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, 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

Until now, the potential antiarrhythmic benefits of disopyramide have been restricted by anticholinergic side effects. These side effects have included xerostomia (dry mouth, nose or eyes), abdominal discomfort, nausea, constipation and, most importantly, urinary hesitancy and retention. A sustained-release form of pyridostigmine, an acetyl-cholinesterase inhibitor, has been shown to a) prevent the anticholinergic side effects of disopyramide when used prophylactically and b) to eliminate or attenuate these symptoms if they are already present. Pyridostigmine has no measurable effect on disopyramide's antiarrhythmic properties. This represents a beneficial new drug interaction which will improve tolerance of disopyramide and increase patient compliance with disopyramide-containing regimens.
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PMID:The anticholinergic side effects of disopyramide and controlled-release disopyramide. 406 65

A large number of the population, especially the elderly, suffers from dry mouth. The aim of the present investigation was to stimulate the minor salivary glands by the topical application of the cholinesterase inhibitor physostigmine. In eight healthy subjects. 100 microl of the substance, in the concentration interval 2-8 mg/ml, was applied locally to the inside of the lower lip for 1 min. In a separate study comprising 12 dry-mouth patients. 10 ml of 0.4 1.6 mg/ml physostigmine was administered as a mouth rinse solution for 2 min. Secretion from the labial glands. assessed using the Periotron method, increased in a dose-dependent manner in response to physostigmine in both groups. Average peak secretion exceeded baseline by more than 50% throughout the 30- to 45-min observation period; from 1.71 to 2.62 microl cm(-2) min(-1) among the healthy subjects and from 1.17 to 1.84 microl cm 2 min among the dry mouth patients. No systemic effects were registered as reflected by ECG, heart rate or blood pressure. It is assumed that intraorally applied physostigmine diffuses through the oral mucosa and acts by preserving acetylcholine released from the cholinergic, parasympathetic nerves that innervate the minor salivary glands. The topical application of physostigmine to the oral mucosa may, therefore, be an interesting approach for the treatment of dry mouth.
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PMID:Stimulation of minor salivary glands by intraoral treatment with the cholinesterase inhibitor physostigmine in man. 1176 72

Parasympathomimetics or cholinesterase inhibitors taken orally may relieve dry-mouth symptoms, but this route of administration is often associated with adverse systemic reactions. In the present study, an animal model was worked out aimed at stimulating the submucosal glands and avoiding systemic effects. In the anesthetized ferret, saliva from the parotid, sublingual and submandibular glands was prevented from reaching the mouth. Vehicle or physostigmine was applied topically for 10 min on the buccal and labial mucosa on one side, while the other side served as a control. Fluid from each side was collected every 5 min Mean basal secretion was 0.17 mg 5 min(-1). The response to physostigmine 0.1% did not exceed that of the vehicle. At higher concentrations the responses lasted 80-120 min. Peak secretion was nine (0.25% physostigmine), 13 (0.5% physostigmine) and 40 (1% physostigmine) times higher than baseline. At 1% physostigmine, the secretion from the control side was elevated, and a small flow from the duct-cannulated parotid gland occurred, indicating systemic effects. Arterial blood pressure was well maintained. Additional observations on the duct-cannulated zygomatic gland showed that secretion from this gland increased already within the 10-min period of application of physostigmine to the overlying mucosa. The distance between the mucosa and the zygomatic gland was only about 1 mm. Physostigmine-induced secretion was abolished by atropine. Local gland stimulation may be an attractive alternative for the treatment of dry mouth.
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PMID:Secretion from submucosal salivary glands of the ferret in response to a cholinesterase inhibitor applied onto the oral mucosa. 1212 Jul 9

