Gastrointestinal Adverse Events Research Articles

A Novel Tetrahydroacridine Derivative with Potent Acetylcholinesterase Inhibitory Properties and Dissociative Capability against Aβ42 Fibrils Confirmed by In Vitro Studies.

Alzheimer's disease (AD) is one of the most common causes of dementia, accounting for more than 60% of all cases. It is a neurodegenerative disease in which symptoms such as a decline in memory, thinking, learning, and organizing skills develop gradually over many years and eventually become more severe. To date, there is no effective treatment for the cause of Alzheimer's disease, and the existing pharmacological options primarily help manage symptoms. Treatment is mainly based on acetylcholinesterase (AChE) inhibitors such as donepezil, rivastigmine, and galantamine, which exhibit numerous adverse cardiovascular and gastrointestinal effects due to excessive stimulation of peripheral cholinergic activity involving muscarinic receptors. Therefore, in addition to the obvious drugs that act on the cause of the disease, new drugs based on AChE inhibition that show the fewest side effects are needed. One potential drug could be a new compound under study, tetrahydroacridine derivative (CHDA), which showed significant potential to inhibit the AChE enzyme in previous in vitro studies. The present study shows that while having very potent AChE inhibitory properties, CHDA is a compound with low toxicity to nerve cell culture and living organisms. In addition, it exhibits dissociative activity against amyloid β fibrils, which is extremely important for applications in Alzheimer's disease therapy.

Efficacy and safety of SKCPT in patients with knee osteoarthritis: A multicenter, randomized, double-blinded, active-controlled phase III clinical trial

Ethnopharmacological relevanceOsteoarthritis (OA) is the most prevalent type of arthritis worldwide and a leading cause of years lost to pain and disability. Among the current pharmacological treatments for OA, symptomatic slow-acting drugs for OA (SYSADOA) induce pain relief and aim to improve joint function by relieving inflammation while causing fewer gastrointestinal and cardiovascular adverse events than non-steroidal anti-inflammatory drugs (NSAIDs). SKCPT is a herbal SYSADOA formulated from Clematis mandshurica, Trichosanthes kirilowii, and Prunella vulgaris powdered extracts. This preparation has been shown to induce cartilage protection and anti-inflammatory effects in preclinical studies and inhibit glycosaminoglycan degradation and catabolic gene expression in human OA chondrocytes and cartilage. Aim of the studyWe aimed to evaluate the non-inferiority of SKCPT to celecoxib and safety for treating knee OA. Materials and methodsThis multicenter, randomized, double-blind, phase III clinical trial enrolled adults with primary knee OA who were randomized (1:1) to SKCPT 300 mg twice daily or celecoxib 200 mg once daily for 12 weeks. ResultsIn total, 278 patients were assigned to treatment (SKCPT, 136; celecoxib, 142) for approximately 12 weeks. The primary endpoint was the mean change of Korean Western Ontario and McMaster Universities Osteoarthritis Index (K-WOMAC) pain subscale scores from baseline to Day 84. The mean change (least squares [LS] mean ± standard error) from baseline to Day 84 was −23.74 ± 1.48 for SKCPT and −25.88 ± 1.44 for celecoxib. The two-sided 95% confidence interval of the difference (LS mean) between groups was [−1.94, 6.20], confirming that the upper limit was less than the non-inferiority margin of 10. Additionally, there were no significant differences in the secondary endpoints (mean changes of K-WOMAC pain, physical, stiffness subscale, and total score, and the frequency and number of doses of rescue medications) between groups at all time points. Differences between groups in adverse events and adverse drug reactions were not significant, and no serious adverse events occurred. ConclusionsSKCPT efficacy was non-inferior, and its safety profile was similar, to celecoxib. Building on previous results showing that SYSADOA reduce NSAID intake, the present results suggest that the SYSADOA SKCPT could effectively replace NSAIDs in knee OA treatment while avoiding long-term side effects.

