Domperidone in Parkinson’s Disease: A Perilous Arrhythmogenic or the Gold Standard?

Lertxundi, Unax; Domingo-Echaburu, Saioa; Soraluce, Amaia; Garcia, Montserrat; Osante, Borja Ruiz; Aguirre, C

doi:10.2174/1574886311308010009

Cited by 42 publications

(43 citation statements)

References 43 publications

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“…Domperidone was found to be the drug of choice for treating gastrointestinal symptoms in patients with Parkinson's disease because there is a minimal risk of developing extrapyramidal side effects compared to other drugs. They reported that patients receiving a daily dose of above 30mg should be treated with special caution, considering its potential cardiac effects (26).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Oral Bioavailability of Domperidone with Piperine in Male Wistar Rats: Involvement of CYP3A1 and P-gp Inhibition

Athukuri

Prasad

2017

J Pharm Pharm Sci

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-Purpose: Domperidone is a commonly used antiemetic drug. The oral bioavailability of domperidone is very low due to its rapid first pass metabolism in the intestine and liver. Piperine, the main alkaloid present in black pepper has been reported to show inhibitory effects on Cytochrome P-450 (CYP-450) enzymes and P-glycoprotein (P-gp). In the present study we investigated the effect of piperine pretreatment on the intestinal transport and oral bioavailability of domperidone in male Wistar rats. Methods: The intestinal transport of domperidone was evaluated by an in-vitro non-everted sac method and in-situ single pass intestinal perfusion (SPIP) study. The oral pharmacokinetics of domperidone was evaluated by conducting oral bioavailability study in rats. Results: A statistically significant improvement in apparent permeability (Papp) was observed in rats pretreated with piperine compared to the respective control group. The effective permeability (Peff) of domperidone was increased in the ileum of the piperine treated group. Following pretreatment with piperine, the peak plasma concentration (C max ) and area under the concentration-time curve (AUC) were significantly increased. A significant decrease in time to reach maximum plasma concentration (T max ), clearance and elimination rate constant (K el ) was observed in rats pretreated with piperine. Conclusions: Piperine enhanced the oral bioavailability of domperidone by inhibiting CYP3A1 and P-gp in rats. This observation suggests the possibility that the combination of piperine with other CYP3A4 and P-gp dual substrates may also improve bioavailability. Further clinical studies are recommended to verify this drug interaction in human volunteers and patients.

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Section: Discussionmentioning

confidence: 99%

Enhanced Oral Bioavailability of Domperidone with Piperine in Male Wistar Rats: Involvement of CYP3A1 and P-gp Inhibition

Athukuri

Prasad

2017

J Pharm Pharm Sci

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“…Dopamine antagonists such as domperidone, a dopamine D2 receptor antagonist that does not readily cross the blood brain barrier [23], has been reported to accelerate gastric emptying of a solid meal [39,46] and to increase plasma l -dopa concentration [35] in PD patients treated with l -dopa/AACD inhibitors. However domperidone is not licensed in every country and safety issue has been recently pointed out due to potential cardiotoxic effects at high dose in elderly patients [26]. Another potential candidate is ghrelin (acylated, “active” form), a gut peptide hormone that has potent gastric prokinetic effects [9].…”

Section: Introductionmentioning

confidence: 99%

Preventive effect of rikkunshito on gastric motor function inhibited by l-dopa in rats

et al. 2014

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We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson’s disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2 mg kg−1) decreased significantly GE to 26.3 ± 6.0% compared to 61.2 ± 3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9 ± 5.8% compared to 72.9 ± 5.2% in og vehicle monitored 60 min after a nutrient meal. Rikkunshito (0.5 or 1.0 g kg−1) reduced the LD/CD (20/2 mg kg−1) inhibition of GE of non-nutrient meal (36.9 ± 7.4% and 46.6 ± 4.8% respectively vs. 12.1 ± 7.4% in og vehicle plus LD/CD) while having no effect alone (56.6 ± 8.5%). The ghrelin antagonist, [d-Lys3]-GHRP-6 (1 mg kg−1) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD-inhibited GE. Rikkunshito (1.0 g kg−1) blocked LD/CD (20/2 mg kg−1)-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson’s disease rat model, rikkunshito (1.0 g kg−1, og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naïve and PD rat model in part through ghrelin-related mechanisms.

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“…Patients in the APO group (43) showed moderate improvement on Non Motor Symptom Scale associated to a robust improvement in motor symptoms and complications; particularly, APO showed a significantly greater effect on mood and apathy symptoms. Only four new cases of impulse control disorder, none of them requiring discontinuations of therapy developed in APO group [39].…”

Section: Phase Iii-iv Studymentioning

confidence: 98%

Apomorphine hydrochloride for the treatment of Parkinson’s disease

Unti

Ceravolo

Bonuccelli

2015

Expert Review of Neurotherapeutics

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Apomorphine (APO) is a potent D1 and D2 dopamine agonist. Plasma maximal concentration is reached in 8-16 min with a plasma half-life of 34-70 min. Bioavailability is close to 100%. It has a rapid antiparkinsonian action after subcutaneous (s.c.) administration with a size effect comparable with that of levodopa. Trials of s.c., oral, sublingual, intravenous, rectal, intranasal and iontophoretic transdermal administration of APO have been attempted in Parkinson's disease (PD), each of these routes have shown some potential for clinical effectiveness but the majority of studies indicate that APO intermittent s.c. administration, on which this review is mainly focused, is an effective therapy for the management of motor symptoms in PD, particularly in advanced phases mainly characterized by motor fluctuations, such as wearing OFF and unpredictable "off". Data on the effect of APO on non-motor symptoms in PD patients are limited but there is strong suggestion of a beneficial effect that warrants further investigation.

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Domperidone in Parkinson’s Disease: A Perilous Arrhythmogenic or the Gold Standard?

Cited by 42 publications

References 43 publications

Enhanced Oral Bioavailability of Domperidone with Piperine in Male Wistar Rats: Involvement of CYP3A1 and P-gp Inhibition

Enhanced Oral Bioavailability of Domperidone with Piperine in Male Wistar Rats: Involvement of CYP3A1 and P-gp Inhibition

Preventive effect of rikkunshito on gastric motor function inhibited by l-dopa in rats

Apomorphine hydrochloride for the treatment of Parkinson’s disease

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