Non-steroidal anti-inflammatory drugs(NSAIDs) and neuroprotection in the elderly a view from the mitochondria

The most important risk factor for stroke and neurodegeneration is aging. In fact, survival after stroke diminishes largely with aging. In fact, recovery after brain artery occlusion is dramatically worsened by aging, even normal aging is associated with neuron damage and cognitive decline. Mechanisms involved in aging-related, cognitive decline and susceptibility to neuron damage in stroke and neurode- generation are largely unknown. One of the most important mech- anisms contributing to neural dysfunction and death is excitotox- icity. This process is based on the fact that the excessive glutamate receptor stimulation may lead to neuronal damage. This overstim- ulation may be due to increased concentration of glutamate, or the prolonged activation of receptors.

Unbalance of the Physiological System May Cause Trouble —The Other Side of the Story from the Very Successful Drug, VIOXX

Selective cyclo-oxygenase-2 (CQX-2) inhibitor, VIOXX (rofecoxib), wasvoluntarily withdrawn worldwide from drugstores by its maker Merck & Co., Inc. on September 30,2004, for its potential lethal side effects of heart attack or stroke, The Merck' s decision wasbased on new, three-year data from a prospective, multi-center, randomized, placebo-controlled,double-blind clinical trial of VIOXX with an unrelated study, the APPROVe (Adenomatous PolypPrevention on VIOXX) trial. The trial has been enrolling 2 600 patients and comparing 156 weeks(three years) of treatment with VIOXX 25 mg to placebo since 2000.

芳基烷酸类非甾体抗炎药的手性药动学和药效学研究

非甾体抗炎药(nonsteroidal antiinflammatory drugs,NSAIDs)是一类常见的具有抗炎、解热、镇痛及抗风湿作用的药物,临床应用广泛。大多数芳基烷酸类非甾体抗炎药都具有手性,它们的2个对映体在体内的药理活性、代谢过程及不良反应存在显著的差异。文中对常见芳基烷酸类NSAID对映体的药效学和药动学特点,年龄、性别、疾病状态等因素对其药动学过程的影响,以及临床应用进行了综述。

氯诺昔康对福尔马林炎症痛大鼠血液一氧化氮和β-内啡肽含量的影响

目的：应用福尔马林炎症痛模型，观察氯诺昔康对大鼠血液中一氧化氮（NO）和β-内啡肽（β-EP）含量的影响，以探讨其镇痛机制。方法：选择Wistar大鼠30只，随机等分为5组：Ⅰ组：右后脚趾部皮下注射5％福尔马林0．1ml；Ⅱ组-Ⅴ组：腹腔分别注射生理盐水2ml以及2mg／kg、4mg／kg、8mg／kg氯诺昔康2ml；25min后记录注射福尔马林后0～5min（Ⅰ相）和15～60min（Ⅱ相）的累计痛评分及血液中NO和B．EP含量。结果：氯诺昔康抑制福尔马林Ⅱ相痛反应（P〈0．01），对Ⅰ相无影响（P〉0．05）；Ⅰ组和Ⅱ组间NO和B．EP含量无差异（P〉0．05），而Ⅲ-Ⅴ组分别与Ⅰ和Ⅱ组比较，差异非常显著（P〈0．01）。结论：在福尔马林炎症痛模型中，氯诺昔康通过降低血液内NO和增加β-EP含量，发挥镇痛作用。

武汉地区21家医院2000～2002年非甾体抗炎药物市场分析

目的 :目的 :探讨非甾体抗炎药 (NSAIDs)的使用状况及发展趋势。方法 :采用武汉地区 2 1家医院NSAIDs的购入数据 ,应用金额排序法 ,统计分析 2 0 0 0～ 2 0 0 2年购药金额。结果 :NSAIDs的购入金额逐年增加 ;双氯芬酸和布洛芬的购入金额以绝对优势占据NSAIDs市场的前两位 ,但呈下降趋势 ;不良反应较小的新型环氧合酶 2抑制剂的市场份额迅速上升 ,但长期使用的安全性尚待观察。结论 :NSAIDs市场将进一步扩大 ;开发能选择性地抑制外周前列腺素 (PG)的合成又不影响胃肠道等部位的生理PG合成的药物具有广阔的市场前景。

