Gastrointestinal Tolerability Research Articles

Comparison of the effects of deferasirox film-coated tablets (Jadenu®) and deferasirox dispersible tablets (Exjade®) in patients with beta thalassemia major: a preliminary report of the effects on the satisfaction, convenience, cardiac/liver MRI T2*, serum ferritin level, and biochemical profiles.

Deferasirox (DFX) is a once-daily oral iron chelator with proven dose-dependent efficacy in patients with thalassemia major (TM). The reason for switching from DFX dispersible tablets (Exjade®) to DFX film-coated tablets (Jadenu®) was intolerance. Many patients also reported that deferasirox® did not taste good. In this study, we compared the effect of Jadenu® and Exjade® on satisfaction, convenience, cardiac/liver MRI T2*, serum ferritin levels, and biochemical profiles in patients with thalassemia major. Sixty-two patients with thalassemia over 2years of age, who had iron overload indicated by chelation therapy, were randomly divided into two groups. The first group (n = 32) is treated with Exjade®, and the second group (n = 30) is treated with Jadenu®. Laboratory investigations included alkaline phosphatase (ALK), alanine transferase (ALT), aspartate transferase (AST), and serum ferritin levels. Cardiac/liver MRI T2* levels and patient satisfaction and convenience, were assessed before and 1year after starting therapy. The study found that 53.3% of Jadenu® patients were satisfied with the taste of the medication compared to only 12.5% of Exjade® patients, which was statistically significant (p = 0.001). Additionally, 40% of Jadenu® patients were satisfied with the ease of taking the medication compared to 28.1% of Exjade® patients, and again, the difference was statistically significant (p = 0.047). A comparison of the cardiac MRI T2* levels between the two studied groups showed no significant difference (p = 0.851). Jadenu® offers patients an improved formulation that can be taken on an empty stomach, has a better taste, and presents fewer gastrointestinal tolerability concerns. Overall, patient satisfaction is higher with Jadenu®, which may improve adherence and reduce the frequency and severity of complications associated with iron overload. This, in turn, may help mitigate cardiovascular and hepatic complications from iron overload in the long term. https://irct.behdasht.gov.ir/search/result?query=IRCT20210830052346N1.

Survodutide, a glucagon receptor/GLP-1 receptor (GCGR/GLP-1R) dual agonist, improves cardiometabolic parameters in adults with obesity: analysis of a placebo-controlled, randomised phase 2 trial

Abstract Background Obesity increases the risk of cardiovascular (CV) disease and contributes to CV risk factors, such as hypertension (HTN) and dyslipidaemia. Survodutide is a GCGR/GLP-1R dual agonist in clinical development for obesity. In a phase 2 clinical trial in individuals with obesity without diabetes, survodutide elicited up to 18.7% mean reduction in body weight after 46 weeks (primary endpoint) according to actual treatment.1 Purpose We explored the effect of survodutide on cardiometabolic parameters in this trial cohort. Methods 387 people aged ≥18 to <75 years with body mass index (BMI) ≥27 kg/m2 without diabetes were randomised 1:1:1:1:1 to once-weekly subcutaneous survodutide (0.6, 2.4, 3.6, 4.8 mg) or placebo (PBO) for 46 weeks (wk), comprising an initial 20-wk escalation period when the dose could be adjusted for gastrointestinal (GI) tolerability, followed by a 26-wk maintenance period. We evaluated changes from baseline (BL) to wk 46 in waist circumference; lipid parameters (triglyceride [TG], high-density lipoprotein [HDL], very low-density lipoprotein [VLDL], low-density lipoprotein [LDL], total cholesterol [TC], and non-HDL cholesterol [non-HDL-C]); and blood pressure (BP) by presence/absence of HTN before and at screening. Data were analysed descriptively for all participants receiving ≥1 dose of study drug with data for ≥1 efficacy endpoint, i.e. full analysis set (FAS), according to doses received during the maintenance period (actual treatment) and according to doses assigned at randomization (planned treatment) using on-treatment data. Results In the FAS (n=384), BL demographic and clinical characteristics were similar across treatment groups: overall mean age 49.1 years, BMI 37.1 kg/m2, 262 (68.2%) female, 301 (78.4%) White, 40 (10.4%) Asian, and 37 (9.6%) Black. Before and at screening, 133 (34.6%) participants had hypertension and 108 (28.1%) had dyslipidaemia. Waist circumference was reduced in all survodutide doses vs PBO; the largest mean reduction was 16.6 cm (4.8 mg group; actual treatment). Survodutide was associated with reductions of up to 10.2 mmHg in SBP and 4.8 mmHg in DBP from BL to wk 46 by actual treatment; similar reductions were observed for planned treatment, and reductions were comparable with/without HTN before and at screening (Figure 1). A marked decrease in mean TG was observed in all survodutide groups by planned treatment (Figure 2). Mean HDL was relatively unchanged over the period. Small decreases occurred in mean VLDL (all survodutide doses) and mean LDL (2.4 and 3.6 mg doses). Mean TC and non-HDL-C decreased in 0.6, 2.4, and 3.6 mg groups. Conclusion In people living with obesity, the GCGR/GLP-1R dual agonist survodutide was associated with clinically meaningful reductions in waist circumference, BP (with/out HTN before and at screening), and TG.

