Integrative Roles of Dopamine Pathway and Calcium Channels Reveal a Link between Schizophrenia and Opioid Use Disorder.

Several theories have been proposed to explain the mechanisms of substance use in schizophrenia. Brain neurons pose a potential to provide novel insights into the association between opioid addiction, withdrawal, and schizophrenia. Thus, we exposed zebrafish larvae at 2 days post-fertilization (dpf) to domperidone (DPM) and morphine, followed by morphine withdrawal. Drug-induced locomotion and social preference were assessed, while the level of dopamine and the number of dopaminergic neurons were quantified. In the brain tissue, the expression levels of genes associated with schizophrenia were measured. The effects of DMP and morphine were compared to vehicle control and MK-801, a positive control to mimic schizophrenia. Gene expression analysis revealed that α1C, α1Sa, α1Aa, drd2a, and th1 were up-regulated after 10 days of exposure to DMP and morphine, while th2 was down-regulated. These two drugs also increased the number of positive dopaminergic neurons and the total dopamine level but reduced the locomotion and social preference. The termination of morphine exposure led to the up-regulation of th2, drd2a, and c-fos during the withdrawal phase. Our integrated data implicate that the dopamine system plays a key role in the deficits in social behavior and locomotion that are common in the schizophrenia-like symptoms and opioid dependence.

The effect of different exogenous kisspeptins on sex hormones and reproductive indices of the goldfish (Carassius auratus) broodstock.

Despite several studies on fish hormone therapy, finding new candidates may provide more reproductive efficiency in artificial propagation. Kisspeptins, being upstream of the hypothalamic-pituitary-gonadal axis, appear to play a key role in the reproduction process. In the present study, the effect of different variants of kisspeptide, including goldfish (Carassius auratus) kiss1 kisspeptin (Kiss1), human kisspeptin (Hkiss), and their combination (Kiss1 + H), on the reproductive indices of goldfish broodstock in comparison to Ovaprim (a typical synthetic Gnrh hormone) was investigated. Peptides (Kiss1 and Hkiss) were synthesized using a solid-phase synthesis approach. Kiss1 and Hkiss were injected at a dose of 100 µg kg-1 body weight, blood samples were taken 6 h after injection and sex hormones (E2, Dhp, and 11-Kt), gonadotropins (Lh and Fsh), cortisol and reproductive indices (fecundity, fertilization and hatching percentage) were measured. The results showed a significant increase of plasma sex hormones and gonadotropins in fish treated with kisspeptins. In addition, the cortisol and lipoprotein lipase in Kiss1, Hkiss and Kiss1 + H were remarkably increased compared to Ovaprim. In conclusion, kisspeptins could be a more suitable candidate than Ovaprim for accelerating and synchronizing oocyte maturation in the fisheries industry.

Oral galactagogues (natural therapies or drugs) for increasing breast milk production in mothers of non-hospitalised term infants.

