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PloS One 2023Polypharmacy can be a consequence of overprescribing that is prevalent in older adults with multimorbidity. Polypharmacy can cause adverse reactions and result in...
BACKGROUND
Polypharmacy can be a consequence of overprescribing that is prevalent in older adults with multimorbidity. Polypharmacy can cause adverse reactions and result in hospital admission. This study predicted risks of adverse drug reaction (ADR)-related and emergency hospital admissions by medicine classes.
METHODS
We used electronic health record data from general practices of Clinical Practice Research Datalink (CPRD GOLD) and Aurum. Older patients who received at least five medicines were included. Medicines were classified using the British National Formulary sections. Hospital admission cases were propensity-matched to controls by age, sex, and propensity for specific diseases. The matched data were used to develop and validate random forest (RF) models to predict the risk of ADR-related and emergency hospital admissions. Shapley Additive eXplanation (SHAP) values were calculated to explain the predictions.
RESULTS
In total, 89,235 cases with polypharmacy and hospitalised with an ADR-related admission were matched to 443,497 controls. There were over 112,000 different combinations of the 50 medicine classes most implicated in ADR-related hospital admission in the RF models, with the most important medicine classes being loop diuretics, domperidone and/or metoclopramide, medicines for iron-deficiency anaemias and for hypoplastic/haemolytic/renal anaemias, and sulfonamides and/or trimethoprim. The RF models strongly predicted risks of ADR-related and emergency hospital admission. The observed Odds Ratio in the highest RF decile was 7.16 (95% CI 6.65-7.72) in the validation dataset. The C-statistics for ADR-related hospital admissions were 0.58 for age and sex and 0.66 for RF probabilities.
CONCLUSIONS
Polypharmacy involves a very large number of different combinations of medicines, with substantial differences in risks of ADR-related and emergency hospital admissions. Although the medicines may not be causally related to increased risks, RF model predictions may be useful in prioritising medication reviews. Simple tools based on few medicine classes may not be effective in identifying high risk patients.
Topics: Humans; Aged; Polypharmacy; Risk Factors; Hospitalization; Drug-Related Side Effects and Adverse Reactions; Hospitals; Primary Health Care
PubMed: 36753492
DOI: 10.1371/journal.pone.0281466 -
Drugs in R&D Mar 2023Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis.
METHODS
We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI).
RESULTS
We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs.
CONCLUSIONS
The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions.
REGISTRATION
PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).
Topics: Adult; Child; Humans; Domperidone; Metoclopramide; Gastroparesis; Dopamine Antagonists
PubMed: 36749528
DOI: 10.1007/s40268-023-00413-x -
International Journal of Physiology,... 2022Deep vitrectomy is one of the most frequently performed ophthalmic procedures. Postoperative pain is a common complaint among patients. Consequently, we investigated...
BACKGROUND
Deep vitrectomy is one of the most frequently performed ophthalmic procedures. Postoperative pain is a common complaint among patients. Consequently, we investigated whether metoclopramide and aminophylline could decrease pain intensity following deep vitrectomy.
METHODS
This double-blinded clinical trial study that was approved by the Ethical Committee of Isfahan University of Medical Sciences (IR.MUI.REC.1396.3.217) (Thesis Reg. number: 396217) and registered at the Iranian Registry of Clinical Trials (IRCT) (Reg. number: IRCT20170716035104N5, available at https://www.irct.ir/trial/59146) aimed to evaluate 105 patients who were candidates for deep vitrectomy. They were randomly assigned into three groups: metoclopramide (received 0.1 mg/kg diluted in 10 ml of normal saline), aminophylline (received 4 mg/kg diluted in 10 ml of normal saline), and placebo (received 10 ml of normal saline). Postoperative pain was evaluated in all groups.
RESULTS
The postoperative pain levels of the three groups differed significantly from the start of the recovery to 30 minutes, 60 minutes, 2 hours, and 4 hours postoperatively, with metoclopramide and aminophylline groups experiencing less postoperative pain than the placebo group. Moreover, there was a significant difference between the groups regarding patient satisfaction (P<0.05).