The Effects of Multiple Acute Turkesterone Doses on Indirect Measures of Hypertrophy and Metabolic Measures: A Preliminary Investigation

Turkesterone is a naturally occurring plant steroid touted for its medicinal, pharmacological, and biological properties with no reported adverse side effects compared with traditional anabolic androgenic steroids (AAS). However, this ostensible enhancement to increase muscle protein synthesis and facilitate augmented thermogenesis remains undescribed despite uninformed and potentially haphazard consumption. To investigate whether turkesterone enhances insulin-like growth factor-1 (IGF-1) and resting metabolic rate (RMR), eleven apparently healthy males (23.3 ± 2.2) volunteered to participate in the present study with samples collected pre-, 3H post-, and 24H post-ingestion. Subsequent analyses failed to reveal any significant main condition, time, or interaction main effects for serum IGF-1, RMR, lipid, and carbohydrate metabolism (p > 0.05). However, non-significant serum IGF-1 concentrations increased with both turkesterone conditions and remained elevated when compared with placebo. Similarly, RMR remained elevated above baseline across the 3 h assessed. Although these data fail to fully support turkesterone as a potent anabolic supplement, nevertheless, our findings are foundational to persistently tease apart this supplement’s purported ergogenic effects and underscore its favorable hemodynamic and gastrointestinal tolerability profile. Future investigations should, therein, aim to assess turkesterone-mediated IGF-1 increases on long-term whole-muscle growth across several training sessions to further substantiate its efficacy on anabolism.

Long-term effectiveness and safety of lomitapide in patients with homozygous familial hypercholesterolemia: an observational case series

BackgroundWe assessed long-term real-world effectiveness and safety of lomitapide in patients with homozygous familial hypercholesterolemia (HoFH).MethodsRetrospective case series of six patients with HoFH treated with lomitapide in an Italian clinic. Changes in low-density lipoprotein cholesterol (LDL-C) during lomitapide treatment were assessed. The effect on LDL-C of PCSK9 inhibitors, apheresis and lomitapide was evaluated. Additionally, high-density lipoprotein cholesterol (HDL-C), gastrointestinal tolerability, hepatic steatosis/elasticity, transaminases, and cardiovascular events and symptoms were assessed.ResultsMedian age at HoFH clinical and molecular diagnoses was 25 (range 2–49) and 40 (29–71) years, respectively. Five (83.3%) had prior cardiovascular events. One patient received apheresis, which was subsequently discontinued. All patients received PCSK9 inhibitors but discontinued due to minimal effectiveness. Median (range) age at lomitapide initiation was 44 (28–73) years, with a median 47 (18–85) months’ treatment (mean dose 17.5 [5–40] mg/day). Mean (SD) baseline LDL-C was 263.2 (148.1) mg/dL, which decreased by 80% at nadir (52.8 [19.2] mg/dL) and 69% at last follow-up (81.3 [30.5] mg/dL). Four patients (66.7%) achieved LDL-C < 70 mg/dL sometime during follow-up, all of whom also achieved LDL-C < 55 mg/dL. Adverse events (AEs) were generally mild to moderate, hepatic steatosis was either absent or mild/moderate and hepatic elasticity remained normal in all but two patients (> 70 years old). All patients with reported cardiovascular symptoms had improvements in symptoms, and all patients reported stabilization or regression of intima-media thickness and atheromatous plaques.ConclusionsThese long-term, real-world data demonstrate that lomitapide substantially reduced LDL-C for up to seven years. Most patients achieved LDL-C goal at some point, consistent with published Phase III trial and real-world evidence data. No patient discontinued lomitapide treatment. Further long-term follow-up in a larger patient population will be important to determine cardiovascular and other outcomes.

