Predicting gastric emptying of drug substances taken under postprandial conditions by combination of biorelevant dissolution and mechanistic in silico modeling.

Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.

Consensus practice recommendations for management of gastrointestinal dysfunction in Parkinson disease.

BACKGROUND: Gastrointestinal (GI) dysfunction is a common non-motor feature of Parkinson disease (PD). GI symptoms may start years before the onset of motor symptoms and impair quality of life. Robust clinical trial data is lacking to guide screening, diagnosis and treatment of GI dysfunction in PD. OBJECTIVE: To develop consensus statements on screening, diagnosis, and treatment of GI dysfunction in PD. METHODS: The application of a modified Delphi panel allowed for the synthesis of expert opinions into clinical statements. Consensus was predefined as a level of agreement of 100 % for each item. Five virtual Delphi rounds were held. Two movement disorders neurologists reviewed the literature on GI dysfunction in PD and developed draft statements based on the literature review. Draft statements were distributed among the panel that included five movement disorder neurologists and two gastroenterologists, both experts in GI dysmotility and its impact on PD symptoms. All members reviewed the statements and references in advance of the virtual meetings. In the virtual meetings, each statement was discussed, edited, and a vote was conducted. If there was not 100 % consensus, further discussions and modifications ensued until there was consensus. RESULTS: Statements were developed for screening, diagnosis, and treatment of common GI symptoms in PD and were organized by anatomic segments: oral cavity and esophagus, stomach, small intestine, and colon and anorectum. CONCLUSIONS: These consensus recommendations offer a practical framework for the diagnosis and treatment of GI dysfunction in PD.

Symptoms from the Gastroparesis Cardinal Symptom Index and clinical factors associated with delayed gastric emptying in patients with suspected gastroparesis.

BACKGROUND: The association between upper gastrointestinal symptoms and delayed gastric emptying (GE) shows conflicting results. This study aimed to assess whether the symptoms of the Gastroparesis Cardinal Symptom Index (GCSI) and/or the scores were associated with the result of GE tests and whether they could predict delayed GE. METHODS: Patients referred for suspected gastroparesis (GP) were included in a prospective database. Demographical data, medical history, and symptoms of the GCSI score were collected for each patient. A GE scintigraphy was then performed with a 4-hour recording. Delayed GE was defined as a retention rate ≥ 10% at 4 h. RESULTS: Among 243 patients included in this study, 110 patients (45%) had delayed GE. The mean age (49.9 vs. 41.3 years; p < 0.001) and weight loss (9.4 kg vs. 5.6 kg; p = 0.025) were significantly higher in patients with delayed GE. Patients with diabetes or a history of surgery had a higher prevalence of delayed GE (60% and 78%, respectively) than patients without comorbidity (17%; p < 0.001). The GCSI score was higher in patients with delayed GE (3.06 vs. 2.80; p = 0.045), but no threshold was clinically relevant to discriminate between patients with normal and delayed GE. Only vomiting severity was significantly higher in patients with delayed GE (2.19 vs. 1.57; p = 0.01). CONCLUSION: GE testing should be considered when there are symptoms such as a higher weight loss, comorbidities (diabetes, and history of surgery associated with GP), and the presence of vomiting. Other symptoms and the GCSI score are not useful in predicting delayed GE.

An observational study of gastric contents in pediatric patients with long bone fracture using gastric ultrasound.