A 45-year-old-man presented with severe vomiting, constipation, abdominal distention and bilateral ocular abductor palsy. Evaluation revealed diffuse autonomic dysfunction characterized by intestinal pseudo-obstruction, xerophthalmia, xerostomia, postural hypotension, erectile dysfunction and loss of sinus arrhythmia. Paraneoplastic work-up revealed thymoma. Most symptoms resolved after surgical removal of the thymoma. Six weeks later he developed worsening of external ophthalmoparesis with ptosis, responding to acetylcholinesterase inhibitor, confirming myasthenia gravis.
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PMID:Intestinal pseudo-obstruction as initial presentation of thymoma. 1709 Aug 54

Dry mouth produces a deterioration in oral health and impairs quality of life. There is a need for a novel approach to the pharmacological treatment of dry mouth. With a view to enhancing the cholinergic drive on minor salivary glands, whilst at the same time minimising adverse systemic effects, the cholinesterase inhibitor physostigmine was therefore sprayed, in a fixed volume, onto the oral mucosa of seven healthy subjects. Three concentrations (0.5%, 1% and 2%) were tested. The mean salivary output over time (0-105 min) was higher than that of placebo (p<0.05), as the area under the curve increased by 61%, 91% and 66% at physostigmine 0.5%, 1% and 2%, respectively. Two subjects experienced nausea at the highest physostigmine concentration, thus reflecting systemic effects. Heart rate, blood pressure and respiration were unaffected by the physostigmine treatment.
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PMID:Intraoral stimulation of salivary secretion with the cholinesterase inhibitor physostigmine as a mouth spray: a pilot study in healthy volunteers. 1765 55

The human sweating response is subject to the influence of diverse classes of drugs. Some act centrally at the hypothalamus or at spinal thermoregulatory centres, while others act at sympathetic ganglia or at the eccrine-neuroeffector junction. Pharmacological disturbances of sweating have broad clinical implications. Drugs that induce hyperhidrosis, or sweating in excess of that needed to maintain thermoregulation, can cause patient discomfort and embarrassment, and include cholinesterase inhibitors, selective serotonin reuptake inhibitors, opioids and tricyclic antidepressants. Drugs that induce hypohidrosis, or deficient sweating, can increase the risk of heat exhaustion or heat stroke and include antimuscarinic anticholinergic agents, carbonic anhydrase inhibitors and tricyclic antidepressants. As acetylcholine is the principal neuroeccrine mediator, anhidrosis is one of the clinical hallmarks by which acute anticholinergic toxicity may be recognized. The symptom of dry mouth often accompanies the less apparent symptom of hypohidrosis because the muscarinic M(3) acetylcholine receptor type predominates at both sweat and salivary glands. Management options include dose reduction, drug substitution or discontinuation. When compelling medical indications require continuation of a drug causing hyperhidrosis, the addition of a pharmacological agent to suppress sweating can help to reduce symptoms. When hypohidrotic drugs must be continued, deficient sweating can be managed by avoiding situations of heat stress and cooling the skin with externally applied water. The availability of clinical tests for the assessment of sudomotor dysfunction in neurological disease has enhanced recognition of the complex effects of drugs on sweating. Advances in the understanding of drug-induced anhidrosis have also enlarged the therapeutic repertoire of effective treatments for hyperhidrosis.
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PMID:Drug-induced hyperhidrosis and hypohidrosis: incidence, prevention and management. 1821 88

Understanding drug pharmacology and mechanism of action can help explain not only therapeutic effects and side effects, but also potential adverse effects when drugs are discontinued. This series of articles will broadly review the potential adverse effects associated with the discontinuation of various psychotropic drugs. This first article focuses on adrenergic, cholinergic, and histamine drugs. After chronic use, abruptly stopping adrenergic receptor drugs can cause rebound anxiety, restlessness, and heart palpitations. Abruptly stopping anticholinergic drugs can lead to an anticholinergic discontinuation syndrome characterized by cholinergic rebound, symptoms of which include nausea, sweating, and urinary urgency. Discontinuation of acetylcholinesterase enzyme inhibitor drugs may be associated with mild anticholinergic-like effects such as dry mouth, constipation, and blurred vision. Abrupt discontinuation of histamine-blocking drugs can be associated with activation, insomnia, and a mild anticholinergic withdrawal syndrome. Tapering, rather than abruptly discontinuing, medication can avoid or minimize medication discontinuation effects.
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PMID:Potential adverse effects of discontinuing psychotropic drugs. Part 1: Adrenergic, cholinergic, and histamine drugs. 2050 69