7018 Improved Tolerability After Transitioning from Glucagon-like Peptide-1 Receptor Agonists to Tirzepatide

Abstract Disclosure: S. Hudson: None. J. Aurora: None. F. Erenler: None. Background: Tirzepatide is a dual incretin targeting glucagon-like peptide-1 receptor agonist (GLP-1RA) and glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA) with potent reductions in HbA1c and weight, especially compared to semaglutide, a GLP-1RA (1). Gastrointestinal (GI)-related events are commonly associated with incretins. As an imbalanced dual agonist, tirzepatide has a stronger affinity for GIP compared to GLP-1 receptors (2). This stronger affinity for GIP receptors may be related to the improved tolerability of tirzepatide, as GIP is not as associated with GI effects as compared to GLP-1 (2). There is a reported dose-dependent increase in GI events and treatment discontinuation with tirzepatide compared to semaglutide in RCTs, although this has not been corroborated in real-world data (1). Additionally, there is no literature evaluating GI tolerability when switching from GLP-1 receptor agonists to tirzepatide. We present a case series to highlight improved tolerability and sustained clinical outcomes observed in patients transitioning from GLP-1RA to tirzepatide, who previously had GI intolerances. Clinical Case A retrospective review was conducted of five patients who started on GLP-1RA for either T2DM (n=3) or obesity (n=2) but stopped due to GI-related events. All patients were female with a mean age of 57 years. On average, patients with T2DM had a 23-year duration of diabetes, HbA1c 8.4%, weight 78.4 kg, and BMI 29.5 kg/m2 prior to starting tirzepatide. For patients without T2DM, the average weight was 75.9 kg and BMI 30.0 kg/m2 prior to starting tirzepatide. Before switching to tirzepatide, three patients were on maximally tolerated dulaglutide and two patients were on semaglutide. Patients were initially transitioned to tirzepatide 2.5 mg (n=2), 5 mg (n=2), and 7.5 mg (n=1). All patients tolerated tirzepatide with no GI-related events after an average of 6 months of treatment. Of the three patients with T2DM, they saw an additional average HbA1c reduction of 1.1% and an average weight loss of 3%. For patients who transitioned to tirzepatide for weight loss, they saw an additional average weight loss of 9%. Clinical Implications Tirzepatide may offer improved tolerability in patients who are intolerant of GLP-1RA drugs, while yielding further glycemic lowering and weight loss. Given tirzepatide’s stronger affinity to GIP than GLP-1 receptors, this may explain improved GI tolerability as seen in our case series. Further research is needed to evaluate tolerability improvement with tirzepatide using real-world data and larger sample sizes.

Improved viability of probiotics by co-encapsulation of wheat germ oil under storage and gastrointestinal conditions: Effects of drying methods and wall composition

To improve the viability of probiotics during food storage and gastrointestinal digestion, this study developed solid microcapsules co-loaded with probiotics and wheat germ oil using W1/O/W2 emulsion pre-encapsulation, followed by spray drying (SD), freeze drying (FD) and spray freeze drying (SFD), respectively. The effects of drying methods and wall materials on the microstructure, physicochemical properties, storage stability, and gastrointestinal tolerability were highlighted. Firstly, all samples showed high encapsulation efficiency for probiotics (86%–99.2%) and wheat germ oil (72%–85%), low moisture content (2.8%–5.3%) and hygroscopicity (6.3%–11.6%), and wall materials exhibited structural stability during the drying process. The results of viable cell counts indicated that SFD caused more damage to bacterial cells than the other two drying methods, as evidenced by the total death of encapsulated probiotics within 90 days. In contrast, SD and FD encapsulated probiotics remained at 8.8–9.9 log CFU/g after 150 days of storage at 4 °C and 25 °C. Furthermore, the viability of probiotics in the co-encapsulated and pectin-added microcapsules was significantly enhanced in storage stability and simulated gastrointestinal digestion tests. Based on the above results, it was suggested that the co-encapsulation strategy of combining the W1/O/W2 structure and SD or FD to prepare microencapsulated powders can obtain probiotic products with high activity and high stability. Meanwhile, composite wall material (whey protein isolate and pectin) could enhance probiotics' protective effect and colonic targeted release behavior. In conclusion, the current research provides a valuable reference for the application of probiotics and functional oils in the food industry.

Optimizing metformin therapy in practice: Tailoring therapy in specific patient groups to improve tolerability, efficacy and outcomes.

Metformin is the first-line medication for type 2 diabetes. It is effective and safe, provided some caution is taken in specific populations. In patients with chronic kidney disease, metformin may provide long-term benefits, and it is a first-line therapy for diabetes, but the estimated glomerular filtration rate (eGFR) must be assessed regularly, to minimize the risk for metformin accumulation. When eGFR is 30-60 mL/min/1.73m2, the dose should be reconsidered, and sick-days education provided. Metformin should be discontinued when eGFR falls below 30 mL/min/1.73m2. Metformin accumulation may increase the risk for lactic acidosis if concomitant risk factors for hyperlactataemia (liver or respiratory insufficiency, sepsis, acute heart failure) are present; in these conditions, metformin is contraindicated, even although the available evidence is reassuring. Patients on metformin often complain of gastrointestinal side effects (mainly diarrhoea and nausea) during therapy initiation, but they may sometimes occur after years of stable therapy. These usually resolve if the dose is carefully titrated, or by switching to the extended-release formulation. Patients with obesity may benefit from the significant, although modest, metformin-associated weight loss and appetite reduction. During pregnancy, metformin is associated with a reduction of pregnancy complications, especially in obese women, but some concern remains, because metformin crosses the placenta, and it is associated with a significantly lower mean birth weight than insulin. In the elderly, gastrointestinal tolerability and renal function must be reassessed more often. Vitamin B-12 should be screened regularly in long-time metformin users because metformin may induce clinical vitamin B-12 deficiency.

