showed that low doses of Pyr (less than or equal to 12 mg/kg) had an onset latency within 40-80 min and a duration of 20-80 min, whereas high doses (greater than or equal to 24 mg/kg) had an onset latency of 20-40 min and a duration greater than 80 min. These results suggest the recommended human therapeutic or prophylactic regimen of 30-120.mg Pyr, orally taken each 8 hours, might adversely affect behavioral performance.
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PMID:Acute effects of oral pyridostigmine bromide on conditioned operant performance in rats. 206 91

Five subjects exercised on a cycle ergometer for 30 min at 55% peak oxygen consumption on two occasions in an environmental test chamber (ambient temperature = 29 degrees C; dew point temperature = 10 degrees C). Pyridostigmine bromide (PYR), an acetylcholinesterase (AChE) inhibitor, was ingested (30 mg) approximately 150 min before one experiment, and no drug was administered during the other experiment (control). Red blood cell AChE inhibition averaged 40 (+/- 7)% during PYR treatment. Esophageal temperature (Tes), an eight site-derived mean skin temperature, forearm blood flow (FBF; venous occlusion plethysmography), skin blood flow (SkBF; laser-Doppler velocimetry), and metabolic rate (indirect calorimetry) were measured. SkBF decreased 37% after PYR treatment compared with control (P less than or equal to 0.05). The Tes threshold for initiation of cutaneous vasodilation was 36.8 (+/- 0.3) degrees C for the control treatment and 37.0 (+/- 0.3) degrees C for the PYR treatment (P less than or equal to 0.01). FBF was not significantly different between treatments, whereas heart rate was reduced by 7 and 9 beats/min during rest and exercise, respectively (P less than or equal to 0.01). The increased threshold for initiation of cutaneous vasodilation with AChE inhibition by PYR is compatible with nonthermal modulation of the control of thermoregulation through increased acetylcholine (ACh) accumulation. This could potentiate preganglionic transmission to enhance adrenergic vasoconstrictor tone. One suggested mechanism possible at the neuroeffector junction of the sweat gland may be that accumulated ACh diffusion across the adventitia of adjacent arterioles to muscarinic receptors initiates contraction of the smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylcholinesterase inhibitor, pyridostigmine bromide, reduces skin blood flow in humans. 218 85

Pyridostigmine bromide, a reversible cholinesterase inhibitor, was administered orally (capsule gavage) to beagle dogs (10-15 months of age) of both sexes once daily at 5, 10, or 20 mg/kg for 14 days; every 8 hr at 2 or 5 mg/kg for 28 days; or every 8 hr at 0.05, 0.5, or 2 mg/kg for 3 months as part of its preclinical safety assessment. A small portion of the dogs receiving pyridostigmine for 3 months were allowed an untreated recovery period of an additional 3 months. Daily doses of 10 or 20 mg/kg were lethal to some of the dogs when given for up to 14 days and caused severe intestinal distress, including diarrhea, emesis, and reddened feces in all animals. The cause of death was intestinal intussusception. Signs of systemic toxicity apparent at these doses included hypersalivation and tremors. Similar but less severe effects were produced by 5 mg/kg per day; plasma cholinesterase activities were inhibited by all three doses in a dose-related manner. Signs of toxicity in the 28-day and 3-month studies were generally limited to the gastrointestinal tract and included diarrhea or soft stools and reddened or mucoid-containing stools; these signs appeared to reverse upon discontinuation of the drug. A single dog at 2 mg/kg every 8 hr developed an apparent intussusception. There were no pathological changes in clinical chemistry, hematology, or urinalysis parameters associated with doses of 0.05, 0.5, or 2 mg/kg every 8 hr for up to 3 months, nor were any drug-related lesions observed upon gross necropsy and microscopic evaluation of the major tissues and organs. Red blood cell (RBC) acetylcholinesterase (AChE) activities in the 3-month study were inhibited by approximately 10, 50, and 70% in the 0.05, 0.5, and 2 mg/kg every 8-hr dose groups, respectively, and these degrees of inhibition were maintained throughout the period of treatment. These data suggest that prolonged oral administration of pyridostigmine at doses sufficient to cause profound and sustained inhibition of RBC AChE activity (i.e., as high as 70%) cause mainly local, gastrointestinal distress related to altered intestinal motility. At the extreme, this can be manifested as a life-threatening intestinal intussusception. Systemic anticholinesterase effects (other than enzyme inhibition) were observed only at doses of 2 mg/kg and greater, while local (gastrointestinal) effects and inhibition of RBC AChE were observed at doses as low as 0.05 mg/kg.
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PMID:Pharmacological and toxicological evaluation of orally administered pyridostigmine in dogs. 230 21

