Protection by a new synthetic protease inhibitor, ONO3307, of the rat exocrine pancreas during acute edematous pancreatitis induced by a supramaximal dose of caerulein in comparison with FOY007.

The present study investigated the protective effects of the new potent synthetic protease inhibitors, ONO3307 (4-sulfamoyl phenyl-4-guanidinobenzoate methanesulfonate) and FOY007 (gabexate misilate), on the exocrine pancreas in rat caerulein-induced acute pancreatitis in both in vitro and in vivo experiments. These protease inhibitors prevented hyperamylasemia, pancreatic edema, congestion of amylase, redistribution of lysosomal enzyme in acinar cells, and lactic dehydrogenase (LDH) discharge from dispersed acini. They also inhibited the cathepsin B leakage from the lysosomes in a dose-dependent manner in doses of 2-10 mg/kg.h of ONO3307 and 20-50 mg/kg.h of FOY007. These results indicate that both ONO3307 and FOY007 exert protective effects against pancreatitis at subcellular levels in lysosomes and cellular or organelle membranes. Proteases appear to be important in the pathogenesis and development of acute pancreatitis, and low-molecular-weight protease inhibitors may be of clinical use in the treatment of acute pancreatitis.     

Acute pancreatitis in patients with type 2 diabetes mellitus treated with dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase (DPP)-4 inhibitors are approved for use in monotherapy or in combination therapy for patients with type 2 diabetes mellitus for <1 decade. However, numerous reports of DPP-4 inhibitors induced acute pancreatitis were made through the US Food and Drug Administration Adverse Event Reporting System, and this led to a revision in the prescribing information for these drugs. Therefore, this study is designed to evaluate DPP-4 inhibitors induced acute pancreatitis via the spontaneous adverse drug reactions (ADRs) reporting system in a medical center. In four of 2305 ADR cases, it is suspected that DPP-4 inhibitors induced moderate to serious acute pancreatitis. Beyond drugs, other factors also contribute to acute pancreatitis and affect the possibility of ADRs assessed using the Naranjo algorithm. Finally, our results indicate that the incidence of DPP-4 inhibitors induced acute pancreatitis is low.     

二肽基肽酶Ⅳ抑制剂与急性胰腺炎

二肽基肽酶IV（DPP-4）抑制剂是新型口服降糖药物,该类药物能有效降低糖化血红蛋白,耐受性与安全性较好,急性胰腺炎是其少见而严重的不良反应。DPP-4抑制剂致急性胰腺炎潜伏期为14～515d,临床表现为上腹部疼痛,实验室检查可见血清淀粉酶、脂肪酶和弹性蛋白酶水平显著升高。病理学检查可见胰腺和胰周组织水肿和坏死。DPP-4抑制剂致急性胰腺炎的机制主要涉及变态反应和药物或代谢产物对胰腺的直接毒性。有胰腺炎病史者应慎用DPP-4抑制剂。密切注意患者用药情况并监测血清淀粉酶、脂肪酶和弹性蛋白酶水平,是预防DPP-4抑制剂致急性胰腺炎发生和发展的有效措施。     

Tyrosine kinase inhibitors, pancreatic hyperenzymemia and acute pancreatitis: a review

The advent of new drugs can rapidly increase the number of substances causing acute pancreatitis. This is the case of tyrosine kinase inhibitors; these drugs are currently used for chronic myeloid leukemia, gastrointestinal stromal tumors, unresectable hepatocellular carcinomas and advanced renal cell carcinomas that and they have been reported to cause acute pancreatitis or asymptomatic elevations of serum pancreatic enzymes. Of the classes of drugs capable of inducing acute pancreatitis, we aimed to evaluate, in which class tyrosine kinase inhibitors can be allocated. A search was carried out using the MEDLINE database in order to select the data existing in the literature on pyrimidines and acute pancreatitis or serum lipase/amylase elevation covering the period from January 1966 to January 2010; thirteen papers were found and utilized for this review. Based on the data in the literature, we found that tyrosine kinase inhibitors may often cause an increase in pancreatic enzymes in plasma and patients treated with these drugs, especially those who are treated with sorafenib, might be at risk of developing acute pancreatitis. Whether acute pancreatitis due to tyrosine kinase inhibitors is associated only with sorafenib or may also be caused by other drugs of the same class remains an open question. Recent patents on tyrosine kinase inhibitors and acute pancreatitis are pointed out in this review.     