TIRZEPATIDE: Trending ‘Weight loss’ Drug– Potential Influence in Tackling Obesity Epidemic

Obesity is a chronic disease that is associated with severe complications. A lifestyle involving an increased appetite and reduced energy expenditure promotes weight gain. A better understanding of the endocrine regulation of appetite has led to the development of newer medications for the treatment of obesity. Among these medications is an incretin-based drug named tirzepatide. Many studies have been conducted in obese, insulin-resistant, and lipid-diet-fed mice to evaluate the effect of tirzepatide and its combination of GIP and GLP-1 agonism demonstrated higher anorectic activity by increasing satiety and satiation, decreasing liking for high-fat diets and decreasing sweet taste reference as compared to the effects of semaglutide. Adverse effects of mild gastrointestinal events and decreased appetite were reported with tirzepatide (which reduced after some time) than with placebo. In phase 3 SURPASS clinical trial optimized dose escalation scheme was adopted to improve gastrointestinal tolerability with an initial low dose of tirzepatide. The results of the SURPASS-1 trial showed significant improvement in glycemic control and durable bodyweight reductions with all the doses (3 doses) of tirzepatide compared to placebo in type 2 diabetic patients along with diet and exercise. Weight loss occurred regardless of whether participants reported any gastrointestinal adverse events and did not elevate over the period.

Honey Added to Yogurt with Bifidobacterium animalis subsp. lactis DN-173 010/CNCM I-2494 Supports Probiotic Enrichment but Does Not Reduce Intestinal Transit Time in Healthy Adults: A Randomized, Controlled, Crossover Trial

BackgroundHoney improves probiotic survival in vitro. However, if this effect translates to humans has not been investigated. ObjectivesWe aimed to determine effects of honey plus yogurt containing the probiotic Bifidobacterium animalis subsp. lactis DN-173 010/CNCM I-2494 (B. animalis) on intestinal transit time, probiotic enrichment, digestive health, mood, and cognition in adults. MethodsSixty-six healthy adults (34 female; 33.6 ± 9.8 y; 24.6 ± 3.0 kg/m2) in a crossover trial were randomly assigned to 2-wk yogurt conditions in a counterbalanced order with ≥4-wk washout: 1) Honey (HON): yogurt plus honey and 2) Negative Control (NC): heat-treated yogurt plus sugar. Of the participants, n = 62 completed the trial, and n = 37 (17 female; 32.0 ± 8.3 y; 25.0 ± 2.9 kg/m2) elected to enroll in a third condition (a nonrandomized study extension) after ≥4-wk washout with a reference Positive Control (PC): yogurt plus sugar. At baseline and end of each of the 3 conditions, intestinal transit time was measured with dye capsules; probiotic abundance with fecal DNA 16S sequencing; digestive health with symptom/function records, Bristol stool consistency, Gastrointestinal Tolerability, and Gastrointestinal Quality of Life Index; mood with Positive and Negative Affect Schedule-Short Form, Depression Anxiety Stress Scales-42, Patient-Reported Outcomes Measurement Information System questionnaires, and an emotional image task; and cognition with a spatial reconstruction task. Data were analyzed using linear mixed-effects models (LMMs) with significance at P ≤ 0.05. Baseline and end data were included in the LMM, with fixed effects being treatment, time, treatment by time interaction, and baseline covariate, and the random effect being the participant. ResultsB. animalis was enriched in HON (d = 3.54; P = 0.0002) compared to controls with linear discriminant analysis effect size. Intestinal transit time, gastrointestinal health, mood, and cognition did not differ between conditions (LMM: Ps > 0.05). ConclusionsYogurt + honey enriched B. animalis but did not reduce intestinal transit time or have other functional gastrointestinal, mood, or cognitive effects in adults.This trial was registered at www.clinicaltrials.gov as NCT04187950 and NCT04901390.

Fulvestrant with or without the cyclin-dependent kinase 7 (CDK7) inhibitor samuraciclib in advanced hormone receptor positive (HR+) breast cancer after CDK4/6 inhibition: Phase II SUMIT-BC study.

