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Pharmaceutics Aug 2022Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the...
Comparison of the Blood-Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug-Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging.
Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood−brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging in rats with the radiolabeled analogs [11C]domperidone and [11C]metoclopramide. In P-gp-overexpressing cells, the IC50 of tariquidar, a potent P-gp inhibitor, was drastically different using [11C]domperidone (221 nM [198−248 nM]) or [11C]metoclopramide (4 nM [2−8 nM]) as the substrate. Complete P-gp inhibition led to a 1.8-fold higher increase in the cellular uptake of [11C]domperidone compared with [11C]metoclopramide (p < 0.0001). Brain PET imaging revealed that the baseline brain exposure (AUCbrain) of [11C]metoclopramide was 2.4-fold higher compared with [11C]domperidone (p < 0.001), consistent with a 1.8-fold higher BBB penetration (AUCbrain/AUCplasma). The maximal increase in the brain exposure (2.9-fold, p < 0.0001) and BBB penetration (2.9-fold, p < 0.0001) of [11C]metoclopramide was achieved using 8 mg/kg of tariquidar. In comparison, neither 8 nor 15 mg/kg of tariquidar increased the brain exposure of [11C]domperidone (p > 0.05). Domperidone is an avid P-gp substrate that was in vitro compared with metoclopramide. Domperidone benefits from a lower brain exposure and a limited risk for P-gp-mediated drug−drug interaction involving P-gp inhibition at the BBB.
PubMed: 36015284
DOI: 10.3390/pharmaceutics14081658 -
Pakistan Journal of Medical Sciences 2022To compare the efficacy of Ondansetron versus Domperidone for treating vomiting in acute gastroenteritis (AGE) in children at a resource limited emergency setting of...
OBJECTIVES
To compare the efficacy of Ondansetron versus Domperidone for treating vomiting in acute gastroenteritis (AGE) in children at a resource limited emergency setting of South Punjab, Pakistan.
METHODS
This open label randomized controlled trial was conducted at The Pediatric Emergency Department of Tehshil Headquarter Hospital, Liaqatpur, Pakistan, from July 2020 to June 2021. A total of 300 children of both genders aged below 12 years of age having 3 or more non-bilious, non-bloody vomiting episodes within 24 hours and with suggestive signs and symptoms of AGE were enrolled and randomized (150 in each group). Efficacy of both drugs was compared in terms of need of 2 dose within 15 minutes, cessation of vomiting at 6-hour and 24-hour follow up.
RESULTS
Out of a total of 300 children, 162 (54.0%) were male. Mean age was 4.7±2.3 years. Twenty seven (18.0%) children in Ondansetron group required 2 dose within 15 minutes while 38 (25.3%) children in Domperidone group required the 2 dose (p=0.1232). Cessation of vomiting at 6-hour interval was noted among 126 (84.0%) children in Ondansetron group in comparison to 118 (78.7%) in Domperidone group (p=0.2359). It was revealed that 127/142 (89.4%) children in Ondansetron group had cessation of vomiting at 24-hours follow up while this was noted to be among 108/134 (80.6%) children in Domperidone group (p=0.0390).
CONCLUSION
In comparison to Domperidone, Ondansetron was found to have better efficacy aiming cessation of AGE associated vomiting among children with mild to moderate dehydration.
PubMed: 35991241
DOI: 10.12669/pjms.38.6.5532 -
Case Reports in Oncology 2022Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most severe complications associated with chemotherapy for breast cancer. We encountered a case in which...
