BACKGROUND & AIMS: Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.

背景与目标： 前列腺素和血栓烷是花生四烯酸通过环氧合酶（CO）酶代谢的产物，它们是炎症部位常见的疼痛和肿胀的原因。非甾体类抗炎药（NSAIDs）抑制这些物质的产生，并用于治疗炎症性疾病，例如关节炎。但是，NSAID治疗的主要副作用之一是胃溃疡。通过5-脂氧合酶（5-LO）酶促途径抑制前列腺素的产生以及白三烯形成的相关增加可能是吸引炎症细胞，引起局部炎症和产生溃疡的原因。为了确定5-LO抑制对这一假设的影响，在大鼠中进行了研究以评估替泊沙林（一种双重CO / LO抑制剂）对胃粘膜白三烯B4水平和肠系膜小静脉中性粒细胞粘附的影响。在大鼠中，长期口服NSAID，消炎痛（2天每天2 mg / kg，共4天）可导致40％的死亡率，并在第四剂药物后24小时进行评估，并伴有肠粘连和穿孔。另外，在肠系膜小静脉中嗜中性粒细胞的粘附增加，并且在肠系膜间质中细胞浸润明显。在每天消炎痛治疗前30分钟，给另一组大鼠服用tepoxalin（20 mg / kg，p.o）抑制这些胃肠道副作用。进行了进一步的研究以确定替泊沙林对与NSAID诱导的胃肠道炎症相关的早期事件的影响，包括中性粒细胞粘附，脂质过氧化物的产生和LTB4的产生。吲哚美辛（100 mg / kg，p.o.）给药90分钟后，大鼠胃黏膜中LTB4的水平升高。另外，在该剂量下并通过使用另一种NSAID萘普生，肠系膜小静脉中的中性粒细胞粘附增加。在这个时间点在胃粘膜中没有明显的脂质过氧化物的产生。 Tepoxalin（最高400 mg / kg，p.o.）对胃粘膜LTB4的产生和脂质过氧化物的水平没有影响。在最高剂量下观察到嗜中性粒细胞粘附性降低。在另一项研究中，用替泊沙林（ED50 = 7.5 mg / kg，口服）或选择性5-LO抑制剂齐留通（100 mg / kg，口服）预处理可防止吲哚美辛（100 mg / kg）引起的胃粘膜LTB4水平升高和中性白细胞粘附/ kg，po）。这些数据表明，LO抑制可能在预防NSAID引起的胃部炎症中起着至关重要的作用，从而提供了对特泊沙林缺乏致溃疡性的认识，并提供了可预防胃部副作用的新的抗炎治疗方法。

BACKGROUND & AIMS: :Eosinophilic with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome) is a rare systemic disease characterized by a small-vessel necrotizing vasculitis. Cardiac manifestations are broad-ranging and are associated with a poor prognosis. Coronary vasospasm is uncommon.Here, we report a case of an acute coronary vasospasm in a patient with EGPA after corticosteroids withdrawal and nonsteroidal antiinflammatory drug (NSAID) introduction. This patient was initially misdiagnosed as bradykinin-mediated angioedema. A 30-year-old man presented with recurrence of abdominal pain and acute dyspnea. NSAID administration for pain during a flare was followed by coronary vasospasms leading to cardiac arrest. Corticosteroid treatment was recently interrupted by the patient.This case reports a rare cardiac complication of EGPA. NSAID might contribute to coronary vasospasm by eosinophilic degranulation in EGPA. Moreover, corticosteroid compliance must be emphasized among patients who display EGPA with high cardiac risk to prevent fatal issues.

背景与目标： 嗜酸性粒细胞增多性血管炎（EGPA，前身为Churg-Strauss综合征）是一种罕见的全身性疾病，其特征是小血管坏死性血管炎。心脏表现范围广泛，与预后不良有关。冠状动脉痉挛并不常见。在这里，我们报道了在停用皮质类固醇和使用非甾体抗炎药（NSAID）后，EGPA患者发生急性冠脉血管痉挛的病例。该患者最初被误诊为缓激肽介导的血管性水肿。一名30岁男子出现腹痛和急性呼吸困难复发。在发作期间使用NSAID止痛，然后进行冠状血管痉挛，导致心脏骤停。该患者最近中断了皮质类固醇的治疗。此例报告了罕见的EGPA心脏并发症。 NSAID可能通过EGPA中的嗜酸性脱粒而促进冠状动脉痉挛。此外，在显示EGPA且具有高心脏风险的患者中必须强调皮质类固醇的依从性，以防止致命问题。

BACKGROUND & AIMS: :The occurrence of upper gastrointestinal disease and the relevance of nonsteroidal antiinflammatory drug (NSAID) usage were documented in 511 consecutive patients (321 women, 190 men) over 70 yr old, referred for upper gastrointestinal endoscopy in a district general hospital. The findings were benign esophageal disease (43%), normal (15%), gastric ulcer (11.5%), and duodenal ulcer (11%). Gastric ulcers were more common in women taking NSAIDs (25%) than in NSAID abstainers (7%) p less than 0.001 and male NSAID users (8%) p less than 0.001. Esophagitis and esophageal stricture were not influenced by NSAID usage, but gastric erosions were more common (10% vs. 3%) p less than 0.01. Of 142 patients receiving NSAIDs, 41% presented with hemorrhage, compared with 20.5% of NSAID abstainers (p less than 0.001). Hemorrhage was as common in aspirin takers (15 of 33, 45%) as in standard-dose NANSAID takers (43 of 109, 39%), even though 86% were taking 300 mg of aspirin per day or less. In elderly patients, esophageal disease is common. NSAID use, even low-dose aspirin, is associated with an increased risk of hemorrhage. In females, NSAID usage is associated with gastric ulcer.