Stratified analysis of the association between anti-obesity medications and digestive adverse events: a real-world study based on the FDA adverse event reporting system database

BackgroundNumerous digestive system adverse events (dsAEs) have been observed during the use of anti-obesity medications (AOMs), leading to concerns about the safety of these medications. However, most current studies are limited to the association of one class of drugs with specific digestive disorders, and there is no cascading analysis of AOMs in the digestive system. This study aims to use data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) for a stratified analysis of the reported associations between AOMs and dsAEs.MethodsWe analyzed adverse event reports submitted to FAERS between January 2015 and December 2023 related to obesity treatment. It is important to note that FAERS data cannot establish causality or incidence rates. Pharmacovigilance (PV) signals were detected by disproportionate analyses through proportionate reporting ratio (PRR), reporting odds ratios (ROR), and information components (IC) to detect dsAEs associated with AOMs. Reporting rates, severity, and response outcomes of digestive adverse events were compared across AOMs by multivariate logistic regression analysis.ResultsAmong 34,396 adverse events (AEs) related to obesity treatment, 8844 dsAEs were analyzed. Comparing with semaglutide and liraglutide, tirzepatide exhibited fewer reported dsAEs while semaglutide and liraglutide showed a high correlation with non-lethal pancreatitis reports. Bupropion-naltrexone (31.65%) reported the highest number of dsAEs, and a PV signal was detected in mouth and lips AEs (ROR = 2.97, 95% CI: 2.42–3.6). Orlistat (ROR = 3.30, 95% CI: 3.08–3.55) exhibited the highest association with gastrointestinal AEs compared to other AOMs. PV signal for hepatobiliary AEs (ROR = 6.13, 95% CI: 3.45–10.88) with phentermine-topiramate still needs further clarification.ConclusionsTirzepatide may be considered for patients with a history of digestive system disease or an elevated risk of pancreatitis based on the pattern of reported dsAEs. Caution is needed for the orofacial AEs when using bupropion-naltrexone. Orlistat has a higher reporting rate of gastrointestinal AEs, but these events are typically less severe. Phentermine-topiramate’s association with liver impairment requires further clinical investigation. This article provides insights into the reported associations between AOMs and dsAEs, which may aid clinicians in making more informed decisions about individualizing medication and managing potential adverse events.

Multiple Gastrointestinal Immune-Related Adverse Events From Immune Checkpoint Inhibitor Therapy.

We aimed to describe immune-related adverse events (irAEs) affecting multiple organs of the gastrointestinal system in patients who received immune checkpoint inhibitors. Within a 2,843 patient retrospective cohort consisting of patients with cancer treated with immune checkpoint inhibitors, we used the Electronic Medical Record Search Engine, an information retrieval system, to search free text in the medical record to identify patients with multiple gastrointestinal irAEs. Thirteen patients developed multiple gastrointestinal irAEs (0.46%). The most common patterns of multisystem gastrointestinal irAE were colitis + pancreatitis and colitis + enteritis. Multisystem gastrointestinal irAEs are rare but warrant further characterization and attention.

Liraglutide for Children 6 to

No medications are currently approved for the treatment of nonmonogenic, nonsyndromic obesity in children younger than 12 years of age. Although the use of liraglutide has been shown to induce weight loss in adults and adolescents with obesity, its safety and efficacy have not been established in children. In this phase 3a trial, which consisted of a 56-week treatment period and a 26-week follow-up period,we randomly assigned children (6 to <12 years of age) with obesity, in a 2:1 ratio, to receive either once-daily subcutaneous liraglutide at a dose of 3.0 mg (or the maximum tolerated dose) or placebo, plus lifestyle interventions. The primary end point was the percentage change in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters). The confirmatory secondary end points were the percentage change in body weight and a reduction in BMI of at least 5%. A total of 82 participants underwent randomization; 56 were assigned to the liraglutide group and 26 to the placebo group. At week 56, the mean percentage change from baseline in BMI was -5.8% with liraglutide and 1.6% with placebo, representing an estimated difference of -7.4 percentage points (95% confidence interval [CI], -11.6 to -3.2; P<0.001). The mean percentage change in body weight was 1.6% with liraglutide and 10.0% with placebo, representing an estimated difference of -8.4 percentage points (95% CI, -13.4 to -3.3; P = 0.001), and a reduction in BMI of at least 5% occurred in 46% of participants in the liraglutide group and in 9% of participants in the placebo group (adjusted odds ratio, 6.3 [95% CI, 1.4 to 28.8]; P = 0.02). Adverse events occurred in 89% and 88% of participants in the liraglutide and placebo groups, respectively. Gastrointestinal adverse events were more common in the liraglutide group (80% vs. 54%); serious adverse events were reported in 12% and 8% of participants in the liraglutide and placebo groups, respectively. Among children (6 to <12 years of age) with obesity, treatment with liraglutide for 56 weeks plus lifestyle interventions resulted in a greater reduction in BMI than placebo plus lifestyle interventions. (Funded by Novo Nordisk; SCALE Kids ClinicalTrials.gov number, NCT04775082.).

Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial

Most patients with myelofibrosis develop ruxolitinib intolerance or disease that is relapsed or refractory, and survival rates after ruxolitinib discontinuation are poor. We aimed to evaluate the safety and efficacy of fedratinib versus best available therapy (BAT) in patients with myelofibrosis previously treated with ruxolitinib. FREEDOM2 was a multicentre, open-label, randomised, controlled, phase 3 trial in 86 clinics in 16 countries, in which patients aged at least 18 years with intermediate-2 or high-risk myelofibrosis that was relapsed or refractory or intolerant to ruxolitinib with Eastern Cooperative Oncology Group performance status 0-2 were stratified by spleen size by palpation, platelet count, and previous ruxolitinib treatment, and randomly assigned 2:1 by interactive response technology to receive fedratinib 400 mg per day (4 × 100 mg capsules orally once daily, open-label) or BAT. Patients received prophylactic antiemetics and thiamine supplementation, and symptomatic antidiarrhoeals as required. Primary endpoint was proportion of patients reaching spleen volume reduction (SVR) of at least 35% (SVR35) at end of cycle 6 in the intention-to-treat population. This manuscript reports the primary analysis of the trial; follow-up is ongoing. This trial is registered at clinicaltrials.gov, NCT03952039. Between Sept 9, 2019 and June 24, 2022, of 316 patients screened, 201 were randomly assigned and treated (134 to fedratinib, 67 to BAT [including 52 receiving ruxolitinib]); 46 patients from the BAT group crossed over to fedratinib. Approximately half of enrolled patients were male (fedratinib 75 [56%] of 134; BAT 30 [45%] of 67) and most were White (fedratinib 106 [79%] of 134; BAT 58 [87%] of 67). At data cutoff (Dec 27, 2022), median survival follow-up was 64·5 weeks (IQR 37·9-104·9). SVR35 at end of cycle 6 was seen in 48 (36%) of 134 patients receiving fedratinib versus four (6%) of 67 patients receiving BAT (30% difference; 95% CI 20-39; one-sided p-value <0·0001). During the first six cycles 53 (40%) of 134 patients in the fedratinib group and 8 (12%) of 67 patients in the BAT group had grade 3 or greater treatment-related adverse events, most frequently anaemia (fedratinib 12 [9%] of 134; BAT 6 [9%] of 67) and thrombocytopenia (fedratinib 16 [12%] of 134; BAT 2 [3%] of 67); one patient in the fedratinib group died from acute kidney injury suspected to be related to study drug (no treatment-related deaths in the BAT group). Gastrointestinal adverse events occurred more frequently in the fedratinib group compared with the BAT group, but were mostly grade 1-2 in severity and more frequent in early cycles, and were less frequent than in prior clinical trials. A total of 28 (21%) of 134 patients in the fedratinib group and 3 (4%) of 67 patients in the BAT group had thiamine levels below lower limit of normal per central laboratory assessment, with only one case of low thiamine in the fedratinib arm after the introduction of prophylactic thiamine supplementation. Findings from FREEDOM2 support fedratinib as a second-line Janus kinase inhibitor option to reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis, and shows effective strategies for management of gastrointestinal adverse events and low thiamine concentrations through prophylaxis, monitoring, and treatment. Bristol Myers Squibb.

