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PloS One 2019Autosomal dominant polycystic kidney disease (ADPKD) is caused mostly by mutations in polycystin-1 or polycystin-2. Fluid flow leads to polycystin-dependent calcium...
Autosomal dominant polycystic kidney disease (ADPKD) is caused mostly by mutations in polycystin-1 or polycystin-2. Fluid flow leads to polycystin-dependent calcium influx and nuclear export of histone deacetylase 5 (HDAC5), which facilitates the maintenance of renal epithelial architecture by de-repression of MEF2C target genes. Here, we screened a small-molecule library to find drugs that promotes nuclear export of HDAC5. We found that dopamine receptor antagonists, domperidone and loxapine succinate, stimulate export of HDAC5, even in Pkd1-/-cells. Domperidone targets Drd3 receptor to modulate the phosphorylation of HDAC5. Domperidone treatment increases HDAC5 phosphorylation likely by reducing protein phosphatase 2A (PP2A) activity, thus shifting the equilibrium towards HDAC5-P and export from the nucleus. Treating Pkd1-/-mice with domperidone showed significantly reduced cystic growth and cell proliferation. Further, treated mice displayed a reduction in glomerular cyst and increased body weight and activity. These results suggest that HDAC5 nucleocytoplasmic shuttling may be modulated to impede disease progression in ADPKD and uncovers an unexpected role for a class of dopamine receptors in renal epithelial morphogenesis.
Topics: Active Transport, Cell Nucleus; Animals; Cell Proliferation; Domperidone; Dopamine Antagonists; Drug Evaluation, Preclinical; Epithelial Cells; Histone Deacetylases; Kidney; Mice; Polycystic Kidney, Autosomal Dominant
PubMed: 31059522
DOI: 10.1371/journal.pone.0216220 -
The Canadian Journal of Hospital... Nov 2014Domperidone, an effective prokinetic agent, is commonly used to manage symptoms of gastroparesis. Health regulatory agencies have issued warnings about an increased risk... (Review)
Review
BACKGROUND
Domperidone, an effective prokinetic agent, is commonly used to manage symptoms of gastroparesis. Health regulatory agencies have issued warnings about an increased risk of sudden cardiac death associated with use of this drug.
OBJECTIVE
To evaluate the evidence for domperidone-associated sudden cardiac death and to determine whether this drug can be safely used for gastroparesis in patients undergoing dialysis.
DATA SOURCES
Two databases (MEDLINE [1965 to September 2014] and Embase [1980 to September 2014]) were searched using the Medical Subject Headings "domperidone", "sudden cardiac death", and "cardiac arrhythmia". The search was limited to studies conducted in humans and published in English. Advisories from health regulatory agencies (Health Canada, the European Medicines Agency, and the US Food and Drug Administration) were identified and reviewed.
STUDY SELECTION
Studies eligible for inclusion in this narrative review were randomized controlled trials and cohort, case-control, cross-sectional, and other epidemiological studies comparing use and non-use of domperidone for the outcome of sudden cardiac death in adults. Abstracts of eligible case reports and case series were also included.
DATA SYNTHESIS
Despite inconsistencies in their decisions, the various drug regulatory authorities have acknowledged the potential safety concern of increased risk of sudden cardiac death associated with domperidone. To date, no randomized controlled studies have shown an increased risk of this outcome secondary to domperidone use. Current regulatory recommendations and approval decisions are based on 2 large observational epidemiological studies that generated a signal of increased risk. The strengths and limitations of these studies were evaluated in detail. No direct evidence applicable to patients with end-stage renal disease was found. In vitro evidence suggests that the risk of sudden cardiac death is dose-related.
CONCLUSIONS
Given gaps in the literature, use of domperidone for patients undergoing dialysis should be assessed on a case-by-case basis. Extreme caution should be used for patients taking more than 30 mg/day of this drug.
PubMed: 25548402
DOI: 10.4212/cjhp.v67i6.1407 -
Neurology Dec 2016To determine the safety of domperidone in the treatment of nausea associated with dihydroergotamine (DHE) infusion and headache.
OBJECTIVE
To determine the safety of domperidone in the treatment of nausea associated with dihydroergotamine (DHE) infusion and headache.
METHODS
We audited our use of domperidone for the inpatient management of nausea, focusing on known safety concerns, particularly potential cardiac arrhythmias.