背景与目标： ：在70岁以上的511例连续患者（321例患者，190例男性患者）中，上消化道疾病的发生和使用非甾体类抗炎药的相关性已有文献记载，这些患者在某地区综合医院进行了上消化道内镜检查。结果为：良性食道疾病（43％），正常（15％），胃溃疡（11.5％）和十二指肠溃疡（11％）。服用NSAIDs的女性（25％）的胃溃疡比不服用NSAID的人（7％）的P <0.001，而男性NSAID使用者（8％）的P <0.001。食道炎和食道狭窄不受NSAID使用的影响，但胃糜烂更为常见（10％比3％），p小于0.01。在142名接受NSAID的患者中，有41％出现了出血，而NSAID的弃权者为20.5％（p小于0.001）。阿司匹林服用者出血（33名中的15名，占45％）和标准剂量NANSAID服用者出血（109名中的43名，39％）一样普遍，尽管86％的人每天服用300毫克或更少的阿司匹林。在老年患者中，食道疾病是常见的。使用非甾体抗炎药，即使是小剂量阿司匹林，也会增加出血的风险。在女性中，NSAID的使用与胃溃疡有关。

BACKGROUND & AIMS: :Nonsteroidal anti-inflammatory drugs (NSAIDs) are cyclooxygenase inhibitors with analgesic, anti-inflammatory, antipyretic, and antithrombotic effects. NSAIDs have been implicated in a variety of drug-induced reactions that are proved as or suspected of being mediated through a host immune response. Single-drug-induced reactions are the hallmark of these types of reactions. The types of single-drug-induced reactions are the confluence of 2 variables, the structure of the drug and the specific types of immune responses. This article identifies reactions patterns and the NSAIDs most likely to elicit each immune response.

背景与目标： 非甾体类抗炎药（NSAIDs）是具有止痛，抗炎，解热和抗血栓形成作用的环氧合酶抑制剂。 NSAID已经牵涉到多种药物诱导的反应中，这些反应被证明是或怀疑是通过宿主免疫反应介导的。单药诱导的反应是这些类型反应的标志。单一药物诱导的反应的类型是两个变量的总和，即药物的结构和特定类型的免疫反应。本文确定了最有可能引发每种免疫反应的反应模式和NSAID。

BACKGROUND & AIMS: :Long term nonsteroidal anti-inflammatory drug (NSAID) medication is associated with gastrointestinal (GI) adverse events. This paper aimed to depict main determinants of NSAID drug choice (GI safe/traditional NSAIDs) in a rheumatoid arthritis (RA) patient sample (n=143). According to our logistic regression model, current/prior GI adverse events in the anamnesis was the only significant determinant of GI safer NSAID use (OR 3.1, p = 0.01). There was significant difference regarding most NSAIDs between the RA study sample and the total Hungarian population, suggesting that chronic administration could also influence the NSAID choice. GI safe NSAIDs were much preferred in the RA study sample than in the total population. In conclusion, the NSAID medication of the observed 143 patients was considered to be reasonable regarding both cardiovascular and GI safety.

背景与目标： ：长期非甾体抗炎药（NSAID）药物与胃肠道（GI）不良事件有关。本文旨在描述类风湿关节炎（RA）患者样本（n = 143）中NSAID药物选择的主要决定因素（GI安全/传统NSAID）。根据我们的逻辑回归模型，回忆中当前/以前的胃肠不良事件是胃肠道安全使用NSAID的唯一重要决定因素（OR 3.1，p = 0.01）。 RA研究样本与匈牙利总人口之间有关大多数NSAID的差异很大，这表明长期给药也可能影响NSAID的选择。相对于总人群，在RA研究样本中更优选GI安全的NSAID。总之，就心血管和胃肠道安全性而言，观察到的143例患者的NSAID药物被认为是合理的。

BACKGROUND & AIMS: :Non-steroidal anti-inflammatory drugs (NSAID) target the enzyme cyclooxygenase (COX) thus affording relieve from pain, inflammation or fever. As COX-dependently formed prostanoids not only mediate signals involved in inflammation and pain, but also regulate important physiological cardiovascular functions, some NSAID have recently been reported to be associated with arterial thrombosis or hypertension. This is in contrast to the well-known antiplatelet effects of low-dose aspirin, but in coherence with the specific effects of some NSAID on prostanoid formation in the vasculature. A correlation between the intake of selective inhibitors of the cyclooxygenase 2 (COX-2) isoform and atherothrombotic events has recently been established. Large retrospective analyses of clinical data have repeatedly shown this effect and in some cases have also observed potential hazards for other, rather non-selective NSAID. This review evaluates potential prothrombotic effects of NSAID in vascular ischemic disease in comparison to low-dose aspirin and selective COX-2 inhibitors and discusses pathophysiological backgrounds for such observations.

