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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor used for treatment of myasthenia gravis and for prophylactic protection against organophosphate nerve agent. We previously showed PB can induce apoptotic death in rat brain following systemic treatment. To study mechanisms by which PB induces brain cell death, cultured rat cerebellar granule cells were used. Cytotoxicity was determined after exposure to PB (10-1000 microM) for 24 h; a high concentration of PB (>500 microM) significantly increased lactate dehydrogenase release, which was reduced by pretreatment with the antioxidant, N-t-butyl-alpha-phenyl-nitrone (PBN). Apoptosis, as determined by TUNEL staining, was concentration dependent (10-250 microM) after a 24-h exposure and cytotoxicity was confirmed by gel electrophoresis of DNA, release of cytochrome c from mitochondria, elevation of caspase activity, and electron microscopy. The oxidant-sensitive fluorescent dye 2',7'-dichlorofluorescin diacetate was used to detect reactive oxidative species (ROS) generation. Pretreatment with PBN, superoxide dismutase, catalase, or the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) blocked PB-induced ROS generation and apoptotic cell death. Pretreatment with atropine or MK-801 blocked ROS generation and the subsequent neurotoxicity, showing that both muscarinic and NMDA receptors mediate the response. DNA extracted from PB-treated cells revealed oligonucleosomal fragmentation on gel electrophoresis and antioxidants attenuated the DNA fragmentation, providing further evidence for a link of ROS generation and apoptosis. These results indicate that muscarinic receptor-mediated ROS generation is an initiating factor in PB-induced apoptotic cell death and activation of the NMDA glutamate receptor is directly linked to the response.
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PMID:Reactive oxygen species mediate pyridostigmine-induced neuronal apoptosis: involvement of muscarinic and NMDA receptors. 1170 96

Pyridostigmine, a carbamate cholinesterase (ChE) inhibitor, has been used for decades in the treatment of the autoimmune disorder myasthenia gravis and was used prophylactically to protect soldiers from possible organophosphorus nerve agent exposures during the Persian Gulf War. Pyridostigmine is a charged, quaternary compound and thus would not be expected to easily pass the blood-brain barrier. Some studies have suggested, however, that stress may alter blood-brain barrier integrity and allow pyridostigmine to enter the brain. We evaluated the effects of acute and repeated restraint stress on functional signs of cholinergic toxicity (i.e., autonomic dysfunction and involuntary movements) and brain regional cholinesterase inhibition following either acute or repeated pyridostigmine exposures. The acute, oral maximum-tolerated dosage (MTD) of pyridostigmine was estimated at 30 mg/kg. Peak ChE inhibition in whole blood occurred from 0.5 to 4 h after MTD exposure, whereas minimal (<20%) brain ChE inhibition was noted. For acute restraint studies, rats were either (1) restrained for 90 min and then given pyridostigmine (30 mg/kg, po), (2) given pyridostigmine and immediately restrained for 60 min, or (3) restrained for 3 h, given pyridostigmine, and restrained for an additional 60 min. In all cases, rats were evaluated for cholinergic toxicity (SLUD signs and involuntary movements) and sacrificed 1 h after pyridostigmine treatment. Plasma corticosterone was significantly elevated immediately after a single 60-min session of acute restraint stress, but returned to control levels by 1 and 3 h later. Pyridostigmine-induced toxicity was not enhanced nor was brain ChE inhibition altered by acute restraint stress. Blood-brain barrier permeability, assessed by accumulation of horseradish peroxidase in brain regions following intracardiac injection, was not increased by restraint stress. For repeated restraint studies, rats were given pyridostigmine (0, 3, or 10 mg/kg/day) immediately prior to daily restraint (60 min) for 14 consecutive days. Plasma corticosterone was elevated at 1 and 7 days but not at 14 days. Pyridostigmine-treated rats in both dosage groups exhibited slight signs of toxicity for the first 3-5 days, after which cholinergic signs dissipated. Repeated restraint had little effect on functional signs of pyridostigmine toxicity, however. Whole blood and diaphragm ChE were markedly reduced 1 h after the last treatment, but stress had no influence on ChE inhibition in either peripheral or central tissues. The results suggest that acute and repeated restraint stress have little effect on pyridostigmine neurotoxicity or apparent entry of pyridostigmine into the brain.
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PMID:Acute and repeated restraint stress have little effect on pyridostigmine toxicity or brain regional cholinesterase inhibition in rats. 1221 70

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

Incubation of neostigmine with normal human plasma in vitro results in the formation of two quaternary nitrogen compounds, one of which has been identified as m-hydroxyphenyltrimethylammonium. This hydrolysis is prevented by prior addition of dyflos to plasma in concentrations sufficient to inhibit plasma cholinesterase activity. The significance of these findings is discussed in relation to the occurrence of the same metabolic products in the urine of patients with myasthenia gravis treated with oral neostigmine. No equivalent findings are available for normal subjects since it was not considered justifiable to treat them with neostigmine.
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PMID:Hydrolysis of neostigmine by plasma cholinesterase. 1393 68