Gastrointestinal adverse effects associated with the use of isotretinoin in the management of acne vulgaris

Introduction: Isotretinoin is widely used in the treatment of moderate to severe acne vulgaris due to its proven efficacy. However, the use of this medication is associated with several adverse effects, including gastrointestinal symptoms. The possible association with inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis remains a subject of debate. Methods: A systematic review of the literature was performed in the PubMed, Embase and Cochrane Library databases, covering studies published from 2000 to 2024. The inclusion criteria considered randomized clinical trials, cohort studies, case-control studies and systematic reviews that reported gastrointestinal adverse effects related to the use of isotretinoin. The assessment of methodological quality was performed using the GRADE system, and the data were extracted independently by two reviewers. Results: The review found that mild gastrointestinal side effects, such as abdominal pain, nausea, and dyspepsia, are relatively common during isotretinoin treatment and tend to be transient and manageable. The association with inflammatory bowel disease remains unclear, with some studies indicating an increased risk, while others found no significant correlation. Risk factors such as high dose, prolonged duration of treatment, and history of previous gastrointestinal disease were associated with an increased likelihood of adverse effects. Conclusion: Although isotretinoin remains an effective treatment for acne vulgaris, its use should be accompanied by close monitoring, especially in patients with identified risk factors. A personalized approach is essential to maximize benefits and minimize risks. Future research should focus on identifying predictive risk factors to optimize treatment safety.

Histopathological lesions of the gastrointestinal tract associated with the use of polystyrene sulfonate and sevelamer: a meta-analysis.

Gastrointestinal severe adverse events such as ulceration and perforation have been reported for sodium or calcium polystyrene sulfonate and sevelamer. Howewer, their role in the pathogenesis is unclear. Chronic kidney disease is a well known risk factor, while the role of hypertension and/or diabetes is uncertain. A meta-analysis of the published literature was conducted to review the clinical features, risk factors and histopathological findings of patients who experienced gastrointestinal adverse events after administration of polystyrene sulfonate or sevelamer. The meta-analysis indicated that patients were more likely to show necrosis and/or perforation when the resin used was polystyrene sulfonate compared to sevelamer (p < 0.001). Death was more likely in patients taking polystyrene sulfonate compared to sevelamer (p < 0.001). The results show that sevelamer is more likely to lead to inflammation or ulceration in the gastrointestinal tract than polystyrene sulfonate, which is more likely to be associated with severe gastrointestinal adverse events such as necrosis and/or perforation. Polystyrene sulfonate is significantly associated with death compared to sevelamer.

Effectiveness and safety of semaglutide in overweight/obese adults with or without type 2 diabetes: A systematic review and meta-analysis