CONCLUSION
Both metoclopramide and aminophylline significantly reduce postoperative pain after deep vitrectomy, although metoclopramide has a greater effect.
PubMed: 36741202
DOI: No ID Found -
The Cochrane Database of Systematic... Feb 2023Upper endoscopy is the definitive treatment for upper gastrointestinal haemorrhage (UGIH). However, up to 13% of people who undergo upper endoscopy will have incomplete... (Review)
Review
BACKGROUND
Upper endoscopy is the definitive treatment for upper gastrointestinal haemorrhage (UGIH). However, up to 13% of people who undergo upper endoscopy will have incomplete visualisation of the gastric mucosa at presentation. Erythromycin acts as a motilin receptor agonist in the upper gastrointestinal (GI) tract and increases gastric emptying, which may lead to better quality of visualisation and improved treatment effectiveness. However, there is uncertainty about the benefits and harms of erythromycin in UGIH.
OBJECTIVES
To evaluate the benefits and harms of erythromycin before endoscopy in adults with acute upper gastrointestinal haemorrhage, compared with any other treatment or no treatment/placebo.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was 15 October 2021.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that investigated erythromycin before endoscopy compared to any other treatment or no treatment/placebo before endoscopy in adults with acute UGIH.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were 1. UGIH-related mortality and 2. serious adverse events. Our secondary outcomes were 1. all-cause mortality, 2. visualisation of gastric mucosa, 3. non-serious adverse events, 4. rebleeding, 5. blood transfusion, and 5. rescue invasive intervention. We used GRADE criteria to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 11 RCTs with 878 participants. The mean age ranged from 53.13 years to 64.5 years, and most participants were men (72.3%). One RCT included only non-variceal haemorrhage, one included only variceal haemorrhage, and eight included both aetiologies. We defined short-term outcomes as those occurring within one week of initial endoscopy. Erythromycin versus placebo Three RCTs (255 participants) compared erythromycin with placebo. There were no UGIH-related deaths. The evidence is very uncertain about the short-term effects of erythromycin compared with placebo on serious adverse events (risk difference (RD) -0.01, 95% confidence interval (CI) -0.04 to 0.02; 3 studies, 255 participants; very low certainty), all-cause mortality (RD 0.00, 95% CI -0.03 to 0.03; 3 studies, 255 participants; very low certainty), non-serious adverse events (RD 0.01, 95% CI -0.03 to 0.05; 3 studies, 255 participants; very low certainty), and rebleeding (risk ratio (RR) 0.63, 95% CI 0.13 to 2.90; 2 studies, 195 participants; very low certainty). Erythromycin may improve gastric mucosa visualisation (mean difference (MD) 3.63 points on 16-point ordinal scale, 95% CI 2.20 to 5.05; higher MD means better visualisation; 2 studies, 195 participants; low certainty). Erythromycin may also result in a slight reduction in blood transfusion (MD -0.44 standard units of blood, 95% CI -0.86 to -0.01; 3 studies, 255 participants; low certainty). Erythromycin plus nasogastric tube lavage versus no intervention/placebo plus nasogastric tube lavage Six RCTs (408 participants) compared erythromycin plus nasogastric tube lavage with no intervention/placebo plus nasogastric tube lavage. There were no UGIH-related deaths and no serious adverse events. The evidence is very uncertain about the short-term effects of erythromycin plus nasogastric tube lavage compared with no intervention/placebo plus nasogastric tube lavage on all-cause mortality (RD -0.02, 95% CI -0.08 to 0.03; 3 studies, 238 participants; very low certainty), visualisation of the gastric mucosa (standardised mean difference (SMD) 0.48 points on 10-point ordinal scale, 95% CI 0.10 to 0.85; higher SMD means better visualisation; 3 studies, 170 participants; very low