BACKGROUND: Many women express concern about their ability to produce enough milk, and insufficient milk is frequently cited as the reason for supplementation and early termination of breastfeeding. When addressing this concern, it is important first to consider the influence of maternal and neonatal health, infant suck, proper latch, and feeding frequency on milk production, and that steps be taken to correct or compensate for any contributing issues. Oral galactagogues are substances that stimulate milk production. They may be pharmacological or non-pharmacological (natural). Natural galactagogues are usually botanical or other food agents. The choice between pharmacological or natural galactagogues is often influenced by familiarity and local customs. Evidence for the possible benefits and harms of galactagogues is important for making an informed decision on their use. OBJECTIVES: To assess the effect of oral galactagogues for increasing milk production in non-hospitalised breastfeeding mother-term infant pairs. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), Health Research and Development Network - Phillippines (HERDIN), Natural Products Alert (Napralert), the personal reference collection of author LM, and reference lists of retrieved studies (4 November 2019). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) comparing oral galactagogues with placebo, no treatment, or another oral galactagogue in mothers breastfeeding healthy term infants. We also included cluster-randomised trials but excluded cross-over trials. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two to four review authors independently selected the studies, assessed the risk of bias, extracted data for analysis and checked accuracy. Where necessary, we contacted the study authors for clarification. MAIN RESULTS: Forty-one RCTs involving 3005 mothers and 3006 infants from at least 17 countries met the inclusion criteria. Studies were conducted either in hospitals immediately postpartum or in the community. There was considerable variation in mothers, particularly in parity and whether or not they had lactation insufficiency. Infants' ages at commencement of the studies ranged from newborn to 6 months. The overall certainty of evidence was low to very low because of high risk of biases (mainly due to lack of blinding), substantial clinical and statistical heterogeneity, and imprecision of measurements. Pharmacological galactagogues Nine studies compared a pharmacological galactagogue (domperidone, metoclopramide, sulpiride, thyrotropin-releasing hormone) with placebo or no treatment. The primary outcome of proportion of mothers who continued breastfeeding at 3, 4 and 6 months was not reported. Only one study (metoclopramide) reported on the outcome of infant weight, finding little or no difference (mean difference (MD) 23.0 grams, 95% confidence interval (CI) -47.71 to 93.71; 1 study, 20 participants; low-certainty evidence). Three studies (metoclopramide, domperidone, sulpiride) reported on milk volume, finding pharmacological galactagogues may increase milk volume (MD 63.82 mL, 95% CI 25.91 to 101.72; I² = 34%; 3 studies, 151 participants; low-certainty evidence). Subgroup analysis indicates there may be increased milk volume with each drug, but with varying CIs. There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints, such as tiredness, nausea, headache and dry mouth (very low-certainty evidence). No adverse effects were reported for infants. Natural galactagogues Twenty-seven studies compared natural oral galactagogues (banana flower, fennel, fenugreek, ginger, ixbut, levant cotton, moringa, palm dates, pork knuckle, shatavari, silymarin, torbangun leaves or other natural mixtures) with placebo or no treatment. One study (Mother's Milk Tea) reported breastfeeding rates at six months with a concluding statement of "no significant difference" (no data and no measure of significance provided, 60 participants, very low-certainty evidence). Three studies (fennel, fenugreek, moringa, mixed botanical tea) reported infant weight but could not be meta-analysed due to substantial clinical and statistical heterogeneity (I2 = 60%, 275 participants, very low-certainty evidence). Subgroup analysis shows we are very uncertain whether fennel or fenugreek improves infant weight, whereas moringa and mixed botanical tea may increase infant weight compared to placebo. Thirteen studies (Bu Xue Sheng Ru, Chanbao, Cui Ru, banana flower, fenugreek, ginger, moringa, fenugreek, ginger and turmeric mix, ixbut, mixed botanical tea, Sheng Ru He Ji, silymarin, Xian Tong Ru, palm dates; 962 participants) reported on milk volume, but meta-analysis was not possible due to substantial heterogeneity (I2 = 99%). The subgroup analysis for each intervention suggested either benefit or little or no difference (very low-certainty evidence). There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints such as mothers with urine that smelled like maple syrup and urticaria in infants (very low-certainty evidence). Galactagogue versus galactagogue Eight studies (Chanbao; Bue Xue Sheng Ru, domperidone, moringa, fenugreek, palm dates, torbangun, moloco, Mu Er Wu You, Kun Yuan Tong Ru) compared one oral galactagogue with another. We were unable to perform meta-analysis because there was only one small study for each match-up, so we do not know if one galactagogue is better than another for any outcome. AUTHORS' CONCLUSIONS: Due to extremely limited, very low certainty evidence, we do not know whether galactagogues have any effect on proportion of mothers who continued breastfeeding at 3, 4 and 6 months. There is low-certainty evidence that pharmacological galactagogues may increase milk volume. There is some evidence from subgroup analyses that natural galactagogues may benefit infant weight and milk volume in mothers with healthy, term infants, but due to substantial heterogeneity of the studies, imprecision of measurements and incomplete reporting, we are very uncertain about the magnitude of the effect. We are also uncertain if one galactagogue performs better than another. With limited data on adverse effects, we are uncertain if there are any concerning adverse effects with any particular galactagogue; those reported were minor complaints. High-quality RCTs on the efficacy and safety of galactagogues are urgently needed. A set of core outcomes to standardise infant weight and milk volume measurement is also needed, as well as a strong basis for the dose and dosage form used.

Effects of milking frequency and domperidone injections on milk production and prolactin signaling in the mammary gland of dairy cows.