Background: The objective of the study was to systematically evaluate the efficacy and safety of semaglutide in overweight or obese adults with or without type 2 diabetes. Materials and Methods: The study, registered with PROSPERO (CRD42023450979), was designed as a systematic review and meta-analysis. Using a combination of subject matter and free words, a comprehensive search of Embase, PubMed, and Cochrane Library databases was performed to identify randomized controlled trials of semaglutide in overweight or obese adults with or without Type 2 diabetes mellitus from January 1, 2020, to July 14, 2023. The primary outcomes were the changes in body weight and adverse drug reaction (ADR). Random or fixed effects models were used in meta-analysis, pooling data as relative risks (RRs) or mean difference (MD) with 95% confidence intervals (CIs). Cochrane Collaboration’s Risk of Bias tool was used to assess quality. Meta-analysis was performed using RevMan 5.3. Results: A total of 2490 publications were retrieved. Fifteen publications were finally included, totaling 6984 overweight or obese adult patients. Meta-analysis showed that compared with the control group, the semaglutide group was reduced more significantly in body weight (MD = −7.49, 95% CI [−9.92, −5.07], P &lt; 0.001), body mass index (MD = −3.35, 95% CI [−4.79, −1.92], P &lt; 0.001), waist circumference (MD = −7.26, 95% CI [−9.94, −4.58], P &lt; 0.001), as well as glycosylated hemoglobin (RR = −0.66, 95% CI [−1.07, −0.25], P = 0.002), fasting blood glucose values (RR = −4.81, 95% CI [−7.03, −2.60], P &lt; 0.001), and systolic blood pressure (RR = −3.37, 95% CI [−5.32, −1.42], P &lt; 0.001), and the proportion of patients who lost &gt; 5%, 10%, 15%, and 20% of their overall body weight, respectively (RR = 3.19, 95% CI [1.89, 5.36], P &lt; 0.001), (RR = 4.74, 95% CI [2.78, 8.11], P &lt; 0.001), (RR = 6.17, 95% CI [3.88, 9.82], P &lt; 0.001), and (RR = 9.14, 95% CI [6.05, 13.80], P &lt; 0.001) were also superior to the control group. Regarding safety, the incidence of total ADR in the semaglutide group was close to the placebo group. Still, gastrointestinal adverse effects such as nausea, vomiting, abdominal pain, and diarrhea were higher than those in the control group. Conclusion: Semaglutide can effectively lose weight in overweight or obese adults with or without diabetes, potentially providing cardiovascular benefits; however, gastrointestinal adverse should be closely monitored.

Adverse event reporting of combining SGLT2 inhibitor and GLP1 receptor agonist: a real-world study from FAERS

Background and AimsWe evaluate whether the combination of sodium-glucose cotransporter-2 inhibitor(SGLT2i) and glucagon-like peptide-1 receptor agonist(GLP1RA) disproportionally increases the reporting of adverse events compared with SGLT2i or GLP1RA monotherapy in the FDA adverse event reporting system (FAERS). Methods and ResultsAdverse events related to SGLT2i and GLP1RA were screened and selected, then data from the FAERS was underwent thorough disproportionality analysis. The proportional reporting ratio(PRR) of SGLT2i-related adverse events were compared between patients using SGLT2i alone and those using both SGLT2i and GLP1RA. Similarly, the PRR of GLP1RA-related adverse events were compared between patients using GLP1RA alone and those using both SGLT2i and GLP1RA. The results showed that the PRR of SGLT2i-related adverse events including diabetic ketoacidosis(DKA), ketosis, reproductive tract adverse events, urinary tract infection, and other adverse events, decreased in individuals using both SGLT2i and GLP1RA compared with those using SGLT2i alone, and the signal of fracture was not detected. Likewise, the PRR of GLP1RA-related adverse events including gastrointestinal adverse events, gallbladder and biliary tract disease, pancreatitis, and other adverse events, decreased in individuals using both SGLT2i and GLP1RA compared with those using GLP1RA alone, the PRR of hyperlipasaemia and hyperamylasaemia increased in the combination therapy and no signal of depression, suicidal and self-injurious behaviour was detected. ConclusionAdverse events reporting are not disproportionally higher among those using both SGLT-2i and GLP1RA compared with SGLT2i or GLP1RA monotherapy.

Gastrointestinal adverse events associated with use of biologic therapies available for psoriasis: A systematic review of pharmacovigilance studies

Gastrointestinal adverse events associated with use of biologic therapies available for psoriasis: A systematic review of pharmacovigilance studies

Inadequate Evidence for Acupuncture as an Alternative or Adjunct to Antidepressants/Psychotherapy for Postpartum Depression: A Bayesian Systematic Review and Network Meta-Analysis.