背景与目标： 非甾体类抗炎药（NSAID）靶向环氧合酶（COX），从而缓解疼痛，炎症或发烧。由于COX依赖性形成的类前列腺素不仅可以介导炎症和疼痛相关的信号，而且还可以调节重要的生理心血管功能，所以最近有报道称某些NSAID与动脉血栓形成或高血压有关。这与低剂量阿司匹林的众所周知的抗血小板作用相反，但与某些NSAID对脉管系统中前列腺素形成的特定作用相一致。最近已经建立了环氧合酶2（COX-2）异构体的选择性抑制剂的摄入与动脉粥样硬化血栓形成事件之间的相关性。对临床数据进行的大规模回顾性分析反复表明了这种作用，在某些情况下，还观察到了其他非选择性NSAID的潜在危害。这篇综述评估了与低剂量阿司匹林和选择性COX-2抑制剂相比，NSAID在血管缺血性疾病中的潜在血栓形成作用，并讨论了此类观察的病理生理背景。

BACKGROUND & AIMS: BACKGROUND:Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of heart failure. NSAIDs inhibit the synthesis of renal prostaglandin, which results in a higher total blood volume, cardiac output and preload. The association between recent start of NSAIDs in elderly people and echocardiographic parameters was investigated. METHODS:In the Rotterdam Study, a population-based cohort study, the effect of NSAIDs on left ventricular end-systolic dimension, left ventricular end-diastolic dimension, fractional shortening and left ventricular systolic function was studied in all participants for whom an echocardiogram was available (n=5307). NSAID use was categorised as current NSAID use on the date of echocardiography, past use and never used before echocardiography during the study period. Current use was divided into short-term NSAID use (≤ 14 days) and long-term NSAID use (> 14 days). Associations between drug exposure and echocardiographic measurements were assessed using linear and logistic regression analyses. RESULTS:Current NSAID use for < 14 days was associated with a significantly higher left ventricular end-systolic dimension (+1.74 mm, 95% CI 0.20 to 3.28), left ventricular end-diastolic dimension (+3.69 mm, 95% CI 1.08 to 6.31) and significantly lower fractional shortening (-6.03%, 95% CI -9.81% to -2.26%) compared with non-users. Current NSAID use for > 14 days was associated with a higher left end-diastolic dimension (+1.96 mm, 95% CI 0.82 to 3.11) but there was no change in the other echocardiographic parameters. CONCLUSION:This study is the first to investigate the association between NSAIDs and echocardiographic parameters and suggests that there is a transient effect of short-term use of NSAIDs on the left ventricular dimension and function of the heart.

背景与目标： 背景：非甾体类抗炎药（NSAID）与心力衰竭的风险增加有关。 NSAIDs抑制肾脏前列腺素的合成，从而导致更高的总血容量，心输出量和预负荷。研究了老年人中最近开始使用NSAID与超声心动图参数之间的关联。
方法：在一项基于人群的队列研究鹿特丹研究中，研究了所有接受超声心动图检查的参与者对非甾体抗炎药对左心室收缩末期尺寸，左心室舒张末期尺寸，缩短分数和左心室收缩功能的影响。可用（n = 5307）。在研究期间，将NSAID的使用归类为超声心动图检查日期，过去的使用以及在超声心动图检查之前从未使用过的NSAID的当前使用情况。当前使用分为短期NSAID使用（≤14天）和长期NSAID使用（> 14天）。使用线性和逻辑回归分析评估药物暴露与超声心动图测量之间的关联。
结果：目前使用NSAID的时间少于14天与左心室舒张末期尺寸（1.74 mm，95％CI 0.20至3.28），左心室舒张末期尺寸（3.69 mm，95％CI 1.08至6.31）显着相关与非使用者相比，分数缩短幅度显着降低（-6.03％，95％CI -9.81％至-2.26％）。当前使用NSAID超过14天与左舒张末期尺寸较高（1.96 mm，95％CI 0.82至3.11）相关，但其他超声心动图参数没有变化。
结论：本研究是首次研究NSAIDs与超声心动图参数之间的关系，并表明短期使用NSAIDs对心脏左心室尺寸和功能有短暂影响。

BACKGROUND & AIMS: :Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most highly prescribed drugs in the world. Their analgesic, anti-inflammatory, and antipyretic actions may be beneficial; however, they are associated with severe side effects including gastrointestinal injury and peptic ulceration. Though several approaches for limiting these side effects have been adopted, like the use of COX-2 specific drugs, comedication of acid suppressants like proton pump inhibitors and prostaglandin analogs, these alternatives have limitations in terms of efficacy and side effects. In this paper, the mechanism of action of NSAIDs and their critical gastrointestinal complications have been reviewed. This paper also provides the information on different preventive measures prescribed to minimize such adverse effects and analyses the new suggested strategies for development of novel drugs to maintain the anti-inflammatory functions of NSAIDs along with effective gastrointestinal protection.