BACKGROUND: The retention of gastric contents at surgery presentation is a risk factor for perioperative aspiration. A preoperative fasting (nil per os; NPO) interval is widely used to reduce this risk, but this approach is based on assumptions about the prevalence of typical gastric emptying rates. We assessed NPO guidelines' reliability with ultrasound (US) imaging and suction in pediatric patients presenting for single long-bone fracture repair after appropriate NPO intervals, when nearly all should have had empty stomachs. AIMS AND METHODS: This prospective cross-sectional observational study comprised 200 pediatric surgical patients. As their NPO times varied by food/drink type, we defined "weighted NPO units" as the lowest multiple of elapsed recommended NPO times between consumption and surgery for each type of food or drink. We used US to image the stomach and its contents before anesthesia induction, followed by gastric suction. We evaluated the relationships between weighted NPO units, US gastric contents grade, opioid analgesic dosage and timing, and suctioned volume. RESULTS: Despite meeting typical NPO standards (median 14 h fasting), many patients retained nontrivial quantities of gastric contents at surgery. Weighted NPO units did not exhibit statistically-significant relationships with either suctioned volume or US grade. However, suctioned volume did correspond well to US grade. CONCLUSION: NPO status may be a less reliable predictor of gastric contents at anesthesia induction in this patient population than has been assumed. Bedside US screening appears to provide more useful information for the planning of airway management.

Heat Treatment and Homogenization Influence the Gastric Digestion of Bovine Milk Protein in Growing Pigs as an Adult Human Model.

BACKGROUND: Bovine milk processing influences the structure of the curd formed during gastric digestion, which may alter gastric protein hydrolysis and impact amino acid (AA) release into the small intestine. OBJECTIVES: This study aimed to determine the influence of heat treatment and homogenization on the gastric protein digestion and AA emptying of bovine milk. METHODS: Nine-wk-old pigs (n = 144) consumed either raw, pasteurized nonhomogenized (PNH), pasteurized homogenized (PH), or ultra-high-temperature homogenized (UHT) bovine milk for 10 d. On day 11, fasted pigs received the milk treatment (500 mL) before gastric contents were collected at 0, 20, 60, 120, 180, and 300 min postprandially. The apparent degree of gastric protein hydrolysis (based on the release of free amino groups), apparent gastric disappearance of individual proteins [based on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gel band intensity], and the gastric emptying of digested protein and AA were determined. RESULTS: During the first 60 min, the rate of apparent gastric protein hydrolysis was fastest in pigs fed UHT milk (0.29%/min compared with on average 0.07%/min in pigs fed raw, PNH, and PH milk). Differences in the apparent degree of gastric protein hydrolysis and emptying were reflected in the rate of digested protein entering the small intestine. The AA gastric emptying half-time was generally shorter in pigs fed PH and UHT milk than in pigs fed raw and PNH milk. For example, the gastric release of total essential AA was >2-fold faster (P < 0.01) in pigs fed PH or UHT milk than that in pigs fed raw or PNH milk (i.e., homogenized compared with nonhomogenized milk). CONCLUSIONS: Heat treatment and homogenization increased the apparent gastric degree of protein hydrolysis and the release of digested protein into the small intestine. However, the rate of AA entering the small intestine was mainly increased by homogenization.

Postoperative delayed emptying after total, subtotal, or distal gastrectomy for gastric cancer: a population-based study.

BACKGROUND: This study aimed to examine the rate of delayed emptying and other 90-day postoperative complications after total, subtotal, and distal gastrectomies for gastric adenocarcinoma in a population-based setting. METHODS: This study included all patients who underwent total, subtotal, or distal gastrectomy for gastric cancer in Finland in 2005-2016, with follow-up until December 31, 2019. Logistic regression provided the odds ratios with 95% CIs of 90-day mortality. The results were adjusted for age, sex, year of surgery, comorbidities, pathologic stage, and neoadjuvant therapy. RESULTS: A total of 2058 patients underwent total (n = 1227), subtotal (n = 450), or distal (n = 381) gastrectomy. In the total, subtotal, and distal gastrectomy groups, the rates of 90-day delayed emptying were 1.7%, 1.3%, and 2.1% in the whole cohort and 1.6%, 1.8%, and 3.5% in the subgroup analysis of R0 resections, respectively. The resection type was not associated with the risk of delayed emptying. Subtotal gastrectomy was associated with a lower risk of major complications and reoperations, whereas distal gastrectomy was associated with a lower risk of anastomotic complications. CONCLUSION: The extent of resection did not affect delayed emptying, whereas fewer postoperative complications were observed after subtotal or distal gastrectomy than after total gastrectomy.