TPS1126 Background: CDK7 enhances oncogene transcription and upregulates anti-apoptotic genes, accelerates the cell cycle via CDK phosphorylation, and activates estrogen receptors (ERs) that can drive resistance to hormonal therapy in cancer. CDK7 inhibition therefore represents a potential anticancer strategy in cancer. Samuraciclib (CT7001) is a small molecule, ATP competitive, selective oral inhibitor of CDK7 that inhibits these key effects of CDK7. Samuraciclib had a favorable safety profile and showed clinical activity when combined with fulvestrant in a phase I study in patients with HR+/HER2− advanced breast cancer (BC) who had previously been treated with a CDK4/6 inhibitor. Patients with no detectable TP53 mutation in ctDNA at baseline and those without baseline liver metastases appeared to have better outcomes. The instant release capsule formulation of samuraciclib used in this study released large amounts of samuraciclib high in the gastrointestinal (GI) tract, which may have contributed to the observed low grade GI adverse events, which were managed with prophylaxis and counselling (1). Methods: A phase 2 open-label randomized study has been designed to evaluate the efficacy, safety, pharmacokinetics (PK), and quality of Life (QoL) of samuraciclib combined with fulvestrant compared to fulvestrant monotherapy (SUMIT-BC; NCT05963984). Eligible patients (n=60) are ≥18 years, have histologically or cytologically confirmed ER+/HER2− advanced or metastatic BC not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor combined with a CDK4/6 inhibitor in the adjuvant or advanced setting, are receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal, and have RECIST v1.1 evaluable disease. Prior SERD, mTOR inhibition, or chemotherapy for advanced BC are not permitted. All patients undergo baseline Guardant360 ctDNA analysis to establish TP53 and other mutation status. Patients are randomized 1:1:1 to fulvestrant alone (500 mg IM administered on days 1, 15 and 29 and then monthly), fulvestrant and samuraciclib 240 mg QD, or fulvestrant and samuraciclib 360 mg QD. In preparation for phase 3 development, a novel single tablet formulation of samuraciclib is used, which may enhance GI tolerability. Patients undergo RECIST v1.1 evaluation at baseline, every 8 weeks until week 48, and every 12 weeks thereafter. The primary endpoint is clinical benefit response at 24 weeks. Secondary endpoints are tolerability, progression free survival, overall response rate, duration of response, and PK of fulvestrant and samuraciclib. QoL (Functional Assessment of Cancer Therapy - Breast questionnaire [FACT-B]) and correlations between TP53 mutation and efficacy/safety will be assessed. 1. Coombes et al. Nature Comms 2023. Clinical trial information: NCT05963984 .

Gastrointestinal tolerability of organic infant formula compared to traditional ‎infant formula: A systematic review.

Infants' nutrition significantly influences their growth, development, and overall well-being. With the increasing demand for organic infant formula driven by the perception of health benefits and growing awareness of natural feeding options, it is crucial to conduct a comparative analysis of the gastrointestinal tolerability between organic and traditional infant formulas. To provide a concise and precise analysis of the gastrointestinal tolerability of organic infant formula compared to traditional infant formula. Due to limited direct comparisons, the review synthesizes available literature on each formula type, presenting insights into their potential effects on infants' digestive health. An extensive literature search was conducted, compiling studies on organic and traditional infant formulas, their compositions, and reported effects on gastrointestinal tolerability. We searched academic databases such as PubMed and Google Scholar and specialized ‎nutrition, paediatrics, and infant health journals using relevant keywords till October 1, 2023. ‎. Although specific comparative studies are scarce and formula heterogeneity is a significant limitation, this systematic review provides an in-depth understanding of organic infant formulas' composition and potential benefits. While scientific evidence directly comparing gastrointestinal tolerability is limited, organic formulas strive to use carefully selected organic ingredients to imitate breast milk composition. Potential benefits include improved lipid profiles, higher methionine content, and decreased antibiotic-resistant bacteria levels. Understanding the gastrointestinal tolerability of organic and traditional infant formulas is crucial for parents and healthcare providers to make informed decisions. Despite limitations in direct comparisons, this systematic review provides insights into the composition and potential benefits of organic infant formulas. It emphasizes the need for further research to elucidate their gastrointestinal effects comprehensively.