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most severe complications associated with chemotherapy for breast cancer. We encountered a case in which mirogabalin initially ameliorated, and additional duloxetine further attenuated eribulin-induced CIPN. Herein, we report its management. A 53-year-old woman received eribulin treatment as third-line chemotherapy for recurrent breast cancer. She experienced grade 2 CIPN with adjuvant docetaxel and cyclophosphamide treatment (worst numeric rating scale (NRS) 6/10 for numbness and 6/10 for pain) and had baseline grade 1 symptoms only in the hands (NRS 1/10 for each). CIPN in the hands and feet worsened to NRS 3/10 on day 1 of cycle 4. Mirogabalin (5 mg twice daily) was initiated, resulting in stable symptoms for approximately 6 weeks with grade 1 somnolence and heaviness of the head. The dosage was increased with careful attention to adverse effects to 22.5 mg per day, and the NRS was reduced from 5/10 to 3/10 for numbness and from 8/10 to 5/10 for pain. We administered duloxetine 20 mg with domperidone (10 mg three times a day) for further pain attenuation on day 1 of cycle 15, decreasing the NRS to 1/10 for numbness and 3/10 for pain. Duloxetine was increased due to CIPN degradation (NRS 3/10 and 5/10), resulting in a significant pain attenuation to 1/10. As the CIPN-attenuating mechanisms of mirogabalin and duloxetine are different, we consider that the additive and synergetic effects of this combination affected the results. Combination therapy with these drugs may be a promising strategy.
PubMed: 35949911
DOI: 10.1159/000525059 -
PloS One 2022Staphylococcus aureus is an opportunistic pathogen that causes wide range of nosocomial and community-acquired infections which have spread worldwide leading to an...
BACKGROUND AND OBJECTIVES
Staphylococcus aureus is an opportunistic pathogen that causes wide range of nosocomial and community-acquired infections which have spread worldwide leading to an urgent need for developing effective anti-staphylococcal agents. Efflux is an important resistance mechanism that bacteria used to fight the antimicrobial action. This study aimed to investigate the efflux mechanism in S. aureus and assess diclofenac, domperidone, glyceryl trinitrate and metformin as potential efflux pump inhibitors that can be used in combination with antibiotics for treating topical infections caused by S. aureus.
MATERIALS AND METHODS
Efflux was detected qualitatively by the ethidium bromide Cart-Wheel method followed by investigating the presence of efflux genes by polymerase chain reaction. Twenty-six isolates were selected for further investigation of efflux by Cart-Wheel method in absence and presence of tested compounds followed by quantitative efflux assay. Furthermore, antibiotics minimum inhibitory concentrations in absence and presence of tested compounds were determined. The effects of tested drugs on expression levels of efflux genes norA, fexA and tetK were determined by quantitative real time-polymerase chain reaction.
RESULTS
Efflux was found in 65.3% of isolates, the prevalence of norA, tetK, fexA and msrA genes were 91.7%, 77.8%, 27.8% and 6.9%. Efflux assay revealed that tested drugs had potential efflux inhibitory activities, reduced the antibiotic's MICs and significantly decreased the relative expression of efflux genes.
CONCLUSION
Diclofenac sodium, domperidone and glyceryl trinitrate showed higher efflux inhibitory activities than verapamil and metformin. To our knowledge, this is the first report that shows that diclofenac sodium, glyceryl trinitrate and domperidone have efflux pump inhibitory activities against S. aureus.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Diclofenac; Domperidone; Humans; Metformin; Microbial Sensitivity Tests; Multidrug Resistance-Associated Proteins; Nitroglycerin; Staphylococcal Infections; Staphylococcus aureus
PubMed: 35905077
DOI: 10.1371/journal.pone.0272417 -
Frontiers in Cellular Neuroscience 2022Dopamine (DA) is a cell-signaling molecule that does not readily cross the blood-brain barrier. Despite this, peripherally administered DA enhances DA levels in the...
