Vildagliptin-Induced Acute Pancreatitis

ObjectiveTo describe the first reported case of acute pancreatitis in a patient receiving vildagliptin.MethodsWe present the clinical, biochemical, and radiographic findings of the study patient.ResultsA 61-year-old woman who presented with severe abdominal pain was found to have acute pancreatitis. This occurred 5 weeks after the commencement of vildagliptin, a dipeptidyl-peptidase 4 inhibitor, for the treatment of type 2 diabetes mellitus. The patient’s pancreatic enzymes were elevated (amylase, 1205 U/L; lipase, 8846 U/L), and abdominal computed tomography demonstrated diffuse pancreatic swelling, cyst formation, and necrosis in the body of the pancreas. In the absence of an identifiable cause for the patient’s pancreatitis, vildagliptin was considered a potential trigger. The patient recovered after vildagliptin therapy was ceased.ConclusionsAlthough incretin-based therapy effectively treats type 2 diabetes mellitus, emerging reports of acute pancreatitis in patients receiving sitagliptin and exenatide have prompted the US Food and Drug Administration to issue an alert on these drugs. This appears to be the first reported case of acute pancreatitis in a patient receiving vildagliptin, and it supports the possibility that acute pancreatitis may be a rare effect of incretin-based therapy.(Endocr Pract. 2011;17:e48-e50)     

Case report of acute necrotizing pancreatitis associated with combination treatment of sitagliptin and exenatide

ObjectiveTo report the first postmarketing case of necrotizing pancreatitis in a patient on combination therapy of sitagliptin and exenatide.MethodsWe describe the patient’s clinical presentation, laboratory test results, imaging, and autopsy findings.ResultsA 76-year-old woman with a history of type 2 diabetes mellitus presented with severe abdominal pain, vomiting, and fever requiring hospital admission. She had been treated with exenatide for 3 years to manage her diabetes mellitus. A few weeks before presentation, sitagliptin was added, presumably to further optimize her glycemic control. Acute pancreatitis was diagnosed during hospital admission. At initial presentation, her serum amylase concentration was 1136 U/L (reference range, 10-130 U/L) and her lipase concentration was greater than 3500 U/L (reference range, 0-75 U/L). In addition, computed tomography of the abdomen and pelvis demonstrated extensive pancreatic parenchymal necrosis. She had undergone previous cholecystectomy, reported no alcohol consumption, and had a normal lipid profile. Although she had a long-standing history of diabetes mellitus, she had no history of pancreatitis or other risk factors that would have caused her to develop the underlying condition. After initial brief improvement, her symptoms worsened, and despite aggressive care, her clinical state deteriorated and she died. Autopsy findings demonstrated acute necrotizing pancreatitis with complete digestion of the pancreas.ConclusionsConsidering the temporal relationship of her symptoms to the addition of sitagliptin to her existing exenatide regimen, this case strongly suggests a possible causal link between exenatide or sitagliptin (or the combination of the 2 drugs) and the etiology of pancreatitis in this patient. (Endocr Pract. 2012;18:e10-e13)     

Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents

The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg(-1)·day(-1)) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1β, IL-2, IL-6, MCP-1, IFNγ, and TNFα) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents.     

The effects of 13 wk of liraglutide treatment on endocrine and exocrine pancreas in male and female ZDF rats: a quantitative and qualitative analysis revealing no evidence of drug-induced pancreatitis

A possible association between glucagon-like peptide-1 (GLP-1) analogs and incidences of pancreatitis has been suggested based on clinical studies. In male and female diabetic Zucker diabetic fatty (ZDF) rats, we investigated the effects of continuous administration of liraglutide and exenatide on biochemical [lipase, pancreatic amylase (P-amylase)] and histopathological markers of pancreatitis. Male and female ZDF rats were dosed for 13 wk with liraglutide (0.4 or 1.0 mg·kg(-1)·day(-1) sc once daily) or exenatide (0.25 mg·kg(-1)·day(-1) sc, Alzet osmotic minipumps). P-amylase and lipase plasma activity were measured, and an extended histopathological and stereological (specific cell mass and proliferation rate) evaluation of the exocrine and the endocrine pancreas was performed. Expectedly, liraglutide and exenatide lowered blood glucose and Hb A(1c) in male and female ZDF rats, whereas β-cell mass and proliferation rate were increased with greatly improved blood glucose control. Whereas neither analog affected lipase activity, small increases in P-amylase activity were observed in animals treated with liraglutide and exenatide. However, concurrent or permanent increases in lipase and P-amylase activity were never observed. Triglycerides were lowered by both GLP-1 analogs. The qualitative histopathological findings did not reveal adverse effects of liraglutide. The findings were mainly minimal in severity and focal in distribution. Similarly, the quantitative stereological analyses revealed no effects of liraglutide or exenatide on overall pancreas weight or exocrine and duct cell mass or proliferation. The present study demonstrates that, in overtly diabetic male and female ZDF rats, prolonged exposure to GLP-1 receptor agonists does not affect biochemical or histopathological markers of pancreatitis, and whereas both exenatide and liraglutide increase β-cell mass, they have no effect on the exocrine pancreas. However, clinical outcome studies and studies using primate tissues and/or studies in nonhuman primates are needed to further assess human risk.     