Expert opinion on the clinical use of calcium and vitamin D supplements in osteoporosis in Indian settings

Background: Several clinical studies demonstrated that calcium intake decreases the risk of osteoporosis and osteoporotic fractures. However, understanding the prescription practice of calcium supplements employed in Indian contexts may help in improving patient management and developing evidence-based recommendations for optimizing the treatment. So, this study aimed to gather clinicians’ perspective regarding the use of calcium and vitamin D supplements for the management of osteoporosis in Indian settings. Methods: The current survey involved 17 questions pertaining to current feedback, clinical observations, and clinical experience of specialists on osteoporosis management and the use of calcium and vitamin D supplements. Results: According to 30%, 26%, 25%, and 19% of the experts, higher dietary sodium (salt) intake was generally associated with negative calcium balance and bone mineral loss, increased risk of fracture, decreased calcium excretion in the urine and decreased dietary calcium absorption. Calcium and vitamin D were recommended by 78% of the respondents for the management of osteoporosis. Approximately 72% of the respondents stated calcium aspartate anhydrous as the preferred calcium supplement to manage osteoporosis. Around 49% of the respondents reported a reduced risk of bone fractures among those who consume more calcium than the average amount. Further 48%, 30%, and 25% of the respondents indicated that calcium aspartate anhydrous have better absorption, better bioavailability, and better gastrointestinal tolerability. Conclusions: According to the expert’s opinion, both calcium and vitamin D administration in conjunction with maintaining a balanced sodium intake were recommended for managing osteoporosis.

Consensus statement on the management of hyperkalaemia-An Asia-Pacific perspective.

Hyperkalaemia is an electrolyte imbalance that impairs muscle function and myocardial excitability, and can potentially lead to fatal arrhythmias and sudden cardiac death. The prevalence of hyperkalaemia is estimated to be 6%-7% worldwide and 7%-10% in Asia. Hyperkalaemia frequently affects patients with chronic kidney disease, heart failure, and diabetes mellitus, particularly those receiving treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors. Both hyperkalaemia and interruption of RAAS inhibitor therapy are associated with increased risks for cardiovascular events, hospitalisations, and death, highlighting a clinical dilemma in high-risk patients. Conventional potassium-binding resins are widely used for the treatment of hyperkalaemia; however, caveats such as the unpalatable taste and the risk of gastrointestinal side effects limit their chronic use. Recent evidence suggests that, with a rapid onset of action and improved gastrointestinal tolerability, novel oral potassium binders (e.g., patiromer and sodium zirconium cyclosilicate) are alternative treatment options for both acute and chronic hyperkalaemia. To optimise the care for patients with hyperkalaemia in the Asia-Pacific region, a multidisciplinary expert panel was convened to review published literature, share clinical experiences, and ultimately formulate 25 consensus statements, covering three clinical areas: (i) risk factors of hyperkalaemia and risk stratification in susceptible patients; (ii) prevention of hyperkalaemia for at-risk individuals; and (iii) correction of hyperkalaemia for at-risk individuals with cardiorenal disease. These statements were expected to serve as useful guidance in the management of hyperkalaemia for health care providers in the region.

Research progress on rat model of drug-induced liver injury established by nonsteroidal anti-inflammatory drug (celecoxib) and royal jelly ameliorative effect.

NSAIDs, like celecoxib, are widely used to treat pain, fever, and inflammation, with celecoxib being particularly effective in managing arthritis symptoms and acute or chronic pain especially with its favorable gastrointestinal tolerability. The study aimed at exploring the effect of chronic administration of celecoxib on hepatic tissues in male albino rats. It also examined the royal jelly celecoxib interplay. 50 male albino rats in 5 equal groups; Group 1: received no drug. Group 2: received celecoxib (50 mg/kg/day, orally), for 30 successive days. Group 3: received celecoxib plus royal jelly (300 mg/kg/day, orally) for 30 successive days. Group 4: received celecoxib, for 30 days, then were left untreated for another 30 days. Group 5: received celecoxib plus royal jelly for 30 days, then were left untreated for another 30 days. Chronic celecoxib administration caused hepatotoxicity in male albino rats, with ameliorative effect of royal jelly. Celecoxib discontinuation significantly diminished the celecoxib-induced toxicity, and normal liver enzymes and serum protein levels were regained in the case of dual medications (celecoxib+RJ) discontinuation. Long-term celecoxib administration caused hepatotoxicity, with ameliorative effects of royal jelly against celecoxib-induced oxidative and apoptotic stress. In addition, it could be concluded that royal jelly may prove a useful adjunct in patients being prescribed celecoxib.

Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas.

Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including the USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) in a fasted state. This study evaluated the effect of a low-fat meal on selumetinib PK parameters and gastrointestinal (GI) tolerability in adolescent participants with NF1-PN. Eligible participants aged ≥ 12 to< 18 years took 25mg/m2 selumetinib BID with a low-fat meal (T1) for 28 days, followed by a 7-day washout, and then administration in a fasted state (T2) for another 28 days. Primary objectives were to evaluate the effect of a low-fat meal on AUC0-12,ss and GI tolerability after multiple selumetinib doses in T1 versus T2. Key secondary objectives were additional PK parameters and adverse events (AEs). At primary data cut-off, all 24 participants completed T1, and 23 participants completed T2. There were no significant differences in AUC0-12,ss between T1 and T2. In T1 and T2, 29.2% and 33.3% participants, respectively, reported ≥ 1 GI AE. No GI AEs Grade ≥ 3, or serious AEs, or GI AEs resulting in treatment interruptions, discontinuation, or dose reductions were reported in T1 and T2. Dosing selumetinib with a low-fat meal had no clinically relevant impact on selumetinib AUC0-12,ss nor GI tolerability in adolescents with NF1-PN. NCT05101148.