Acute pancreatitis associated with administration of a nitric oxide synthase inhibitor in tumor-bearing dogs

BACKGROUND: Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia. METHODS: Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity. RESULTS: The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given. CONCLUSIONS: We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.     

Treatment strategies for acute pulmonary embolism

Background: Acute pulmonary embolism (PE) is a life-threatening condition that has been treated with anticoagulation for almost 50 years. Objectives: To review the current treatment options for PE and discuss recently published new features. Methods: We reviewed literature involving the treatment strategies for venous thromboembolism (VTE) and in particular pulmonary embolism. Specific attention was drawn towards the evidence of the present treatment and of drugs being studied in Phase III trials. Results/conclusions: Treatment of acute PE consists of parenteral administration of heparin, low-molecular-weight heparin or fondaparinux overlapped and followed by oral vitamin K antagonists for a minimum of 3 months. Contemporary features include the emergence of new anticoagulant drugs such as oral synthetic inhibitors of thrombin or factor Xa. The duration of anticoagulation for unprovoked VTE remains highly debated.     

小分子抗新型冠状病毒药物的突破性进展

目的 研究蛋白酶抑制剂与依赖RNA的RNA聚合酶抑制剂两种抗新型冠状病毒药物.方法 从作用机制、药代动力学、临床试验等方面对这两类小分子药物进行论述.结果 在诸多抗新型冠状病毒药物中,小分子药物具有易吸收、分子体积小、能够穿透细胞膜、易于大规模工业化生产等优点,是药物研发的重点.在具有抗新型冠状病毒作用的小分子药物中,...     

Optimising outcomes in acute pancreatitis

Acute pancreatitis is a common cause for presentation to emergency departments. Common causes in Western societies include biliary pancreatitis and alcohol (the latter in the setting of chronic pancreatitis). Acute pancreatitis also follows endoscopic retrograde pancreatography in 5 to 10% of patients, a group that could potentially benefit from prophylactic treatment. Although episodes of pancreatitis usually run a relatively benign course, up to 20% of patients have more severe disease, and this group has significant morbidity and mortality. Therefore, attempts have been made to identify, at or soon after presentation, those patients likely to have a poor outcome and to channel resources to this group. The mainstay of treatment is aggressive support and monitoring of those patients likely to have a poor outcome. Pharmacotherapy for acute pancreatitis (both prophylactic and in the acute setting) has been generally disappointing. Efforts initially focused on protease inhibitors, of which gabexate shows some promise as a prophylactic agent. Agents that suppress pancreatic secretion have produced disappointing results in human studies. Infection of pancreatic necrosis is associated with high mortality and requires surgical intervention. In view of the seriousness of infected necrosis, the use of prophylactic antibacterials such as carbapenems and quinolones has been advocated in the setting of pancreatic necrosis. Similarly, data are accumulating to support the use of prophylactic antifungal therapy. Recently, it has become apparent that the intense inflammatory response associated with acute pancreatitis is responsible for much of the local and systemic damage. With this realisation, future efforts in pharmacotherapy are likely to focus on suppression or antagonism of pro-inflammatory cytokines and other inflammatory mediators. Similarly, animal studies have demonstrated the importance of oxidative stress in acute pancreatitis, although to date there is a paucity of information regarding the efficacy of antioxidants. Although the clinical course for most patients with acute pancreatitis is mild, severe acute pancreatitis continues to be a clinical challenge, requiring a multidisciplinary approach of physician, intensivist and surgeon.     