Prognostic Value of Pre-Operative Intragastric Meal Distribution in Gastric Emptying Scintigraphy for Long-Term Success of Gastric Peroral Endoscopic Myotomy in Gastroparesis.

BACKGROUND AND AIMS: Gastric emptying scintigraphy (GES) is the gold standard for the diagnosis of gastroparesis. However, data are lacking regarding the prognostic value of pre-operative intragastric meal distribution during GES, in patients undergoing gastric peroral endoscopic myotomy (GPOEM) for gastroparesis. This study investigated the association of GES morphologic parameters and the long-term clinical success of G-POEM. METHODS: This retrospective study included patients who underwent G-POEM for refractory gastroparesis in a tertiary center with preoperative GES data. Intragastric meal distribution was measured using the proximal to distal count ratio (PDCR) at 0, 1, 2 and 4 hours (h), and the retention index (RI) was calculated. Clinical success was defined as a decrease of at least 50% in the post-G-POEM Gastroparesis Cardinal Symptom Index (GCSI) total score. RESULTS: In total, 77 patients were included with a mean follow-up of 40.14 months. Clinical success was observed in 54.55% of patients. The RI was not associated with clinical success. Only PDCR at 0h (PDCR0) was associated with clinical success. In univariate analysis, the median PDCR0 was 6.0 (IQR 5.59) in patients with clinical success and 4.29 (IQR 4.51) in patients with clinical failure (p=0.019). In multivariate analysis, PDCR0 > 5.25 was associated with clinical success (HR = 4.36 [1.55;12.26], p=0.00524). CONCLUSIONS: This study suggests that in patients with gastroparesis, High PDCR0 value (suggestive for a preferential fundic meal distribution) during preoperative GES is associated with long-term clinical response to G-POEM.

The influence of delayed gastric emptying on quality of life after partial duodenopancreatectomy.

PURPOSE: Quality of life (QoL) is temporarily compromised after pancreatic surgery, but no evidence for a negative impact of postoperative complications on QoL has been provided thus far. Delayed gastric emptying (DGE) is one of the most common complications after pancreatic surgery and is associated with a high level of distress. Therefore, the aim of this study was to analyse the influence of DGE on QoL. METHODS: This single-centre retrospective study analysed QoL after partial duodenopancreatectomy (PD) via the European Organization for Research and Treatment of Cancer core questionnaire (QLQ-C30). The QoL of patients with and without postoperative DGE was compared. RESULTS: Between 2010 and 2022, 251 patients were included, 85 of whom developed DGE (34%). Within the first postoperative year, compared to patients without DGE, those with DGE had a significantly reduced QoL, by 9.0 points (95% CI: -13.0 to -5.1, p < 0.001). Specifically, physical and psychosocial functioning (p = 0.020) decreased significantly, and patients with DGE suffered significantly more from fatigue (p = 0.010) and appetite loss (p = 0.017) than patients without DGE. After the first postoperative year, there were no significant differences in QoL or symptom scores between patients with DGE and those without DGE. CONCLUSION: Patients who developed DGE reported a significantly reduced QoL and reduced physical and psychosocial functioning within the first year after partial pancreatoduodenectomy compared to patients without DGE.

Delayed gastric emptying after laparoscopic pancreaticoduodenectomy: a single-center experience of 827 cases.