Comparative Analysis of Metformin and Imeglimin: Exploring Therapeutic Implications

The landscape of type 2 diabetes mellitus (T2DM) management is evolving with the emergence of imeglimin alongside the longstanding use of metformin. While both drugs share structural similarities and target mitochondrial complex I, they exhibit distinct mechanisms of action and therapeutic effects. Imeglimin, with its mitochondrial modulation and competitive inhibition of complex I, holds promise in mitigating beta-cell dysfunction, improving insulin sensitivity, and offering potential cardiovascular benefits. Efficacy studies suggest comparable outcomes with metformin, underscoring the utility of imeglimin as a valuable addition to the T2DM armamentarium. There is mixed evidence on the cardio-renal benefits of metformin while imeglimin’s tissue-protective effects in preclinical studies offer a glimpse into potential cardiovascular advantages. Studies suggest imeglimin’s superior gastrointestinal tolerability. Imeglimin’s potential as an anti-diabetic agent is further underscored by its diverse combination options. In clinical practice, metformin remains a cornerstone in the management of T2DM. Imeglimin, with its lesser gastrointestinal side effects and theoretically lower risk of lactic acidosis, offers a compelling alternative, particularly in patients intolerant to metformin. With preliminary signs pointing toward potential cardiovascular and renal benefits of imeglimin, exploring its application in patients with atherosclerotic cardiovascular disease presents an enticing prospect. As the field advances, adopting a nuanced and personalized approach to T2DM management could lead to imeglimin carving out a significant niche in the dynamic landscape of diabetes therapeutics.

Management of iron deficiency in women of childbearing age with oral iron intolerance: a prospective, randomised, controlled trial of three doses of an iron-whey-protein formulation

BackgroundNutritional deficit and oral iron gastrointestinal intolerance may be a common cause of iron deficiency, which can be managed by pharmacists.AimTo understand the prevalence of iron deficiency in women of childbearing age with a self-reported history of intolerance to oral iron and the tolerability of three doses of an iron-whey-protein formulation in the care of these women.MethodFerritin and haemoglobin levels were documented in women of childbearing age with oral iron gastrointestinal intolerance. In those with iron deficiency (ferritin < 30 µg/L), adherence, gastrointestinal tolerability, ferritin, transferrin saturation and haemoglobin levels were compared between their prior oral iron product and iron-whey-protein microspheres randomised to three doses (14 mg daily, 25 mg daily and 50 mg daily) for 12 weeks.ResultsMost screened women had low iron stores (128 (62.7%); ferritin < 30 µg/L), 65 (31.9%) had moderate to severe iron deficiency (ferritin < 12 µg/L) and 33 (16.2%) had iron deficiency anaemia (ferritin < 30 µg/L, haemoglobin < 12 g/dL). Amongst the 59 women who participated in the prospective clinical study of iron-whey-protein microspheres over 12 weeks, 48 (81.4%) were classified as adherent/persistent and fewer instances of gastrointestinal intolerance were reported (0.59 ± 0.91) when compared to 12 (20.3%) and (4.0 ± 2.2) respectively while taking the prior oral iron (Fisher’s Exact and T-test respectively, both p < 0.001). There was no difference in adherence or tolerability of different iron-whey-protein formulation doses. Ferritin, haemoglobin and energy levels increased significantly over 12 weeks.ConclusionUndiagnosed iron deficiency is common in women of childbearing age with a history of intolerance to oral iron and iron-whey-protein microspheres can improve adherence, GI tolerability, iron stores, haemoglobin and energy levels in these women.Clinical trial registration Clinicaltrials.gov identifier (registration includes full trial protocol): NCT04778072.