RESULTS
We reviewed 103 consecutive admissions of 90 patients admitted for IV DHE by infusion. Most admissions were to treat chronic migraine with (n = 53) or without (n = 46) aura. Domperidone was administered in 85 of 103 encounters and was well-tolerated at doses up to 80 mg/d. A significant side effect, akathisia, was observed in one patient. Baseline ECG with corrected QT interval (QTc) was obtained on all patients. Repeat ECG after domperidone was obtained in 21 patients, whose baseline characteristics did not differ from the group as a whole. ECG was interpreted blindly by a cardiac electrophysiologist. QTc did not differ before and after domperidone administration (Wilcoxon signed-rank test, median [interquartile range] 435.0 [410.5-453.0] at admission and 427.0 [399.0-452.5] after domperidone; p = 0.15). In combination with other antiemetics, domperidone was effective in treating nausea such that no patients had refractory nausea severe enough to limit DHE dose.
CONCLUSIONS
This retrospective audit demonstrates that domperidone is safe in the treatment of nausea associated with inpatient DHE infusion and headache. While larger prospective trials are necessary to confirm these results and assess efficacy, current evidence and clinical experience suggests that domperidone is safe and useful for nausea and headache management.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that for patients with headache undergoing DHE infusion, domperidone is safe and effective in the treatment of nausea.
Topics: Adolescent; Adult; Aged; Antiemetics; Dihydroergotamine; Domperidone; Female; Headache; Humans; Male; Middle Aged; Migraine Disorders; Nausea; Prospective Studies; Retrospective Studies; Young Adult
PubMed: 27837002
DOI: 10.1212/WNL.0000000000003429 -
Yakugaku Zasshi : Journal of the... 2016The characteristics and functional roles of opioids originally present in vivo (endogenous opioids) in guinea-pig ileum were investigated. The release of endogenous... (Review)
Review
The characteristics and functional roles of opioids originally present in vivo (endogenous opioids) in guinea-pig ileum were investigated. The release of endogenous opioids was determined by the inhibitory twitch response evoked by 0.1 Hz stimulation after 10 Hz stimulation (post-tetanic twitch inhibition). The effects of peptidase inhibitors increased the post-tetanic twitch inhibition, prevented by β-funaltrexamine and nor-binaltorphimine, which are selective μ- and κ-opioid receptor subtype antagonists, respectively. Dopamine receptor antagonists (haloperidol, sultopride and domperidone) increased the post-tetanic twitch inhibition. These results suggest that dopamine receptors are involved in modulation of the ileal opioid system, so as to diminish endogenous opioid release by tetanic stimulation, and dopamine antagonists increase the opioid action, that might depend more on the increased release of endogenous opioids. The post-tetanic twitch inhibition was inhibited by adrenalectomy, and showed the supersensitivity of the opioid receptors, resulting from a decrease of endogenous opioids by adrenalectomy. These findings suggest that the increase in morphine-analgesia by adrenalectomy was due to this process. In the presence of naloxone, an opioid antagonist, an increase in basal tension after tetanic stimulation (10 Hz stimulation) (post-tetanic contraction) was observed, and was blocked by spantide, a substance P antagonist, and indomethacin, a prostaglandins-biosynthesis inhibitor. This contraction increased with morphine or peptidase inhibitor exposure, depending on the length of time the ileum was exposed to the morphine or peptidase inhibitor. Post-tetanic contraction might be a useful indicator of the formation of physical dependence to morphine or endogenous opioids in the ileum.
Topics: Animals; Dopamine Antagonists; Humans; Ileum; Morphine; Morphine Dependence; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Opioid Peptides; Protease Inhibitors; Receptors, Dopamine; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors
PubMed: 27040344
DOI: 10.1248/yakushi.15-00265 -
The Journal of Biological Chemistry Dec 2022Cancer cells intrinsically proliferate in an autonomous manner; however, the expansion of cancer cell areas in a tissue is known to be regulated by surrounding...
Cancer cells intrinsically proliferate in an autonomous manner; however, the expansion of cancer cell areas in a tissue is known to be regulated by surrounding nontransformed cells. Whether these nontransformed cells can be targeted to control the spread of cancer cells is not understood. In this study, we established a system to evaluate the cancer-inhibitory activity of surrounding nontransformed cells and screened chemical compounds that could induce this activity. Our findings revealed that lonidamine (LND) and domperidone (DPD) inhibited expansion of oncogenic foci of KRASG12D-expressing transformed cells, whereas they did not inhibit the proliferation of monocultured KRASG12D-expressing cells. Live imaging revealed that LND and DPD suppressed the movement of nontransformed cells away from the attaching cancer cells. Moreover, we determined that LND and DPD promoted stress fiber formation, and the dominant-negative mutant of a small GTPase RhoA relieved the suppression of focus expansion, suggesting that RhoA-mediated stress fiber formation is involved in the inhibition of the movement of nontransformed cells and focus expansion. In conclusion, we suggest that elucidation of the mechanism of action of LND and DPD may lead to the development of a new type of drug that could induce the anticancer activity of surrounding nontransformed cells.
