Gastrointestinal Side Effects Research Articles

Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice.

Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects.

A179 UNDERSTANDING THE NEED FOR A ZINC DIET TO TREAT ZINC DEFICIENCY IN PATIENTS WITH CELIAC DISEASE

Abstract Background Nutritional deficiencies in celiac disease (CeD) are caused by delayed intestinal healing and a nutrient-lacking gluten-free diet (GFD). At our specialized adult celiac clinic, zinc (Zn) was the most common deficiency present in patients and is clinically treated through Zn supplementation. However, Zn supplements in excess may cause inhibition of other minerals, and gastrointestinal side effects. Alternatively, a Zn diet may be a sustainable option to treat zinc deficiency, however patient preference regarding this treatment method is unknown. Aims To understand patient preference of zinc supplementation compared to a zinc diet to treat Zn deficiency in CeD. We also aim to determine the tolerability and effectiveness of Zn supplements to reduce gastrointestinal and extraintestinal symptoms in the CeD population. Methods This observational prospective pragmatic study was conducted from March 2022-September 2023. Eligible participants had bloodwork indicating plasma Zn levels ampersand:003C 9.4 μ/mol . All participants were prescribed 25 mg per day of Zn gluconate supplements throughout the study. Patients were provided a RedCap link where they completed questionnaires at Visit 1 and at their next clinic appointment in 3-6 months (Visit 2). These surveys included; Celiac Symptom Index (CSI) Questionnaire 2) Extraintestinal Symptoms Visual Analogue Scale (ES-VAS) and 3) Patient Perception Survey (PPS). Continuous data are expressed as Mean (SD), and categorical data is reported as frequencies (%). The Wilcoxon test was used to assess changes in symptoms. Results A total of 42 participants completed the Visit 1 survey, of which 17 participants had their follow up clinic appointment (Visit 2). Out of these 17 participants, 15 were female (88.2%) and the mean age was 33.7 years (+/- 10.6). The mean CSI score at Visit 1 was 35.3 (+/- 10.3) and 33.7 (+/- 13.0) at Visit 2, indicating moderate disease symptoms (p=0.552). The most common extraintestinal symptoms was anxiety (ES-VAS: 5.7), foggy mind (ES-VAS: 4.1), fatigue (ES-VAS: 4.1) and depression (ES-VAS: 3.5). There were no significant changes in extraintestinal symptoms between clinic visits. Out of 42 participants, 15 (35.7%) prefer to treat their Zn deficiency through diet, 26 (59.5%) through supplement, and 1 (2.4%) of participants had no preference. Additionally, 35 (85.4%) participants indicated that they were “likely” to comply to a Zn-diet treatment. Conclusions CeD patients did not experience improvement in gastrointestinal or extraintestinal symptoms on Zn supplementation. However, a portion of CeD patients prefer to treat and are likely to comply with a Zn diet to treat their deficiency. Based on this knowledge, further studies should investigate the efficacy of a Zn diet compared to supplements CeD patients. Funding Agencies CIHR

Efficacy and safety of Mazdutide on weight loss among diabetic and non-diabetic patients: a systematic review and meta-analysis of randomized controlled trials.