氯诺昔康对福尔马林炎症痛大鼠脊髓神经元nNOS表达的影响

目的：观察氯诺昔康对福尔马林炎症痛大鼠脊髓神经元nNOS表达的影响，以探讨其镇痛作用机制。方法：将30只Wistar大鼠随机等分为5组。各组大鼠均在右后脚趾部皮下注射5％福尔马林0．1ml，其中Ⅱ～Ⅴ组大鼠在注射福尔马林前25min分别向腹腔内注射生理盐水2ml、含有2mg／kg，4mg/kg和8m/kg的氯诺昔康2ml。记录注射福尔马林后0～5min和15～60min的累计疼痛评分。用免疫组化法测定脊髓神经元nNOS阳性信号的平均积分光密度值。结果：氯诺昔康抑制福尔马林Ⅱ相反应（P＜0．01），对I相反应无影响（P＞0．05）；nNOS平均积分光密度值Ⅰ组和Ⅱ组间差异无统计学意义（P＞0．05）；Ⅲ～Ⅴ组分别与Ⅰ组和Ⅱ组比较均降低，Ⅲ～Ⅴ组间比较呈逐渐降低趋势，差异均有统计学意义（P＜0．05）。结论：氯诺昔康可能通过抑制脊髓神经元nNOS表达发挥镇痛作用。

解热、镇痛、非甾体抗炎前药的合成

本文报道了以布洛芬为原料,与扑热息痛依次经取代、酯化等反应合成了一种具有解热、镇痛和抗炎作用的前体药物的方法。

非类固醇类抗炎药的小肠黏膜损害

非类固醇类抗炎药(NSAIDs)对胃十二指肠黏膜的损害十分突出,得到临床广泛重视。近年来随着诊断手段的不断发展,发现NSAIDs的小肠黏膜损害的发生率也不低。NSAIDs导致小肠黏膜损伤是一个复杂的多步骤的过程,可导致黏膜通透性增加、炎症、溃疡、出血、狭窄及穿孔等。目前尚无有效的防治方法。本文就NSAIDs导致的小肠黏膜损害作一综述。

Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy

Low-dose aspirin(LDA) is clinically used for the prevention of cardiovascular and cerebrovascular events with the advent of an aging society.On the other hand,a very low dose of aspirin(10 mg daily) decreases the gastric mucosal prostaglandin levels and causes significant gastric mucosal damage.The incidence of LDAinduced gastrointestinal mucosal injury and bleeding has increased.It has been noticed that the incidence of LDA-induced gastrointestinal hemorrhage has increased more than that of non-aspirin non-steroidal anti-inflammatory drug(NSAID)-induced lesions.The pathogenesis related to inhibition of cyclooxygenase(COX)-1 includes reduced mucosal flow,reduced mucus and bicarbonate secretion,and impaired platelet aggregation.The pathogenesis related to inhibition of COX-2 involves reduced angiogenesis and increased leukocyte adherence.The pathogenic mechanisms related to direct epithelial damage are acid back diffusion and impaired platelet aggregation.The factors associated with an increased risk of upper gastrointestinal(GI) complications in subjects taking LDA are aspirin dose,history of ulcer or upper GI bleeding,age > 70 years,concomitant use of non-aspirin NSAIDs including COX-2-selective NSAIDs,and Helicobacter pylori(H.pylori) infection.Moreover,no significant differences have been found between ulcer and non-ulcer groups in the frequency and severity of symptoms such as nausea,acid regurgitation,heartburn,and bloating.It has been shown that the ratios of ulcers located in the body,fundus and cardia are significantly higher in bleeding patients than the ratio of gastroduodenal ulcers in patients taking LDA.Proton pump inhibitors reduce the risk of developing gastric and duodenal ulcers.In contrast to NSAIDinduced gastrointestinal ulcers,a well-tolerated histamine H2-receptor antagonist is reportedly effective in prevention of LDA-induced gastrointestinal ulcers.The eradication of H.pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding.Continuous aspirin therapy for patients with gastrointestinal bleeding may increase the risk of recurrent bleeding but potentially reduces the mortality rates,as stopping aspirin therapy is associated with higher mortality rates.It is very important to prevent LDA-induced gastroduodenal ulcer complications including bleeding,and every effort should be exercised to prevent the bleeding complications.

