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Background Although often overlooked, drug-induced pancreatitis is a frequent cause of pancreatitis. Pancreatic drug toxicity is defined according to the classification by Mallory et al . and Trivedi et al . Isotretinoin is only classified as possibly toxic to the pancreas (class 3). We report the first case of recurrence of pancreatitis after rechallenge, which argues for a modification of the classification of drug-induced pancreatitis. Case presentation We present here the case of a 20-year-old Belgian man who suffered several episodes of acute pancreatitis for which no etiology could be identified despite an exhaustive assessment. Eventually, as a precaution, isotretinoin was discontinued and there was no recurrence until it was reintroduced. Conclusion This is the 25th case described in the literature, but the first with a positive rechallenge on two occasions. This case therefore implies that isotretinoin should definitely be considered a class 1 toxic drug for the pancreas and should be incriminated in acute pancreatitis in patients treated with this drug.

Background Limited data are available on the risk of pancreatic adverse events among people with obesity or type 2 diabetes mellitus (T2DM) initiating glucagon-like peptide-1 receptor agonist (GLP-1 RA). Methods Retrospective study utilizing data from a federated research network (TriNetX). Adult people (≥ 18 years) with a diagnosis of obesity (body mass index ≥ 30 kg/m 2 ) or T2DM (ICD-10-CM: E11) between 2018 and 2024 were subdivided in two mutually exclusive cohorts: (1) GLP-1 RA Users; and (2) Non–GLP-1 RA Users. Primary outcomes were 1-year risk of all-cause death and a composite outcome (acute pancreatitis, chronic pancreatitis). Secondary outcomes included the individual components of the composite outcome and pancreatic cancer. Cox regression analyses were employed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) before and after 1:1 propensity score matching (PSM). Sensitivity analyses stratified follow-up into early (first 6 months) and late (last 6 months) phases. Subgroup analyses were performed based on age (≥ 65 or < 65 years), sex, and the history of smoking and alcohol use, hypertriglyceridemia, cholelithiasis, heart failure, and chronic kidney disease. Results We identified 1,562,626 people who initiated treatment with GLP-1 RA (mean age 55.3 ± 14.0 years; 59.2% female) and 18,652,572 those who did not (mean age 50.6 ± 18.7 years; 54.5% female). Before PSM, GLP-1 RA Users were older, more frequently female, and exhibited a higher burden of endocrine, metabolic and gastrointestinal disorders. After PSM, GLP-1 RA use was associated with a substantially lower risk of all-cause death (HR 0.554, 95% CI 0.542–0.566), and small increased risk of the composite outcome (HR 1.062, 95% CI 1.023–1.102) and acute pancreatitis (HR 1.058, 95% CI 1.015–1.103), with no differences in chronic pancreatitis or pancreatic cancer. The excess risk of acute pancreatitis was more pronounced during the early phase of follow-up (first 6 months). Subgroup analyses showed a higher reduction in death and composite outcome among people aged < 65 years. Additional significant interactions were observed for all-cause death in females and in people with a history of smoking, alcohol use, heart failure, chronic kidney disease, or cholelithiasis. Conclusion GLP-1 RA use was associated with substantially reduced all-cause death but a small increased risk of acute pancreatitis, particularly during early treatment. The survival benefit was more pronounced in younger people and those with cardiometabolic comorbidities, highlighting the need for a careful risk–benefit evaluation when prescribing GLP-1 RAs in high-risk individuals.

Background Acute pancreatitis is rarely seen in children, and, in contrast to cases in adults, it is often drug induced. One possible medication is the antiepileptic drug valproic acid (VPA), which is commonly prescribed for generalized and focal epilepsy, migraine, neuropathic pain, and bipolar disorder. The common side effects associated with VPA are typically benign, but less common but more serious adverse effects may occur. These include hepatotoxicity, hyperammonemic encephalopathy, coagulation disorders, and pancreatitis. Since 1979, a few cases of pancreatitis induced by VPA have been published in the medical literature. Methods We mailed a questionnaire to all members of the “German Section of the International League against Epilepsy,” asking about VPA-induced side effects. We also reviewed the medical literature for VPA-induced pancreatitis. Results Fifty-three publications (90 patients) published from 1979 to 2005 were found. Our survey in Germany, however, yielded 16 cases of pancreatitis from 1994 to 2003 whose original files we could study in detail. None of these patients had been published previously. Conclusions The difference between 90 patients reported worldwide from 1979 to 2005 and the 16 new documented cases from only Germany over 10 years corroborates that the occurrence of this severe side effect is under reported.

Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia–reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia–reperfusion injury model, the high-dose TNF model, and in A20 −/− mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia–reperfusion injury model and no benefit in A20 −/− mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.