Overweight and obesity are increasing global public health problems. Mazdutide is a new dual agonist drug that can potentially reduce weight and blood glucose levels simultaneously. However, the synthesis of evidence on the efficacy and safety of this drug is scarce. Therefore, this study aimed to synthesize evidence on the efficacy and safety of Mazdutide compared to placebo on weight reduction among adults with and without diabetes. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Data were retrieved from six electronic databases: PubMed, Web of Science, Scopus, Cochrane Library, ClinicalTrial.gov, and Google Scholar, and manually searched from the included references. The data were synthesized using a random effect model. This analysis was performed in the R programming language using the Meta package. A total of seven RCTs involving 680 participants were included in this study. Mazdutide was more effective in reducing body weight (mean difference [MD]= -6.22%, 95% confidence interval [CI]: -8.02% to -4.41%, I2 = 90.0%), systolic blood pressure (MD = -7.57 mmHg, 95% CI: -11.17 to -3.98 mmHg, I2 = 46%), diastolic blood pressure (MD = -2.98 mmHg, 95% CI: -5.74 to -0.22 mmHg, I2 = 56%), total cholesterol (MD = -16.82%, 95% CI: -24.52 to -9.13%, I2 = 61%), triglycerides (MD = -43.29%, 95% CI: -61.57 to -25.01%, I2 = 68%), low-density lipoprotein (MD= -17.07%, 95% CI: -25.54 to -8.60%, I2 = 53%), and high-density lipoprotein (MD = -7.54%, 95% CI: -11.26 to -3.83%, I2 = 0%) than placebo. Mazdutide was associated with reduced hemoglobin A1c (HbA1c) and fasting plasma glucose in participants with type 2 diabetes. In the subgroup and meta-regression analyses, weight reduction was more significant in non-diabetics compared to diabetics, and in those who received a longer treatment duration (24 weeks) than in those on shorter durations (12-20 weeks). Participants who received Mazdutide had a higher risk of transient mild or moderate gastrointestinal side effects. Mazdutite appears to be effective in weight reduction among patients with and without diabetes, and it has an advantage over other associated comorbidities. However, it was associated with mild or moderate gastrointestinal side effects. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=403859, identifier CRD42023403859.

Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model

Endogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E2 synthase-1) enzymes are responsible for the inflammatory overexpressed PGE2 production. Among them, mPGES-1 is regarded as a more promising ideal target for anti-inflammatory drugs without the gastrointestinal and cardiovascular side effects. As our continuous research for the discovery of novel mPGES-1 inhibitors, we have characterized MPO-0144 as a selective mPGES-1 inhibitor with a selectivity index of >270 over COX-1 and >25 over COX-2, respectively. Herein, we evaluated the anti-inflammatory effect of MPO-0144 in an adjuvant-induced arthritis rat model. MPO-0144 attenuated the inflammatory responses without severe gastrointestinal side effects and organ toxicities. These overall data suggest a possibility that MPO-0144 downregulates PGE2 production by potent mPGES-1 and weak COX-2 inhibitory activities, thus attenuating the paw swelling in AIA (adjuvant-induced arthritis) rat models. MPO-0144 also exhibited favorable ADMET profiles. However, MPO-0144 did not show any inhibitory effects on human mPGES-1 enzyme at a high concentration. Therefore, MPO-0144 represents a valuable pharmacological tool for the study of regulation of inducible mPGES-1 in an inflammatory arthritis rat model.

Nutritional interventions for preventing and treating pressure ulcers.

Nutritional interventions for preventing and treating pressure ulcers.

Pharmacological therapy with azithromycin, hydroxychloroquine and ivermectin increased gastrointestinal side effects in a population in northeast Brazil

O surgimento da pandemia de COVID-19 impulsionou o consumo de combinações de medicamentos como o Kit COVID Brasileiro composto por azitromicina, hidroxicloroquina e ivermectina. Os efeitos dessas drogas no trato gastrointestinal permanecem incertos, motivando este estudo. Foi realizado um estudo epidemiológico transversal analítico e quantitativo em pacientes (n=124) da macrorregião costeira do estado do Piauí, Brasil, com diagnóstico confirmado de COVID-19, no período de fevereiro e agosto de 2021. Os sintomas gastrointestinais foram avaliados por meio do questionário Gastrointestinal Symptom Rating Scale (GSRS). A renda mostrou-se um fator na escolha do tratamento. Entre os 15 domínios do GSRS, os escores de dor abdominal, dor de fome, diarreia e urgência defecar foram significativamente maiores (p<0,05) no grupo de tratamento do que no grupo não tratado. Em relação às síndromes avaliadas, apenas as síndromes diarreicas apresentaram diferença significativa de frequência entre os grupos. O uso de medicamentos do Kit COVID associado ao desenvolvimento de sintomas gastrointestinais destaca a importância de considerar os potenciais efeitos adversos dos medicamentos em pacientes diagnosticados com COVID-19.