The pathogenesis of myasthenia gravis (MG) involves a T cell-directed antibody-mediated autoimmune attack on the nicotinic acetylcholine receptor (AChR) or, occasionally, on other postsynaptic antigens. The antibodies induce their effects through complement-mediated destruction of the postsynaptic endplate membrane with resultant reduction in endplate AChR, and to a lesser degree by increased turnover of endplate AChR or blockade of AChR function. Considerable progress in the treatment of MG has accrued from so-called symptomatic treatments, including improved critical care of seriously ill patients and medications (e.g., cholinesterase inhibitors) increasing the concentration of acetylcholine at the remaining endplate AChRs. Information from other autoimmune diseases and from the response of the normal immune system to invading pathogens supports the view that the course of MG is characterized by exacerbations and remissions. Therefore, the goal in MG treatment is to induce and maintain a remission. This usually involves combinations of short-term and long-term immunosuppressive agents. Selection of the particular combinations of agents in a given patient is guided by the goal of minimizing the cost/benefit ratio of the regimen in an individual patient. In general, the plan involves an initial forceful attack followed by a slow and measured withdrawal.
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PMID:Treatment principles in the management of autoimmune myasthenia gravis. 1459 15

Autoimmune myasthenia gravis (MG) is associated with antibodies directed against the nicotinic acetylcholine receptor (AChR) in 85% of patients. Other postsynaptic neuromuscular junction antigens are implicated, e.g., muscle-specific receptor tyrosine kinase (MuSK), in a number of the remaining 15% of patients, so-called seronegative MG. The autoimmune attack generally leads to decreased concentrations of the AChR and damage to the structure of the endplate itself. This information has guided the empiric treatment of patients with MG and has suggested new treatment strategies. Whereas the outcome of patients with MG has improved because of more effective symptomatic treatment, including advances in critical care medicine and the use of cholinesterase inhibitors, the greatest advances have come from therapies that directly reduce the autoimmune attack or modify its effects on the AChR and the surrounding endplate. Immune-directed treatment of patients with MG, which is guided by this information and by data from the management of other autoimmune disease, is aimed at inducing an immunologic remission and then maintaining that remission. Remission induction is usually accomplished through the use of high-dose corticosteroids, frequently in conjunction with IV immunoglobulin or plasmapheresis. Maintenance of the remission is usually accomplished by slow tapering of the corticosteroids along with the use of "steroid-sparing" agents, which include azathioprine, thymectomy, and possibly mycophenolate. Therapy usually begins with cholinesterase inhibitors. If necessary, immune-directed treatment is added, beginning with either thymectomy or high-dose corticosteroids. The short-term therapies, i.e., IV immunoglobulin or plasmapheresis, may be effective in the early stages of treatment or later during an exacerbation. Steroid-sparing medications are usually added to facilitate the tapering phase.
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PMID:Treatment of autoimmune myasthenia gravis. 1545 26

Pyridostigmine bromide (PYR) is an anticholinesterase drug indicated for the treatment of myasthenia gravis and neuromuscular blockade reversal. It acts as a reversible cholinesterase inhibitor and was used as a pretreatment for soldiers during Operation Desert Storm to protect against possible nerve gas attacks. Since that time, PYR has been implicated as a possible causative agent contributing to Gulf War Illness. PYR's mechanism of action has been well-delineated with regards to its effects on the nervous system, yet little is known regarding potential effects on immunological function. To evaluate the effects of PYR on immunological function, adult female B6C3F1 mice were gavaged daily for 14 days with PYR (0, 1, 5, 10, or 20 mg/kg/day). Immune parameters assessed were lymphoproliferation, natural killer cell activity, the SRBC-specific antibody plaque-forming cell (PFC) response, thymus and spleen weight and cellularity, and thymic and splenic CD4/CD8 lymphocyte subpopulations. Exposure to PYR did not alter splenic and thymus weight or splenic cellularity. However, 20 mg PYR/kg/day decreased thymic cellularity with decreases in both CD4+/CD8+ (20 mg/kg/day) and CD4-/CD8- (10 and 20 mg/kg/day) cell types. Functional immune assays indicated that lymphocyte proliferative responses and natural killer cell activity were normal; whereas exposure to PYR significantly decreased primary IgM antibody responses to a T-cell dependent antigen at the 1, 5, 10 and 20 mg/kg treatment levels for 14 days. This is the first study to examine the immunotoxicological effects of PYR and demonstrate that this compound selectively suppresses humoral antibody responses.
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PMID:Pyridostigmine bromide (PYR) alters immune function in B6C3F1 mice. 1510 28

We report a patient with polymyositis (PM) associated with myasthenia gravis (MG). Both disorders had been controlled for around 15 years by oral prednisolone and a cholinesterase inhibitor following surgical removal of invasive thymoma and radiotherapy, but muscular weakness due to myalgia and an increase in serum levels of myogenic enzymes, mainly ascribable to the recurrence of PM, reappeared immediately after cessation of these drugs, which was done because the patient had multiple bone fractures and severe osteoporosis due to the long-term corticosteroid therapy. Oral tacrolimus was therefore tried, and produced an improvement in muscular symptoms in association with normalization of myogenic enzymes. PM associated with MG as in this patient might be the best indication for tacrolimus, considering its efficacy in MG, but this drug should also be actively considered as a therapeutic option in refractory cases of PM alone, particularly when either corticosteroids or other immunosuppressive agents are not usable.
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PMID:Efficacy of tacrolimus in treatment of polymyositis associated with myasthenia gravis. 1516 59

Although once a severe and often fatal illness, myasthenia gravis can now be well managed with several relatively safe and effective therapies. Management involves a graded approach, beginning with cholinesterase inhibitors for mild symptoms and advancing to immunomodulating medications for more severe weakness. There are several immunomodulating agents from which to choose; selection is based largely on time to clinical effect and adverse effects. This review will discuss the selection and use of therapies for patients with myasthenia gravis.
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PMID:Management of myasthenia gravis. 1522 91


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