Acupuncture is popular in the treatment of mental illness. This study determined its feasibility and role in managing postpartum depression (PPD) using a network meta-analysis. We systematically searched seven databases up to May 2024 for randomized controlled trials (RCTs) appraising acupuncture's efficacy and safety against waitlist-control, placebo, standard control, or as an add-on treatment. Cochrane criteria were followed. Thirteen studies encompassing 872 participants underwent analysis. Both pairwise and network meta-analysis indicated that acupuncture, psychotherapy, and antidepressants were comparable in clinical efficacy rate and in reducing Hamilton Depression Scale and Edinburgh Postnatal Depression Scalescores. Acupuncture and psychotherapy also effectively mitigated concurrent anxiety symptoms. Combining acupuncture with antidepressants augmented therapeutic efficacy and reduced reported gastrointestinal adverse effects associated with antidepressant use. Acupuncture combined with psychotherapy offered similar benefits with superior safety profile. However, the quality of evidence ranged from very low to low due to significant risks of bias and limited sample sizes. The efficacy of psychotherapy and the combination of acupuncture and psychotherapy might be underestimated, as most RCTs used supportive therapy or individual counseling as positive controls instead of recommended approaches like interpersonal psychotherapy (IPT) or cognitive behavioral therapy (CBT) per PPD guidelines. Current evidence precludes strong recommendations of administering acupuncture in PPD. Rigorous RCTs are essential to validate promising outcomes observed in comparisons between acupuncture, antidepressants, and their combined application. It remains inconclusive whether acupuncture's antidepressive effect is specific or non-specific. Given that psychotherapy is a recommended first-line treatment, investigating the potential efficacy enhancement of combining acupuncture with IPT/CBT is paramount to ascertain the preferred therapeutic approach for PPD.

Endoscopic findings of immune checkpoint inhibitor-related gastrointestinal adverse events.

The use of immune checkpoint inhibitors (ICIs) for the treatment of various malignancies is increasing. Immune-related adverse events can occur after ICI administration, with gastrointestinal adverse events constituting a significant proportion of these events. When ICI-related diarrhea/colitis is suspected, endoscopic evaluation is recommended to differentiate it from other etiologies and assess the severity of colitis. The distribution of intestinal inflammation in ICI-related colitis demonstrates a high frequency of extensive colitis (23-86%). However, isolated right-sided colitis (3-8%) and ileitis (2-16%) are less prevalent. Endoscopic findings vary and predominantly encompass features indicative of inflammatory bowel disease, including aphthae, ulcers, diffuse or patchy erythema, mucosal edema, loss of vascular pattern, and friability. The presence of ulcers and extensive intestinal inflammation are associated with a reduced response to treatment. Microscopic inflammation can be observed even in endoscopically normal mucosa, underscoring the need for biopsies of seemingly normal mucosa. Histological findings present with acute/chronic inflammation and occasionally exhibit characteristics observed in inflammatory bowel disease, microscopic colitis, or ischemic colitis. The first-line therapeutic choice for ICI-related diarrhea/colitis with a common terminology criteria for adverse events grade of 2 or above is corticosteroids, whereas infliximab and vedolizumab are recommended for refractory cases.

Janus kinase inhibitors and tumour necrosis factor inhibitors show a favourable safety profile and similar persistence in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: real-world data from the BIOBADASER registry

ObjectivesTo compare the safety of Janus kinase inhibitors (JAKi) with that of tumour necrosis factor inhibitors (TNFi) and determine drug persistence among patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).MethodsWe...

A comprehensive assessment of the association between common drugs and psychiatric disorders using Mendelian randomization and real-world pharmacovigilance database