Psoriasiform dermatitis in a person of colour with chronic hepatitis B

AbstractA 43‐year‐old patient from Liberia presented with itching scaly plaques, impaired quality of life persisting for 9 months and intermittent joint pain in the knees. Personal and family history was unremarkable. Coexisting diagnoses included type 1 diabetes mellitus and liver cirrhosis due to chronic hepatitis B and D. The patient reported ongoing use of Tenofovir, Propranolol, Glargine and Aspart. Clinical examination showed disseminated brownish, partly confluent hyperkeratotic plaques distributed throughout the integument in a Fitzpatrick skin type V. A skin biopsy revealed histologically a psoriasiform dermatitis. Laboratory findings included lymphocytopenia and elevated liver values. Hepatitis B serology confirmed chronic hepatitis B. Considering the clinical and histopathological findings Psoriasis vulgaris was diagnosed and psoriatic arthritis was ruled out by a rheumatologist. After consulting with the hepatologist, systemic therapy with Apremilast was initiated. Despite an initial positive response, gastrointestinal side effects led to a switch to therapy with Tildrakizumab, with regular monitoring of transaminases and HBV DNA. Despite an initial positive treatment response, a secondary loss of efficacy occurred prompting a switch to Risankizumab. Psoriasis is a chronic inflammatory systemic disease significantly impacting quality of life, necessitating optimal long‐term management. In this case, therapy with Apremilast and biologic therapy targeting IL‐23 blockade, even with concurrent hepatitis B, was well tolerated and effective. However, the evidence on the safety of modern psoriasis therapies in known chronic infections remains limited. Noteworthy in this case report is the patient's dark skin type. Diagnosing inflammatory dermatoses in People of Colour is challenging due to less visible erythema and other clinical nuances, exacerbating the already poorer healthcare for People of Colour. This case aims to raise awareness about the need for increased representation of People of Colour in education, presentations and clinical trials to ensure better care for this patient population.

Formulating extended-release Meloxicam Pellets using the membrane coating technique

Background: Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) with potent anti-inflammatory and analgesic effects but is associated with various side effects such as inducing gastrointestinal ulcers. Extended-release meloxicam pellets offer several advantages, including reducing the frequency of daily medication intake and providing sustained drug release over time, thereby minimizing gastrointestinal side effects. The study was conducted to formulate and develop the manufacturing process for meloxicam pellets, while simultaneously evaluating the physicochemical properties of the formulated pellets. Materials and methods: Meloxicam, HPMC E5, and Ethyl Cellulose N7 were used in the study. Meloxicam pellets were formulated using the layering technique, initially depositing the drug onto inert pellets and subsequently extending the coating with Ethyl Cellulose N7. Results: The pellet formula utilizes EC N7 with the role of providing extended-release kinetics following zero-order kinetics. The pellets exhibit uniform and attractive appearance, with dimensions ranging from 0.7 - 1 mm. The drug content is 2.38% ± 0.11% (w/w), demonstrating the ability to release the drug according to a zero-order kinetic model. Conclusions: The study successfully formulated extended-release meloxicam pellets using a coating technique that involved a gradual deposition phase of the drug onto inert pellets, followed by an extended coating phase using a controlled-release excipient. Key words: Meloxicam, pellet, coating technology.

Unleashing the power of retatrutide: A possible triumph over obesity and overweight: A correspondence.

Overweight and obesity have become global health challenges with increasing prevalence. Several drugs have received Food and Drug Administration approval for nonsyndromic obesity treatment, but most have limitations, including gastrointestinal side effects and limited weight loss efficacy. Retatrutide, a novel incretin mimetic agent, has shown promise in clinical trials for significant weight reduction. It has demonstrated dosage-dependent pharmacokinetics with favorable safety profiles. The primary focus of this paper is to explore retatrutide and critically assess its clinical trials to justify its use and feasibility while highlighting its shortcomings. This paper also delves into the subject of obesity and its health manifestations. It is expected that the use of retatrutide, a triple agonist, will result in significant weight loss among individuals who are obese or overweight.

