Dataset Information

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility.

ABSTRACT:

Background and purpose

Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon.

Experimental approach

Neuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'.

Key results

Prucalopride increased cholinergically mediated contractions (EC50 855?nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100?nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30?nM) together with prucalopride (3, 10??M) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10??M together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3-7, each concentration).

Conclusions and implications

Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction.

SUBMITTER: Broad J

PROVIDER: S-EPMC3838700 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Publications

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility.

Broad J J Kung V W S VW Boundouki G G Aziz Q Q De Maeyer J H JH Knowles C H CH Sanger G J GJ

British journal of pharmacology 20131101 6

<h4>Background and purpose</h4>Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced c ...[more]

PMID: 24032987

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Project description:Background/aimsChagasic megacolon is caused by Trypanosoma cruzi, which promotes in several cases, irreversible segmental colonic dilation. This alteration is the major anatomic-clinical disorder, characterized by the enteric nervous system and muscle wall structural damage. Herein, we investigate how T. cruzi -induced progressive colonic structural changes modulate the colonic contractile pattern activity.MethodsWe developed a murine model of T. cruzi-infection that reproduced long-term modifications of the enlarged colon. We evaluated colonic and total intestinal transit time in animals. The patterns of motor response at several time intervals between the acute and chronic phases were evaluated using the organ bath assays. Enteric motor neurons were stimulated by electric field stimulation. The responses were analyzed in the presence of the nicotinic and muscarinic acetylcholine receptor antagonists. Western blot was performed to evaluate the expression of nicotinic and muscarinic receptors. The neurotransmitter expression was analyzed by real-time polymerase chain reaction.ResultsIn the chronic phase of infection, there was decreased intestinal motility associated with decreased amplitude and rhythmicity of intestinal contractility. Pharmacological tests suggested a defective response mediated by acetylcholine receptors. The contractile response induced by acetylcholine was decreased by atropine in the acute phase while the lack of its action in the chronic phase was associated with tissue damage, and decreased expression of choline acetyltransferase, nicotinic subunits of acetylcholine receptors, and neurotransmitters.ConclusionsT. cruzi -induced damage of smooth muscles was accompanied by motility disorders such as decreased intestinal peristalsis and cholinergic system response impairment. This study allows integration of the natural history of Chagasic megacolon motility disorders and opens new perspectives for the design of effective therapeutic.

Dataset Information

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility.

Similar Datasets

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