certainty), non-serious adverse events (RD 0.00, 95% CI -0.05 to 0.05; 6 studies, 408 participants; very low certainty), rebleeding (RR 1.13, 95% CI 0.63 to 2.02; 1 study, 169 participants; very low certainty), and blood transfusion (MD -1.85 standard units of blood, 95% CI -4.34 to 0.64; 3 studies, 180 participants; very low certainty). Erythromycin versus nasogastric tube lavage Four RCTs (287 participants) compared erythromycin with nasogastric tube lavage. There were no UGIH-related deaths and no serious adverse events. The evidence is very uncertain about the short-term effects of erythromycin compared with nasogastric tube lavage on all-cause mortality (RD 0.02, 95% CI -0.05 to 0.08; 3 studies, 213 participants; very low certainty), visualisation of the gastric mucosa (RR 1.19, 95% CI 0.79 to 1.79; 2 studies, 198 participants; very low certainty), non-serious adverse events (RD -0.10, 95% CI -0.34 to 0.13; 3 studies, 213 participants; very low certainty), rebleeding (RR 0.77, 95% CI 0.40 to 1.49; 1 study, 169 participants; very low certainty), and blood transfusion (median 2 standard units of blood, interquartile range 0 to 4 in both groups; 1 study, 169 participants; very low certainty). Erythromycin plus nasogastric tube lavage versus metoclopramide plus nasogastric tube lavage One RCT (30 participants) compared erythromycin plus nasogastric tube lavage with metoclopramide plus nasogastric tube lavage. The evidence is very uncertain about the effects of erythromycin plus nasogastric tube lavage on all the reported outcomes (serious adverse events, visualisation of gastric mucosa, non-serious adverse events, and blood transfusion).
AUTHORS' CONCLUSIONS
We are unsure if erythromycin before endoscopy in people with UGIH has any clinical benefits or harms. However, erythromycin compared with placebo may improve gastric mucosa visualisation and result in a slight reduction in blood transfusion.
Topics: Female; Humans; Male; Middle Aged; Endoscopy; Erythromycin; Gastrointestinal Hemorrhage; Metoclopramide; Treatment Outcome
PubMed: 36723439
DOI: 10.1002/14651858.CD013176.pub2 -
United European Gastroenterology Journal Mar 2023Gastroparesis and functional dyspepsia are disorders characterized by upper gastrointestinal symptoms and multifaceted etiologies. One of the main therapeutic approaches... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Gastroparesis and functional dyspepsia are disorders characterized by upper gastrointestinal symptoms and multifaceted etiologies. One of the main therapeutic approaches is accelerating gastric emptying (GE) by means of prokinetic agents. Their efficacy has been demonstrated, although the association between symptom improvement and acceleration of emptying is less clear. Meta-analyses have found contradictory results. Differences in applied methodology and included trials might drive these contradictions.
OBJECTIVE
To provide a transparent meta-analysis update to elucidate the association between symptom improvement and acceleration of GE due to gastroprokinetic agents available for long-term use in patients with gastroparesis.
DESIGN
Two approaches from earlier meta-analyses were executed and compared. One analyzed the relative changes on active treatment versus baseline, the other compared the change from baseline on active treatment versus the change from baseline on placebo. Papers that reported sufficient numerical data for both analyses were selected. Both analyses included the same trials.
RESULTS
Overall, both approaches yield the same positive direction of association between symptom improvement and acceleration of emptying (0.291 (-0.391, 0.972), p = 0.4 and 0.453 (0.123, 0.782), p = 0.007 for the active-only and placebo-controlled analysis respectively). The association between symptom improvement and GE acceleration for studies using optimal GE tests was either 0.028 (p > 0.9) or 0.463 (p = 0.007), and for sub-optimal GE tests was either 0.370 (p = 0.4) or 0.052 (p > 0.9) depending on the used meta-analysis methodology.