BACKGROUND: Delayed gastric emptying (DGE) commonly occurs after pancreaticoduodenectomy (PD). Risk factors for DGE have been reported in open PD but are rarely reported in laparoscopic PD (LPD). This study was designed to evaluate the perioperative risk factors for DGE and secondary DGE after LPD in a single center. METHODS: This retrospective cohort study included patients who underwent LPD between October 2014 and April 2023. Demographic data, preoperative, intraoperative, and postoperative data were collected. The risk factors for DGE and secondary DGE were analyzed. RESULTS: A total of 827 consecutive patients underwent LPD. One hundred and forty-two patients (17.2%) developed DGE of any type. Sixty-five patients (7.9%) had type A, 62 (7.5%) had type B, and the remaining 15 (1.8%) had type C DGE. Preoperative biliary drainage (p = 0.032), blood loss (p = 0.014), and 90-day any major complication with Dindo-Clavien score ≥ III (p < 0.001) were independent significant risk factors for DGE. Seventy-six (53.5%) patients were diagnosed with primary DGE, whereas 66 (46.5%) patients had DGE secondary to concomitant complications. Higher body mass index, soft pancreatic texture, and perioperative transfusion were independent risk factors for secondary DGE. Hospital stay and drainage tube removal time were significantly longer in the DGE and secondary DGE groups. CONCLUSION: Identifying patients at an increased risk of DGE and secondary DGE can be used to intervene earlier, avoid potential risk factors, and make more informed clinical decisions to shorten the duration of perioperative management.

Glucagon-Like Peptide-1 Agonists and General Anesthesia: Perioperative Considerations and the Utility of Gastric Ultrasound.

Glucagon-like peptide-1 (GLP-1) agonists are very popular and useful medications for the treatment of type 2 diabetes mellitus and obesity. Potent gastric emptying delay is common with these medications, serving as a major contributor to the postprandial glycemic control and weight loss benefits of these medications. Recently, multiple case reports and studies indicating safety risks for these medications and their use in patients planning to undergo general anesthesia have been published, as retained gastric contents can lead to intraoperative aspiration. New guidelines for these medications have been released to guide clinical practice for anesthesiologists. Some degree of preoperative cessation of these medications is required. At this time, the ideal window for cessation of these medications to optimize clinical efficacy while reducing aspiration risks has not yet been well elaborated on. Aspiration of gastric contents can still occur despite appropriate preoperative fasting in patients taking GLP-1 agonists. Gastric ultrasound appears to be an effective and objective way of preoperatively assessing a patient's stomach contents to make decisions regarding anesthetic management for patients prescribed these medications. This practice is limited by a general lack of training and implementation in current anesthesiology practice.

Glucagon-like peptide-1 receptor agonists: a narrative review of clinical pharmacology and implications for peri-operative practice.

BACKGROUND: Glucagon-like peptide-1 receptor agonists are used increasingly in the management of patients living with type 2 diabetes mellitus and obesity. In patients using glucagon-like peptide-1 receptor agonists, a key concern in the peri-operative period is the increased risk of pulmonary aspiration due to delayed gastric emptying. This review provides an overview of the pharmacodynamic and pharmacokinetic properties of glucagon-like peptide-1 receptor agonists and the risk of delayed gastric emptying and aspiration. METHODS: We conducted searches of MEDLINE and EMBASE databases of articles published before January 2024 using the keywords and medical subject headings: incretins; glucagon-like peptide-1; GLP-1; glucagon-like peptide-1 receptor agonists; GLP-1 RA; peri-operative period; perioperative; peri-operative; stomach emptying; gastric emptying; pulmonary aspiration; aspiration; food regurgitation; and regurgitation. The evidence was analysed, synthesised and reported narratively. RESULTS: A total of 1213 articles were located after duplicates were removed. Two authors screened the titles and abstracts to identify those studies which assessed specifically the risk of delayed gastric emptying and pulmonary aspiration or regurgitation in the peri-operative period. We searched manually the reference lists of relevant studies to identify any additional case reports. Ten studies were identified. Available evidence was limited to case reports, case series and observational work. CONCLUSIONS: There is insufficient evidence to put forward definitive guidance regarding the ideal cessation period for glucagon-like peptide-1 receptor agonists before elective surgery. Precautionary practice is required until more evidence becomes available. We suggest an individualised, evidence-based approach. In patients living with type 2 diabetes mellitus, there is concern that prolonged cessation before surgery will have a detrimental effect on peri-operative glycaemic control and discussion with an endocrinologist is advised. For patients taking glucagon-like peptide-1 receptor agonists for weight management, these drugs should be withheld for at least three half-lives before an elective surgical procedure.