Pyridostigmine bromide is currently the pretreatment of choice for operation in a chemical warfare (CW) environment. Under CW conditions, subjects are exposed to thermal stress caused by CW protective clothing. This investigation was conducted to determine if pyridostigmine affects various physiological and biophysical parameters of human temperature regulation in subjects wearing CW protective clothing. Pyridostigmine was administered orally in a randomized double-blind cross-over study in four doses of 30 mg every 8 h. An average of 33% whole blood cholinesterase inhibition was induced in the pyridostigmine treated group 4 h after ingestion of last tablet. The subjects were exposed to 170 min exercise-heat stress (Tdb = 33 degrees C; rh = 60%) consisting of 60 min in a sitting position and two 50-min walks (1.39 m.s-1, 5% grade) separated by 10 min of rest. Non-evaporative heat exchange was significantly higher, -14.0 and -10.6 W.m-2 (p less than 0.03), for the pyridostigmine-treated subjects. No additional differences were found between treatments in the physiological responses and heat balance parameters at the end of exposure: heart rate (HR) was (mean +/- S.D.) 154 +/- 16 and 151 +/- 24 bpm, rectal temperature (Tre) was 39.0 +/- 0.4 and 38.9 +/- 0.2 degrees C, heat storage over the 2 h of exercise was 62 +/- 15 and 70 +/- 15 W.m-2, and sweat rate was 832 +/- 185 and 748 +/- 52 g.h-1, in the pyridostigmine and placebo treatments, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heat-exercise performance of pyridostigmine-treated subjects wearing chemical protective clothing. 233 65

Pyridostigmine bromide, a quaternary carbamate, is widely used in treatment of myasthenia gravis and has been suggested for use in prophylaxis against intoxication with irreversible cholinesterase inhibitors. Since there are virtually no anatomical data concerning the neuromuscular toxicity of the drug, this study was undertaken to evaluate the effects of acute and subacute doses of pyridostigmine on the ultrastrucutre of nerve terminals in rat diaphragm neuromuscular junctions (NMJs). Pyridostigmine in a Mestinon-equivalent buffer was administered by single, subcutaneous injection (acute exposure; 10-30 min) or by a subcutaneously implanted Alzet osmotic minipump (subacute exposure; 2, 7 or 14 days). Acute exposure doses ranged from 0.0036 mg/kg to 3.6 mg/kg (0.001-1.0 LD50), while subacute exposure doses ranged from 0.43 to 20 mg of the drug. Both acute and subacute exposures resulted in dose dependent alterations of presynaptic elements in diaphragmatic NMJs, which included disruption of organelles in the axon terminal, regional or total withdrawal of the nerve terminal from postsynaptic junctional folds, and invasion of Schwann cell fingers into the synaptic cleft. These ultrastructural observations suggest that the normal cell-to-cell interactions at diaphramatic NMJs are altered by this "reversible," cholinesterase inhibiting drug.
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PMID:Ultrastructural effects of pyridostigmine on neuromuscular junctions in rat diaphragm. 371 19

