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)

We previously reported that gabapentin activates the bulbospinal-spinal noradrenergic-cholinergic pathway to produce analgesia in rats after nerve injury. Also, gabapentin interacts synergistically with a cholinesterase inhibitor donepezil to produce analgesia. Duloxetine, a serotonin/noradrenaline re-uptake inhibitor, has been used for the treatment of neuropathic pain and should amplify the noradrenergic mechanisms recruited by gabapentin. In the present study, we determined the interaction between duloxetine and gabapentin with and without donepezil when administered by the clinically preferred oral route in rats after spinal nerve ligation. The ED(50) value of gabapentin, donepezil, and duloxetine to reduce mechanical hypersensitivity after nerve injury was 45, 3.7, and 32 mg/kg, respectively. In the examination of two drug combinations, oral duloxetine with either gabapentin or donepezil were additive to reduce hypersensitivity. The combination of all three drugs yielded a synergistic interaction with an observed ED(50) at 1/4th the predicted dose of additivity, likely due to the gabapentin-donepezil interaction. This three drug combination did not affect motor coordination or show signs of sedation in the rotarod test. Analgesia by the combination of these three drugs was reversed by intrathecal injection either of the alpha(2)-adrenoceptor antagonist idazoxan or by the muscarinic receptor antagonist atropine. These results suggest that the combination of these drugs, which stimulate and augment the bulbospinal-spinal noradrenergic-cholinergic pathway, lowers the dose requirement for each drug to reduce hypersensitivity after nerve injury without sedative effects. The current study provides the rationale for clinical study of the combination of gabapentin, donepezil and duloxetine to treat neuropathic pain.
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PMID:Multiplicative interactions to enhance gabapentin to treat neuropathic pain. 1882 81

Dyspepsia is a common symptom frequently encountered in general practice. Functional dyspepsia is an exclusion diagnosis after an organic cause has been ruled out, and is a defined entity which can be subdivised in two different subtypes based on the cluster of symptoms, namely epigastric pain and postprandial distress syndromes. The term gastroparesis is used when persistently and severly delayed gastric emptying is found in the absence of mechanical obstruction. Helicobacter pylori infection should be treated, although symptomatic benefice is small. Proton pumps inhibitors offer a clinical benefit in epigastric pain syndrome, whereas prokinetics are probably useful in postprandial distress syndrome. Cisapride has been withdrawn last year due to the risk of potential severe cardiac arrythmies. Domperidone is safer, although caution has to be paid in long-term use because of potential ventricular arrythmies. Dietary advice and psychological therapies might be a useful adjunct. There are difficulties with new treatment development for functional dyspepsia, due to pathophysiological heterogeneity, lack of well-accepted endpoints, a huge placebo effect, and unconfirmed results in large clinical studies after early positive results for promising drugs. Acotiamide, a new cholinesterase inhibitor improving dyspeptic symptoms is not yet available in Europe.
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PMID:[Management of gastroparesis and functional dyspepsia after cisapride withdrawal]. 2309 51