Safe Continuation of Glucagon-like Peptide 1 Receptor Agonists at Endoscopy: A Case Series of 57 Adults Undergoing Endoscopic Sleeve Gastroplasty.

PURPOSE: Glucagon-like receptor agonists (GLP1-RAs) have raised peri-procedural concerns due to their potential to delay gastric emptying. The American Association of Anesthesiologists has advised pausing a single dose before elective endoscopy. However, a subsequent directive from multiple gastroenterology societies underscored the need for further assessment to substantiate this practice. We aimed to evaluate the frequency of serious adverse events and retained gastric products during endoscopic sleeve gastroplasty (ESG) with uninterrupted GLP1-RA use. MATERIALS AND METHODS: We conducted a retrospective evaluation of all patients undergoing ESG while on GLP1-RAs at three centers from August 2022 to February 2024. Per standard protocol, all patients had refrained from solid foods for at least 24 h and maintained nil per os for 12 h preceding their ESG. Records were reviewed for patient characteristics and medication type and doses. Primary outcomes included serious adverse events and retained gastric products based on patient records, procedure reports, and procedural videos. RESULTS: Fifty-seven consecutive adults (89.5% women, mean age of 44 ± 9 years, mean BMI of 40.1 ± 8.1 kg/m2, 35.1% with T2DM, and 26.3% with pre-T2DM) underwent ESG without stopping GLP1-RAs, which included semaglutide (45.6%), liraglutide (19.3%), dulaglutide (22.8%), and tirzepatide (12.3%). During intubation, endoscopy, and recovery, there were no instances of retained gastric solids, pulmonary aspiration, gastroesophageal regurgitation, or hypoxia. CONCLUSION: A ≥ 24-h pre-endoscopy liquid-only diet with ≥ 12-h pre-endoscopy fast may negate the need for GLP1-RA interruption for routine upper endoscopy in adults with native gastric anatomy.

Resolution of severe gastroparesis induced by parasympathetic surge following facial trauma: a case report.

BACKGROUND: Gastroparesis is a condition that affects the motility of the gastrointestinal (GI) tract, causing a delay in the emptying process and leading to nausea, vomiting, bloating, and upper abdominal pain. Motility treatment along with symptom management can be done using antiemetics or prokinetics. This study highlights the diagnostic and therapeutic challenges of gastroparesis and suggests a potential link between facial trauma and symptom remission, indicating the need for further investigation. CASE PRESENTATION: A 46-year-old Hispanic man with hypertension, type 2 diabetes (T2D), and hyperlipidemia on amlodipine 10 mg, lisinopril 5 mg, empagliflozin 25 mg, and insulin glargine presented with a diabetic foot ulcer with probable osteomyelitis. During hospitalization, the patient developed severe nausea and vomiting. The gastroenterology team advised continuing antiemetic medicine and trying very small sips of clear liquids. However, the patient didn't improve. Therefore, the gastroenterology team was contacted again. They advised having stomach emptying tests to rule out gastroparesis as the source of emesis. In addition, they recommended continuing metoclopramide, and starting erythromycin due to inadequate improvement. Studies found a 748-min stomach emptying time. Normal is 45-90 min. An uneventful upper GI scope was done. Severe gastroparesis was verified, and the gastroenterology team advised a percutaneous jejunostomy or gastric pacemaker for gastroparesis. Unfortunately, the patient suffered a mechanical fall resulting in facial trauma. After the fall, the patient's nausea eased, and emesis stopped. He passed an oral liquids trial after discontinuation of erythromycin and metoclopramide. CONCLUSION: This case exemplifies the difficulties in diagnosing and treating gastroparesis. An interesting correlation between parasympathetic surges and recovery in gastroparesis may be suggested by the surprising remission of symptoms following face injuries.