Loss of Bace1 in Mice Does Not Alter the Severity of Caerulein Induced Pancreatitis

ContextBeta-site alpha-amyloid protein cleaving enzyme1 (BACE1) plays a key role in the pathogenesis of Alzheimer’s disease. Additional to its moderate expression in the brain, high levels of BACE1 mRNA were found in the pancreas. Murine Bace1 has been immunohistochemicaly detected at the apical pole of acinar cells within the exocrine pancreas of mice and Bace1 activity was observed in pancreatic juice. In vitro experiments revealed enteropeptidase as a putative substrate for Bace1 suggesting a role in acute pancreatitis.ObjectiveThe aim of this study was to address a protective mechanism of Bace1 in acute experimental pancreatitis in mice.MethodsAcute experimental pancreatitis was induced by intraperitoneal injection of caerulein in homozygote Bace1^-/- mice and wild type mice. Serum and tissue analyses were carried out after 4 h, 8 h and 24 h. Measurement of plasma amylase and lipase was performed to confirm pancreatitis induction. In order to assess the severity of pancreatitis H&E stained pancreatic sections were examined regarding edema, inflammation and apoptosis. Immunohistochemical detection of myeloperoxidase (MPO) positive cells was carried out to further quantify the extent of inflammation. Expression of Bace2 within the pancreas was analyzed by immunohistochemistry and RT-qPCR.ResultsWe demonstrate that total loss of Bace1 in mice leads to no alterations in the course of acute experimental caerulein-pancreatitis. Bace1^-/- mice develop a moderate pancreatitis that is comparable in histomorphological and serological features with those seen in wild type mice.DiscussionWe discuss the results in the context of the applied caerulein induced edematous pancreatitis model and possible compensatory mechanisms via Bace2 that might be responsible for the observed results.     

急性胰腺炎伴脾脏密度减低的研究现状

急性胰腺炎是临床上较常见的急腹症,以急性上腹痛和血尿淀粉酶或脂肪酶升高为其主要的临床特点,急性胰腺炎除了对胰腺自身组织的产生损伤外,对胰腺外器官也会产生不同的损伤,并引起一系列的并发症。在急性胰腺炎的脾脏并发症中,脾梗死在CT图像中表现为脾脏密度不均匀性减低,除此之外脾脏实质的密度在CT图像中是相对比较固定的,但是在有些急性胰腺炎患者的CT图像中会出现脾脏密度一过性弥漫性减低的影像表现,治疗后复查CT显示脾脏密度恢复正常,该现象的形成原因尚不清楚,国内外有关该现象的文献报道及研究十分的有限,本文通过分析急性胰腺炎的病因及发病机制,回顾相关的文献病例,探讨急性胰腺炎伴脾脏密度一过性弥漫性减低产生的可能性原因。     

Activity of Ligustrum vulgare L extracts against acute pancreatitis in murine models by regulation of p38 MAPK and NF-κB signaling pathways