CONCLUSIONS
The applied methodology for GE testing, and the meta-analysis substantially impacts the conclusion. When considering the clinically relevant outcome of improvement from baseline, symptoms and emptying improve with prokinetics, but no correlation is found between both aspects. When the change over placebo is considered, limiting the analysis to scientifically more rigorous study approaches, changes in emptying rate and symptom improvement are positively associated.
Topics: Humans; Gastric Emptying; Gastroparesis; Gastrointestinal Agents; Cisapride; Dyspepsia
PubMed: 36714973
DOI: 10.1002/ueg2.12362 -
Frontiers in Neurology 2022Tardive dystonia/dyskinesia (TDD) occurs as a side effect of anti-dopaminergic drugs, including metoclopramide, and is often refractory to medication. While pallidal...
OBJECTIVES
Tardive dystonia/dyskinesia (TDD) occurs as a side effect of anti-dopaminergic drugs, including metoclopramide, and is often refractory to medication. While pallidal deep brain stimulation (DBS) has become an accepted treatment for TDD secondary to neuroleptic medication, there is much less knowledge about its effects on metoclopramide-induced TDD.
METHODS
We present the case of a woman with metoclopramide-induced TDD, whose symptoms were initially misjudged as "functional." After 8 years of ineffective medical treatments, she received bilateral implantation of quadripolar electrodes into the posteroventral lateral globus pallidus internus (GPi).
RESULTS
GPi DBS led to significant symptom reduction [Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score 24/44 at admission and 7/44 at discharge]. Chronic stimulation led to full recovery from TDD symptoms 9 years after surgery. The BFMDRS motor score decreased to 0.5 (98% improvement).
DISCUSSION
Pallidal DBS may result in sustained improvement of TDD secondary to chronic metoclopramide intake in the long term.
PubMed: 36712453
DOI: 10.3389/fneur.2022.1076713 -
Archives of Academic Emergency Medicine 2023Induction of anesthesia for emergency procedures, without prior gastric preparation and incomplete fasting, is associated with the risk of reflux of stomach contents and...
INTRODUCTION
Induction of anesthesia for emergency procedures, without prior gastric preparation and incomplete fasting, is associated with the risk of reflux of stomach contents and aspiration. This study aimed to evaluate the effect of intravenous (IV) metoclopramide administration on gastric emptying in opium users, candidate for procedural sedation and analgesia (PSA).
METHODS
In the present case-control study, opium-dependent (case) and non-dependent (control) patients in need of PSA were administered with 10 mg IV metoclopramide after undergoing gastric ultrasonography for determination of its area and contents. Then, 30 minutes after the administration of metoclopramide, the area and contents of the stomach were measured again and compared with the measures obtained before the intervention.
RESULTS
135 patients were evaluated in three groups of 45, including the case, control, and placebo groups. The three groups were similar regarding mean age (p = 0.068), sex (p = 0.067), weight (p = 0.596), height (p = 0.671), body mass index (BMI) (p = 0.877), duration of fasting (p = 0.596), and type of gastric contents (p = 0.124). Mean antral cross-sectional area (CSA) of the study participants in the case, control, and placebo groups before the administration of the drug was 8.49 ± 1.40, 8.31 ± 2.56, and 6.56 ± 1.72 cm, respectively. Mean gastric area in the case (p < 0.001) and control (p < 0.001) groups had significantly decreased after the intervention. Mean antral gastric grade of gastric contents in the case (p < 0.001) and control (p < 0.001) groups had significantly decreased after the intervention.
CONCLUSION
It seems that metoclopramide administration in opium users in need of PSA leads to a significant decrease in mean gastric area and increases gastric emptying.
PubMed: 36620740
DOI: 10.22037/aaem.v11i1.1892 -
International Journal of Molecular... Dec 2022Previous studies have confirmed that the binding of D receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D...