Pediatric nutritional surgery and its implications: results from a unicentric retrospective analysis.

PURPOSE: Existing guidelines provide weak recommendations on the surgical management of nutritional problems in children. The objective was to design a management pathway to address the best nutritional surgery (NS) procedure in a given patient. METHODS: Retrospective analysis of children treated at our department from January 2015 to December 2019. The sample was divided into two groups according to presence or absence of neurological impairment (NI). Patients with NI (Group 1) were classified in three subgroups based on presenting symptoms: A-Dysphagia without gastroesophageal reflux (GER); B-GER with or without dysphagia; C-Symptoms associated with a delayed gastric emptying. RESULTS: A total of 154 patients were included, 111 with NI. One-hundred-twenty-eight patients underwent only one procedure. Complications and mortality were superior in Group 1. In subgroup A, isolated gastrostomy was the first NS in all patients. In subgroup B most of patients were subjected to a Nissen fundoplication, while in 5 cases total esophagogastric dissociation (TEGD) was the first intervention. Considering the entire sample, 92.3% patients who underwent a TEGD did not require further procedures. CONCLUSION: NS encompasses various procedures depending on presenting symptoms and neurological status. A management flowchart for these patients is proposed.

Randomized, crossover trial: comparing the effects of standardized egg-white meal and Vital® on global gastric emptying parameters and intragastric meal distribution in healthy Asian participants.

BACKGROUND AND AIM: Measurements of gastric emptying and accommodation for alternative test-meal protocol during gastric emptying scintigraphy (GES), such as high-calorie nutrient drinks, are not fully established. We aimed to compare the effects of standardized egg-white meal (EWM) versus high-calorie nutrient drink (Vital®; Abbott Laboratories) on global GES parameters and intragastric meal distribution at immediate scan (IMD0h). METHODS: Of 84 screened participants, 60 asymptomatic healthy Asian population (38 females; 24.0 ± 1.5 years; 23.8 ± 2.6 kg/m2) were recruited in this 2 × 2 (AB/BA) crossover trial. Participants were randomized to a 4-h GES with 99mTc-radiolabeled EWM (~255.8 kcal), followed by a 200 mL Vital® (300 kcal), or vice versa, separated by a 2-week washout period. Global meal retention (GMR), power-exponential model emptying parameters (half-emptying [T1/2], lag phases [Tlag2%, Tlag5%, Tlag10%]), and IMD0h were determined and compared. RESULTS: GMRs for both test meals were within the international standard references for solid GES. Compared to EWM, Vital® exhibited significantly lower GMRs (faster emptying) from 0.5 to 3 h (all P < 0.001) but comparable at 4 h (P = 0.153). Similar observations were found for the model-based T1/2 and the different Tlag thresholds (all P < 0.001). Furthermore, IMD0h was found to be lower with Vital®, indicating lower gastric accommodation (faster antral filling) immediately post-ingestion (P < 0.001). Both test meals showed significant moderate-to-strong positive associations at the late-phase GE (GMR 2-4 h, T1/2) (all P < 0.05). CONCLUSIONS: Overall, Vital® is an acceptable alternative test meal to the EWM for GES; however, exercise caution when interpreting early-phase GE. The normative values for global GES parameters and IMD0h are also established.

Gastric emptying in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes and the impact of 4-week insulin pump therapy.