背景与目标： 非甾体类抗炎药（NSAIDs）是世界上处方最严格的药物。它们的止痛，消炎和退热作用可能是有益的；然而，它们与严重的副作用有关，包括胃肠道损伤和消化性溃疡。尽管已采用了几种限制这些副作用的方法，例如使用COX-2特异性药物，酸抑制剂（如质子泵抑制剂和前列腺素类似物）的喜剧性药物，但这些替代品在功效和副作用方面都有局限性。本文综述了非甾体抗炎药的作用机制及其严重的胃肠道并发症。本文还提供了有关采取不同预防措施以最大程度减少此类不良反应的信息，并分析了开发新药以维持NSAIDs的抗炎功能以及有效的胃肠道保护的新策略。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVE:To investigate whether preemptive administered lornoxicam changes perioperative platelet function during thoracic surgery. METHODS:A total of 20 patients scheduled for elective thoracic surgery were randomly assigned to receive either lornoxicam (16 mg, i.v.; n = 10) or placebo (n = 10) preoperatively. All patients underwent treatment of solitary lung metastasis and denied any antiplatelet medication within the past 2 weeks. Blood samples were drawn via an arterial catheter directly into silicone-coated Vacutainer tubes containing 0.5 mL of 0.129 M buffered sodium citrate 3.8% before, 15 min, 4 h and 8 h after the study medication was administered. Platelet aggregation curves were obtained by whole blood electrical impedance aggregometry (Chrono Log). RESULTS:Platelet aggregation was significantly reduced 15 min, 4 h and 8 h after lornoxicam administration compared to placebo (P < 0.05) for collagen, adenosine diphosphate and arachidonic acid as trigger substances. Adenosine diphosphate-induced platelet aggregation decreased by 85% 15 min after lornoxicam administration, and remained impaired for 8 h. CONCLUSION:Platelet aggregation assays are impaired for at least 8 h after lornoxicam application. Therefore perioperative analgesia by use of lornoxicam should be carefully administered under consideration of subsequent platelet dysfunction.

背景与目标： 背景与目的：探讨氯诺昔康在胸外科手术中是否能抢先使用围手术期血小板功能。
方法：总共20例计划进行择期胸外科手术的患者被随机分配为术前接受氯诺昔康（16 mg，i.v .; n = 10）或安慰剂（n = 10）。在过去的两周内，所有患者均接受了孤立性肺转移的治疗，并拒绝使用任何抗血小板药物。在施用研究药物之前，15分钟，4小时和8小时之后，通过动脉导管将血液样品直接抽取到装有0.5 mL 0.129 M柠檬酸钠3.8％的硅胶涂层的Vacutainer管中，该溶液的浓度为3.8％。通过全血电阻抗凝集法（Chrono Log）获得血小板聚集曲线。
结果：与安慰剂相比，氯诺昔康给药后15 min，4 h和8 h血小板聚集明显减少（P <0.05），其中胶原，腺苷二磷酸和花生四烯酸为触发物质。氯诺昔康给药后15分钟，二磷酸腺苷诱导的血小板凝集减少了85％，并持续受损8小时。
结论：氯诺昔康应用后至少8 h血小板聚集测定受损。因此，在考虑随后的血小板功能障碍时，应谨慎使用氯诺昔康围手术期镇痛。

BACKGROUND & AIMS: BACKGROUND:Nonsteroidal anti-inflammatory drug (NSAID) use may reduce the incidence of post-cardiothoracic surgery (CTS) atrial fibrillation (AF). The cerebrovascular and cardiovascular safety of using NSAIDs for post-CTS AF has not been determined. OBJECTIVE:To evaluate whether NSAIDs could reduce the incidence of post-CTS atrial fibrillation without increasing patients' risk of stroke or myocardial infarction (MI). METHODS:Patients (n = 555) undergoing CTS from the Atrial Fibrillation Suppression Trials I, II and III were evaluated in this nested cohort study. Demographic, surgical and medication use characteristics were prospectively collected as part of the AFIST trials. Endpoints included post-CTS atrial fibrillation, stroke, MI and the need for red blood cell transfusion. Multivariable logistic regression was used to control for potential confounders and calculate adjusted odds ratios with 95% confidence intervals. RESULTS:The population was 67.8 +/- 8.6 years old and 77.1% male with 127 (22.9%) patients receiving an NSAID postoperatively. Overall, 14.6% underwent valve surgery, 6.1% had prior AF, 12.6% had heart failure and 84.0% and 44.1% received postoperative beta-blockade and prophylactic amiodarone. NSAID use was associated with reductions in the adjusted odds of post-CTS atrial fibrillation (0.54 (0.32-0.90)) and the need for RBC transfusions (0.63 (0.41-0.97)). No elevation in the odds of developing stroke (1.10 (0.21-5.66)) or MI (1.70 (0.40-7.10)) was observed. LIMITATIONS:Patients were not randomized to receive NSAIDs versus a control. We may not have had adequate power to evaluate stoke or MI in this analysis. CONCLUSIONS:NSAIDs decreased the odds of developing post-CTS atrial fibrillation, further supporting the hypothesis of inflammation as a trigger for post-CTS atrial fibrillation. The need for RBC transfusions was also reduced with NSAID use. We may have been underpowered to evaluate stroke or MI incidence, but the qualitative elevations in these variables suggest more safety data is needed before NSAIDs can be routinely recommended.