Eleven mid-lactation Holstein cows were milked twice daily during the first 2 experimental weeks. During wk 3 to 10, the cows were differentially milked: right quarters were milked thrice daily (3×) and left quarters were milked once daily (1×). During wk 11 to 14, all quarters were milked twice daily. After 4 wk of differential milking, the cows received daily i.m. injections of the dopamine antagonist domperidone (DOMP; 300 mg; n = 6) or of dimethyl sulfoxide as the control (CTL; n = 5) for 8 wk (wk 7-14). During the differential milking period (wk 3-6), milk production was greater for quarters milked 3× than for those milked 1× but did not differ between DOMP and CTL cows. During the differential milking + injection period (wk 7-10), milk production continued to differ according to milking frequency. However, DOMP injection did not have an effect or interact with milking frequency on milk production. During the injection period (wk 11-14), milk production remained greater in the quarters previously milked 3× and milk production increased in DOMP injected cows but not in CTL cows. Injections of DOMP increased prolactin concentration, which was greater in the serum of DOMP cows than in that of CTL cows during the differential milking + injection and the injection periods. The expression of genes that are directly related to milk synthesis (CSN2, LALBA, and ACACA) was greater in the 3× quarters than in the 1× quarters. In addition, DOMP increased CSN2 expression during the injection period. The expression of both isoforms of the PRLR gene was greater in the 3× quarters during the differential milking + injection and the injection periods. At the protein level, injections of DOMP tended to increase the number of long PRLR isoform during the differential milking + injection period. The number of short PRLR isoform was greater in the 1× quarters than in the 3× quarters during the differential milking, the differential milking + injection, and the injection periods. The total amount of STAT3 protein was greater in the 1× quarters during the differential milking and the differential milking + injection periods. The amount of phosphorylated STAT3 protein was greater in the 1× quarters during the differential milking period. The total amount of phosphorylated STAT5 protein was greater in the 3× quarters during the differential milking and the differential milking + injection periods. The results of this experiment support the hypothesis that the responsiveness of the mammary gland to PRL is modulated by milking frequency, although the underlying mechanism remains to be determined.

Effect of Chronic Domperidone Use on QT Interval: A Large Single Center Study.

GOALS: The goal of this study was to determine the effect and safety of domperidone on QTc interval at the commonly prescribed doses of 30 to 80 mg daily. BACKGROUND: Domperidone is a dopamine receptor antagonist used for the treatment of gastroparesis. However, it has been associated with QT prolongation, ventricular arrhythmias, and sudden cardiac death. STUDY: This study analyzed patients prescribed domperidone for treatment of gastroparesis between January 2012 and September 2017 at a single center. This study reviewed EKGs, primarily the QTc interval, taken at baseline, 2 to 6 months after initiation of domperidone, 6 to 12 months after initiation, and ≥12 months after initiation. Concurrent QTc prolonging medications were recorded for each patient. The primary endpoint was QTc prolongation >500 ms. Secondary endpoints were QTc >450 ms for males, a QTc>470 ms for females, QTc prolongation ≥20 ms above baseline, and QTc prolongation >60 ms above baseline. RESULTS: In total, 246 patients were included for analysis (age, 46.3±17.4 y; F 209). EKGs were available for all 246 patients before treatment, 170 patients at 2 to 6 months, 135 at 6 to 12 months, and 152 patients at least 1 year after domperidone initiation.Of 246 subjects, 15 patients (6.1%, 9 female) had clinically important QTc prolongation; 11 had QTc >450 ms for males or >470 ms for females; none had QTc prolongation >500 ms; 5 (2.0%) had >60 ms over baseline and 61 (24.7%) patients had QTc increase of ≥20 ms but <60 ms from baseline. CONCLUSIONS: Domperidone at the conventionally used doses to treat gastroparesis (30 to 80 mg/d) was associated with QTc prolongation in only 6% of patients with no QT interval reaching the point considered to be clinically significant. These data suggest that domperidone can be safely prescribed at doses of 30 to 80 mg daily for the treatment of gastroparesis.

Safety and Efficacy of Low-dose Domperidone for Treating Nausea and Vomiting Due to Acute Gastroenteritis in Children.