Muscarinic acetylcholine receptors (mAChRs) have five known subtypes which are widely distributed in both the peripheral and central nervous system for regulation of a variety of cholinergic functions. Atropine is a well known muscarinic subtype non-specific antagonist that competitively inhibits acetylcholine (ACh) at postganglionic muscarinic sites. Atropine is used to treat organophosphate (OP) poisoning and resulting seizures in the warfighter because it competitively inhibits acetylcholine (ACh) at the muscarinic cholinergic receptors. ACh accumulates due to OP inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh. However, atropine produces several unwanted side-effects including dilated pupils, blurred vision, light sensitivity, and dry mouth. To overcome these side-effects, our goal was to find an alternative to atropine that emphasizes M1 (seizure prevention) antagonism but has minimum M2 (cardiac) and M3 (e.g., eye) antagonism so that an effective less toxic medical countermeasure may be developed to protect the warfighter against OP and other chemical warfare agents (CWAs). We adopted an in silico pharmacophore modeling strategy to develop features that are characteristics of known M1 subtype-selective compounds and used the model to identify several antagonists by screening an in-house (WRAIR-CIS) compound database. The generated model for the M1 selectivity was found to contain two hydrogen bond acceptors, one aliphatic hydrophobic, and one ring aromatic feature distributed in a 3D space. From an initial identification of about five hundred compounds, 173 compounds were selected through principal component and cluster analyses and in silico ADME/Toxicity evaluations. Next, these selected compounds were evaluated in a subtype-selective in vitro radioligand binding assay. Twenty eight of the compounds showed antimuscarinic activity. Nine compounds showed specificity for M1 receptors and low specificity for M3 receptors. The pK(i) values of the compounds range from 4.5 to 8.5 nM in comparison to a value of 8.7 nM for atropine. 2-(diethylamino)ethyl 2,2-diphenylpropanoate (ZW62841) was found have the best desired selectivity. None of the newly found compounds were previously reported to exhibit antimuscarinic specificity. Both theoretical and experimental results are presented.
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PMID:Discovery of subtype selective muscarinic receptor antagonists as alternatives to atropine using in silico pharmacophore modeling and virtual screening methods. 2352 85

Introduction. Decreased salivary flow and xerostomia are frequent findings in Parkinson's disease (PD), possibly caused by alterations in the parasympathetic tonus. Here we explore salivary acetylcholinesterase (AChE) activity as a potential biomarker in PD. Methods. We measured salivary flow, AChE activity, and total protein concentration in 30 PD patients and 49 healthy controls. We also performed exploratory correlation analyses with disease duration, motor symptom severity, autonomic complaints, and other nonmotor symptoms. Results. PD patients displayed significantly decreased salivary flow rate, significantly increased salivary AChE activity, and total protein concentration. Importantly, the AChE activity/total protein ratio was significantly increased in PD patients, suggesting that increased AChE activity cannot be explained solely by upconcentration of saliva. The Unified PD Rating Scale (UPDRS) score displayed significant correlation with total salivary protein (P = 0.002) and near-significant correlation with salivary flow (P = 0.07). Color vision test scores were also significantly correlated with AChE activity (P = 0.04) and total protein levels (P = 0.002). Conclusion. Salivary AChE activity is increased in PD patients compared to healthy controls. Future studies are needed to elucidate whether this parameter reflects the extent of neuronal damage and parasympathetic denervation in the salivary glands of PD patients.
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PMID:Salivary acetylcholinesterase activity is increased in Parkinson's disease: a potential marker of parasympathetic dysfunction. 2576 37


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