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)

Recombinant human granulocyte colony-stimulating factor, rhG-CSF, is widely applied to ameliorate neutropenia following chemotherapy. However, rhG-CSF can exert negative effects on megakaryocytopoiesis that might cause a delay of megakaryocyte recovery. Therefore, the present study was designed to test different rhG-CSF administration protocols with regard to their megakaryocytic inhibitory potential in a 5-fluorouracil (5-FU)-induced experimental model system. Splenectomized B6D2F1 mice received a single injection of 5-FU (150 mg/kg) on day 0 followed by 50 micrograms/kg/day rhG-CSF given daily for either zero, four, or eight days. Five days after 5-FU, bone marrow and blood hematopoiesis were reduced significantly when compared with controls, independent of whether or not animals received rhG-CSF. However, nine days after 5-FU, granulopoietic recovery from 5-FU-induced toxicity was faster for rhG-CSF-treated versus untreated mice as demonstrated by higher values for colony forming unit-granulocyte macrophage (CFU-GM) and granulocytes (CFU-GM: 7.2 +/- 0.4 versus 5 +/- 0.6 x 10(4)/femur, granulocytes: 4.3 +/- 2 versus 1.4 +/- 0.4 x 10(5)/ml, respectively). Furthermore, significant mobilization of CFU-megakaryocyte (CFU-Meg) and CFU-GM into the peripheral blood was induced by the eight-day administration of rhG-CSF following 5-FU (day 9: 911 +/- 102 CFU-Meg/ml, 2330 +/- 152 CFU-GM/ml). However, megakaryocytic cells in these same mice were considerably lower when compared with those of animals receiving no rhG-CSF (CFU-Meg: 2.7 +/- 0.2 x 10(3) versus 4.2 +/- 0.2 x 10(3)/femur; small acetylcholinesterase positive (SAChE+) cells: 4.9 +/- 0.3 x 10(3) versus 7.3 +/- 0.9 x 10(3)/femur; megakaryocytes: 2.5 +/- 0.2 x 10(3) versus 4.1 +/- 0.7 x 10(3)/femur; platelets: 2.67 +/- 0.5 x 10(9) versus 3.1 +/- 0.5 x 10(9)/ml, respectively). On the other hand, the shortening of the rhG-CSF treatment from eight to four days caused a rapid granulopoietic recovery comparable to animals receiving eight days of G-CSF with no significant delay in megakaryocytic recovery when compared with mice treated with 5-FU alone; however, with four days of rhG-CSF, the mobilization of CFU into the peripheral blood was significantly less effective. Taken together, the results showed that a shortening of rhG-CSF treatment after chemotherapy is capable of ameliorating neutropenia without negatively affecting megakaryocytopoietic recovery. If, however, maximum recruitment of CFU into the peripheral blood circulation by rhG-CSF for subsequent harvest and transplantation is needed, any shortening of rhG-CSF administration is not advisable.
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PMID:Influence of rhG-CSF scheduling on megakaryocytopoietic recovery following 5-fluorouracil-induced hematotoxicity in splenectomized B6D2F1 mice. 955 39

Systemic and localised adverse effects of local anaesthetic drugs usually occur because of excessive dosage, rapid absorption or inadvertent intravascular injection. Small children are more prone than adults to methaemoglobinaemia, and the combination of sulfonamides and prilocaine, even when correctly administered, should be avoided in this age group. The incidence of true allergy to local anaesthetics is rare. All local anaesthetics can cause CNS toxicity and cardiovascular toxicity if their plasma concentrations are increased by accidental intravenous injection or an absolute overdose. Excitation of the CNS may be manifested by numbness of the tongue and perioral area, and restlessness, which may progress to seizures, respiratory failure and coma. Bupivacaine is the local anaesthetic most frequently associated with seizures. Treatment of CNS toxicity includes maintaining adequate ventilation and oxygenation, and controlling seizures with the administration of thiopental sodium or benzodiazepines. Cardiovascular toxicity generally begins after signs of CNS toxicity have occurred. Bupivacaine and etidocaine appear to be more cardiotoxic than most other commonly used local anaesthetics. Sudden onset of profound bradycardia and asystole during neuraxial blockade is of great concern and the mechanism(s) remains largely unknown. Treatment of cardiovascular toxicity depends on the severity of effects. Cardiac arrest caused by local anaesthetics should be treated with cardiopulmonary resuscitation procedures, but bupivacaine-induced dysrhythmias may be refractory to treatment. Many recent reports of permanent neurological complications involved patients who had received continuous spinal anaesthesia through a microcatheter. Injection of local anaesthetic through microcatheters and possibly small-gauge spinal needles results in poor CSF mixing and accumulation of high concentrations of local anaesthetic in the areas of the lumbosacral nerve roots. In contrast to bupivacaine, the hyperbaric lidocaine (lignocaine) formulation carries a substantial risk of neurotoxicity when given intrathecally. Drugs altering plasma cholinesterase activity have the potential to decrease hydrolysis of ester-type local anaesthetics. Drugs inhibiting hepatic microsomal enzymes, such as cimetidine, may allow the accumulation of unexpectedly high (possibly toxic) blood concentrations of lidocaine. Reduction of hepatic blood flow by drugs or hypotension will decrease the hepatic clearance of amide local anaesthetics. Special caution must be exercised in patients taking digoxin, calcium antagonists and/or beta-blockers.
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PMID:Adverse effects and drug interactions associated with local and regional anaesthesia. 956 36