BACKGROUND: This study was conducted based on a request from the European Medicines Agency to generate robust data on domperidone efficacy in children in the relief of symptoms of nausea and vomiting by assessing the effect of a low-dose and short treatment duration. METHODS: In this randomized, double-blind, phase 3 study, children ages 6 months to 12 years with acute gastroenteritis randomly (1:1) received oral domperidone 0.25 mg/kg with oral rehydration therapy (ORT) or matching placebo thrice daily for 2 to 7 days. The proportion of patients with no vomiting episodes (primary endpoint) and patients ages ≥4 years with no nausea episodes (key secondary endpoint) within 48 hours of first treatment administration were evaluated. RESULTS: The study was terminated early following futility analysis. At early termination, 292 patients randomly received domperidone (n = 147) or placebo (n = 145). The proportion of patients with no vomiting episodes within 48-hours of first treatment administration was similar between domperidone (32.0%) and placebo groups (33.8%). Similarly, there was no significant difference in proportion of patients ages ≥4 years with no nausea episodes within 48 hours of first treatment administration between domperidone (35.7%) and placebo (38.6%). Total 13 patients (domperidone, 3.4% [5/147] vs placebo, 5.5% [8/145]) reported ≥1 treatment-emergent adverse events. No deaths or adverse events of special interest (extrapyramidal symptoms and QT prolongation) were reported. CONCLUSIONS: Low-dose of domperidone with ORT did not significantly differ from placebo in reducing vomiting and nausea episodes in pediatric patients with acute gastroenteritis (AG), and the safety profile was similar between both groups.

Increased risk of all-cause mortality associated with domperidone use in Parkinson's patients: a population-based cohort study in the UK.

AIMS: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease (PD) and is linked to an increased risk of mortality. We sought to examine the risk of all-cause mortality associated with domperidone exposure in PD. METHODS: We conducted a cohort study using data from the Clinical Practice Research Datalink database (1987-2011). The first recorded PD diagnosis defined index date. Time-dependent Cox proportional hazards models estimated hazard ratios (HRs) of all-cause mortality associated with domperidone use. PD patients were stratified by domperidone use (current/recent/past), with never used as the referent. Current domperidone users were stratified by daily dose, domperidone duration and other anti-Parkinson's medications. A secondary analysis compared PD patients to matched (1:1) non-PD patients. RESULTS: A total of 5114 PD patients were identified. Current use of domperidone among PD patients was associated with a two-fold increase in all-cause mortality (HRadj  = 2.00, 95% confidence interval [CI]: 1.64-2.45), as compared to patients never exposed to domperidone. All-cause mortality risk was highest in those starting domperidone in the previous month [HRadj  = 2.97, 95% CI: 2.06-4.27]. When compared to matched non-PD patients, PD was associated with a 43% increased risk of all-cause mortality, yet this increased to a 2.4-fold increased risk among PD patients currently using domperidone. CONCLUSION: Current use of domperidone was associated with a two-fold increased mortality risk in PD patients, as compared to PD patients that never used domperidone. The risk is highest in the first month of use and does not appear to be attributable to PD alone.

Domperidone prolongs oral to duodenal transit time in video capsule endoscopy.

PURPOSE: Domperidone is thought to accelerate gastric emptying via D2 receptor antagonism at the gastro-oesophageal and gastro-duodenal junctions. Listed in the BNF as a prokinetic anti-emetic, it has been used in video capsule endoscopy (VCE) to accelerate capsule delivery to the small intestine. We audited VCEs performed at UHCW from 2011, when as standard practice, domperidone was given pre-VCE, to 2012, after its discontinuation due to doubts about its effectiveness. METHODS: Thirty-one patients received oral domperidone 20 mg pre-VCE. Thirty-three patients underwent VCE without domperidone pre-treatment. After 2 h, if the capsule remained intra-gastric, gastroscopy-assisted duodenal delivery was performed. Data was analysed using Mann-Whitney testing. RESULTS: Median oro-duodenal transit was 13 and 30 min in the untreated and domperidone groups, respectively (p = 0.01). Median oro-caecal transit was 242 and 267 min in the untreated and domperidone groups, respectively (p = 0.02). No difference in duodenal-caecal transit was seen (p = 0.60). Six percent of untreated and 13% of domperidone VCEs required gastroscopy-assisted duodenal capsule delivery (p = 0.65). CONCLUSIONS: Unexpectedly domperidone delayed VCE gastric transit. Most studies on domperidone prokinetic effects have been in diabetic gastroparesis, demonstrating that domperidone can achieve good symptomatic relief, but with mixed results for gastric emptying. Our study suggests that any antiemetic effects of domperidone are not mediated through accelerated gastric transit.

Domperidone for insufficient lactation in England 2002-2015: A drug utilization study with interrupted time series analysis.