Dopamine (DA) is a cell-signaling molecule that does not readily cross the blood-brain barrier. Despite this, peripherally administered DA enhances DA levels in the nucleus accumbens and alters DA-related behaviors. This study was designed to investigate whether DA subtype-2 receptors are involved in the enhancement of nucleus accumbens (NAc) DA levels elicited by intravenous DA administration. This was accomplished by using microdialysis in the NAc and extracellular single unit recordings of putative DA neurons in the ventral tegmental area (VTA). Additionally, the reinforcing properties of intravenous DA were investigated using a place conditioning paradigm and the effects of intravenous DA on ultrasonic vocalizations were assessed. Following administration of intravenous dopamine, the firing rate of putative DA neurons in the VTA displayed a biphasic response and DA levels in the nucleus accumbens were enhanced. Pretreatment with domperidone, a peripheral-only DA D2 receptor (D2R) antagonist, reduced intravenous DA mediated increases in VTA DA neuron activity and NAc DA levels. Pretreatment with phentolamine, a peripheral α-adrenergic receptor antagonist, did not alter the effects of IV DA on mesolimbic DA neurotransmission. These results provide evidence for peripheral D2R mediation of the effects of intravenous DA on mesolimbic DA signaling.
PubMed: 35903367
DOI: 10.3389/fncel.2022.944243 -
Children (Basel, Switzerland) Jul 2022The aim of this study was to evaluate the effect of galactogogue management in mothers of very preterm infants with varying breast milk volumes prior to initiating this...
The aim of this study was to evaluate the effect of galactogogue management in mothers of very preterm infants with varying breast milk volumes prior to initiating this treatment. Data were utilized from 90 women who participated in a trial employing domperidone. Three groups were formed according to their breast milk volumes (based on their infants' birth weight) at the time of randomization and study entry to the trial protocol: (1) ≤100 mL/kg/d; (2) 101-200 mL/kg/d; and (3) ≥201 mL/kg/d. Breast milk volumes were evaluated at the 14- and 28-day study treatment periods. All three groups showed a significant volume increase and volume percent increase both at the 14-day measure and also the 28-day measure. Mothers who started in the two lower volume groups showed the greatest % volume change overall, with 356.2% in the ≤100 mL/kg/d and 106.1% in the 101-200 mL/kg/d groups, compared to those mothers in the higher group of ≥201 mL/kg/d, showing a change of 45.2%, where = 0.001. Mothers producing varying low volumes were able to demonstrate an effect from the use of domperidone and increase their volumes as much as three-hundred-fold over 14- and 28-day study periods. However, those mothers whose volumes were ≤100 mL/kg/d continued to maintain low absolute milk volumes, putting these mothers at ongoing risk of ceasing lactation.
PubMed: 35884026
DOI: 10.3390/children9071042 -
BioMed Research International 2022The goal of this study was to use polymeric konjac glucomannan (KGM), Kollidon VA 64 (KVA64), and glutaraldehyde to ameliorate stomach specific floating microspheres...
The goal of this study was to use polymeric konjac glucomannan (KGM), Kollidon VA 64 (KVA64), and glutaraldehyde to ameliorate stomach specific floating microspheres (SSFM) using domperidone (DoN) to increase bioavailability and emerging health pathologies. The SSFM were made using the emulsion cross-linking process, and the polymer was chosen based on its ability to get cross-linked. The thermodynamic parameters were used to determine the A classes of phase solubility curves using ideal complexes produced with KVA64. The optimal interaction constants at 25 and 37°C were found to be 116.14 and 128.05 M, respectively. The prepared SSFM had an average particle size (PS) of 163.71 ± 2.26 mm and a drug content of 96.66 ± 0.32%. It can be determined from drug release experiments that drug release is good in terms of regulated drug release after 12 h (92.62 ± 2.43%). The SSFMs were approximately sphere-shaped and had smooth surfaces, according to the morphological data. SSFMs were investigated using Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and differential scanning calorimetry (DSC), and no chemical structural changes were identified. The SSFMs produces a considerable gastric residence time with optimal DoN release and absorption in stomach fluid, and the mean residence time (17.36 ± 1.4 h) and (10.47 ± 0.6 h) were considerably longer ( < 0.05) than those obtained following i.v. treatment (MRT = 8.42 ± 1.2 h; = 9.07 ± 0.7 h). The SSFMs maintained good physical stability for three months when stored at room temperature.