背景与目标： 背景：非甾体类抗炎药（NSAID）的使用可以减少心动胸外科手术（CTS）后心房纤颤（AF）的发生。尚未确定将NSAID用于CTS后AF的脑血管和心血管安全性。
目的：评估非甾体抗炎药是否可以降低CTS后房颤的发生率，而又不增加患者发生中风或心肌梗塞（MI）的风险。
方法：在这项嵌套队列研究中，对来自房颤抑制试验I，II和III的接受CTS的患者（n = 555）进行了评估。作为AFIST试验的一部分，前瞻性地收集了人口统计学，手术和药物使用特征。终点包括CTS后的心房纤颤，中风，心肌梗死以及是否需要输注红细胞。多变量逻辑回归用于控制潜在的混杂因素，并以95％的置信区间计算调整后的优势比。
结果：该人群为67.8 /-8.6岁，男性为77.1％，其中127名（22.9％）术后接受NSAID治疗。总体而言，进行瓣膜手术的比例为14.6％，先前房颤的比例为6.1％，心力衰竭的比例为12.6％，术后进行了β受体阻滞剂和预防性胺碘酮的比例分别为84.0％和44.1％。使用NSAID可以降低CTS后房颤的调整几率（0.54（0.32-0.90））和需要进行RBC输血（0.63（0.41-0.97））。没有观察到发展中风（1.10（0.21-5.66））或MI（1.70（0.40-7.10））的几率升高。
局限性：与对照组相比，患者没有被随机分配接受NSAIDs治疗。在此分析中，我们可能没有足够的能力来评估卒中或心肌梗塞。
结论：NSAIDs降低了CTS后房颤发生的可能性，进一步支持了炎症假说是CTS后房颤触发的假设。 NSAID的使用也减少了对RBC输血的需要。我们可能没有足够的能力来评估中风或MI发生率，但是这些变量的定性升高提示，在常规推荐使用NSAID之前，需要更多的安全性数据。

BACKGROUND & AIMS: :Many drugs have the potential to cause drug-induced liver injury (DILI); however, underlying mechanisms are diverse. The concept of adverse outcome pathways (AOPs) has become instrumental for risk assessment of drug class effects. We report AOPs specific for immune-mediated and drug hypersensitivity/allergic hepatitis by considering genomic, histo- and clinical pathology data of mice and dogs treated with diclofenac. The findings are relevant for other NSAIDs and drugs undergoing iminoquinone and quinone reactive metabolite formation. We define reactive metabolites catalyzed by CYP monooxygenase and myeloperoxidases of neutrophils and Kupffer cells as well as acyl glucuronides produced by uridine diphosphoglucuronosyl transferase as molecular initiating events (MIE). The reactive metabolites bind to proteins and act as neo-antigen and involve antigen-presenting cells to elicit B- and T-cell responses. Given the diverse immune systems between mice and dogs, six different key events (KEs) at the cellular and up to four KEs at the organ level are defined with mechanistic plausibility for the onset and progression of liver inflammation. With mice, cellular stress response, interferon gamma-, adipocytokine- and chemokine signaling provided a rationale for the AOP of immune-mediated hepatitis. With dogs, an erroneous programming of the innate and adaptive immune response resulted in mast cell activation; their infiltration into liver parenchyma and the shift to M2-polarized Kupffer cells signify allergic hepatitis and the occurrence of granulomas of the liver. Taken together, diclofenac induces divergent immune responses among two important preclinical animal species, and the injury pattern seen among clinical cases confirms the relevance of the developed AOP for immune-mediated hepatitis.

背景与目标： ：许多药物都有可能引起药物性肝损伤（DILI）；但是，潜在的机制是多种多样的。不良结局途径（AOP）的概念已成为评估药物类别影响的工具。通过考虑用双氯芬酸治疗的小鼠和狗的基因组，组织学和临床病理数据，我们报告了特异性针对免疫介导的和药物超敏性/过敏性肝炎的AOP。该发现与其他非甾体抗炎药和正在经历亚氨基醌和醌反应性代谢产物形成的药物有关。我们定义了由CYP单加氧酶和嗜中性粒细胞和Kupffer细胞的髓过氧化物酶以及尿苷二磷酸葡萄糖醛糖苷转移酶产生的酰基葡萄糖醛酸苷作为分子引发事件（MIE）催化的反应性代谢产物。反应性代谢物与蛋白质结合并充当新抗原，并涉及抗原呈递细胞以引发B细胞和T细胞反应。考虑到小鼠和狗之间的免疫系统各不相同，在细胞水平上定义了六个不同的关键事件（KE），在器官水平上定义了多达四个KE，并且对于肝脏炎症的发生和发展具有机理上的合理性。对于小鼠，细胞应激反应，干扰素γ，脂肪细胞因子和趋化因子信号传导为免疫介导的肝炎的AOP提供了理论依据。对于狗，先天和适应性免疫反应的错误编程导致肥大细胞激活。它们浸润到肝实质中，并转移到M2极化的Kupffer细胞，这表示过敏性肝炎和肝肉芽肿的发生。综上所述，双氯芬酸在两种重要的临床前动物物种之间诱导不同的免疫反应，临床病例中观察到的损伤模式证实了已开发的AOP与免疫介导的肝炎的相关性。