PURPOSE: Our aim was to describe trends in the prescription of domperidone for insufficient lactation in England, the characteristics of women prescribed it postpartum, and the impact of a 2014 European Medicines Agency (EMA) recommendation to restrict its use due to a potential increased risk of sudden cardiac death associated with its use. METHODS: We conducted a population-based cohort study with interrupted time series analysis using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified women with live births from 2002 to 2015, excluding those with nonlactation indications for domperidone (n = 247 349). We evaluated trends in the prescription rate of domperidone in the 6 months postpartum and differences in this rate before and after the EMA recommendation. RESULTS: Domperidone was prescribed among 1438 deliveries at a rate of 1.24 per 100 person-years. This rate increased from 0.56 to 2.1 per 100 person-years between 2002-2004 and 2011-2013 (rate ratio: 3.8; 95% confidence interval [CI], 3.2-4.6). Prescribing decreased in level by 0.35 (95% CI, -0.86 to 0.16) per 100 person-years immediately following the recommendation with little change in trend (0.003; 95% CI, -0.059 to 0.065 per 100 person-years). Following the recommendation, prescription of doses >30 mg and coprescription of drugs with a risk of torsade de pointes decreased. No arrhythmic events were observed among domperidone users. CONCLUSIONS: Although we observed an important increase in prescribing during the study period, domperidone remains infrequently prescribed postpartum in England. While overall prescribing changed little, some prescribing practices became more restricted following the EMA's recommendation.

Case report: domperidone use as a galactagogue resulting in withdrawal symptoms upon discontinuation.

We present a case of domperidone withdrawal in a woman using the medication as a galactagogue. Our primary goal is to increase the literature available to providers who work with women who are breastfeeding. We evaluated a woman presenting to our reproductive psychiatry clinic for consultation regarding anxiety and agitation in the context of domperidone discontinuation. We evaluated the available literature regarding domperidone as a galactagogue, as well as the literature regarding adverse effects. The patient presented with withdrawal symptoms after gradual taper and discontinuation of domperidone. After restarting the medication, her symptoms resolved. She was able to successfully discontinue domperidone with a slow, gradual taper. Domperidone is occasionally used as a galactagogue in women with inadequate milk supply. We report a case in which a woman experienced withdrawal symptoms after domperidone discontinuation.

Effect of the concentration of circulating prolactin on dairy cows' responsiveness to domperidone injection.

The objective of this study was to determine whether the responsiveness of the mammary gland to prolactin (PRL) is affected by the concentration of the hormone. After 1 pre-experimental week (d -7 to -1), 18 Holstein cows in mid to late lactation were injected intramuscularly twice daily with either 0.5 mg of quinagolide (QN) or 2 mL of water (control) for 2 wk (d 1 to 14; treatment period). After the treatment period, all cows received daily subcutaneous injections of 300 mg of domperidone (DOMP) for 3 wk (d 15 to 35; DOMP period). The cows were monitored for an additional 2 wk as a posttreatment period (d 36 to 49). Blood and milk samples were collected 3 times per week. Additionally, blood samples were collected during the a.m. milking on d -4, 14, and 35. Milk production was not affected by QN during the treatment period but was increased during the DOMP and posttreatment periods in the QN cows. With respect to milk composition, the treatments affected only the protein content, which was greater in the QN cows during the treatment period. Blood PRL concentration declined during QN injections and was lower in the QN cows than in the control cows between d 5 and 14. The basal concentration of PRL was increased by DOMP injections during the DOMP and posttreatment periods but was not affected by previous QN injections. Prolactin concentration in milk was not affected by the QN treatments but was increased by DOMP injections during the DOMP and posttreatment periods. Milking-induced PRL release was decreased by QN on d 14. On d 35, milking did not induce a significant release of PRL above the baseline for both treatments. In conclusion, the results of this experiment support the contention that the mammary gland's responsiveness to PRL is modulated by the previous level of the hormone.

Development of Domperidone Solid Lipid Nanoparticles: In Vitro and In Vivo Characterization.

