Neostigmine for Refractory Constipation in Advanced Cancer Patients

Rubiales, Álvaro Sanz; Hernansanz, S.; Gutiérrez, Celia; Valle, María Luisa del; Flores, Luis Alberto

doi:10.1016/j.jpainsymman.2006.05.002

Cited by 17 publications

(12 citation statements)

References 10 publications

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“…We observed enhanced chronotropic effects in both corpus and antral muscles and the force of contractile activity was manifest in increased gastric movements. Attempts have been made to exploit the increased contractile force elicited by inhibiting AChE as a therapy for post-operative ileus, 27 refractory constipation induced by opiates, 28 and intestinal pseudo-obstruction. 29 Unfortunately, diarrhea and nausea are prevalent complicating side effects of AChE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Gastric Electrical and Mechanical Activity by Cholinesterases in Mice

Worth

Forrest

Peri

et al. 2015

J Neurogastroenterol Motil

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Background/AimsGastric peristalsis begins in the orad corpus and propagates to the pylorus. Directionality of peristalsis depends upon orderly generation and propagation of electrical slow waves and a frequency gradient between proximal and distal pacemakers. We sought to understand how chronotropic agonists affect coupling between corpus and antrum. Methods Electrophysiological and imaging techniques were used to investigate regulation of gastric slow wave frequency by muscarinic agonists in mice. We also investigated the expression and role of cholinesterases in regulating slow wave frequency and motor patterns in the stomach. Results Both acetycholinesterase (Ache) and butyrylcholine esterase (Bche) are expressed in gastric muscles and AChE is localized to varicose processes of motor neurons. Inhibition of AChE in the absence of stimulation increased slow wave frequency in corpus and throughout muscle strips containing corpus and antrum. CCh caused depolarization and increased slow wave frequency. Stimulation of cholinergic neurons increased slow wave frequency but did not cause depolarization. Neostigmine (1 M) increased slow wave frequency, but uncoupling between corpus and antrum was not detected. Motility mapping of contractile activity in gastric muscles showed similar effects of enteric nerve stimulation on the frequency and propagation of slow waves, but neostigmine (＞ 1 M) caused aberrant contractile frequency and propagation and ectopic pacemaking. Conclusions Our data show that slow wave uncoupling is difficult to assess with electrical recording from a single or double sites and suggest that efficient metabolism of ACh released from motor neurons is an extremely important regulator of slow wave frequency and propagation and gastric motility patterns.

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Section: Discussionmentioning

confidence: 99%

Regulation of Gastric Electrical and Mechanical Activity by Cholinesterases in Mice

Worth

Forrest

Peri

et al. 2015

J Neurogastroenterol Motil

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“…Unfortunately, although these agonists were found to be effective in the treatment of constipation in PD patients, those prokinetic agents have been removed from the US market or have not been approved by the FDA due to possible adverse cardiovascular effects (less than 1% of patients) [141, 143–145]. Other medicinal agents are also under investigation, such as misoprostol (a prostaglandin E 1 analogue; 55% efficacy) [32, 146], neostigmine (an acetylcholinesterase inhibitor; 50% efficacy) [7, 147], and domperidone (a DA antagonist; about 35% efficacy) [148]. However, even if the promotility agent domperidone could be potentially effective, due to its absence of permeation through the blood-brain barrier (BBB) [149], there is insufficient evidence to recommend its utilization for constipation, as in the case of trimebutine (an enkephalinergic agonist) and erythromycin (the well-known macrolide antibiotic) [143].…”

Section: Therapeutic Approaches To Gi Symptomsmentioning

confidence: 99%

Gastrointestinal Dysfunctions in Parkinson’s Disease: Symptoms and Treatments

Poirier

Aubé

Côté

et al. 2016

Parkinson's Disease

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A diagnosis of Parkinson's disease is classically established after the manifestation of motor symptoms such as rigidity, bradykinesia, and tremor. However, a growing body of evidence supports the hypothesis that nonmotor symptoms, especially gastrointestinal dysfunctions, could be considered as early biomarkers since they are ubiquitously found among confirmed patients and occur much earlier than their motor manifestations. According to Braak's hypothesis, the disease is postulated to originate in the intestine and then spread to the brain via the vagus nerve, a phenomenon that would involve other neuronal types than the well-established dopaminergic population. It has therefore been proposed that peripheral nondopaminergic impairments might precede the alteration of dopaminergic neurons in the central nervous system and, ultimately, the emergence of motor symptoms. Considering the growing interest in the gut-brain axis in Parkinson's disease, this review aims at providing a comprehensive picture of the multiple gastrointestinal features of the disease, along with the therapeutic approaches used to reduce their burden. Moreover, we highlight the importance of gastrointestinal symptoms with respect to the patients' responses towards medical treatments and discuss the various possible adverse interactions that can potentially occur, which are still poorly understood.

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“…Further, neostigmine is an unattractive treatment option in any patient due to side effects of abdominal pain, excess salivation, nausea and/or vomiting, bradycardia (necessitating cardiac monitoring; Saunders, 2007;McNamara and Mihalakis, 2008), hypotension and bronchospasm (Turégano-Fuentes et al, 1997;Amaro and Rogers, 2000). For these reasons, the use of cholinesterase inhibitors beyond acute colonic pseudo-obstruction has been limited to anecdotal reports of patients with cancer and opioid-induced chronic constipation (Rubiales et al, 2006;Papa and Turconi, 2010), chronic constipation associated with spinal injury (Singal et al, 2006;Ebert, 2012) and patients with autonomic neuropathies (Bharucha et al, 2008).In recent years, new cholinesterase inhibitors have been developed for treatment of Alzheimer's disease (Birks, 2006), with improved selectivity for AChE, retaining therapeutic benefit while minimizing adverse events in the elderly (Imbimbo, 2001). These include donepezil, rivastigmine and galantamine.…”

mentioning

confidence: 99%

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

Broad

Kung

Boundouki

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSECholinesterase 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 APPROACHNeuronally 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 RESULTSPrucalopride 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 μM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3-7, each concentration). CONCLUSIONS AND IMPLICATIONSPotential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction. AbbreviationsAUC, area under the curve; Cmax, peak concentration of drug measured in blood after a single dose; EFS, electrical field stimulation; Emax, maximum response to agonist; GI, gastrointestinal; L-NAME, Nω-nitro-L-arginine methyl ester; NK, neurokinin; TTX, tetrodotoxin BJP IntroductionRestoration of normal intestinal motility is a key objective in treatment of a range of acute and chronic digestive motility disorders. In the most common -chronic constipation, laxatives remain the mainstay of pharmacological intervention, although new drugs have recently been introduced. These include prucalopride, a selective 5-HT4 receptor agonist, which facilitates enteric cholinergic and nitrergic activities to promote intestinal motility (Cellek et al., 2006), and lubiprostone and linaclotide, which, respectively, activate chloride type-2 channels and guanylate cyclase type-C receptors to promote defecation primarily by increasing fluid secretion into the lumen (Lembo et al., 2011;Chey et al., 2012). Such breakthroughs have renewed interest in how best to treat other conditions associated with hypomotility and also with acute or chronic small...

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Neostigmine for Refractory Constipation in Advanced Cancer Patients

Cited by 17 publications

References 10 publications

Regulation of Gastric Electrical and Mechanical Activity by Cholinesterases in Mice

Regulation of Gastric Electrical and Mechanical Activity by Cholinesterases in Mice

Gastrointestinal Dysfunctions in Parkinson’s Disease: Symptoms and Treatments

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

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