Low-dose sugammadex reverses moderate rocuronium-induced neuromuscular block in horses.

Neuromuscular block (NMB) during general anaesthesia has an implicit risk of inadvertent residual NMB during recovery. Reversal of NMB is commonly encouraged to decrease this risk, and has historically been performed with neostigmine/atropine, two agents with important cardiac and gastrointestinal side effects. Sugammadex is a new selective relaxant binding agent that can reverse rocuronium-induced NMB efficiently and without these complications. Recommended doses are possibly cost-prohibitive. To measure the recovery time from rocuronium-NMB after administration of low-dose sugammadex, compared with spontaneous recovery. Nonrandomised in vivo experiments. Fourteen adult horses undergoing different research procedures were anaesthetised with detomidine and isoflurane. All horses received NMB with rocuronium 0.3 mg/kg IV. Neuromuscular function was measured with acceleromyographic train-of-four (TOF) ratio. Recovery occurred spontaneously in five horses weighing (median [range]) 548 (413-594) kg and was enhanced with sugammadex 200 mg (total dose) in nine horses (433 [362-515]) kg. Recovery time from moderate NMB to a TOF ratio 1.0, and total duration of NMB were compared between groups. Cases of recurarisation (decrease in the TOF ratio <0.9 after recovery) were identified within 30 min after sugammadex. The dose of sugammadex was 0.46 (0.39-0.55) mg/kg. The recovery period lasted 21 (17-39) minutes for spontaneous and 4 (3-7) minutes for sugammadex. Total duration of NMB was 58 (41-70) minutes for spontaneous and 36 (21-43) for sugammadex (both p ≤ 0.003). There were no instances of recurarisation. Small sample size. A dose of sugammadex of approximately 0.5 mg/kg substantially shortened the recovery period from rocuronium-induced NMB from a median of 21 to 4 min, when given at a moderate depth of NMB. No recurarisation was observed within the next 30 min.

Oral iron therapy: Current concepts and future prospects for improving efficacy and outcomes.

Iron deficiency (ID) and iron-deficiency anaemia (IDA) are global public health concerns, most commonly afflicting children, pregnant women and women of childbearing age. Pathological outcomes of ID include delayed cognitive development in children, adverse pregnancy outcomes and decreased work capacity in adults. IDA is usually treated by oral iron supplementation, typically using iron salts (e.g. FeSO4 ); however, dosing at several-fold above the RDA may be required due to less efficient absorption. Excess enteral iron causes adverse gastrointestinal side effects, thus reducing compliance, and negatively impacts the gut microbiome. Recent research has sought to identify new iron formulations with better absorption so that lower effective dosing can be utilized. This article outlines emerging research on oral iron supplementation and focuses on molecular mechanisms by which different supplemental forms of iron are transported across the intestinal epithelium and whether these transport pathways are subject to regulation by the iron-regulatory hormone hepcidin.

Outcomes and Attributes Patients Value When Choosing Glucose-Lowering Medications: A Mixed-Methods Study.

This mixed-methods study sought to identify pharmacotherapy preferences among 40 noninsulin-treated adults with type 2 diabetes receiving care at two U.S. health care systems. Participants ranked by relative importance various health outcomes and medication attributes and then contextualized their rankings. Most participants ranked blindness (63%), death (60%), heart attack (48%), and heart failure (48%) as the most important health outcomes and glucose-lowering efficacy (68%) as the most important medication attribute, followed by oral administration (45%) and lack of gastrointestinal side effects (38%).

Berotralstat in hereditary angioedema due to C1 inhibitor deficiency: first real-world evidence from a Canadian center.

Hereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased quality of life. Long-term prophylaxis (LTP) to prevent angioedema episodes is a key component of disease management. Berotralstat, an oral, once-daily plasma kallikrein inhibitor, was approved for LTP by Health Canada in 2022. We conducted a retrospective, real-world study investigating the effectiveness and adverse effects of berotralstat. Data on angioedema frequency, disease control, and adverse events were tabulated. Patient satisfaction with treatment was scored on a 5-point Likert scale, with 1 representing very unsatisfied and 5 representing very satisfied with therapy. From June, 2022 and May, 2023, 8 patients with HAE type 1 or type 2 received berotralstat. Effectiveness data were available for 7 patients who continued the drug for at least 3 months, 4 of whom switched to berotralstat from plasma-derived C1 inhibitor LTP. In these 7 patients, the average number of attacks per month decreased from 3.3 to 1.6 (p<0.05), representing a ~52% reduction in attack frequency. Median angioedema control test score numerically improved from 8 to 13 (p=0.0781). Of the 8 patients who received berotralstat, 3 reported no adverse effects and 5 experienced gastrointestinal side effects, which were mild and transient in 3 and led to discontinuation in 1. Average treatment satisfaction was between satisfied and very satisfied at 4.3. Berotralstat is an effective agent for long-term prophylaxis in HAE. Most patients experienced no adverse effects or mild, transient gastrointestinal symptoms.

Long-term effectiveness and tolerability of ketogenic diet therapy in patients with genetic developmental and epileptic encephalopathy onset within the first 6 months of life.

To investigate the effectiveness and tolerability of ketogenic diet therapy (KDT) in patients with developmental and epileptic encephalopathy (DEE) associated with genetic etiology which onset within the first 6 months of life, and to explore the association between response to KDT and genotype/clinical parameters. We retrospectively reviewed data from patients with genetic DEE who started KDT at Beijing Children's Hospital between January 1, 2016, and December 31, 2021. A total of 32 patients were included, involving 14 pathogenic or likely pathogenic single genes, and 16 (50.0%) patients had sodium/potassium channel gene variants. The median age at onset of epilepsy was 1.0 (IQR: 0.1, 3.0) months. The median age at initiation of KDT was 10.0 (IQR: 5.3, 13.8) months and the median duration of maintenance was 14.0 (IQR: 7.0, 26.5) months, with a mean blood β-hydroxybutyrate of 2.49 ± 0.62 mmol/L. During the maintenance period of KDT, 26 (81.3%) patients had a ≥50% reduction of seizure frequency, of which 12 (37.5%) patients achieved seizure freedom. Better responses were observed in patients with STXBP1 variants, with four out of five patients achieving seizure freedom. There were no statistically differences in the age of onset, duration of epilepsy before KDT, blood ketone values, or the presence of ion channel gene variants between the seizure-free patients and the others. The most common adverse effects were gastrointestinal side effects, which occurred in 21 patients (65.6%), but all were mild and easily corrected. Only one patient discontinued KDT due to nephrolithiasis. KDT is effective in treating early onset genetic DEE, and no statistically significant relationship has been found between genotype and effectiveness in this study. KDT is well tolerated in most young patients, with mild and reversible gastrointestinal side effects being the most common, but usually not the reason to discontinue KDT. This study evaluated the response and side effects of ketogenic diet therapy (KDT) in patients who had seizures within the first 6 months of life, and were diagnosed with genetic developmental and epileptic encephalopathy (DEE), a type of severe epilepsy with developmental delay caused by gene variants. Thirty-two patients involving 14 gene variants who started KDT at Beijing Children's Hospital between were included. KDT was effective in treating early onset genetic DEE in this cohort, and patients with STXBP1 variants responded better; however, no statistically significant relationship was found between gene variant and response. Most young patients tolerated KDT well, with mild and reversible gastrointestinal side effects being the most common.

Low-Dose Colchicine for the Prevention of Cardiovascular Events After Acute Coronary Syndrome.