Domperidone (DOP) is extensively applied orally in the management of nausea and vomiting. Upon oral administration, its bioavailability is very poor due to its poor solubility in alkaline media. Therefore, the aim of this work was to investigate DOP-loaded solid lipid nanoparticles (DOP-SLNs) in order to sustain its release pattern and to enhance oral bioavailability. DOP-SLNs were prepared using four different lipids. Prepared DOP-SLNs were characterized for "polydispersity index (PDI), particle size, zeta potential, % entrapment efficiency (% EE), and drug release behavior." Differential scanning calorimetry (DSC) study was carried out to illustrate the physical form of DOP and excipients. The morphology of DOP-SLNs was confirmed by scanning electron microscopy (SEM). Pharmacokinetic study on optimized DOP-SLN in comparison to tablet was performed in rats. The "particle size, PDI, zeta potential, and % EE" of optimized formulation (F5) were recorded as 201.4 nm, 0.071, - 6.2 mV, and 66.3%, respectively. DSC thermograms suggested amorphous state of DOP in various SLNs. Surface morphology of SLNs using SEM suggested spherical shape of the nanoparticles within nanometer size range. In vitro release studies confirmed that all SLN formulations possessed a sustained release over a period of 12 h (51.3% from optimized formulation) in comparison with immediate release from conventional tablets (100% after 90 min). Pharmacokinetic study showed significant enhancement in oral absorption of DOP from optimized SLN in comparison with DOP tablet. The enhancement in relative bioavailability of DOP from optimized SLN was 2.62-fold in comparison with DOP tablet.

Domperidone is Commonly Prescribed With QT-Interacting Drugs: Review of a Community-based Practice and a Postmarketing Adverse Drug Event Reporting Database.

INTRODUCTION: Domperidone, a peripheral D2 dopamine receptor antagonist, has efficacy for treatment of nausea, dyspepsia, and gastroparesis. Domperidone prolongs the QT interval (QTc), and may cause life-threatening arrhythmias. METHODS: Electronic medical records for all patients receiving domperidone in the NorthShore University HealthSystem from January 1, 2008 to December 1, 2013 were reviewed. All concomitant medications were noted. The coadministration of QT-interacting medications was determined. Electrocardiogram (EKG) evaluation before and during domperidone therapy was noted. A query of the FDA Adverse Event Reporting System (FAERS) database was also performed. Individual reports from the FAERS Web site from January 2008 to June 2014 were downloaded and analyzed. The database was queried for all reports of adverse events with domperidone. Coadministration of QT-interacting medications was noted. Cardiac events that potentially were related to prolongation of the QTc were examined. RESULTS: In total, 108 of 155 patients (69.7%) were coprescribed QT-interacting drugs along with domperidone. Fifty-nine of 155 patients (38.1%) underwent a baseline EKG and 9 (15.3%) had prolongation of the QTc at initiation. Forty patients (25.8%) had a follow-up EKG and 13 (32.5%) had prolongation of the QTc. All 13 were coprescribed QT-interacting medications. On the FAERS, 221 nonfatal cardiac events were reported in domperidone patients; of these, 162 (73.3%) occurred in patients receiving QT-interacting medications. Coprescription occurred in 53 of 151 deaths (35.1%) and in 16 of 61 cardiac arrests (26.2%). CONCLUSIONS: Coprescribing of QT-prolonging medications and inconsistent EKG monitoring occur in patients receiving domperidone, placing these patients at risk for arrhythmias.

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

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 (Cmax) and area under the concentration- time curve (AUC) were significantly increased. A significant decrease in time to reach maximum plasma concentration (Tmax), clearance and elimination rate constant (Kel) 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. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Impact of lubiprostone on gastric-emptying profile and the possible effect of concomitant domperidone in healthy adults
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BACKGROUND: Lubiprostone is effective for patients with chronic constipation. This agent sometimes causes upper gastrointestinal symptoms, such as nausea, which is one of the chief reasons for discontinuation. However, the etiology of and strategy against bothersome gastrointestinal symptoms of lubiprostone remain unclear. AIMS: The goal of this study was to investigate the influence of lubiprostone on the gastric-emptying profile of healthy adults. The effect of domperidone on gastric emptying and gastrointestinal symptoms after lubiprostone administration were also assessed. MATERIALS AND METHODS: 80 healthy male participants underwent 13C acetate breath testing to evaluate gastric emptying. The test meal comprised 200 kcal of a standard liquid nutrient. Each participant underwent 3 random breath tests with: 1) no premedication; 2) 24 µg of lubiprostone 30 minutes prior to the study; and 3) 24 µg of lubiprostone plus 10 mg of domperidone 30 minutes prior to the study. Gastrointestinal symptoms (heartburn, regurgitation, epigastric pain, fullness, distress feeling) during testing were evaluated using a 7-point scoring system. RESULTS: Gastric emptying was significantly delayed by the administration of lubiprostone. Among all 8 subjects, 4 reported heartburn after taking lubiprostone, whereas this symptom was not found when subjects received concomitant domperidone. However, gastric emptying showed little change between lubiprostone alone and lubiprostone plus domperidone. CONCLUSION: Lubiprostone delayed gastric emptying of liquid in healthy adults, which could be associated with the gastrointestinal symptoms caused by the agent. Domperidone seemed effective against such gastrointestinal symptoms after administration of lubiprostone. This effect seemed unrelated to gastric motility.
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Relationship between glucocorticoids and prolactin during mammary gland stimulation in dairy cows.

