orlistat and Pancreatitis

Obesity in adolescents presents many challenges for the patient, family, and physician. The myriad problems involving the GI tract will be managed more effectively when the treating physician has an understanding of the presentations, pathophysiology, appropriate laboratory evaluation, and approaches to treatment for these complications. In addition to being familiar with the pharmacotherapeutic options available, having an approach to behavioral change, such as MI, can be an extremely useful tool.

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Anti-Obesity Agents; Constipation; Contraceptives, Oral, Combined; Diabetes Mellitus, Type 2; Digestive System Diseases; Fecal Incontinence; Gallstones; Gastroesophageal Reflux; Humans; Hypoglycemic Agents; Lactones; Metformin; Non-alcoholic Fatty Liver Disease; Orlistat; Pancreatitis; Pediatric Obesity

Obesity is an important risk factor for severe acute pancreatitis. The necrosis of epididymal adipose tissue occurs in severe acute pancreatitis. Adipose tissue macrophages play an important role in metabolic related inflammation. Therefore, we explored the potential mechanisms between adipose tissue macrophages and obesity-related severe acute pancreatitis.. Severe acute pancreatitis mice model was induced by caerulein with lipopolysaccharide. The severity of severe acute pancreatitis was evaluated according to the morphological, general, and biochemical change. We assessed the injury of epididymal white adipose tissue, pancreas, and adipose tissue macrophages in obese mice and lean mice with severe acute pancreatitis. Outcomes of caerulein-induced severe acute pancreatitis were studied in lean and obese mice with or without lipase inhibitor orlistat.. Fat necrosis and pancreatic injury increased in the SAP groups. High levels of serum free fatty acid and triglyceride were increased significantly in the SAP group. The NLRP3-caspase1 inflammasome signal pathway in adipose tissue macrophages markedly enhanced in the SAP groups compared with control group. Free fatty acid can trigger macrophages inflammation through NLRP3-caspase1. Lipase inhibited by orlistat remarkably decreased in adipose tissue necrosis, and the levels of serum lipase, amylase, and pancreatic tissue damage decreased in the orlistat group compared with the SAP group. The NLRP3-caspase1 inflammasome pathway in adipose tissue macrophages markedly decreased in the orlistat groups compared with SAP group. The levels of serum free fatty acid and triglyceride were decreased significantly in the orlistat group.. Inflammation increases in adipose tissue macrophages of obese mice with severe acute pancreatitis. Free fatty acid generated via adipocyte lipolysis worsens inflammation in adipose tissue macrophages and the outcome of severe acute pancreatitis in obese mice through the NLRP3-caspase1 inflammasome pathway.

Topics: Acute Disease; Adipose Tissue; Animals; Caspase 1; Ceruletide; Fatty Acids, Nonesterified; Inflammasomes; Inflammation; Lipase; Macrophages; Mice; Necrosis; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Orlistat; Pancreatitis; Triglycerides

Visceral fat necrosis has been associated with severe acute pancreatitis (SAP) for over 100 years; however, its pathogenesis and role in SAP outcomes are poorly understood. Based on recent work suggesting that pancreatic fat lipolysis plays an important role in SAP, we evaluated the role of pancreatic lipases in SAP-associated visceral fat necrosis, the inflammatory response, local injury, and outcomes of acute pancreatitis (AP). For this, cerulein pancreatitis was induced in lean and obese mice, alone or with the lipase inhibitor orlistat and parameters of AP induction (serum amylase and lipase), fat necrosis, pancreatic necrosis, and multisystem organ failure, and inflammatory response were assessed. Pancreatic lipases were measured in fat necrosis and were overexpressed in 3T3-L1 cells. We noted obesity to convert mild cerulein AP to SAP with greater cytokines, unsaturated fatty acids (UFAs), and multisystem organ failure, and 100% mortality without affecting AP induction or pancreatic necrosis. Increased pancreatic lipase amounts and activity were noted in the extensive visceral fat necrosis of dying obese mice. Lipase inhibition reduced fat necrosis, UFAs, organ failure, and mortality but not the parameters of AP induction. Pancreatic lipase expression increased lipolysis in 3T3-L1 cells. We conclude that UFAs generated via lipolysis of visceral fat by pancreatic lipases convert mild AP to SAP independent of pancreatic necrosis and the inflammatory response.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Ceruletide; Enzyme Inhibitors; Inflammation; Intra-Abdominal Fat; Lactones; Lipase; Lipolysis; Mice; Mice, Obese; Necrosis; Orlistat; Pancreas; Pancreatitis; Triglycerides

Currently, there is no therapy for severe acute pancreatitis (AP) except for supportive care. The lipase inhibitor orlistat, the peroxisome proliferator-activated receptor γ agonist rosiglitazone, and the chemokine receptor 2 antagonists attenuate the severity of AP in rodents if administered before or at the time of induction of pancreatitis. However, it is unknown whether these treatments are effective if administered therapeutically after induction of pancreatitis.. Male C57BL6 mice with diet-induced obesity received 2 injections of mrIL-12 (150 ng per mouse) and mrIL-18 (750 ng per mouse) intraperitoneally at 24-hour intervals. The mice were injected 2, 24, and 48 hours after the second injection of IL-12 + IL-18 with orlistat (2 mg per mouse), rosiglitazone (0.4 mg per mouse), RS102895 (0.3 mg per mouse), or vehicle (20 μL of DMSO and 80 μL of canola oil) and euthanized after 72 hours.. Orlistat decreased intra-abdominal fat necrosis compared with vehicle (P < 0.05). However, none of the drug treatments produced significant decreases in pancreatic edema, acinar necrosis, or intrapancreatic fat necrosis.. Drugs previously shown to improve the severity of AP when given before or at the time of induction of pancreatitis failed to do so when administered therapeutically in the IL-12 + IL-18 model.