Pancreatitis is a fatal disease associated with significant mortality and morbidity. At present, no specific treatment is available for pancreatitis and the patients are mainly treated with supportive medication. The need for specific antipancreatitic chemotherapy is an urgent medical obligation. In the current study, protective effects of the methanolic extract of the Ligustrum vulgare berries were investigated in the rat model of acute pancreatitis. Acute pancreatitis (AP) was induced in the male Sprague-Dawley (SD) rats by cerulein injection. Fruit extract of L. vulgare L extract was prepared using the methanol. Treatment effects of L. vulgare were evaluated in AP rats. Serum levels of lipase, amylase, proinflamatory cytokines (TNF-α, IL-6, TL-1β), lipid peroxidase (LPO), myeloperoxidase (MPO) were determined. Histological changes in the pancreas were assessed. L. vulgare treatment prevented the increase in serum amylase and lipase levels, reduced the disease progression in pancreas, and reduced the serum levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in AP rats. Moreover, L. vulgare significantly suppressed pancreatic edema, inhibited oxidative damage (MPO activity and SOD activity), and inhibited the expression of NF-κB/p65 and activation (phosphorylation) of the inhibitor of NF-κB (IκBα) and p38 MAPKs. Histological examinations showed that L. vulgare significantly reduced the inflammatory and fibrotic changes. The results indicated the potent pancreato-protective effects of L. vulgare in AP.     

血清CRP, PCT, 脂肪酶与胰腺炎分型及预后的相关性研究

目的:探讨血清CRP、PCT和脂肪酶和胰腺炎分型及预后的相关性。方法:87例急性胰腺炎患者,其中轻型急性胰腺炎65例,重症急性胰腺炎22例。在入院后1 d、3 d、7 d、14 d测定血清CRP、PCT、脂肪酶水平并进行APACHEⅡ评分。对比分析两组患者间不同时间点CRP、PCT、脂肪酶及APACHEⅡ评分差异,采用多元线性回归分析影响胰腺炎预后的影响因素。结果:胰腺炎发病严重程度和糖尿病、饮酒史、胆源性结石病有一定的相关性(P0.05)。轻型组CRP、PCT水平1 d、3 d水平和重型组无统计学差异(p0.05);7 d及14 d差异有统计学意义(P0.05)。轻型组脂肪酶水平和重型组3 d、7 d及14 d差异有统计学意义(P0.05)。轻型组APACHEⅡ评分和重型组相比,在发病后1 d、3 d、7 d及14 d差异有统计学意义(p0.05)。回归方程:Logit P=0.0017×PCT+0.0297×胆源性结石病史+0.093×APACHEⅡ评分-0.193。结论:糖尿病和胆源性结石和重症胰腺炎相关,PCT、APACHEⅡ持续不下降提示胰腺炎预后不佳。     

Tracheal adenoid cystic carcinoma masquerading asthma: A case report

Background

Hemorrhagic pleural effusion, especially in the right hemithorax rarely occurs as the sole presentation of pancreatitis.

Case Presentation

This article reports massive right-sided hemorrhagic pleural effusion as the sole manifestation of pancreatitis in a 16-year-old Iranian boy. The patient referred to Nemazee Hospital, the main hospital of southern Iran, with right-sided shoulder and chest pain accompanied with dyspnea. His chest x-ray showed massive right-sided pleural effusion. The pleural fluid amylase was markedly elevated (8840 U/L), higher than that in the serum (3318 U/L). Abdominal CT scan showed a cystic structure measuring about 5·2 cm in the head of pancreas, highly suggestive of a pancreatic pseudocyst. Pleural effusion resolved after 3 weeks of chest tube insertion but not completely. After this period of conservative therapy another CT scan showed that pseudocyst was still in the head of pancreas. So, external drainage was done with mushroom insertion and the patient was discharged after 40 days of hospitalization. The cause of pancreatitis could not be identified.

Conclusion

Pancreatitis should be taken into consideration when hemorrhagic pleural effusion, especially in the right hemithorax occurs.     

Obese Rats Exhibit High Levels of Fat Necrosis and Isoprostanes in Taurocholate-Induced Acute Pancreatitis

Background

Obesity is a prognostic factor for severity in acute pancreatitis in humans. Our aim was to assess the role of oxidative stress and abdominal fat in the increased severity of acute pancreatitis in obese rats.

Methodology

Taurocholate-induced acute pancreatitis was performed in lean and obese Zucker rats. Levels of reduced glutathione, oxidized glutathione, L-cysteine, cystine, and S-adenosylmethionine were measured in pancreas as well as the activities of serine/threonine protein phosphatases PP1 and PP2A and tyrosin phosphatases. Isoprostane, malondialdehyde, triglyceride, and free fatty acid levels and lipase activity were measured in plasma and ascites. Lipase activity was measured in white adipose tissue with and without necrosis and confirmed by western blotting.