AIM: To evaluate gastric emptying (GE) and the glycaemic response to a 75-g oral glucose load in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes (T2D) before insulin pump therapy, after 4 weeks of insulin pump therapy, and 12-15 months after insulin pump therapy. MATERIALS AND METHODS: Twenty participants with T2D (baseline glycated haemoglobin [± SD] 10.7% [± 1.2%] 93 [± 10] mmol/mol) ingested a 75-g glucose drink containing 150 mg 13C-acetate, to determine the gastric half-emptying time, and underwent assessment of plasma glucose and serum insulin, C-peptide and glucagon-like peptide-1 (GLP-1) over 180 min before and after 4 weeks of insulin pump therapy (discontinued for 48 h before re-assessment). Data were compared to those in 19 healthy participants matched for sex and age. After 12-15 months, GE was re-measured in 14 of the T2D participants. RESULTS: At baseline, participants with T2D exhibited substantially augmented fasting and post-glucose glycaemia, diminished insulin secretion, and more rapid GE (p < 0.05 each), but comparable GLP-1, compared to healthy participants. Following insulin pump therapy, insulin secretion increased, GLP-1 secretion was attenuated, fasting and post-glucose glycaemia were lower, and GE was slowed (p < 0.05 each). The slowing of GE in T2D participants was sustained over 12-15 months of follow-up. CONCLUSIONS: In newly diagnosed Han Chinese with T2D, GE is often accelerated despite poor glycaemic control and is slowed by short-term insulin pump therapy. The effect on GE is maintained for at least 12 months.

Gastric emptying is slower in women than men with type 2 diabetes and impacts on postprandial glycaemia.

AIM: To evaluate sex differences in gastric emptying and the glycaemic response to a glucose drink and a high carbohydrate meal in type 2 diabetes (T2D). METHODS: In cohort 1, 70 newly diagnosed, treatment-naïve Chinese patients with T2D (44 men) recruited from a diabetes outpatient clinic ingested a 75-g glucose drink containing 150 mg 13C-acetate. In cohort 2, 101 Australian patients with T2D (67 male) recruited from the community, managed by diet and/or metformin monotherapy, ingested a semi-solid mashed potato meal, labelled with 100 µl 13C-octanoic acid. Breath samples were collected over 3 and 4 h, respectively, for assessment of gastric emptying, and venous blood was sampled for evaluation of glycaemia (with and without adjustment for each participant's estimated total blood volume). RESULTS: Gastric emptying was slower in female than male subjects in both cohorts (both p < .01). Multiple linear regression analyses revealed that gastric emptying was independently associated with sex (both p < .05). Without adjustment for blood volume, the glycaemic responses to oral glucose and the mixed meal were greater in female subjects (both p < .001). However, after adjustment for blood volume, the glycaemic responses were greater in men (both p < .05). CONCLUSIONS: Gastric emptying is slower in women than men with T2D, associated with a reduced blood volume-adjusted glycaemic response to oral glucose and a mixed meal in women. These observations highlight the sex difference in postprandial glucose handling, which is relevant to the personalized management of postprandial glycaemia in T2D.

Drug dissolution and transit in a heterogenous gastric chyme after fed administration: Semi-mechanistic modeling and simulations for an immediate-release and orodispersible tablets containing a poorly soluble drug.

Mathematical models that treat the fed stomach content as a uniform entity emptied with a constant rate may not suffice to explain pharmacokinetic profiles recorded in clinical trials. In reality, phenomena such as the Magenstrasse or chyme areas of different pH and viscosity, play an important role in the intragastric drug dissolution and its transfer to the intestine. n this study, we investigated the data gathered in the bioequivalence trial between an immediate-release tablet (Reference) and an orally dispersible tablet (Test) with a poorly soluble weak base drug administered with or without water after a high-fat high-calorie breakfast. Maximum concentrations (Cmax) were significantly greater after administering the Reference product than the Test tablets, despite similar in vitro dissolution profiles. To explain this difference, we constructed a novel semi-mechanistic IVIVP model including a heterogeneous gastric chyme. The drug dissolution in vivo was modeled from the in vitro experiments in biorelevant media simulating gastric and intestinal fluids in the fed state (FEDGAS and FeSSIF). The key novelty of the model was separating the stomach contents into two compartments: isolated chyme (the viscous food content) that carries the drug slowly, and aq_chyme open for rapid Magenstrasse-like routes of drug transit. Drug distribution between these two compartments was both formulation- and administration-dependent, and recognized the respective drug fractions from the clinical pharmacokinetic data. The model's assumption about the nonuniform mixing of the API with the chyme, influencing differential drug dissolution andl transit kinetics, led to simulating plasma concentration profiles that reflected well the variability observed in the clinical trial. The model indicated that, after administration, the Reference product mixes to a greater extent with aq_chyme, where the released drug dissolves better and transfers faster to the intestine. In conclusion, this novel approach underlines that diverse gastric emptying of different oral dosage forms may significantly impact pharmacokinetics and affect the outcomes of bioequivalence trials.