Gastrointestinal Tolerability and Acute Glycemic Response of Oligosaccharides and Polysaccharides from Cellulose and Xylan in Healthy Adults: Two Double-Blinded, Randomized, Controlled, Cross-over Trials

Objective The aim of this study was to investigate the gastrointestinal tolerability, glycemic and insulinemic responses of Plant Fiber Extract (PFE), a mixture comprising of oligosaccharides and polysaccharides derived from cellulose and xylan. Methods Two double-blind, randomized, controlled, cross-over trials were conducted in healthy adults. In the first trial, participants (n = 29) consumed either 25, 35 or 45 g per day of PFE or resistant maltodextrin (Control) for 14 days. The occurrence and severity of gastrointestinal (GI) symptoms, stool parameters, and safety outcomes were evaluated with a combination of surveys and blood analysis respectively. In the second trial (n = 20), the post-prandial glycemic and insulinemic responses after the ingestion of 20 g of PFE diluted in water or incorporated into chocolate chips was measured and then compared to that of glucose and regular chocolate, respectively. Results For all timepoints (0, 7 and 14 days), within any given dose group, there was no statistically significant difference in the GI symptoms score between PFE and Control. Further, for each test product (PFE or Control), no difference was observed in the same dose group from days 0 and 14. Stool consistency score and number of participants experiencing loose or watery stools was similar between products. No serious adverse events were reported and neither PFE nor Control significantly altered blood or urine safety parameters. The glycemic and insulinemic responses after PFE ingestion in comparison to glucose were 12% and 8% respectively. The glycemic and insulinemic responses after consuming chocolate containing PFE were 20% of that of regular chocolate. Conclusion PFE was well-tolerated by healthy volunteers in doses up to 45 g/day and it elicited comparatively low glycemic and insulinemic responses when consumed alone or when incorporated into a food product.

Real-world treatment preferences among health care providers in the United States in selecting disease modifying therapies for patients with multiple sclerosis: a discrete choice experiment

AimsHealth care providers (HCPs) treating multiple sclerosis (MS) in clinical practice have numerous disease-modifying therapies (DMTs) to consider when evaluating treatment options. This study assessed the treatment preferences of HCPs in the United States, both direct (explicit) and derived (explicit and implicit), when selecting MS DMTs based on clinical and logistical treatment attributes.Materials and methodsA 45-minute web-enabled questionnaire was administered to HCPs who manage patients with MS to assess the importance of treatment attributes. HCPs were recruited through an online panel. This study examined treatment attributes relevant to treatment decisions in MS, with a focus on the burden to HCPs and their staff, as well as HCP attitudes toward various aspects of MS care such as diagnosis, treatment prioritization, and ease of initiating or switching DMTs. The study also employed a discrete choice experiment (DCE) to assess direct and derived treatment preferences.ResultsThe study recruited 145 HCPs. Direct assessments (a score of greater than 7.0 was considered important) suggested that safety (mean importance rating = 7.8/9) and relative risk reduction in relapses (7.6/9) and disability progression (7.5/9) were most important when selecting DMTs. In contrast, derived importance from the DCE (higher points corresponding to greater importance) suggested that logistical attributes such as dose frequency (mean relative attribute importance = 17.5%), dose titration (10.3%), formulation (9.4%), and volume of calls (9.1%) were important considerations, along with efficacy (16.5%), safety (9.8%), and gastrointestinal tolerability (9.4%).LimitationsThis study may have been subject to selection bias due to the application of eligibility criteria, the convenient sampling recruitment methodology, and recruitment of HCPs with internet access.ConclusionIn the direct assessment, clinical attributes were chosen as the most important treatment attributes by HCPs. However, in the DCE, derived treatment decisions rated logistical attributes as also being as important in treatment choice.

Comparison of gastrointestinal adverse events between fast release tablets and regular acetylsalicylic acid (aspirin) galenics after short-term use: a meta-analysis of randomized clinical trials.

This study aimed at determining whether there is a difference in the safety profile between fast release (FR) aspirin tablets and regular galenic formulations of aspirin. This study was based on a clinical study database pool (Bayer HealthCare) including 84clinical studies and 16,095human subjects. The meta-analysis included 72studies applying a single dose of aspirin of at most 1000mg and was, therefore, based on individual data from 9288subjects. Of these, 6029subjects took aspirin and 3259subjects took placebo. Endpoints were adverse events (AEs) of any kind and, especially of gastrointestinal (GI) nature. Event incidence and odds ratios (OR) based on Mantel-Haenszel risk estimates were calcuated. Subjects on aspirin FR had a significantly decreased OR of 0.65 [0.48, 0.90] [95% confidence interval] for all AEs and of 0.39 [0.20, 0.79] for drug-related all AEs versus placebo. The risk of all GI AEs tended to be reduced for subjects on aspirin FR (0.65 [0.41; 1.03]), but not for drug-related GI AEs. Subject on aspirin mono and aspirin mono (plain only, w/o FR) showed an increased risk of drug-related all AEs compared to placebo (1.34 [1.11; 1.62] and 1.43 [1.13; 1.80]). However, subjects on aspirin FR and those on regular aspirin had almost the same risk of all determined AEs. In conclusion, aspirin FR tablets showed a comparable GI tolerability to regular galenic formulations of aspirin after short-term treatment. Major GI complication did not occur after intake of any galenic formulation of aspirin.