Topics: Calorimetry, Differential Scanning; Domperidone; Mannans; Microspheres; Particle Size; Polymers; Spectroscopy, Fourier Transform Infrared; Stomach
PubMed: 35872840
DOI: 10.1155/2022/3670946 -
Frontiers in Pharmacology 2022[This corrects the article DOI: 10.3389/fphar.2022.831912.].
[This corrects the article DOI: 10.3389/fphar.2022.831912.].
PubMed: 35770095
DOI: 10.3389/fphar.2022.920925 -
Pharmaceutics May 2022Single-photon emission computed tomography (SPECT) imaging using intravenous radioactive ligand administration to indirectly evaluate the time-dependent effect of...
Single-photon emission computed tomography (SPECT) imaging using intravenous radioactive ligand administration to indirectly evaluate the time-dependent effect of intranasal drugs with poor blood-brain barrier permeability on brain drug distributions in mice was evaluated. The biodistribution was examined using domperidone, a dopamine D2 receptor ligand, as the model drug, with intranasal administration at 0, 15, or 30 min before intravenous [I]IBZM administration. In the striatum, [I]IBZM accumulation was significantly lower after intranasal (IN) domperidone administration than in controls 15 min after intravenous [I]IBZM administration. [I]IBZM SPECT was acquired with intravenous (IV) or IN domperidone administration 15 min before [I]IBZM, and time-activity curves were obtained. In the striatum, [I]IBZM accumulation was clearly lower in the IN group than in the control and IV groups. Time-activity curves showed no significant difference between the control and IV groups in the striatum, and values were significantly lowest during the first 10 min in the IN group. In the IN group, binding potential and % of receptor occupancy were significantly lower and higher, respectively, compared to the control and IV groups. Thus, brain-migrated domperidone inhibited D2R binding of [I]IBZM. SPECT imaging is suitable for research to indirectly explore nose-to-brain drug delivery and locus-specific biological distribution.
PubMed: 35631611
DOI: 10.3390/pharmaceutics14051026 -
Current Drug Safety 2023The risk of sudden cardiac death (SCD) can be increased with the use of drugs. However, it has been described heterogeneously in the literature. (Review)
Review
BACKGROUND
The risk of sudden cardiac death (SCD) can be increased with the use of drugs. However, it has been described heterogeneously in the literature.
OBJECTIVE
This study aims to systematically review epidemiological studies dealing with druginduced sudden death, describe their methodologies, and summarize the results found.
METHODS
A scoping review has been carried out using Medline electronic database. The search was limited up to 2020. Epidemiological studies were included, and case reports or case series were excluded.
RESULTS
Out of 3,114 potential articles, 74 were included. Most studies originated from North America (40.5%) or Europe (39.2%). Case-control (47.3%) or cohort (40.5%) studies were the most common designs. The data for outcomes and exposure were retrieved mainly from administrative databases (37.8%) or medical charts/hospital discharge reports (32.4%), but most studies used several sources of information. A composite variable of sudden death or SCD, mainly with ventricular arrhythmia, was the most frequently used endpoint. Only 18.9% of the studies included autopsy results to confirm the death. Psychotropic drugs were the most frequently studied. An increased risk of different outcomes for typical antipsychotics, tricyclic antidepressants, domperidone, and antiepileptics is suggested.
CONCLUSION
The methodologies used were highly heterogeneous, and the results were, in general, not conclusive. An improvement of the methodologies is needed to achieve a conclusion regarding the risk of SCD associated with drug use.
Topics: Humans; Arrhythmias, Cardiac; Domperidone; Death, Sudden, Cardiac; Antipsychotic Agents; Risk Factors
PubMed: 35619276
DOI: 10.2174/1574886317666220525115232