1. Pyridostigmine bromide was administered subcutaneously in mice, in a dose of 4.0 or 2.0 mu moles/kg, and the activity of the predominant (G1, G4 and A12) molecular forms of acetylcholinesterase were examined in diaphragm, extensor digitorum longus (EDL), and soleus muscles at 3 h, 6 h, 24 h and 5 days. 2. In diaphragm, no effect was apparent after the low dose, but after the high dose there was a reduction in activity of the functional A12 form at 24 h, followed by an increase which had overshot the control level at 5 days. 3. In the fast EDL, after the low dose, all three molecular forms were decreased at 3 h but had returned to normal by 6 h. This effect was not apparent after the high dose. 4. In the slow soleus the low dose caused a significant increase in total enzyme activity at 5 days, but the high dose caused significant increases in all molecular forms at 3 hours. 5. Thus pyridostigmine had delayed effects on the levels of acetylcholinesterase. The three muscles displayed different sensitivities to the drug, but the changes were consistent with initial inhibition of the activity leading to down-regulation of the enzyme followed by up-regulation, which could overshoot the normal levels.
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PMID:Effects of pyridostigmine on acetylcholinesterase in different muscles of the mouse. 902 71

1. Pyridostigmine bromide was administered subcutaneously (0.4 mumoles/kg) in mice twice a day for 3 weeks. The activities of the predominant (G1, G4 and A12) molecular forms of acetylcholinesterase were determined in diaphragm, extensor digitorum longus (EDL) and soleus muscles. 2. After the treatment the G4 and A12 forms were reduced in diaphragm, but increased in EDL and soleus. One week later all forms were elevated in all three muscles. At 2 weeks the activity had returned to normal in diaphragm but not in EDL and soleus. 3. A single dose of pyridostigmine was administered in mice which had been pretreated for 3 weeks and left untreated for 2 weeks, and in control mice. 4. In the controls there was no significant effect on the enzyme activities in diaphragm up to 5 days, but there were decreases in EDL, and increases in soleus. In the pretreated group all three forms were increased in diaphragm, especially the A12 form. In soleus and EDL there was a prolonged decrease in all forms, although in the soleus the A12 activity remained above normal. 5. Repeated treatment with pyridostigmine caused delayed changes in functional acetylcholinesterase. Furthermore the treatment had altered the sensitivity of the muscles to the drug.
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PMID:Effect of repeated treatment with pyridostigmine on acetylcholinesterase in mouse muscles. 908 69

Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor used routinely in the treatment of myasthenia gravis and recently by the US Army as a prophylactic agent against potential nerve gas attack in the Persian Gulf War. Pyridostigmine has been implicated as one of several possible causative factors associated with Persian Gulf illnesses. To investigate toxic interactions between PB and other drugs, male ICR mice received contralateral ip injections of either a selected adrenergic drug or caffeine, followed 15 min later by PB. Representative isobolograms plotted for each drug interaction illustrate that a beta-adrenoceptor agonist (isoproterenol), selective beta 2-adrenoceptor agonists (salbutamol, terbutaline), alpha 1- and alpha 2-adrenoceptor antagonists (yohimbine, phentolamine, prazosin), as well as the stimulant caffeine, strongly potentiate the lethal effect of PB. Agents with agonist activity at both alpha- and beta-adrenoceptors (epinephrine, norepinephrine) additively increase PB-induced lethality. The potentiation of toxicity between PB and these agents was counteracted by pretreatment with atropine and atropine methyl nitrate. An alpha 2-adrenoceptor agonist (clonidine) and beta-adrenoceptor antagonists (propranolol, nadolol, acebutolol) did not increase PB-induced lethalities. These data demonstrate a toxic synergism between PB, several commonly used classes of adrenergic agents and caffeine when exposure occurs in different combinations. Future studies into the mechanism(s) of these interactions may bring into question the usage of PB as a protective agent in combat conditions as well as delineate any possible contributions of the drug to Persian Gulf illnesses.
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PMID:Potentiation of pyridostigmine bromide toxicity in mice by selected adrenergic agents and caffeine. 925 Nov 70


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