Findings

Under basal conditions obese rats exhibited lower reduced glutathione levels in pancreas and higher triglyceride and free fatty acid levels in plasma than lean rats. S-adenosyl methionine levels were markedly increased in pancreas of obese rats. Acute pancreatitis in obese rats led to glutathione oxidation and lower reduced glutathione levels in pancreas together with decreased activities of redox-sensitive phosphatases PP1, and PP2A. S-adenosyl methionine levels decreased but cystine levels increased markedly in pancreas upon pancreatitis. Acute pancreatitis triggered an increase in isoprostane levels in plasma and ascites in obese rats. Free fatty acid levels were extremely high in pancreatitis-associated ascitic fluid from obese rats and lipase was bound with great affinity to white adipose tissue, especially to areas of necrosis.

Conclusions

Our results show that oxidative stress occurs locally and systemically in obese rats with pancreatitis favouring inactivation of protein phosphatases in pancreas, which would promote up-regulation of pro-inflammatory cytokines, and the increase of isoprostanes which might cause powerful pulmonary and renal vasoconstriction. Future studies are needed to confirm the translational relevance of the present findings obtained in a rat model of taurocholate-induced pancreatic damage and necrosis.     

Electro-deposit polyaniline on carbon electrode for voltammetric detection of lipase

Normally, the pancreatic digestive enzymes are created and carried into the duodenum in an inactive form. During pancreatitis attacks, these enzymes are inhibited from reaching the duodenum, become activated while still in the pancreas, and begin to autodigest and destroy the pancreas. In order to accurately detect lipase within seconds, a square wave technique was explored without immobilizing enzyme and any other biomolecules over the electrode surface. The cyclic voltammetric (CV) technique was used to coat a carbon electrode with a thin layer of polyaniline. This modified electrode proved to be highly sensitive and specific to detect lipase between 0 and 225 IU/L, which is well within the normal physiological range. The consistency and reliability of this technique proved to be a very formidable detector of lipase present in abnormal quantities due to pancreatitis and other pathological disorders. The interference test has been performed to detect the lipase in the presence of amylase 50, 100, and 150 IU/L to understand the interference phenomenon with lipase detection. There is no significant effect of the amylase concentration over lipase detection resulting from using a modified carbon electrode. The response time of the modified carbon electrode is approximately 5s and the electrode has shown to be stable for 4 weeks at room temperature without special storage condition.     

急性胰腺炎患者的CT、MRI影像学表现及其诊断价值对比研究

摘要 目的：比较急性胰腺炎患者的电子计算机断层扫描（CT）、磁共振成像（MRI）影像学表现及其诊断价值。方法：选择2018年1月-2019年12月我院收治并初步诊断为急性胰腺炎的患者124例，所有患者均同时行CT和MRI检查，并比较两种检查方式诊断急性胰腺炎的影像学表现，以临床最终诊断结果作为参考，比较两种检查方式诊断急性胰腺炎的价值。结果：124例患者，经临床最终诊断为急性胰腺炎96例，28例为非急性胰腺炎，以临床最终诊断结果为"金标准"，CT诊断急性胰腺炎的灵敏度、特异度、阳性预测值、阴性预测值和准确度分别为84.38%、75.00%、92.05%、58.33%、82.26%，MRI诊断急性胰腺炎的灵敏度、特异度、阳性预测值、阴性预测值和准确度分别为95.83%、78.57%、93.88%、84.62%、91.94%，MRI诊断急性胰腺炎的灵敏度、阴性预测值和准确度显著高于CT（P<0.05），两种检查方式诊断急性胰腺炎的特异度、阳性预测值比较无统计学差异（P>0.05）。结论：CT和MRI影像学表现有利于急性胰腺炎的诊断，两者对急性胰腺炎诊断均具有较高的灵敏度、特异度和准确度， 但MRI诊断急性胰腺炎的灵敏度、准确度优于CT。     