Colchicine, an established anti-inflammatory drug, is examined for its potential in mitigating adverse cardiovascular events following acute coronary syndrome (ACS). ACS, primarily triggered by plaque rupture and subsequent thrombosis, is a critical cardiovascular condition. Colchicine's mechanism of action involves inhibiting microtubule activity, leading to immobilization of white blood cells and reducing inflammation. Clinical data from studies, including low-dose colchicine for secondary prevention of cardiovascular disease two and colchicine cardiovascular outcomes trial, support its efficacy in reducing major cardiovascular events post-ACS, though some studies report varying results. Colchicine can cause transient gastrointestinal side effects and is prescribed with caution in patients with certain medical conditions. The recent FDA approval of a low dose of colchicine reiterates its benefit in reducing cardiovascular risk. The cost-effectiveness of colchicine products (0.5 and 0.6 mg doses) are compared, suggesting the generic 0.6 mg dose of colchicine to be an alternative to branded forms of the drug.

The Impact of Glucagon-like Peptide 1 Receptor Agonists on Obstructive Sleep Apnoea: A Scoping Review.

Obstructive sleep apnoea (OSA) and associated hypopnoea syndromes are chronic conditions of sleep-disordered breathing with significant sequelae if poorly managed, including hypertension, cardiovascular disease, metabolic syndrome and increased mortality. Glucagon-like peptide 1 receptor agonists (GLP-1RA) have recently garnered significant interest as a potential therapeutic, attributed to their durable effects in weight loss and glycaemic control in metabolic syndromes, such as obesity and type 2 diabetes mellitus. This has led to significant investment into companies that produce these medications and divestment from traditional gold standard methods of OSA management such as continuous positive airway pressure machines. Despite these sentiments, the impacts of these medications on OSA outcomes are poorly characterised, with no high-quality evidence at this stage to support this hypothesis. This scoping review therefore aims to address the research question of whether GLP-1RAs lead to a direct improvement in OSA and associated hypopnoea syndromes. A scoping review was performed following a computer-assisted search of Medline, Embase and Cochrane Central databases. Papers that evaluated the use of GLP-1RA medications related to sleep-disordered breathing, OSA or other sleep-related apnoeic or hypopnoeic syndromes were included. Literature search and evaluation identified 9 articles that were eligible for inclusion. Of these, 1 was a study protocol, 1 was a case report, 1 was an abstract of a randomised controlled trial (RCT), 1 was a non-randomised clinical trial and the remaining 5 were randomised clinical trials of variable rigour. All studies evaluated the outcomes of GLP-1RAs in patients with diagnosed OSA or symptoms suggestive of this condition. This scoping review identified early evidence to suggest that GLP-1RAs may improve OSA as defined by reduction in apnoea-hypopnoea index (AHI). This evidence is however conflicting due to contradicting results demonstrated from other studies. Overall, these medications were tolerated well, with minor gastrointestinal side-effects reported in some cases. Of all included studies, the quality of evidence was low, with short lengths of follow-up to identify durable effects of these medications on OSA outcomes and identify adverse events. More rigorous, RCTs with sufficient length of follow-up are required before consideration of formalising these medications into OSA treatment guidelines, frameworks and policies are warranted.

Effects of Carbohydrate Mouth Rinse on Gastrointestinal Disorders in Triathletes

In long-term efforts, such as triathlon, the requirement for carbohydrate intake can also work as an ergogenic strategy. However, the literature has reported and recorded gastrointestinal discomfort by athletes during the race when performing this practice, which can compromise performance. Mouth rinses with carbohydrates, followed by the disposal (spitting) of the solution, is a strategy to maintain performance, without generating side effects. Therefore, this study aimed to verify the potential side effects of carbohydrate mouth rinse in triathlon athletes during cycling practice. Twelve trained male - triathletes were subjected to two experimental situations, in which they have completed 1.5 km of swimming, followed by 40 km of cycling, within the shortest time possible and self-regulated intensity (time trial test). Throughout the cycling, blindly and crossed-wise, the volunteers rinsed their mouths using a bolus of 25 ml of 0% CHO placebo solution and 16% CHO (maltodextrin) solution, for each 12.5% of the distance to be covered. A gastrointestinal symptoms questionnaire was answered at the end of the 40 km cycling. Only one volunteer (8.33%) reported discomfort, while 91.66% of them presented no type of symptoms according to the CHO rinse protocol. Therefore, carbohydrate mouth rinse presents no gastrointestinal side effects during long-term exertion.

