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Eur J Clin PharmacolDOI 10.1007/s00228-012-1324-4 Case series: paradoxical action of domperidone leadsto increased vomiting Marco Pozzi & Sandra Strazzer & Federica Locatelli &Sara Galbiati & Francesca Formica & Luciano Maestri &Emilio Clementi & Sonia Radice Received: 3 May 2012 / Accepted: 24 May 2012 Within one day from its administration, domperidone Dysphagic children who receive enteral nutrition may de- caused the onset of emesis, evolving from slight regurgita- velop gastroparesis, for which the prokinetic domperidone tions to sustained alimentary vomiting. Six children dis- has become the drug of choice. The most common adverse played persistent stagnation of enteral nutrition (50 % to drug reactions (ADRs) to domperidone reported by post- 80 % of the administered volumes), and gastric aspiration marketing surveillance only comprise gastrointestinal upset and moderate induction of hyperprolactinemia []. We now Drug withdrawal led to a rapid decrease in the severity of report on domperidone inducing severe vomiting in ten vomiting, followed after 2–3 days by a reduction in the paediatric inpatients with severe acquired brain injury, hos- pitalized in a neuro-rehabilitation unit. These patients shared One patient underwent gastric emptying scintigraphy as pathological features spastic tetraparesis, minimal con- during domperidone treatment: an episode of gastro- sciousness, and inability to assume solids or liquids orally, esophageal reflux was observed in real time; examination none of them having gastric outlet obstruction. Pharmaco- of the pylorus revealed an initial complete stenosis, fol- logical therapy comprised baclofen, diazepam, valproate, lowed by an insufficient relaxation, which led to minimal omeprazole and antibiotics when needed. To favour gastric emptying, therapeutic doses of domperidone were adminis- This is the first report on an ADR to domperidone in tered 15 to 20 minutes before meals, four times a day.
paediatric patients, highly homogeneous in terms of patho-logical manifestations and drug treatment, that is opposite tothe therapeutic action of this drug. The Naranjo adversedrug reactions probability scale identified the relationshipbetween the patient’s development of ADR and the drug as M. Pozzi : S. Strazzer : F. Locatelli : S. Galbiati : F. Formica : Two aspects related to the disease state, dysphagia and reduced vagal tone, contribute to explain the paradoxical Scientific Institute, IRCCS Eugenio Medea, effect of domperidone. Dysphagia has a disruptive im- pact on the triggering of peristalsis, as it subtracts up- stream nervous and hormonal signals essential for this highly coordinated process ]. That this condition is Paediatric Surgery Department, V. Buzzi Children’s Hospital, relevant in the mechanism of this ADR is supported by our observation that in two patients an increase in con- sciousness and the reacquisition of feeding ability led to Unit of Clinical Pharmacology, Department of Biomedical both spontaneous ADR resolution and improvement of and Clinical Sciences, L. Sacco University Hospital, Vagal innervation plays a prominent role in gastric emp- Via GB Grassi 74, 20157 Milan, Italye-mail: [email protected] tying and nitrergic fibres also reach the antral-duodenal Table 1 Domperidone-relatedsymptoms and effect of drug stomy; - : unchanged; + : in-creased; IC: improvement due to region to stimulate pyloric relaxation []. Vagal tone reduc- Domperidone use in the paediatric patients affected by tion is known to cause gastroparesis and in severe cases can brain injury may be optimised, and the risk of vomiting, also impair pyloric relaxation. In this complex scenario, minimised, by performing a gastric transit examination early domperidone may trigger pyloric stenosis. At the pyloric after initiating domperidone administration to recognise im- level, dopamine stimulates nitrergic fibres responsible for relaxation. Since domperidone blocks D2 receptors, it causesa reduction in the activity of the neuronal nitric oxide-synthase The financial support by Agenzia Italiana del enzyme, which may lead to an insufficient relaxation capabil- Farmaco (AIFA) and Regione Lombardia (MEAP Project, Monitorag- ity of the pylorus. This may explain why domperidone gio degli Eventi Avversi in Pediatria) is gratefully acknowledged.
increases peristalsis while triggering vomiting. This is sup-ported by the observation of pyloric stenosis in one patient.
Domperidone is far from being unanimously accepted as a safe drug, and inhibition of dopamine receptors isexpected to have inconstant or unforeseen effects when 1. Reddymasu SC, Soykan I, McCallum RW (2007) Domperidone: dopaminergic signalling is already altered Knowledge review of pharmacology and clinical applications in gastroenterol- of neuronal transmission impairments in the context of ogy. Am J Gastroenterol 102(9):2036–2045 gastroparesis is still partially understood; studying specific 2. Huizinga JD, Lammers WJ (2009) Gut peristalsis is governed by a subpopulations as we did may unmask pharmacological multitude of cooperating mechanisms. Am J Physiol GastrointestLiver Physiol 296(1):G1–G8 effects not evident in standard patients, thus contributing 3. Rivera LR, Poole DP, Thacker M, Furness JB (1995) The involve- to elucidating the drug mechanism of action, and hence ment of nitric oxide synthase neurons in enteric neuropathies. Neu-

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J Clin Gastroenterol 2001;33(3):206–209. © 2001 Lippincott Williams & Wilkins, Inc. Does Short-term Treatment With Proton PumpInhibitors Cause Rebound Aggravationof Symptoms?Per G. Farup, Ph.D., P.H. Juul-Hansen, M.D., and A. Rydning, Ph.D. Abstract cussed.4,9 This trial compares symptoms before, during, and Background: Rebound acid hypersecretion might occur after after 5 days

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PROGRAMME DAY 1 – Wednesday 16 February 2011 PHYSICOCHEMICAL CONSIDERATIONS IN DEVELOPING A DOSAGE Professor Thomas Rades, Convenor, Formulation and Delivery of Bioactives Research Theme, University of Otago, Dunedin, NZ SESSION 1 Chairs – Dr Arlene McDowell & Mr Nicky Thomas Drug delivery systems for problem drugs – and they’re all problem drugs Professor Th

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