Exenatide can reduce glucose independent of islet hormones or gastric emptying

Exenatide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic used in the treatment of type 2 diabetes. There is increasing evidence that GLP-1 can influence glycemia not only via pancreatic (insulinotropic and glucagon suppression) and gastric-emptying effects, but also via an independent mechanism mediated by portal vein receptors. The aim of our study was to investigate whether exenatide has an islet- and gastric-independent glycemia-reducing effect, similar to GLP-1. First, we administered mixed meals, with or without exenatide (20 microg sc) to dogs. Second, to determine whether exenatide-induced reduction in glycemia is independent of slower gastric emptying, in the same animals we infused glucose intraportally (to simulate meal test glucose appearance) with exenatide, exenatide + the intraportal GLP-1 receptor antagonist exendin-(9-39), or saline. Exenatide markedly decreased postprandial glucose: net 0- to 135-min area under the curve = +526 +/- 315 and -536 +/- 197 mg.dl(-1).min(-1) with saline and exenatide, respectively (P < 0.05). Importantly, the decrease in plasma glucose occurred without a corresponding increase in postprandial insulin but was accompanied by delayed gastric emptying and lower glucagon. Significantly lower glycemia was induced by intraportal glucose infusion with exenatide than with saline (92 +/- 1 vs. 97 +/- 1 mg/dl, P < 0.001) in the absence of hyperinsulinemia or glucagon suppression. The exenatide-induced lower glycemia was partly reversed by intraportal exendin-(9-39): 95 +/- 3 and 92 +/- 3 mg/dl with exenatide + antagonist and exenatide, respectively (P < 0.01). Our results suggest that, similar to GLP-1, exenatide lowers glycemia via a novel mechanism independent of islet hormones and slowing of gastric emptying. We hypothesize that receptors in the portal vein, via a neural mechanism, increase glucose clearance independent of islet hormones.     

1,8-cineole (eucalyptol) ameliorates cerulein-induced acute pancreatitis via modulation of cytokines,oxidative stress and NF-κB activity in mice

AimsAcute pancreatitis (AP) is an inflammatory condition wherein pro-inflammatory mediators, oxidative stress, and NF-κB signaling play a key role. Currently, no specific therapy exists and treatment is mainly supportive and targeted to prevent local pancreatic injury and systemic inflammatory complications. This study was aimed to examine whether 1,8-cineole, a plant monoterpene with antioxidant and anti-inflammatory properties could ameliorate cerulein-induced acute pancreatitis.Main methodsAP was induced in Swiss mice by six one hourly injections of cerulein (50 μg/kg, i.p.). 1,8-cineole (100, 200 and 400 mg/kg, p.o.) was administered 1 h prior to first cerulein injection, keeping vehicle and thalidomide treated groups as controls. Blood samples were taken 6-h later to determine serum levels of amylase and lipase, and cytokines. The pancreas was removed for morphological examination, myeloperoxidase (MPO) and malondialdehyde (MDA) assays, reduced glutathione (GSH) levels, and for nuclear factor (NF)-κB immunostaining.Key findings1,8-cineole effectively reduced the cerulein-induced histological damage, pancreatic edema and NF-κB expression, levels of MPO activity and MDA, and replenished the GSH depletion. Cerulein increased serum levels of amylase and lipase, and pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were also decreased by 1,8-cineole pretreatment, similar to thalidomide, a TNF-α inhibitor. The anti-inflammatory IL-10 cytokine level was, however, enhanced by 1,8-cineole.SignificanceThese findings indicate that 1,8-cineole can attenuate cerulein-induced AP via an anti-inflammatory mechanism and by combating oxidative stress. Further studies are needed to clearly elucidate its benefits in patients on acute pancreatitis.     

Acute pancreatitis and reduction of H+ ion concentration in gastric secretions in experimental acute myocarditis produced by Indian red scorpion, Buthus tamulus, venom

Crude venom (4 mg/kg) of scorpion (B. tamulus) was given in saline to anaesthetized dogs and rabbits. It produced a reduction in gastric H+ ion concentration in dogs with acute myocarditis. Simultaneously an increase in circulating amylase and lipase level was also observed. However 60% venom poisoned rabbits showed an elevated lipase level without a parallel increase in amylase. It is suggested that the venom acts directly on exocrine pancreas to cause acute pancreatitis.     

Ghrelin attenuates the development of acute pancreatitis in rat.