Medications prescribed for chronic diseases can lead to short-term neuropsychiatric symptoms, but their long-term effects on brain structures and psychiatric conditions remain unclear. We comprehensively analyzed the FDA Adverse Event Reporting System database and conducted drug target Mendelian Randomization (MR) studies on six categories of common drugs, 477 brain imaging-derived phenotypes (IDPs) and eight psychiatric disorders. Genetic instruments were extracted from expression quantitative trait loci (eQTLs) in blood, brain, and other target tissues, protein quantitative trait loci (pQTLs) in blood, and genome-wide association studies (GWAS) of hemoglobin and cholesterol. Summary statistics for brain IDPs, psychiatric disorders, and gut microbiome were obtained from the BIG40, Psychiatric Genomics Consortium, and MiBioGen. A two-step MR and mediation analysis were employed to screen possible mediators of drug-IDP effects from 119 gut microbiota genera and identify their mediation proportions. Among 19 drug classes, six drugs were found to be associated with higher risks of psychiatric adverse events, while 11 drugs were associated with higher risks of gastrointestinal adverse events in the FAERS analysis. We identified ten drug-psychiatric disorder associations, 202 drug-IDP associations, 16 drug-microbiota associations, and four drug-microbiota-IDP causal links. For example, PPARG activation mediated HbA1c reduction caused a higher risk of bipolar disorder (BD) II. Genetically proxied GLP-1R agonists were significantly associated with an increase in the volume of the CA3-head of the right hippocampus and the area of the left precuneus cortex, both of which have been shown to correlate with cognition in previous studies. Common drugs may affect brain structure and risk of psychiatric disorder. Oral medications in particular may exert some of these effects by influencing gut microbiota. This study calls for greater attention to be paid to the neuropsychiatric adverse effects of drugs and encourages drug repurposing. National Natural Science Foundation of China (grant No. 82330035, 82130043, 82172685, and 82001223), National Natural Science Foundation of Hunan Province (grant No. 2021SK1010), and the Science Foundation for Distinguished Young Scholars of Changsha (grant No. kq2209006).

Effect of antiemetics on zolbetuximab-induced gastric injury and emesis in ferrets

Claudin-18 splice variant 2 (CLDN18.2), a tight junction protein, is a highly cell type–specific antigen that is expressed by differentiated gastric mucosa cells. The expression of CLDN18.2 in gastric mucosa cells may be retained upon malignant transformation and is displayed on the surface of several tumors, including gastric/gastroesophageal junction adenocarcinoma. Zolbetuximab is a genetically engineered, highly purified chimeric (mouse/human IgG1) antibody directed against CLDN18.2. Nausea and vomiting were observed as adverse events of zolbetuximab. To investigate the mechanism of nausea and vomiting in humans, we evaluated emesis (retching and vomiting) and conducted histopathologic assessment in ferrets after the administration of zolbetuximab. Emesis was frequently observed in all ferrets treated with zolbetuximab in the first hour after administration. Histopathologic assessment revealed the surface of the gastric mucosa was the primary site of emesis-associated tissue damage. The effect of antiemetics (dexamethasone, ondansetron, fosaprepitant, and olanzapine) on emesis induced by zolbetuximab was investigated. Fosaprepitant showed suppressive effects on emesis, and use of dexamethasone or concomitant use of fosaprepitant with other antiemetics tended to alleviate gastric tissue damage. The onset of emesis in humans receiving zolbetuximab may be associated with damage in the gastric mucosa, and antiemetics may mitigate gastrointestinal adverse events.

Efficacy and safety of Resmetirom, a selective thyroid hormone receptor-β agonist, in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD): a systematic review and meta-analysis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity and mortality secondary to progressive liver disease and cardiovascular events. Resmetirom, a selective thyroid hormone receptor-β agonist has been developed as a therapeutic modality for MASLD. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of resmetirom compared to a placebo in the treatment of MASLD. Eligible studies were systematically identified by screening PubMed, Scopus, Web of Science, Cochrane library, Embase, and ClinicalTrials.gov from 2014 to 2024. Only randomized controlled trials comparing the efficacy and safety of resmetirom in the treatment of MASLD against placebo were included in the analysis. Meta-analysis was performed using RevMan 5.4 software. Four studies with low risk of bias and involving a total of 2359 participants were identified. The metanalysis included only three clinical trials with 2234 participants. A significant reduction in MRI-proton density fat fraction (MRI-PDFF) with 80 mg Resmetirom compared to that with placebo [SMD − 27.74 (95% CI − 32.05 to − 32.42), p < 0.00001] at 36–52 weeks as well as at 12–16 weeks [SMD − 30.92 (95% CI − 36.44 to − 25.40), p < 0.00001]. With Resmetirom 100 mg dose at 36–52 weeks [SMD − 36.05 (95% CI − 40.67 to − 31.43), p < 0.00001] and 12–16 weeks [SMD − 36.89 (95% CI − 40.73 to − 33.05), p < 0.00001] were observed. Resmetirom treatment was associated with a significant reduction in LDL-c triglyceride, lipoproteins. and liver enzymes. There was significant reduction FT4 and increase in SHBG and sex steroids with Resmetirom compared to placebo. There was no major difference in the overall treatment emergent adverse events at 80 mg [OR 1.55 (95% CI 0.84 to 2.87), and 100 mg [OR 1.13 (95% CI 0.78 to 1.63), doses of Resmetirom compared to placebo. However, gastrointestinal adverse events diarrhoea and nausea occurred in ≥ 10% in the Resmetirom group compared to placebo at < 12 week. Resmetirom treatment showed modest efficacy in treating MASLD with reduction in MRI-PDFF, LDL-c, triglyceride, lipoproteins, liver enzymes and NASH biomarkers without significant safety concerns. Larger and long-term RCTs may further confirm this promising outcomes of Resmetirom use in MASLD.