BACKGROUND & AIMS: BACKGROUND:In up to 70%-80% of patients with a suspected non-steroidal anti-inflammatory drug hypersensitivity (NSAIDH), challenge tests with the culprit drug yield negative results. On the other hand, there could be a NSAIDH overdiagnosis when anaphylaxis is the clinical manifestation. We hypothesize that some negative NSAID challenge tests and an overdiagnosis of NSAIDH occur in patients with food-dependent NSAID-induced hypersensitivity (FDNIH). METHODS:We studied 328 patients with a suspected acute NSAIDH. FDNIH was diagnosed in patients meeting all the following: (1) tolerance to the food ingested more temporally closed before the reaction, later the episode, (2) respiratory or cutaneous symptoms or anaphylaxis related to NSAID, (3) positive skin prick test to foods and/or specific IgE to food allergens (Pru p 3, Tri a 19, Pen a 1) involved in the reaction, and (4) negative oral provocation test to the culprit NSAID. RESULTS:199 patients (60%) were diagnosed with NSAIDH and 52 (16%) with FDNIH. Pru p 3 was involved in 44 cases (84.6%) and Tri a 19 in 6 cases (11%). FDNIH subjects were younger (p < .001), with a higher prevalence of rhinitis (p < .001) and previous food allergy (p < .001), together with a higher proportion of subjects sensitized to pollens (p < .001) and foods (p < .001). Using just four variables (Pru p 3 sensitization, Tri a 19 sensitization, anaphylaxis, and any NSAID different from pyrazolones), 95.3% of cases were correctly classified, with a sensitivity of 92% and specificity of 96%. CONCLUSION:Evaluation of FDNIH should be included in the diagnostic workup of NSAIDH.

背景与目标： 背景：在高达70％-80％的怀疑患有非甾体类抗炎药超敏反应（NSAIDH）的患者中，使用该罪魁祸首药物进行的激发试验得出阴性结果。另一方面，当过敏反应为临床表现时，可能存在NSAIDH过度诊断。我们假设在食物依赖性NSAID引起的超敏反应（FDNIH）患者中发生了一些阴性的NSAID挑战试验和NSAIDH的过度诊断。
方法：我们研究了328例疑似急性NSAIDH的患者。在满足以下所有条件的患者中诊断出FDNIH：（1）对反应前，后发作更短暂地进食的食物具有耐受性，（2）与NSAID相关的呼吸或皮肤症状或过敏反应，（3）皮肤点刺试验阳性食物和/或与反应有关的食物过敏原的特定IgE（Pru p 3，Tri a 19，Pen a 1），以及（4）对罪魁祸首NSAID的口服刺激试验为阴性。
结果：199例患者（60％）被确诊为NSAIDH，52例（16％）被诊断为FDNIH。 Pru p 3涉及44例（84.6％），Tri a 19涉及6例（11％）。 FDNIH受试者年龄较小（p <.001），鼻炎患病率较高（p <.001），既往食物过敏（p <.001）以及对花粉敏感的受试者比例较高（p <.001）和食物（p <.001）。仅使用四个变量（Pru p 3致敏，Tri a 19致敏，过敏反应以及与吡唑啉酮不同的任何NSAID），正确分类了95.3％的病例，敏感性为92％，特异性为96％。
结论：FDAIH的评估应包括在NSAIDH的诊断检查中。

BACKGROUND & AIMS: BACKGROUND:NSAIDs appear to moderately reduce prostate cancer risk. However, evidence is limited on whether NSAIDs protect against prostate cancer mortality (death from prostate cancer among men without a cancer history) and case fatality (death from prostate cancer among men with prostate cancer), and whether benefits are consistent in white and black men. This study investigated associations of aspirin and non-aspirin (NA) NSAID use with prostate cancer incidence, mortality, and case fatality in a population-based cohort of white and black men. METHODS:We included 6,594 men (5,060 white and 1,534 black) from the Atherosclerosis Risk in Communities study without a cancer history at enrollment from 1987 to 1989. NSAID use was assessed at four study visits (1987-1998). Cancer outcomes were ascertained through 2012. Cox proportional hazards regression was used to estimate adjusted HRs, overall and by race. RESULTS:Aspirin use was not associated with prostate cancer incidence. However, aspirin use was inversely associated with prostate cancer mortality [HR, 0.59; 95% confidence interval (CI), 0.36-0.96]. This association was consistent among white and black men and appeared restricted to men using aspirin daily and/or for cardiovascular disease prevention. Aspirin use was inversely associated with case fatality (HR, 0.45; 95% CI, 0.22-0.94). NA-NSAID use was not associated with these endpoints. CONCLUSIONS:Aspirin use was inversely associated with prostate cancer mortality and case fatality among white and black men. IMPACT:If confirmed by additional studies, benefits of aspirin for preventing prostate cancer mortality may need to be factored into risk-benefit calculations of men considering an aspirin regimen.

