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

The National Institute for Health and Clinical Excellence (NICE) recently issued updated guidance on the use of cholinesterase inhibitors in the treatment of Alzheimer's disease. NICE initially recommended that cholinesterase inhibitors no longer be used, but final guidance restricted treatment to patients with disease of a moderately severe stage. This decision was based largely on results from a heavily criticised economic evaluation that used an adaptation of the Assessment of Health Economics in Alzheimer's Disease (AHEAD) model. As the developers of the AHEAD model, we examined the appropriateness of NICE's economic analyses and presentation of results. We attempted to replicate NICE's results by modifying the original AHEAD model. Sensitivity analyses were then run using the modified AHEAD model to evaluate the extent of uncertainty in predictions. The AHEAD(NICE) analyses resulted in an incremental cost-effectiveness ratio for galantamine of 82,000 pound per QALY gained (year 2003 values) from the perspective of the UK NHS and Personal Social Services. This was later revised to 46,000 pound per QALY, compared with < 9000 pound per discounted QALY gained (year 2001 values) in the original AHEAD model. Using our modified AHEAD with effectiveness estimates matching those of AHEAD(NICE), we show that NICE's choice and presentation of sensitivity analyses obscured the instability of their estimates. In the final NICE evaluation, the recommendation to delay treatment with cholinesterase inhibitors until patients have moderately severe disease was based on critical assumptions in the economic analyses that had little evidence to support them. The case of NICE's guidance on cholinesterase inhibitors highlights the importance of transparent and valid economic evaluations and the dangers of using inappropriate modelling technologies, basing analyses on a limited subset of the available data, and insufficiently reflecting the uncertainty in estimates that are intended to inform decision makers.
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PMID:NICE cost-effectiveness appraisal of cholinesterase inhibitors: was the right question posed? Were the best tools used? 1804 85

We developed a dual piezoelectric/amperometric sensor for the detection of two unrelated analytes in one experiment that uses propidium to anchor acetylcholinesterases (AChE) at the surface. This mass-sensitive sensor does not only allow the examination of the interaction between AChE and the modified surface but also the detection of in situ inhibition of the surface-bound AChE. Here we describe the application of the propidium-based sensor in combination with a modified AChE. For this reason the cocaine derivative benzoylecgonine (BZE) was coupled via a 10A long hydrophilic linker - 1,8-diamino-3,4-dioxaoctane - to carboxylic groups of the AChE after EDC/NHS activation. Thus the modified AChE (BZE-AChE) possesses an additional recognition element besides the inhibitor binding site. After the deposition of BZE-AChE on the sensor surface the binding of an anti-BZE-antibody to the BZE-AChE can be monitored. This makes it possible to determine two analytes - cocaine and organophosphate - in one experiment by measuring antibody binding and decrease in enzymatic activity, respectively. Furthermore it was also shown that other cocaine-binding enzymes, e.g., butyrylcholinesterase, can bind to the modified BZE-AChE. The competitive immunoassay allowed the detection of cocaine with a dynamic range from 10(-9) to 10(-7)M. The organophosphate chlorpyrifos-oxon could be detected in concentrations from 10(-6) down to 10(-8)M after 20 min of injection time (equals to 500 microL sample volume.
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PMID:Development of a bifunctional sensor using haptenized acetylcholinesterase and application for the detection of cocaine and organophosphates. 1846 82

This paper reviews previously published data and presents new results to address the hypothesis that fluorinated aminophosphonates (FAPs), (RO)(2)P(O)C(CF(3))(2)NHS(O)(2)C(6)H(5), R=alkyl, inhibit serine esterases by scission of the P-C bond. Kinetics studies demonstrated that FAPs are progressive irreversible inhibitors of acetylcholinesterase (AChE, EC 3.1.1.7.), butyrylcholinesterase (BChE, EC 3.1.1.8.), carboxylesterase (CaE, EC 3.1.1.1.), and neuropathy target esterase (NTE, EC 3.1.1.5.), consistent with P-C bond breakage. Chemical reactivity experiments showed that diMe-FAP and diEt-FAP react with water to yield the corresponding dialkylphosphates and (CF(3))(2)CHNHS(O)(2)C(6)H(5), indicating lability of the P-C bond. X-ray crystallography of diEt-FAP revealed an elongated (and therefore weaker) P-C bond (1.8797 (13)A) compared to P-C bonds in dialkylphosphonates lacking alpha-CF(3) groups (1.805-1.822A). Semi-empirical and non-empirical molecular modeling of diEt-FAP and (EtO)(2)P(O)C(CH(3))(2)NHS(O)(2)C(6)H(5) (diEt-AP), which lacks CF(3) groups, indicated lengthening and destabilization of the P-C bond in diEt-FAP compared to diEt-AP. Active site peptide adducts formed by reacting diEt-FAP with BChE and diBu-FAP with NTE catalytic domain (NEST) were identified using peptide mass mapping with mass spectrometry (MS). Mass shifts (mean+/-SE, average mass) for peaks corresponding to active site peptides with diethylphosphoryl and monoethylphosphoryl adducts on BChE were 136.1+/-0.1 and 108.0+/-0.1Da, respectively. Corresponding mass shifts for dibutylphosphoryl and monobutylphosphoryl adducts on NEST were 191.8+/-0.2 and 135.5+/-0.1Da, respectively. Each of these values was statistically identical to the theoretical mass shift for each dialkylphosphoryl and monoalkylphosphoryl species. The MS results demonstrate that inhibition of BChE and NEST by FAPs yields dialkylphosphoryl and monoalkylphosphoryl adducts, consistent with phosphorylation via P-C bond cleavage and aging by net dealkylation. Taken together, predictions from enzyme kinetics, chemical reactivity, X-ray crystallography, and molecular modeling were confirmed by MS and support the hypothesis that FAPs inhibit serine esterases via scission of the P-C bond.
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PMID:Kinetics and mechanism of inhibition of serine esterases by fluorinated aminophosphonates. 2003 29