PIONEER REAL Japan: Primary results from a multicenter, prospective, real-world study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice.

PIONEER REAL Japan was a non-interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice. Adults naïve to injectable glucose-lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34-44 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study; the co-primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged <75 and ≥75 years. A total of 624 participants initiated oral semaglutide; 578 completed the study. Mean baseline HbA1c and bodyweight were 7.7% and 72.4 kg, respectively. At end of study, estimated change (95% confidence interval [CI]) in HbA1c from baseline was -0.7 percentage points (-0.77, -0.61) overall, -0.8 percentage points (-0.86, -0.67) in the <75 years subgroup and -0.5 percentage points (-0.68, -0.41) in the ≥75 years subgroup (all P < 0.0001). Estimated change (95% CI) in bodyweight was -2.8 (-3.19, -2.50) kg overall, -2.9 (-3.38, -2.49) kg in the <75 years subgroup and - 2.7 (-3.18, -2.14) kg in the ≥75 years subgroup (all P < 0.0001). AEs occurred in 161 (25.8%) participants: 99 of 423 (23.4%) and 62 of 201 (30.8%) participants in the <75 and ≥75 years subgroups, respectively. Gastrointestinal AEs were the AEs most frequently leading to oral semaglutide discontinuation. In routine clinical practice, HbA1c and bodyweight were significantly reduced from baseline in adults initiating oral semaglutide, including those aged ≥75 years, with no new safety concerns.

Potential of phosphodiesterase 4B inhibitors in the treatment of interstitial lung disease associated with autoimmune diseases.

Patients with autoimmune disease-related interstitial lung disease may develop pulmonary fibrosis, which may become progressive. Progressive pulmonary fibrosis (PPF) is associated with poor outcomes. Antifibrotic therapies have shown efficacy as treatments for PPF in patients with autoimmune diseases, but new treatments are needed to slow or halt disease progression. Phosphodiesterases (PDEs) are enzymes that mediate the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Pre-clinical data suggest that preferential inhibition of PDE4B has the potential to slow the progression of pulmonary fibrosis by inhibiting inflammatory and fibrotic pathways, with a lower risk of gastrointestinal adverse events than associated with pan-PDE4 inhibitors. Nerandomilast (BI 1015550) is a preferential PDE4 inhibitor that has demonstrated anti-inflammatory and antifibrotic effects in pre-clinical studies. In a phase II trial in patients with idiopathic pulmonary fibrosis, nerandomilast (given alone or on top of background antifibrotic therapy) prevented a decrease in lung function over 12 weeks with an acceptable safety and tolerability profile. The phase III FIBRONEER-ILD trial is evaluating the efficacy and safety of nerandomilast, given alone or on top of nintedanib, in patients with PPF, including PPF associated with autoimmune diseases. In this article, we review the potential of PDE4B inhibition in the treatment of ILD associated with autoimmune diseases, including the pre-clinical and early clinical data available to date.

Novel anti-inflammatory agents featuring phenoxy acetic acid moiety as a pharmacophore for selective COX-2 inhibitors: Synthesis, biological evaluation, histopathological examination and molecular modeling investigation

Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein–ligand interactions at COX-2 active sites indicative of therapeutic potential.