Topics: Domperidone; Indazoles; Antineoplastic Agents; Neoplasms; Animals; Mice; Epithelial Cells; Mammary Glands, Animal; Drug Screening Assays, Antitumor
PubMed: 36273581
DOI: 10.1016/j.jbc.2022.102635 -
Farmacia Hospitalaria : Organo Oficial... Sep 2014To assess the association of the use of domperidone in infants with QTc interval prolongation and proarrhythmic events. (Review)
Review
AIMS
To assess the association of the use of domperidone in infants with QTc interval prolongation and proarrhythmic events.
METHODS
A systematic search of the scientific literature was conducted without any date or language restriction. The electronic database MEDLINE and the sources LILACS, ScIELO and Cochrane library were consulted.
RESULTS
From the twelve identified studies, eight were excluded because they did not meet the inclusion criteria. One case report and three pilot studies were selected. Rocha et al (2005) reported the case of an infant (age 3 months) with QTc interval = 463 ms after being treated during one month with 1.8 mg/kg/day of oral domperidone. Djeddi et al (2008) administered an average dose of 1.3 mg/kg/day to 31 neonates; QTc interval prolongation > 30 ms was observed in nine neonates. Hegar et al (2009) studied 10 infants (mean age 5.6 months) who received 0.8 mg/ kg/day of oral domperidone; QTc interval prolongation was not observed. Günlemez et al (2010) enrolled 40 premature infants who were administered 1 mg/kg/day of oral domperidone; the QTc interval increased to above 450 ms in two infants.
CONCLUSIONS
Although evidence that orally administrated domperidone in infants produces prolongation of QTc interval was found, further studies are needed in order to quantify the risk associated with the drug in that population. We suggest that heath professionals should conduct ECGs to infants treated with domperidone and inform the pharmacovigilance system the occurrence of any case of adverse event.
Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Cisapride; Contraindications; Cytochrome P-450 CYP3A; Domperidone; Dopamine Antagonists; Drug Interactions; Gastroesophageal Reflux; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Long QT Syndrome; Pilot Projects; Prospective Studies
PubMed: 25344138
DOI: 10.7399/fh.2014.38.5.7957 -
Cureus Dec 2023The commonest medications prescribed in functional dyspepsia are prokinetic agents, specifically domperidone. However, its administration at times elevates serum...
The commonest medications prescribed in functional dyspepsia are prokinetic agents, specifically domperidone. However, its administration at times elevates serum prolactin levels, which can lead to pathological hyperprolactinemia. The present study investigated the effect of 28 days of 30 mg domperidone therapy on prolactinemia in functional dyspepsia patients. We recruited 97 patients (60 men and 37 women, aged 18-80 years) who had functional dyspepsia diagnosed as per the Rome IV criteria. After taking a preliminary clinical history, we measured and compared serum prolactin levels at day 'zero' and day 'twenty-eight'. We found increased prolactin levels from day '0' to day '28' after treatment with domperidone in functional dyspepsia patients, specifically in male participants aged less than 40 years, who are married and belong to middle socioeconomic status. The most common functional dyspepsia symptom found was pain in the epigastric region. To conclude, our pragmatic domperidone-induced-hyperprolactinemia link warrants this side effect to be robustly taken into account while treating functional dyspepsia patients with domperidone.
PubMed: 38249246
DOI: 10.7759/cureus.50927 -
Alcoholism, Clinical and Experimental... Mar 2022Dopamine neuron firing in the ventral tegmental area (VTA) and dopamine release in the nucleus accumbens have been implicated in reward learning. Ethanol is known to...
BACKGROUND
Dopamine neuron firing in the ventral tegmental area (VTA) and dopamine release in the nucleus accumbens have been implicated in reward learning. Ethanol is known to increase both dopamine neuron firing in the VTA and dopamine levels in the nucleus accumbens. Despite this, some discrepancies exist between the dose of ethanol required to enhance firing in vivo and ex vivo. In the present study we investigated the effects of peripheral dopamine 2 subtype receptor antagonism on ethanol's effects on dopamine neurotransmission.