The objectives of this study were to determine the role of glucocorticoids in the regulation of prolactin (PRL) release induced by mammary gland stimulation and to investigate whether the milk depression induced by glucocorticoids in dairy cows is due to a decrease in PRL release. In experiment 1, 8 dairy cows were used in a 4 × 4 Latin square design. Four hours after the morning milking, the cows received 1 of the following treatments: (1) a 5-min manual stimulation of the mammary gland; (2) an i.v. injection of 1 mg of dexamethasone; (3) 2 infusions of 2.5 g of metyrapone (an inhibitor of cortisol biosynthesis) in the omasum 4 and 2 h before a 5-min stimulation of the mammary gland; or (4) no treatment. Sixty minutes later, the mammary gland of each cow was stimulated for 5 min. Blood samples were collected from 20 min before to 120 min after the start of the treatment. When the mammary gland was stimulated twice in 60 min, less PRL and cortisol were released during the second stimulation. Metyrapone did not affect PRL or cortisol release. Dexamethasone decreased serum cortisol concentration but did not affect PRL concentration. In experiment 2, 16 cows were used in a crossover experimental design consisting of 2 experimental weeks separated by 1 resting week. During the first week, cows were treated as follows: (1) 4 cows were injected with 0.5 g of domperidone (a PRL secretagogue) in canola oil on d 1 and 2 and 20 mg of dexamethasone on d 1; (2) 4 cows were injected with 0.5 g of domperidone on d 1 and 2; (3) 4 cows were injected with canola oil on d 1 and 2 and with 20 mg of dexamethasone on d 1; and (4) 4 cows were injected with canola oil on d 1 and 2. During the second experimental week, the same 4 treatments were repeated, except the cows that did not receive dexamethasone in the first week received it on d 1 of the second week, and cows that did receive it in the first week did not receive it in the second week. On d 1 and 2 of each week, blood samples were collected during morning milking for PRL determination. Dexamethasone reduced milk production and decreased both basal and milking-induced PRL release. It also increased milk fat and protein percentages and decreased milk lactose content. Domperidone increased basal PRL levels in serum and milk but did not affect milk yield. Although we cannot rule out the possibility that inhibition of PRL secretion or reduction of mammary gland PRL responsiveness play a role in the inhibition of milk production by glucocorticoids, the fact that enhancement of PRL secretion by domperidone could not prevent the depression of milk yield suggests that other mechanisms are involved.

Ventricular tachyarrhythmia and sudden cardiac death with domperidone use in Parkinson's disease.

AIM: Domperidone is preferentially used over other antiemetic agents to treat digestive symptoms in Parkinson's disease (PD). Concerns have been raised regarding an increased risk of ventricular tachyarrhythmia and sudden cardiac death (VT/SCD) associated with domperidone in the general population. However, the risk in PD is unknown. METHODS: We conducted a multicentre retrospective cohort study using administrative databases from seven Canadian provinces and the UK Clinical Practice Research Datalink. Using a nested case-control analysis, we estimated the rate ratios (RRs) of VT/SCD associated with domperidone use compared to no use in patients newly-diagnosed with PD. VT/SCD events were identified using administrative medical records and vital statistics with a manual review of all potential cases. Meta-analytic methods were used to estimate overall effects across sites. RESULTS: Among 214 962 patients with PD, 2907 cases of VT/SCD were identified during 886 581 person-years of follow-up (incidence rate 3.28 per 1000 persons per year). Current use of domperidone was associated with a non-statistically significant 22% increased risk of VT/SCD (RR 1.22; 95% CI 0.99-1.50) compared with no use. The risk was significantly elevated in those with a history of cardiovascular disease (RR 1.38; 95% CI 1.07-1.78), but not in those without (RR 1.21; 95% CI 0.81-1.81). Dose and duration of use did not affect the magnitude of the risk. CONCLUSION: Domperidone use may increase the risk of VT/SCD in patients with PD, particularly those with a history of cardiovascular disease. This risk may be underestimated because of imprecision in identifying VT/SCD events.