Saxagliptin, a new oral antihyperglycemic drug in the DPP-4 inhibitor class, had no effect on the risk of cardiovascular events in patients with type 2 diabetes. Although the drug does not increase cardiovascular risk, it also does not provide cardiovascular benefit. Type 2 diabetes mellitus doubles the risk of major cardiovascular complications in patients with and in patients without established cardiovascular disease, 1 – 3 such that the majority of patients with diabetes die of cardiovascular diseases. 4 Although improved glycemic control has repeatedly been shown to reduce microvascular diabetic complications, 5 uncertainty remains regarding whether any particular glucose-lowering strategy, or specific therapeutic agent, is safe from a cardiovascular standpoint or can actually lower cardiovascular risk. With the possible exception of trials of metformin 6 and insulin, 7 most reported trials to date evaluating the effects on cardiovascular outcomes of specific glucose-lowering strategies or medications either have . . .

In two randomized trials, eluxadoline was more effective than placebo in reducing abdominal pain and improving stool consistency in patients who had irritable bowel syndrome with diarrhea. Pancreatitis developed in 5 of 1666 patients (0.3%) who received eluxadoline. The irritable bowel syndrome (IBS) with diarrhea is a common functional gastrointestinal disorder that is characterized by recurring abdominal pain, bloating, and loose, frequent stools in the absence of structural, inflammatory, or biochemical abnormalities. IBS with diarrhea is associated with impairment in health-related quality of life, places a considerable financial burden on society because of reduced work productivity, and increases the use of health-related resources. 1 , 2 IBS is the most frequent diagnosis in gastroenterology practices and one of the most frequent diagnoses in primary care practices. 3 Current treatment options for IBS with diarrhea are limited. Initial therapies include dietary and . . .

After evaluating a safety signal regarding pancreatitis and pancreatic cancer in patients using incretin-based drugs, the Food and Drug Administration and the European Medicines Agency conclude that assertions of a causal association are inconsistent with the data. With approximately 25.8 million diabetic patients in the United States and 33 million in the European Union alone, the growing prevalence of diabetes worldwide poses a major public health challenge. Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are committed to ensuring the safety of drug products marketed for the treatment of diabetes, and postmarketing reports of pancreatitis and pancreatic cancer in patients taking certain antidiabetic medications have been of concern to both agencies. Working in parallel, the agencies have reviewed nonclinical toxicology studies, clinical trial data, and epidemiologic data pertaining to blood glucose–lowering . . .

Background. Chronic pancreatitis is one of the main risk factors for pancreatic cancer. In acute and chronic pancreatitis, oxidative stress is thought to play a key role. In this respect, the recently described mitochondria-targeted antioxidant SkQ1 effectively scavenges reactive oxygen species at nanomolar concentrations. Therefore, we aimed to characterize the influence of SkQ1 on tissue injury and pain in acute and chronic pancreatitis. Methods. Both acute and chronic pancreatitis were induced in C57BL/6 mice by intraperitoneal cerulein injections and treatment with SkQ1 was carried out by peroral applications. Hyperalgesia was assessed by behavioral observation and measurement of abdominal mechanical sensitivity. Blood serum and pancreatic tissue were harvested for analysis of lipase and histology. Results. SkQ1 did not influence pain, serological, or histological parameters of tissue injury in acute pancreatitis. In chronic pancreatitis, a highly significant reduction of pain-related behavior ( p < 0.0001 ) was evident, but histological grading revealed increased tissue injury in SkQ1-treated animals ( p = 0.03 ). Conclusion. After SkQ1 treatment, tissue injury is not ameliorated in acute pancreatitis and increased in chronic pancreatitis. However, we show an analgesic effect in chronic pancreatitis. Further studies will need to elucidate the risks and benefits of mitochondria-targeted antioxidants as an analgesic.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

BackgroundAcute kidney injury (AKI) is a frequent complication of severe acute pancreatitis (SAP). Ferroptosis is involved in a range of diseases. However, the role of ferroptosis in SAP-induced AKI has yet to be elucidated.AimsWe aimed to investigate whether ferroptosis is induced in the kidney after SAP and whether inhibition of ferroptosis ameliorates AKI in a rat model of SAP.MethodsSodium taurocholate (5%) was retrogradely perfused into the biliopancreatic duct to establish a model of SAP with AKI in rats. The levels of serum amylase, lipase, tumor necrosis factor (TNF)-α, interleukin (IL)-6, creatinine (Cr) and blood urea nitrogen (BUN) in rats were measured. We also determined the biochemical and morphological changes associated with ferroptosis in renal tissue, including iron accumulation, lipid peroxidation assays, and mitochondrial shrinkage. H&E staining was used to assess pancreatic and renal histological changes. Western blot analysis, RT-PCR, and immunofluorescence staining were performed to analyze the expression of ferroptosis-related proteins and genes.ResultsSAP-induced AKI was followed by iron accumulation, increased lipid peroxidation, and upregulation of ferroptosis-related proteins and genes. Twenty-four hours after SAP, TEM confirmed the presence of typical shrunken mitochondria. Furthermore, treatment with liproxstatin-1 lowered the levels of serum amylase, TNF-α, IL-6, Cr and BUN, decreased kidney lipid peroxidation and alleviated pancreatic and renal histopathology injury in SAP rats.ConclusionOur findings are the first to demonstrate the involvement of ferroptosis in SAP-associated renal damage and present ferroptosis as a therapeutic target for effective treatment of SAP-induced AKI.