葛根素注射液配伍低分子肝素钙治疗肺心病急性发作期疗效的超声心动图评价

目的 应用超声心动图评价葛根素注射液加低分子肝素钙治疗慢性肺源性心脏病(肺心病)急性发作期患者的疗效.方法 将60例肺心病患者完全随机分成研究组(30例)及对照组(30例).对照组采用传统的综合疗法,研究组在对照组的基础上加用葛根素注射液400 mg静脉滴注、1 次/d和低分子肝素钙0.4 ml皮下注射、2次/d,疗程为10 d.治疗前、后使用彩色多普勒超声心动图评价2组患者的右心功能.结果 与治疗前比较,研究组治疗后右心室射血分数增加[(25.0±1.6)%比(40.0±2.3)%,P＜0.01],肺动脉血流加速时间延长[(0.11±0.01)s比(0.14±0.01)s],右心室射血前时间与射血时间的比值降低[(0.650±0.053)比(0.300±0.039),P＜0.01].对照组治疗前后和2组治疗后心功能改变各指标差异均有统计学意义(P＜0.05和P＜0.01)研究组总有效率为93.3%(28/30),对照组总有效率为73.3%(22/30),2组总有效率比较差异有统计学意义(P＜0.05).结论 葛根素加低分子肝素钙能降低肺心病急性发作期患者肺动脉压力,对肺心病右心功能具有明显的恢复作用,疗效满意.     

非手术治疗急性胰腺炎的临床探讨

目的:探讨急性胰腺炎的非手术治疗方法,寻求最佳治疗方案。方法:选择收治的急性胰腺炎患者49例,对其临床资料进行回顾性分析。结果:49例患者治愈47例,死亡2例,治愈率为95.9%。平均住院时间为24.3 d,在治疗过程中发生并发症13例,均得到治愈。结论:采用非手术综合治疗急性胰腺炎的方案疗效显著,只要严格观察病情变化,合理用药,采取非手术治疗急性胰腺炎是可行的。     

Aprotinin revisited: formulation,characterization, biodistribution and therapeutic potential of new aprotinin microemulsion in acute pancreatitis

The aim of this study was to develop aprotinin-loaded microemulsion (M_A) for intravenous administration and evaluate the biodistribution and therapeutic potential of developed formulation in acute pancreatitis models in rats. Phase diagrams were constructed to identify microemulsion region and the optimal microemulsion was evaluated for physicochemical properties and treatment effect in rats, and comparisons made with the solution of aprotinin (S_A). To evaluate the biodistribution of the drug by gamma scintigraphy aprotinin was radiolabeled with ^99mTc radionuclide. Mild and severe acute pancreatitis was induced in rats by subcutaneous injections of cerulein and introductal infusion of 3% sodium taurocholate into the bile-pancreatic duct, respectively. In addition, serum amylase and pancreatic tissue myeloperoxidase activities were measured to evaluate the pancreatic damage. According to gamma scintigraphy and biodistribution studies, accumulation times and distribution of ^99mTc-M_A and S_A were different. While M_A was highly uptake by reticuloendothelial system, S_A was mostly excreted by kidneys and bladder. Compared with the mild acute pancreatitis group, treatment with M_A significantly decreased the serum amylase activity and pancreas myeloperoxidase activity. Furthermore, the protease inhibitor molecule aprotinin has therapeutic potential in acute pancreatitis. Finally, M_A may be suggested as a promising alternative for treatment of acute pancreatitis.     

Clinical pharmacology of HIV protease inhibitors: focus on saquinavir, indinavir, and ritonavir

In this review the clinical pharmacology of HIV protease inhibitors, a new class of antiretroviral drugs, is discussed. After considering HIV protease function and structure, the development of inhibitors of HIV protease is presented. Three protease inhibitors are reviewed in more detail: saquinavir, indinavir, and ritonavir. Clinical trial results with these agents are evaluated. Furthermore, adverse effects, resistance, dosage and administration, clinical pharmacokinetics, pharmacokinetic-pharmacodynamic relationships, and drug interactions are discussed.     