The association between domperidone and ventricular arrhythmia in the postpartum period.

PURPOSE: The aim of this study is to examine the relationship between domperidone (commonly used off-label for lactation stimulation), ventricular arrhythmia and all-cause mortality during the postpartum period. METHODS: This is a retrospective, population-based cohort study of all women with a live birth between 1 January 2002 and 31 December 2011 in British Columbia, Canada. Cox proportional hazards models, yielding hazard ratios (HRs), were used to estimate the risk of hospitalization for ventricular arrhythmia associated with domperidone exposure within six months postpartum. RESULTS: The study population consisted of 225 532 women with 320 351 live births. There was only one death during the six-month postpartum period among the study population, and thus we did not perform any analyses of all-cause mortality. We identified 21 hospitalizations for ventricular arrhythmia. Adjusting for age, smoking and prior history of ventricular arrhythmia and cardiovascular disease, the risk of ventricular arrhythmia hospitalization was approximately double among those exposed to domperidone, but the results were not statistically significant (HR = 2.25, 95%CI 0.84-6.01). Adjustment for body mass index in the 74% of women for whom it was known further reduced the association (HR = 1.69, 95%CI 0.48-5.96). CONCLUSIONS: We found a possible association between exposure to domperidone and hospitalization for ventricular arrhythmia among a cohort of women who have recently given birth. Future studies are needed to confirm this association. Copyright © 2016 John Wiley & Sons, Ltd.

Survey of the use of domperidone and the association with QTc prolongation in general practice.

PURPOSE OF THE STUDY: Domperidone is associated with QTc prolongation, predisposing to the development of ventricular arrhythmias. In 2014, The Medicines and Healthcare Regulatory Agency (MHRA) recommended restricting its use. We assessed whether these recommendations have been implemented in a general practice. STUDY DESIGN: We conducted a prospective study using the general practitioner (GP) computer database on patients who had at least one repeat prescription for domperidone in 12 months. Data were presented to the doctors and the survey was repeated 7 months later. RESULTS: Sixty-four patients (mean age 61.3±16.4 years) were identified who had received at least one repeat prescription of domperidone. Twenty patients were being prescribed over the recommended daily dose. Nineteen patients were coprescribed medications known to prolong the QTc interval and two CYP3A4 inhibitors. The repeat survey performed 7 months later demonstrated a 70% reduction in the number of patients prescribed domperidone to a total of 19 (three patients prescribed above the recommended dose) none of which had a history of cardiac disease or were being coprescribed drugs known to prolong the QTc interval. CONCLUSIONS: Following the publication of the MHRA recommendations and presentation of our initial survey, there has been a significant reduction in the number of patients treated with domperidone and those coprescribed drugs known to prolong the QTc interval. We suggest that regular review of GP practice database should be performed to identify those patients prescribed domperidone and at risk of life-threatening arrhythmias and measures taken to use alternative pharmacological agents.

Effect of conventional diet schedule, early feeding and early feeding plus domperidone on postcesarean diet tolerance: A randomized controlled trial.

AIM: To compare time to regular diet tolerance among conventional schedule, early oral feeding and early oral feeding plus domperidone in postcesarean women and to investigate these protocols on other aspects of postoperative well-being. METHODS: During July 2014 to June 2015, 120 postcesarean women were randomly assigned to three groups. Group A, conventional schedule: women fasted for 18-24 h postoperatively, then sipped water, had a liquid diet, soft diet, and regular diet, consecutively. Group B, early oral feeding: women started sipping water at 3-8 h postoperatively, followed by a soft and then a regular diet. Group C consumed the same as group B, plus domperidone. RESULTS: Median time to regular diet tolerance was 52.3 (50.8-54.7), 28.5 (24.8-31.4), and 29.6 (26.5-44.8) h (P < 0.001) in groups A, B and C, respectively. The two early feeding groups had significantly earlier ambulation and shorter hospitalization compared with the control. There were no differences between the two early feeding groups. The rate of postoperative gastrointestinal symptoms, pain scores and patients' satisfaction scores were similar among the three groups. CONCLUSION: Early oral feeding does not significantly increase postoperative complications; however, is associated with earlier regular diet intake. Apparently, domperidone does not enhance postoperative gastrointestinal function.