BACKGROUND: Ghrelin, a circulating growth hormone-releasing peptide isolated from human and rat stomach, stimulates growth hormone secretion, food intake and exhibits gastroprotective properties. Ghrelin is predominantly produced by a population of endocrine cells in the gastric mucosa, but its presence in bowel, pancreas, pituitary and hypothalamus has been reported. In human fetal pancreas, ghrelin is expressed in a prominent endocrine cell population. In adult pancreatic islets the population of these cell is reduced. The aim of present study was to investigate the influence of ghrelin administration on the development of acute pancreatitis. METHODS: Acute pancreatitis was induced in rat by caerulein injection. Ghrelin was administrated twice (30 min prior to the first caerulein or saline injection and 3 h later) at the doses: 2, 10 or 20 nmol/kg. Immediately after cessation of caerulein or saline injections the following parameters were measured: pancreatic blood flow, plasma lipase activity, plasma interleukin-1beta (IL-1beta) and interleukin 10 (IL-10) concentration, pancreatic DNA synthesis, and morphological signs of pancreatitis. RESULTS: Administration of ghrelin without induction of pancreatitis did not affect significantly any parameter tested. Caerulein led to the development of acute edematous pancreatitis. Treatment with ghrelin at the dose 2 nmol/kg, during induction of pancreatitis, was without effect on pancreatic histology or biochemical and functional parameters. Treatment with ghrelin at the dose 10 and 20 nmol/kg attenuated the development of pancreatitis and the effects of both doses were similar. Administration of ghrelin (10 or 20 nmol/kg) reduced inflammatory infiltration of pancreatic tissue and vacuolization of acinar cells. Also, plasma lipase activity and plasma IL-1beta concentration were reduced, and caerulein-induced fall in pancreatic DNA synthesis was reversed. Administration of ghrelin at the dose 10 and 20 nmol/kg was without effect on caerulein-induced pancreatic edema and pancreatitis-related fall in pancreatic blood flow. CONCLUSIONS: (1) Administration of ghrelin attenuates pancreatic damage in caerulein-induced pancreatitis; (2) Protective effect of ghrelin administration seems Background: Ghrelin, a circulating growth hormone-releasing peptide isolated from human and rat stomach, stimulates growth hormone secretion, food intake and exhibits gastroprotective properties. Ghrelin is predominantly produced by a population of endocrine cells in the gastric mucosa, but its presence in bowel, pancreas, pituitary and hypothalamus has been reported. In human fetal pancreas, ghrelin is expressed in a prominent endocrine cell population. In adult pancreatic islets the population of these cell is reduced. The aim of present study was to investigate the influence of ghrelin administration on the development of acute pancreatitis. Methods: Acute pancreatitis was induced in rat by caerulein injection. Ghrelin was administrated twice (30 min prior to the first caerulein or saline injection and 3 h later) at the doses: 2, 10 or 20 nmol/kg. Immediately after cessation of caerulein or saline injections the following parameters were measured: pancreatic blood flow, plasma lipase activity, plasma interleukin-1beta (IL-1beta) and interleukin 10 (IL-10) concentration, pancreatic DNA synthesis, and morphological signs of pancreatitis. Results: Administration of ghrelin without induction of pancreatitis did not affect significantly any parameter tested. Caerulein led to the development of acute edematous pancreatitis. Treatment with ghrelin at the dose 2 nmol/kg, during induction of pancreatitis, was without effect on pancreatic histology or biochemical and functional parameters. Treatment with ghrelin at the dose 10 and 20 nmol/kg attenuated the development of pancreatitis and the effects of both doses were similar. Administration of ghrelin (10 or 20 nmol/kg) reduced inflammatory infiltration of pancreatic tissue and vacuolization of acinar cells. Also, plasma lipase activity and plasma IL-1beta conc; concentration were reduced, and caerulein-induced fall in pancreatic DNA synthesis was reversed. Administration of ghrelin at the dose 10 and 20 nmol/kg was without effect on caerulein-induced pancreatic edema and pancreatitis-related fall in pancreatic blood flow. Conclusions: (1) Administration of ghrelin attenuates pancreatic damage in caerulein-induced pancreatitis; (2) Protective effect of ghrelin administration seems to be related the inhibition in inflammatory process and the reduction in liberation of pro-inflammatory IL-1beta.     