Topics: Acute Disease; Animals; Anti-Obesity Agents; Benzoxazines; Interleukin-12; Interleukin-18; Lactones; Male; Mice, Inbred C57BL; Obesity; Orlistat; Pancreatitis; Piperidines; Receptors, CCR2; Rosiglitazone; Severity of Illness Index; Thiazolidinediones; Treatment Failure; Vasodilator Agents

Orlistat is a pancreatic lipase inhibitor licensed for the treatment of obesity. As obesity rates increase and non-prescription dispensing of orlistat increases, an awareness of its adverse effects is of crucial importance as complications arise more frequently from increased use. Orlistat induced pancreatitis has been described only once previously, but without a diagnostic increase in serum amylase.. We report the case of two patients who developed severe acute abdominal pain and elevated pancreatic enzymes at 2 and 10 days after starting orlistat. In one case no alterative precipitant was identified. In the other, a predisposing history of pancreatic injury was present. In both cases all other contributory causes were excluded.. Our reports suggest orlistat can trigger drug induced acute pancreatitis in certain patients. For patients presenting with abdominal pain soon after commencing orlistat, a diagnosis of pancreatitis must be considered. We also recommend cautious use of orlistat in patients at risk of pancreatic injury.

Topics: Acute Disease; Aged; Anti-Obesity Agents; Female; Humans; Lactones; Middle Aged; Obesity; Orlistat; Pancreatitis

Topics: Anti-Obesity Agents; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Lactones; Middle Aged; Orlistat; Pancreatitis; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Topics: Anti-Obesity Agents; Drug Interactions; Humans; Kidney Diseases; Lactones; Nonprescription Drugs; Orlistat; Pancreatitis

Topics: Acute Disease; Anti-Obesity Agents; Female; Humans; Lactones; Middle Aged; Obesity; Orlistat; Pancreatitis

Orlistat is an anti-obesity drug licensed in the United Kingdom for 7 years. We present a case of a patient who developed pancreatitis four days after commencing orlistat.. A 36 year old man presented to hospital with acute severe pancreatitis four days after starting a course of Orlistat, a lipase inhibitor used in the treatment of obesity. A diagnosis of drug related pancreatitis was made by exclusion of other causes of pancreatitis; he was a teetotaller, had a normal serum calcium, had no family history of pancreatitis or hyperlipidaemia, no history of trauma and had no evidence of gallstones on Computerised Tomography scan (CT).. Orlistat was the only drug that had been started recently and has been associated with pancreatitis previously. We found no case reports of similar cases, however 99 cases of orlistat related pancreatitis have been reported to the Food and Drug Administration (FDA), but no causative link has been found in clinical trials by the drug company. It is therefore not on the list of possible complications or side effects of the drug.

Topics: Abdominal Pain; Acute Disease; Adult; Amylases; Anti-Obesity Agents; Body Mass Index; C-Reactive Protein; Humans; L-Lactate Dehydrogenase; Lactones; Leukocyte Count; Male; Orlistat; Pancreatitis; Tomography, X-Ray Computed; Vomiting

Lipolytic enzymes may play a role in the pathogenesis of acute pancreatitis. Therefore, the effects of a lipase inhibitor, THL (tetrahydrolipstatin), a protease inhibitor, FUT (nafamostat mesilate), and albumin under different conditions in rats were investigated. (a) Isolated pancreatic acini were incubated with pancreatic homogenates and triglycerides or lecithin with or without albumin and the degree of cellular destruction quantitated. (b) Taurocholate was injected into the pancreatic duct of isolated pancreas and the organ continuously perfused with either FUT, THL, or albumin. Organ damage was evaluated by measurement of pancreatic enzymes in the portal effluence. (c) Necrotizing pancreatitis was induced in vivo via retrograde taurocholate injection. FUT, THL, or albumin was applied either intravenously or injected into the pancreatic parenchyma. (a) Albumin prevented the cellular damage caused by both fatty acids and lysolecithin. (b) THL was ineffective, FUT lowered the release of pancreatic enzymes into the portal effluence, and albumin was most effective. (c) Albumin prevented the development of panlobular necrosis and lowered the degree of extrapancreatic fat necrosis. Albumin, via its ability to bind detergents, may have therapeutic implications.

Topics: Albumins; Animals; Benzamidines; Guanidines; Lactones; Male; Orlistat; Pancreas; Pancreatitis; Perfusion; Rats; Rats, Sprague-Dawley; Taurocholic Acid