Acid-suppressing drugs and gastroesophageal reflux disease as risk factors for acute pancreatitis--results from a Swedish Case-Control Study

PURPOSE: To study risk factors for acute pancreatitis, here with emphasis on gastro-intestinal diseases and their treatments. METHODS: Population based case-control study covering four areas in Sweden encompassing 2.2 million inhabitants. Included were 462 incident cases of acute pancreatitis aged 20-85 years, hospitalized from 1 January 1995-31 May 1998, and 1,781 unmatched controls randomly selected from the study base using a population register. Information was captured from medical records and structured telephone interviews. RESULTS: Current use of H(2) antagonists starting within 6 months of index-date was associated with acute pancreatitis with an adjusted OR of 4.9 (95% confidence interval (CI) 1.6-15), and current use of proton pump inhibitors (PPIs) with an adjusted OR of 3.2 (95%CI 1.4-7.4). For both drug classes, the ORs tended to be higher at higher doses. Gastritis/gastro-esophageal reflux disease (GERD) within the last 12 months not treated with PPIs or H(2)-antagonists and inflammatory bowel disease (IBD) not treated with anti-inflammatory or immunosuppressive drugs were associated with development of acute pancreatitis with adjusted odds ratios (OR) of 1.9 (95%CI 1.2-3.0) and 5.1 (95%CI 2.0-13) respectively. CONCLUSIONS: Current IBD without treatment and gastritis/GERD without treatment were found to be associated with increased risks to develop acute pancreatitis but the nature of the latter association needs to be further evaluated. On balance, we judge that the observed associations between current use of H(2)-antagonists and PPIs and increased risk of acute pancreatitis are unlikely to be explained by bias.     

Mechanism of kinin release during experimental acute pancreatitis in rats: evidence for pro- as well as anti-inflammatory roles of oedema formation

1 Kinin B(2) receptor antagonists or tissue kallikrein (t-KK) inhibitors prevent oedema formation and associated sequelae in caerulein-induced pancreatitis in the rat. We have now further investigated the mechanism of kinin generation in the pancreas. 2 Kinins were elevated in the pancreatic tissue already before oedema formation became manifest. Peak values (421+/-59 pmol g(-1) dry wt) were reached at 45 min and remained elevated for at least 2 h; a second increase was observed at 24 h. Pretreatment with the B(2) receptor antagonist icatibant abolished kinin formation, while post-treatment was ineffective. 3 Total kininogen levels were very low in the pancreas of controls, but increased 75-fold during acute pancreatitis. This increase was absent in rats that were pretreated with icatibant. 4 During pancreatitis, t-KK-like and plasma kallikrein (p-KK)-like activity in the pancreas, as well as trypsinogen activation peptide (TAP) increased significantly. Icatibant pretreatment further augmented t-KK about 100-fold, while p-KK was significantly attenuated; TAP levels remained unaffected. 5 Endogenous protease inhibitors (alpha(1)-antitrypsin, alpha(2)-macroglobulin) were low in normal tissues, but increased 45- and four-fold, respectively, during pancreatitis. This increase was abolished when oedema formation was prevented by icatibant. 6 In summary, oedema formation is initiated by t-KK; the ensuing plasma protein extravasation supplies further kininogen and active p-KK to the tissue. Concomitantly, endogenous protease inhibitors in the oedema fluid inhibit up to 99% of active t-KK. Our data thus suggest a complex interaction between kinin action and kinin generation involving positive and negative feedback actions of the inflammatory oedema.     

基于美国FDA不良事件报告系统评价钠-葡萄糖共转运蛋白2抑制剂致急性胰腺炎的风险

目的:评价钠葡萄糖共转运蛋白2抑制剂致急性胰腺炎的风险.方法:检索美国FDA不良事件报告系统中2013年1月1日至2020年10月31日的数据,采用报告比值比法(ROR)分析钠-葡萄糖共转运蛋白2(SGLT-2)抑制剂与急性胰腺炎的相关性.结果:共检索到SGLT-2抑制剂致急性胰腺炎报告264份,整体SGLT-2抑制剂...