Beneficial Effects of Trypsin Inhibitors Derived from a Spider Venom Peptide in L-Arginine-Induced Severe Acute Pancreatitis in Mice

HWTI is a 55-residue protein isolated from the venom of the spider Ornithoctonus huwena. It is a potent trypsin inhibitor and a moderate voltage-gated potassium channel blocker. Here, we designed and expressed two HWTI mutants, HWTI-mut1 and HWTI-mut2, in which the potassium channel inhibitory activity was reduced while the trypsin inhibitory activity of the wild type form (approximately 5 EPU/mg) was retained. Animal studies showed that these mutants were less toxic than HWTI. The effects of HWTI and HWTI-mut1 were examined in a mouse model of acute pancreatitis induced by intraperitoneal injection of a large dose of L-arginine (4 mg/kg, twice). Serum amylase and serum lipase activities were assessed, and pathological sections of the pancreas were examined. Treatment with HWTI and HWTI-mut1 significantly reduced serum amylase and lipase levels in a dose dependent manner. Compared with the control group, at 4 mg/kg, HWTI significantly reduced serum amylase level by 47% and serum lipase level by 73%, while HWTI-mut1 significantly reduced serum amylase level by 59% and serum lipase level by 72%. Moreover, HWTI and HWTI-mut1 effectively protected the pancreas from acinar cell damage and inflammatory cell infiltration. The trypsin inhibitory potency and lower neurotoxicity of HWTI-mut1 suggest that it could potentially be developed as a drug for the treatment of acute pancreatitis with few side effects.     

Suppressibility of Parathyroid Hormone in Primary Hyperparathyroidism

ObjectiveTo describe an unusual case of pathologically confirmed primary hyperparathyroidism in a patient presenting with severe hypercalcemia and an undetectable parathyroid hormone (PTH) level.MethodsWe present a detailed case report and outline the serial laboratory findings. In addition, the possible causes of low serum PTH levels in the setting of primary hyperparathyroidism are discussed.ResultsA 16-year-old female patient presented with severe epigastric pain, found to be attributable to acute pancreatitis. At hospital admission, her serum calcium concentration was high (14.0 mg/dL); the patient also had a normal serum phosphorus level of 3.6 mg/dL and an undetectable PTH level (< 0.2 pmol/L). An evaluation for non-PTH-mediated causes of hypercalcemia revealed a partially suppressed thyroid-stimulating hormone concentration and a below normal 1,25-dihydroxyvitamin D level, consistent with her suppressed PTH. One week after the patient was dismissed from the hospital, repeated laboratory studies showed a serum calcium value of 11.1 mg/dL, a serum phosphorus level of 2.8 mg/dL, and an elevated PTH concentration of 11.0 pmol/L, consistent with primary hyperparathyroidism. A repeated 1,25-dihy-droxyvitamin D measurement was elevated. A parathyroid scan showed a parathyroid adenoma in the left lower neck area, and she subsequently underwent successful surgical resection of a pathologically confirmed parathyroid adenoma.ConclusionThis case demonstrates that the serum PTH level can be suppressed in patients with primary hyperparathyroidism. Moreover, it emphasizes the need for careful evaluation of the clinical context in which the PTH measurement is determined. Consideration should be given to repeating measurement of PTH and serum calcium levels when the initial laboratory evaluation of hypercalcemia is unclear because dynamic changes in calcium metabolism may occur in the presence of secondary contributing factors. (Endocr Pract. 2007;13:785-789)     

Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic medication: a follow-up study

Aims Previously, a retrospective cohort study found no increased risk of acute pancreatitis with current or recent use of exenatide twice daily compared with use of other anti-diabetic drugs. This follow-up study investigated incident acute pancreatitis, with the use of a different data source and analytic method, in patients exposed to exenatide twice daily compared with patients exposed to other anti-diabetic medications. Methods A large US health insurance claims database was used. Eligible patients had ≥?9?months continuous enrollment without a claim for pancreatitis and a claim for a new anti-diabetic medication on or after 1 June 2005 to 31 March 2009. Cases of acute pancreatitis were defined as hospitalized patients with an Internation Classification of Disease?9 code of 577.0 in the primary position. A discrete time survival model was used to evaluate the relationship between exenatide twice daily and acute pancreatitis. Results Of 482?034 eligible patients, 24?237 initiated exenatide twice daily and 457?797 initiated another anti-diabetic medication. Initiators of exenatide twice daily had more severe diabetes compared with initiators of other anti-diabetic medications. After adjustments for propensity score, insulin and use of medication potentially associated with acute pancreatitis, the odds ratio with exenatide twice daily exposure was 0.95 (95%?CI 0.65-1.38). A secondary analysis that examined current, recent and past medication exposure found no increased risk of acute pancreatitis with exenatide twice daily, regardless of exposure category. Conclusion This study indicates that exposure to exenatide twice daily was not associated with an increased risk of acute pancreatitis compared with exposure to other anti-diabetic medications. These results should be interpreted in light of potential residual confounding and unknown biases.