There is increasing evidence suggesting that beta-amyloid (Abeta) has a direct influence on cholinergic activity. In particular, Abeta has been shown to induce the expression of acetylcholinesterase in the brains of CT-100-expressing transgenic mice and in cell culture experiments. These data indicate a link exists between Abeta production and acetylcholinesterase expression in the human CNS. To test this hypothesis, Abeta levels and cholinesterase activity were measured in 110 human CSF samples. Abeta levels were found to have a significant and positive correlation with cholinesterase activity. This correlation was particularly strong in individuals > 50 years of age. These data support the hypothesis that Abeta can effect cholinergic activity and that this effect may be enhanced in the elderly.
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PMID:Beta-amyloid levels predict cholinesterase activity in human cerebrospinal fluid. 1009 47

The glycosylation of acetylcholinesterase (AChE) in CSF was analyzed by lectin binding. AChE from Alzheimer's disease (AD) patients was found to bind differently to two lectins, concanavalin A and wheat germ agglutinin, than AChE from controls. As multiple isoforms of AChE are present in both CSF and brain, we examined whether the abnormal glycosylation of AD AChE was due to changes in a specific molecular isoform. Globular amphiphilic dimeric (G2a) and monomeric (G1a) isoforms of AChE were found to be differentially glycosylated in AD CSF. Glycosylation of AChE was also altered in AD frontal cortex but not in cerebellum and was also associated with an increase in the proportion of light (G2 and G1) isoforms. This study demonstrates that the glycosylation of AChE is altered in the AD brain and that changes in AChE glycosylation in AD CSF may reflect changes in the distribution of brain isoforms. The study also suggests that glycosylation of AChE may be a useful diagnostic marker for AD.
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PMID:Molecular isoform distribution and glycosylation of acetylcholinesterase are altered in brain and cerebrospinal fluid of patients with Alzheimer's disease. 1009 67

As clinical diagnosis of Alzheimer's disease is only 80%-90% accurate, there is a need to identify biochemical markers of Alzheimer's disease. Previous studies have shown an abnormality in the glycosylation of acetylcholinesterase (AChE) in the CSF collected postmortem from patients with Alzheimer's disease. This abnormality was very specific for Alzheimer's disease, as it was not detected in other illnesses causing dementia. We report here that the glycosylation of AChE is also altered in lumbar CSF collected antemortem. The altered glycosylation was due to increased concentrations of a minor AChE isoform that does not bind to concanavalin A (Con A). Glycosylation of AChE may eventually be of diagnostic value, especially when used in combination with other CSF markers.
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PMID:Altered glycosylation of acetylcholinesterase in lumbar cerebrospinal fluid of patients with Alzheimer's disease. 1103 25