Coexpressed δ-, μ-, and κ-Opioid Receptors Modulate Voltage-Gated Ca2+ Channels in Gastric-Projecting Vagal Afferent Neurons.

Opioid analgesics are frequently associated with gastrointestinal side effects, including constipation, nausea, dysphagia, and reduced gastric motility. Though it has been shown that stimulation of opioid receptors expressed in enteric motor neurons contributes to opioid-induced constipation, it remains unclear whether activation of opioid receptors in gastric-projecting nodose ganglia neurons contributes to the reduction in gastric motility and emptying associated with opioid use. In the present study, whole-cell patch-clamp recordings were performed to determine the mechanism underlying opioid receptor-mediated modulation of Ca2+ currents in acutely isolated gastric vagal afferent neurons. Our results demonstrate that CaV2.2 channels provide the majority (71% ± 16%) of Ca2+ currents in gastric vagal afferent neurons. Furthermore, we found that application of oxycodone, U-50488, or deltorphin II on gastric nodose ganglia neurons inhibited Ca2+ currents through a voltage-dependent mechanism by coupling to the Gα i/o family of heterotrimeric G-proteins. Because previous studies have demonstrated that the nodose ganglia expresses low levels of δ-opioid receptors, we also determined the deltorphin II concentration-response relationship and assessed deltorphin-mediated Ca2+ current inhibition following exposure to the δ-opioid receptor antagonist ICI 174,864 (0.3 µM). The peak mean Ca2+ current inhibition following deltorphin II application was 47% ± 24% (EC50 = 302.6 nM), and exposure to ICI 174,864 blocked deltorphin II-mediated Ca2+ current inhibition (4% ± 4% versus 37% ± 20%). Together, our results suggest that analgesics targeting any opioid receptor subtype can modulate gastric vagal circuits. SIGNIFICANCE STATEMENT: This study demonstrated that in gastric nodose ganglia neurons, agonists targeting all three classical opioid receptor subtypes (μ, δ, and κ) inhibit voltage-gated Ca2+ channels in a voltage-dependent mechanism by coupling to Gαi/o. These findings suggest that analgesics targeting any opioid receptor subtype would modulate gastric vagal circuits responsible for regulating gastric reflexes.

Safety and Efficacy of GLP-1 Receptor Agonists in Type 2 Diabetes Mellitus with Advanced and End-Stage Kidney Disease: A Systematic Review and Meta-Analysis.