METHODS
Plasma catecholamine levels were assessed following ethanol administration across four different doses of EtOH. Microdialysis and voltammetry were used to assess the effects of domperidone pretreatment on ethanol-mediated increases in dopamine release in the nucleus accumbens. A place conditioning paradigm was used to assess conditioned preference for ethanol and whether domperidone pretreatment altered this preference. Open-field and loss-of-righting reflex paradigms were used to assess the effects of domperidone on ethanol-induced sedation. A rotarod apparatus was used to assess the effects of domperidone on ethanol-induced motor impairment.
RESULTS
Domperidone attenuated ethanol's enhancement of mesolimbic dopamine release under non-physiological conditions at intermediate (1.0 and 2.0 g/kg) doses of ethanol. Domperidone also decreased EtOH-induced sedation at 2.0 g/kg. Domperidone did not alter ethanol conditioned place preference nor did it affect ethanol-induced motor impairment.
CONCLUSIONS
These results show that peripheral dopamine 2 receptors mediate some of the effects of ethanol on nonphysiological dopamine neurotransmission, although these effects are not related to the rewarding properties of ethanol.
Topics: Domperidone; Dopamine; Ethanol; Nucleus Accumbens; Ventral Tegmental Area
PubMed: 35040146
DOI: 10.1111/acer.14775 -
Cureus Mar 2023Introduction The global proton pump inhibitors (PPIs) market was valued at US$ 2.9 billion in 2020 and is expected to exhibit a compound aggregated growth rate of 4.30%...
Introduction The global proton pump inhibitors (PPIs) market was valued at US$ 2.9 billion in 2020 and is expected to exhibit a compound aggregated growth rate of 4.30% during the forecast period (2020-2027), as they are regularly prescribed for many gastrointestinal disorders, and the treatment usually lasts for a longer period. PPIs are usually combined with antiemetics and prokinetic drugs. The price of PPIs for the same combination varies a lot, which can lead to a lot of financial burden on the patients. Objective To evaluate the cost ratio and percentage cost variation of commonly used PPIs in various combinations. Methodology The cost of different brands of commonly used PPIs in combination with other drugs was analyzed in our study. A total of 21 different combinations (10 capsules/tablets for oral use) were tabulated by referring to the "Monthly Index of Medical Specialities" October-December 2021, and 1mg online pharmacy. The cost ratio and percentage cost variation for various brands of a particular strength and dosage form were calculated and compared. Cost ratio > 2 and cost variation > 100% were considered significant. Results The results show a huge variation (1788.88%) in costs of different brands with the highest being rabeprazole 20 mg and domperidone 10 mg (cost ratio: 18.88, percentage cost variation: 1788.88%) in oral formulation, followed by pantoprazole 40 mg and itopride 150 mg. The minimum cost ratio (1.35) and percentage cost variation (1.35%) is for pantoprazole 40 mg and levosulpiride 75 mg. Logistic regression analysis between the number of brands and percentage cost variation gives an R value of 0.0923. Conclusion There is a wide variation in the prices of PPIs available in the market, which can inadvertently increase the financial burden of therapy on patients. Physicians need to be made aware of these price differences so that they can choose the best available alternative for patients, which can help in increasing compliance with the prescribed drugs.
PubMed: 37065352
DOI: 10.7759/cureus.36112 -
Proceedings (Baylor University. Medical... Jan 2020Gastroparesis is delayed gastric emptying in the absence of mechanical obstruction. Cases are attributed to narcotic use, smoking, diabetes, and postsurgical...
Gastroparesis is delayed gastric emptying in the absence of mechanical obstruction. Cases are attributed to narcotic use, smoking, diabetes, and postsurgical complications; however, several incidences are unknown. Treatment options include diet modification, gut-stimulating medications (e.g., metoclopramide, domperidone), laparoscopic pyloroplasty, and, in the most severe cases, partial gastrectomy with Roux-en-Y reconstruction. Recently, a novel therapy has been developed, peroral endoscopic pyloromyotomy (POP). This procedure is similar to a laparoscopic pyloroplasty; however, it is performed completely endoscopically, thus negating the need for incisions. Here we present a case of gastroparesis treated with this novel technique.
PubMed: 32063767
DOI: 10.1080/08998280.2019.1656007