A proportion of Alzheimer's disease (AD) patients treated for several months with cholinesterase (ChE) inhibitors have shown some favorable response on cognition, but the characteristics of the responders are still unclear. This study attempts to identify the characteristics of individuals with a positive behavioral response after a double-blind randomized administration of a single oral dose of tacrine (40 mg) and placebo to AD patients. Furthermore, the relationship between single-dose and long-term responders are examined. Twenty-four mildly to very mildly demented AD patients participated in the study. They all fulfilled the diagnosis of probable AD according to NINCDS-ADRDA criteria. Active treatment (tacrine 40 mg) and placebo was administered in random order on 2 consecutive days, and the effects were evaluated within 2 h using neuropsychological tests (assessing visuospatial ability, episodic memory and attention), registration of EEG activity and measurement of red blood cells (RBC) acetylcholinesterase (AChE), ChE activity and concentrations of tacrine and its metabolites in plasma. Results demonstrated significant improvement, tacrine compared to placebo, in measures of attention, but not in episodic memory or visuospatial ability. A single-dose response was therefore defined in terms of improvement in attention. The tacrine plasma concentration (pcTHA) showed a positively skewed distribution (mean +/- SD: 10.5 +/- 11.8, range: 1.0-51.8 ng/ml). There were no significant differences between single-dose responders compared to nonresponders in pcTHA, metabolites of tacrine, inhibition of AChE in RBC, tau levels in CSF, AChE activity in CSF or plasma and demographic variables. However, single-dose responders showed a higher right frontal alpha/theta ratio on EEG and had lower glucose metabolism in the parietal-temporal association cortex at baseline. In addition, the frequency of apolipoprotein E (APOE) epsilon 4 alleles was higher in responders. Interestingly, the single-dose response was related to the long-term response, although not significantly, which probably was due to lack of power. To conclude, the present study identified single-dose responders in terms of improved attentional performance associated with a relatively higher alpha/theta activity in the right frontal regions of the brain measured on EEG and predominance of APOE epsilon 4 allele.
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PMID:Responder characteristics to a single oral dose of cholinesterase inhibitor: a double-blind placebo-controlled study with tacrine in Alzheimer patients. 1112 38

The extracellular deposition of amyloid beta-peptide (Abeta) in the form of cerebrovascular amyloid and extracellular plaques is one of the major neuropathological manifestations of Alzheimer's disease (AD). Abeta is generated proteolytically from the large beta-amyloid precursor protein (APP). APP is cleaved by a group of proteases called "secretase" to generate soluble derivatives of APP (sAPP), which are secreted in human plasma, CSF and cultured cells. Neurochemically, there is a severe loss of cholinergic neurons and a decreased synthesis of acetylcholine in neocortex in AD. Current approved AD drugs, such as aricept and tacrine, are based on the use of cholinesterase inhibitors (ChEIs) and have been reported to improve memory deficits and cognitive decline in some patients with AD. To compare the effects of ChEIs on APP processing, we have tested a series of ChEIs such as tacrine, physostigmine, metrifonate, phenserine and cymserine in cultured human neuroblastoma cells. We analyzed levels of sAPP by immunochemical techniques with APP-specific antibodies and assayed levels of Abeta by a sensitive sandwich ELISA. Based on these results, ChEIs can be divided into three groups: the first group of ChEIs had no effect on sAPP secretion, the second decreased the sAPP secretion only, and third group affected the secretion of sAPP and Abeta. The difference in the action of metrifonate, physostigmine, phenserine and tacrine on APP processing is independent of their selectivity for the cholinesterase enzymes. This possibly is due to the different targets that are used by ChEIs. Studying the effects of ChEIs on different targets is useful to maximize the benefit of ChEIs for the treatment of AD subjects.
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PMID:Cholinesterase inhibitors, beta-amyloid precursor protein and amyloid beta-peptides in Alzheimer's disease. 1127 93

During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) resulted into three drugs being registered for the first time in USA and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6 months to one year period of treatment as compared to placebo. Additional drug effects are slowing cognitive deterioration and improving behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and direct cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission experimental or pathological (AD) leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. In order to explain the long-term effect of ChEI, a mechanism based on beta-amyloid metabolism, is postulated. Evidence for such an effect is available at experimental as well as at clinical level. Does cholinergic stabilization imply slowing down disability or delaying disease progression?
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PMID:Long-term stabilizing effect of cholinesterase inhibitors in the therapy of Alzheimer' disease. 1245 62

The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.
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PMID:Dementia with Lewy bodies. 1256 32

Early diagnosis of Alzheimer's disease (AD) is needed to initiate symptomatic treatment with acetylcholinesterase inhibitors, and will be of even greater significance if drugs aimed at slowing down the degenerative process, such as vaccination regimes and beta-secretase and gamma-secretase inhibitors, prove to affect AD pathology and to have clinical effect. However, there is no clinical method to determine in which patients mild cognitive impairment (MCI) will progress to AD with dementia, and in which patients MCI is benign. Hence, there is a great clinical need for biomarkers to identify incipient AD in patients with MCI. The CSF biomarkers total tau protein, phosphorylated tau protein, and the 42 amino-acid residue form of amyloid-beta may, if put in the right clinical context, prove to have high enough diagnostic accuracy to meet this challenge.
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PMID:CSF markers for incipient Alzheimer's disease. 1450 82


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