背景与目标： 背景：NSAIDs似乎可适度降低前列腺癌的风险。但是，关于NSAID是否能预防前列腺癌的死亡率（无癌症病史的男性死于前列腺癌）和病死率（前列腺癌的男性死于前列腺癌），以及白人和黑人的益处是否一致，目前的证据有限。 。这项研究调查了阿司匹林和非阿司匹林（NA）NSAID的使用与白人和黑人人群中前列腺癌的发生率，死亡率和病死率之间的关系。
方法：我们纳入了从1987年至1989年入组的无动脉粥样硬化史的来自社区动脉粥样硬化风险研究的6,594名男性（5,060名白人和1,534名黑人）。在四次研究访问（1987年至1998年）中评估了NSAID的使用。在2012年之前确定癌症的结局。使用Cox比例风险回归法估算总体和种族的调整后HR。
结果：阿司匹林的使用与前列腺癌的发病率无关。然而，阿司匹林的使用与前列腺癌的死亡率呈负相关[HR，0.59； H。 95％置信区间（CI），0.36-0.96]。白人和黑人男性之间的这种联系是一致的，并且似乎仅限于每天使用阿司匹林和/或预防心血管疾病的男性。阿司匹林的使用与病死率成反比（HR，0.45； 95％CI，0.22-0.94）。 NA-NSAID的使用与这些端点无关。
结论：阿司匹林的使用与白人和黑人男性的前列腺癌死亡率和病死率成反比。
影响：如果通过其他研究证实，在考虑使用阿司匹林方案的男性的风险收益计算中，可能需要考虑阿司匹林预防前列腺癌死亡的益处。

BACKGROUND & AIMS: OBJECTIVE:To evaluate the efficacy and safety of oxaprozin in comparison with diclofenac in patients with periarthritis pain of the shoulder previously unsuccessfully treated with nonsteroidal anti-inflammatory drugs other than diclofenac and oxaprozin. METHODS:In this open, multicentre, randomised, controlled study, eligible patients with periarthritis of the shoulder were randomised to receive either oxaprozin 1200 mg once daily (n = 49) or diclofenac 50 mg three times daily (n = 47). The treatment period was 15 +/- 1 days. The study was planned on a hypothesis of equivalence between the two study drugs. The primary study endpoint was the change from baseline at day 15 in the patient-assessed shoulder pain score. Secondary efficacy variables included investigator-assessed shoulder function, patient-assessed quality of life on the Short-Form-36 (SF-36) Acute Health Survey and both patients' and investigators' overall assessment of efficacy. RESULTS:At day 15, the mean changes in shoulder pain score from baseline in the oxaprozin and diclofenac groups were -5.85 +/- SD 4.62 and -5.54 +/- SD 4.41, respectively. The difference between the two groups was not statistically significant, confirming the hypothesis of the study that oxaprozin is as effective as diclofenac. Investigator-assessed shoulder function improved in both groups but more so in the oxaprozin group (p = 0.028 at day 15). Quality of life as measured by SF-36 total score was also improved in both treatment groups, with a trend toward greater improvement in the oxaprozin group. Furthermore, a significantly more favourable effect on the SF-36 'mental health' item was observed in oxaprozin compared with diclofenac-treated patients at day 15 (p = 0.0202). As assessed by investigators, the overall efficacy of oxaprozin was superior to that for diclofenac at visit 3 (8 +/- 1 days) (p = 0.0067). Patients also assessed the overall efficacy of oxaprozin as superior to that of diclofenac at visits 3 (8 +/- 1 days) (p = 0.0235) and 4 (15 +/- 1 days) (p = 0.0272). Only six adverse events, all of which were mild or moderate in intensity and occurred in four diclofenac recipients, were observed in the study. CONCLUSIONS:As expected, once-daily oxaprozin proved to be as effective as diclofenac three times daily in reducing the primary efficacy variable of patient-assessed shoulder pain score in patients with periarthritis of the shoulder refractory to previous treatments with other NSAIDs. Oxaprozin was shown to be superior to diclofenac in improving shoulder function and was considered by investigators and patients to have greater overall efficacy than diclofenac. In addition, oxaprozin showed a trend toward superior results in improving patients' quality of life compared with diclofenac. A trend towards better tolerability results for oxaprozin compared with diclofenac was also noted.