Background and Objectives: Limited evidence exists regarding the safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) patients with advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD). Thus, we conducted a systematic review and meta-analysis to assess the safety and efficacy of GLP-1RAs in T2DM patients with advanced CKD and ESKD. Materials and Methods: We performed a systematic literature search in MEDLINE, EMBASE, and Cochrane database until 25 October 2023. Included were clinical trials and cohort studies reporting outcomes of GLP-1RAs in adult patients with T2DM and advanced CKD. Outcome measures encompassed mortality, cardiovascular parameters, blood glucose, and weight. Safety was assessed for adverse events. The differences in effects were expressed as odds ratios with 95% confidence intervals (CIs) for dichotomous outcomes and the weighted mean difference or standardized mean difference (SMD) with 95% confidence intervals for continuous outcomes. The Risk of Bias In Non-randomized Studies-of Interventions (ROBIN-I) tool was used in cohort and non-randomized controlled studies, and the Cochrane Risk of Bias (RoB 2) tool was used in randomized controlled trials (RCTs). The review protocol was registered in the International Prospective Register of Systematic Reviews (CRD 42023398452) and received no external funding. Results: Eight studies (five trials and three cohort studies) consisting of 27,639 patients were included in this meta-analysis. No difference was observed in one-year mortality. However, GLP-1RAs significantly reduced cardiothoracic ratio (SMD of -1.2%; 95% CI -2.0, -0.4) and pro-BNP (SMD -335.9 pmol/L; 95% CI -438.9, -232.8). There was no significant decrease in systolic blood pressure. Moreover, GLP-1RAs significantly reduced mean blood glucose (SMD -1.1 mg/dL; 95% CI -1.8, -0.3) and increased weight loss (SMD -2.2 kg; 95% CI -2.9, -1.5). In terms of safety, GLP-1RAs were associated with a 3.8- and 35.7-time higher risk of nausea and vomiting, respectively, but were not significantly associated with a higher risk of hypoglycemia. Conclusions: Despite the limited number of studies in each analysis, our study provides evidence supporting the safety and efficacy of GLP-1RAs among T2DM patients with advanced CKD and ESKD. While gastrointestinal side effects may occur, GLP-1RAs demonstrate significant improvements in blood glucose control, weight reduction, and potential benefit in cardiovascular outcomes.

Low‐Dose Prophylactic Oral Iron Supplementation (Ferrous Fumarate, Ferrous Bisglycinate, and Ferrous Sulphate) in Pregnancy Is Not Associated With Clinically Significant Gastrointestinal Complaints: Results From Two Randomized Studies

Background: Many pregnant women are reluctant to follow the recommendation concerning oral iron prophylaxis due to concerns about gastrointestinal (GI) side effects.Objective: To assess the frequency of GI complaints during low‐dose oral iron prophylaxis and compare three iron formulas in equipotent doses: ferrous fumarate versus ferrous bisglycinate versus ferrous sulphate, in healthy women with an uncomplicated single pregnancy.Methods: Results from two randomized, double‐blind studies are reported: the Gentofte study comprising 404 women allocated into four groups taking 20, 40, 60, and 80 mg of elemental iron as ferrous fumarate/day and the Naestved study comprising 78 women allocated into two groups: 25 mg of elemental iron as ferrous bisglycinate/day and 50 mg of elemental iron as ferrous sulphate/day between meals from 15 to 19 weeks of gestation to delivery. GI complaints (nausea, vomiting, epigastric pain/pyrosis, belching, meteorism, borborygmi, intestinal colic, flatulence, loose stools, constipation, and use of laxatives), as well as black stools, were recorded by interview at the time of inclusion and at regular intervals during gestation.Results: At inclusion, the frequency of total combined GI complaints in all women (n = 482) was 21%. The Gentofte study showed that in the groups taking 20–60 mg iron/day as fumarate, there was no association between the iron dose and the frequency of GI side effects. An iron dose of 80 mg as fumarate was associated with significantly higher frequencies of constipation and the use of laxatives. Comparing the three equipotent doses of iron formulas, which can prevent iron deficiency, ferrous bisglycinate 25 mg iron had the most favourable GI side effect profile, while ferrous fumarate 40 mg iron and ferrous sulphate 50 mg iron had higher but similar GI side effect profiles. The frequency of black stools increased with the iron dose. Ferrous bisglycinate 25 mg iron had a lower frequency of black stools (8%) than ferrous fumarate 40 mg iron (22%) and ferrous sulphate 50 mg iron (31%).Conclusion: Low‐dose iron supplementation appears to have no clinically significant GI side effects, as none of the included women presented with GI complaints of such severity that it necessitated either reduction of iron dose, change to an alternative iron formula, or discontinuation of iron supplement. However, ferrous bisglycinate 25 mg iron/day is associated with significantly fewer GI complaints than ferrous fumarate 40 mg iron/day and ferrous sulphate 50 mg iron/day. Ferrous bisglycinate may be preferred for iron prophylaxis, especially in women experiencing GI side effects when taking other conventional iron formulas.