Risks of peri- and postoperative complications with glucagon-like peptide-1 receptor agonists.

AIM: To assess whether adults with diabetes on oral hypoglycaemic agents undergoing general endotracheal anaesthesia during nine common surgical procedures who are glucagon-like peptide-1 receptor agonist (GLP1-RA) users, compared with non-users, are at increased risk of six peri- and post-procedure complications. MATERIALS AND METHODS: A retrospective observational cohort analysis of over 130 million deidentified US adults with diabetes (defined as being on oral hypoglycaemic agents) from a nationally representative electronic health dataset between 1 January 2015 and 1 April 2023 was analysed. Cohorts were matched by high-dimensionality propensity scoring. We compared the odds of six peri- and postoperative complications in GLP1-RA users and non-users. A sensitivity analysis compared these odds in GLP1-RA users to non-users with diabetes and obesity. We measured the odds of (a) a composite outcome of postoperative decelerated gastric emptying, including antiemetic use, ileus within 7 days post-procedure, gastroparesis diagnosis, gastric emptying study; (b) postoperative aspiration or pneumonitis; (c) severe respiratory failure; (d) postoperative hypoglycaemia; (e) inpatient mortality; and (f) 30-day mortality. RESULTS: Among 13 361 adults with diabetes, 16.5% were treated with a GLP1-RA. In the high-dimensionality propensity score-matched cohort, GLP1-RA users had a lower risk of peri- and postoperative complications for decelerated gastric emptying and antiemetic use compared with non-users. The risk of ileus within 7 days, aspiration/pneumonitis, hypoglycaemia and 30-day mortality were not different. A sensitivity analysis showed similar findings in patients with diabetes and obesity. CONCLUSION: No increased risk of peri- and postoperative complications in GLP1-RA users undergoing surgery with general endotracheal anaesthesia was identified.

Is there a fast track ("Darmstrasse") for fluids in the small intestine? Evidence from magnetic resonance imaging.

BACKGROUND: The transit and distribution pattern of fluids in the small intestine is a key parameter for the dissolution and absorption of drugs. Although some information is known about the small intestinal water content after administration of fluid volumes and meals, the intestinal transit of orally ingested fluids and solutions has been barely investigated. The aim of this three-arm, cross-over, 9-subject human study was to investigate the transit of orally ingested water in the small intestine under fasting and postprandial conditions using MRI. To identify the ingested water, manganese gluconate, which can be identified with T1-weighted MRI sequences, was added as a marker. Using Horos (DICOM software), quantification of the distribution of Mn2+ ions in the gastrointestinal tract in fasted versus fed state (standard meal by FDA guidance and a light meal) was possible. The distribution and approximate wetted intestinal length was very similar in the fasting and postprandial states, suggesting rapid transport of water ingested after a meal through the chyme-filled small intestine in continuation of the "Magenstrasse" (stomach road). In some subjects, manganese gluconate reached deeper parts of the small intestine even more quickly in the postprandial state than in the fasting arm of the study. A deeper understanding of the behaviour of solutes in the gastrointestinal tract is fundamental to a mechanistic explanation for the kinetic interaction between food and drug intake (food effects).