背景与目标： 目的：评价奥沙普嗪与双氯芬酸相比，以前用双氯芬酸和奥沙普嗪以外的非甾体类抗炎药治疗失败的肩周炎患者的疗效和安全性。
方法：在这项开放性，多中心，随机，对照研究中，将符合条件的肩周炎患者随机接受每日一次1200毫克奥沙普嗪（n = 49）或每天三次3次（n = 47）双氯芬酸50 mg。治疗期为15±1天。这项研究是根据两种研究药物之间的等效性假设进行计划的。主要研究终点是患者评估的肩痛评分与第15天基线相比的变化。次要功效变量包括研究者评估的肩部功能，36型简表（SF-36）急性健康调查中患者评估的生活质量以及患者和研究者对功效的总体评估。
结果：在第15天，奥沙普嗪和双氯芬酸组的肩膀疼痛评分相对于基线的平均变化分别为-5.85 /-SD 4.62和-5.54 /-SD 4.41。两组之间的差异无统计学意义，证实了该研究的假设，即奥沙普嗪与双氯芬酸一样有效。在两组中，研究者评估的肩部功能均得到改善，但在奥沙普嗪组中则更为明显（第15天时p = 0.028）。在两个治疗组中，以SF-36总评分衡量的生活质量也得到了改善，而在oxaprozin组中有改善的趋势。此外，在第15天，与双氯芬酸治疗的患者相比，在奥沙普嗪中观察到对SF-36“心理健康”项目的明显更有利的影响（p = 0.0202）。根据研究人员的评估，在第3次就诊（8 /-1天），奥沙普嗪的总体疗效优于双氯芬酸（p = 0.0067）。患者在第3（8 /-1天）（p = 0.0235）和第4（15 /-1天）（p = 0.0272）的访视中也评估了奥沙普嗪的总体疗效优于双氯芬酸。在这项研究中，仅观察到了六种不良事件，全部为轻度或中度强度，并发生在四名双氯芬酸接受者中。
结论：如预期的那样，每天一次的奥沙普嗪被证明与双氯芬酸一样有效，每天三次，可降低以前用其他NSAID治疗的难治性肩周炎患者的患者评估的肩痛评分的主要疗效变量。奥沙普嗪在改善肩部功能方面显示出优于双氯芬酸，并且被研究者和患者认为比双氯芬酸具有更高的总体疗效。此外，与双氯芬酸相比，奥沙普嗪在改善患者生活质量方面显示出趋向于优异结果的趋势。还发现与双氯芬酸相比，奥沙普嗪具有更好的耐受性的趋势。

BACKGROUND & AIMS: BACKGROUND:Non-steroidal anti-inflammatory drugs (NSAIDs) are effective for arthritis but cause gastrointestinal injury. Bovine colostrum is a rich source of growth factors and is marketed as a health food supplement. AIMS:To examine whether spray dried, defatted colostrum or milk preparations could reduce gastrointestinal injury caused by indomethacin. METHODS:Effects of test solutions, administered orally, were examined using an indomethacin restraint rat model of gastric damage and an indomethacin mouse model of small intestinal injury. Effects on migration of the human colonic carcinoma cell line HT-29 and rat small intestinal cell line RIE-1 were assessed using a wounded monolayer assay system (used as an in vitro model of wound repair) and effects on proliferation determined using [3H]thymidine incorporation. RESULTS:Pretreatment with 0.5 or 1 ml colostral preparation reduced gastric injury by 30% and 60% respectively in rats. A milk preparation was much less efficacious. Recombinant transforming growth factor beta added at a dose similar to that found in the colostrum preparation (12.5 ng/rat), reduced injury by about 60%. Addition of colostrum to drinking water (10% vol/vol) prevented villus shortening in the mouse model of small intestinal injury. Addition of milk preparation was ineffective. Colostrum increased proliferation and cell migration of RIE-1 and HT-29 cells. These effects were mainly due to constituents of the colostrum with molecular weights greater than 30 kDa. CONCLUSIONS:Bovine colostrum could provide a novel, inexpensive approach for the prevention and treatment of the injurious effects of NSAIDs on the gut and may also be of value for the treatment of other ulcerative conditions of the bowel.

背景与目标： 背景：非甾体类抗炎药（NSAIDs）对关节炎有效，但会引起胃肠道损伤。牛初乳是生长因子的丰富来源，可作为保健食品的补充品销售。
目的：研究喷雾干燥，脱脂初乳或乳制品是否可以减少消炎痛对胃肠道的伤害。
方法：使用吲哚美辛抑制大鼠胃部损伤模型和吲哚美辛小鼠小肠损伤模型检查口服溶液的效果。使用受伤的单层测定系统（用作伤口修复的体外模型）评估了对人结肠癌细胞系HT-29和大鼠小肠细胞RIE-1迁移的影响，并通过[3H]确定了对增殖的影响胸苷掺入。
结果：用0.5或1毫升初乳制剂预处理可分别在大鼠中减少30％和60％的胃损伤。牛奶制品的功效要差得多。以与初乳制品中所发现的剂量（12.5 ng /大鼠）相似的剂量添加重组转化生长因子β，可减少约60％的伤害。在小肠损伤的小鼠模型中，将初乳添加到饮用水中（10％vol / vol）可以防止绒毛缩短。添加牛奶的准备是无效的。初乳增加了RIE-1和HT-29细胞的增殖和细胞迁移。这些影响主要归因于分子量大于30 kDa的初乳成分。
结论：牛初乳可以为预防和治疗非甾体抗炎药对肠道的伤害提供一种新颖，廉价的方法，也可能对肠其他溃疡性疾病的治疗有帮助。