Previous studies have confirmed that the binding of D receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D receptor affinities (i = 0.8-13.2 nM) with subtype selectivity to the D receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC = 1.3 nM). Computational studies demonstrated that the high potency of and its analogs was the result of interactions with the secondary binding site of the D receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT receptors and TSPO. The results of this study revealed that a new class of selective D receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.
Topics: Ligands; Receptors, Dopamine D2; Receptors, Dopamine D3; Dopamine; Structure-Activity Relationship; Benzamides
PubMed: 36613875
DOI: 10.3390/ijms24010432 -
Saudi Pharmaceutical Journal : SPJ :... Dec 2022The new trends in pharmaceutical studies focus on targeting drug delivery and computer software that help in the body environment simulation, such as Gastroplus®...
The new trends in pharmaceutical studies focus on targeting drug delivery and computer software that help in the body environment simulation, such as Gastroplus® software. The interest of this study is to prepare a gastroretentive film of metoclopramide HCl (MTC) that was followed by applying the approach to estimate the prepared formulations. The films were prepared from HPMC E5 and sodium alginate polymers as primary polymers with the aid of secondary polymers. The sodium alginate high proportions films showed instant and long floating duration reaching 24 h but with variable folding endurance. Moreover, sodium alginate films with their secondary polymers carbopol and HPMC E5 slowed the release of MTC. The floating and slow-release patterns assessed the gastroretentive properties of sodium alginate films and were further examined by a mucoadhesive study that guaranteed mucosal adhesion, and the film's FESEM images showed similar top morphology, but different side view structures. Last, the pharmacokinetic profile of selected films that approached the gastroretentive properties was predicted depending on release study and floating duration employing the physiological-based pharmacokinetic model in Gastroplus® software. The model determines this prediction found successfully of intravenous and immediate oral release tablets (10 and 30 mg) of MTC. The simulation showed a high amount of MTC retained for long periods in the stomach to Sod.Alginate-3, Sod.Alginate-8, and Sod.Alginate-10 films (films of secondary polymers carbopol and HPMC E5) aid in reaching the optimum site of absorption jejunum 1 due to the slow MTC release.
PubMed: 36601510
DOI: 10.1016/j.jsps.2022.10.011 -
Gastroenterology Apr 2023Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of randomized controlled trials (RCTs).
METHODS
We searched the literature to September 7, 2022. We judged the efficacy of drugs based on global symptoms of gastroparesis; individual symptoms, including nausea, vomiting, abdominal pain, bloating, or fullness; and safety according to total adverse events and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of not improving with 95% confidence intervals (CIs), ranking drugs according to P-score.
RESULTS
We identified 29 RCTs (3772 patients). Based on global symptoms, clebopride ranked first for efficacy (RR, 0.30; 95% CI, 0.16-0.57; P-score = .99) followed by domperidone (RR, 0.68; 95% CI, 0.48-0.98; P-score = .76). No other drug was superior to placebo. Only 2 drug classes were efficacious: in rank order, oral dopamine antagonists (RR, 0.58; 95% CI, 0.44-0.77; P-score = .96) and tachykinin-1 antagonists (RR, 0.69; 95% CI, 0.52-0.93; P-score = .83). For individual symptoms, oral metoclopramide ranked first for nausea (RR 0.46; 95% CI, 0.21-1.00; P-score = .95), fullness (RR 0.67; 95% CI, 0.35-1.28; P-score = .86), and bloating (RR 0.53; 95% CI, 0.30-0.93; P-score = .97), based on only 1 small trial. Only prucalopride was more likely to be associated with adverse events than placebo.
CONCLUSIONS
In a network meta-analysis, oral dopamine antagonists and tachykinin-1 antagonists were more efficacious than placebo for gastroparesis, but confidence in the evidence was low to moderate for most comparisons. There is an unmet need for efficacious therapies for gastroparesis.
Topics: Humans; Gastroparesis; Network Meta-Analysis; Nausea; Dopamine Antagonists; Tachykinins
PubMed: 36581089
DOI: 10.1053/j.gastro.2022.12.014