Cyclooxygenases in hepatocellular carcinoma

Many epidemiological studies demonstrate that treatment with non-steroidal anti-inflammatory drugs （NSAIDs） reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase （COX） enzymes are well-known targets of NSAIDs. However, conventional NSAIDs nonselectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by proinflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, malignant, and metastastic cancers, including hepatocellular carcinoma （HCC）. Overexpression of COX-2 in patients with HCC is generally higher in welldifferentiated HCCs compared with less-differentiated HCCs or histologically normal liver, suggesting that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC. In tumors, overexpression of COX-2 leads to an increase in prostaglandin （PG） levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor cells. The availability of novel agents that selectively inhibit COX-2 （COXIB）, has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood. Increasing evidence suggests the involvement of molecular targets other than COX-2 in the antiproliferative effects of COX-2 selective inhibitors. Therefore, COX-inhibitors may use both COX-2- dependent and COX-2-independent mechanisms to mediate their antitumor properties, although their relative contributions toward the in vivo effects remain less clear. Here we review the features of COX enzymes, the role of the expression of COX isoforms in hepatocarcinogenesis and the mechanisms by which they may contribute to HCC growth, the pharmacological properties of COX-2 selective inhibitors, the antitumor effects of COX inhibitors, and the rationale and feasibility of COX-2 inhibitors for the treatment of HCC.

Changes of gastric ulcer bleeding in the metropolitan area of Japan

BACKGROUND The two main causes of gastric ulcer bleeding are Helicobacter pylori(H.pylori)infection and ulcerogenic medicines,although the number of cases caused by each may vary with age.In Japan,the rate of H.pylori infection has fallen over the last decade and the number of prescriptions for non-steroidal anti-inflammatory drugs(NSAIDs)and antithrombotic drugs is increasing as the population ages.Methods of treatment for gastric ulcer bleeding have advanced with the advent of hemostatic forceps and potassium-competitive acid blocker(P-CAB).Thus,causes and treatments for gastric ulcer bleeding have changed over the last decade.AIM To examine the trends of gastric ulcer bleeding over 10 years in the metropolitan area of Japan.METHODS This is a single-center retrospective study.A total of 564 patients were enrolled from inpatients admitted to our hospital with gastric ulcer bleeding between 2006 and 2016.Age,medication history,H.pylori infection,method of treatment,rate of rebleeding,and the length of hospitalization were analyzed.Factors associated with gastric ulcer bleeding were evaluated using Fisher’s exact test,Pearson’s Chi-squared test or Student’s t-test as appropriate.The Jonckheere-Terpstra test was used to evaluate trends.A per-protocol analysis was used to examine the rate of H.pylori infection.RESULTS There was a significant increase in the mean age over time(P<0.01).The rate of H.pylori infection tended to decrease over the study period(P=0.10),whereas the proportion of patients taking antithrombotic agents or NSAIDs tended to increase(P=0.07).Over time,the use of NSAIDs and antithrombotic drugs increased with age.By contrast,the rate of H.pylori infection during the study period fell with age.H.pylori-induced ulcers accounted for the majority of cases in younger patients(<70 years old);however,the rate decreased with age(P<0.01).The method of treatment trend has changed significantly over time.The main method of endoscopic hemostasis has changed from clipping and injection to forceps coagulation(P<0.01),and frequently prescribed medicines have changed from proton pump inhibitor to P-CAB(P<0.01).The rate of rebleeding during the latter half of the study was significantly lower than that in the first half.CONCLUSION These trends,gastric ulcers caused by ulcerogenic drugs were increasing with age and H.pylori-induced ulcers were more common in younger patients,were observed.

State-of-the-Art management of knee osteoarthritis

Osteoarthritis(OA) is the most common type of arthritis found in the United States' population and is also the most common disease of joints in adults throughout the world with the knee being the most frequently affected of all joints. As the United States' population ages along with the increasing trends in obesity prevalence in other parts of the world, it is expected that the burden of OA on the population, healthcare system, and overall economy will continue to increase in the future without making major improvements in managing knee OA. Numerous therapies aim to reduce symptoms of knee OA and continued research has helped to further understand the complex pathophysiology of its disease mechanism attempting to uncover new potential targets for the treatment of OA. This review article seeks to evaluate the current practices for managing knee OA and discusses emerging therapies on the horizon. These practices include non-pharmacological treatments such as providing patient education and self-management strategies, advising weight loss, strengthening programs, and addressing biomechanical issues with bracing or foot orthoses. Oral analgesics and anti-inflammatories are pharmacologicals that are commonly used and the literature overall supports that some of these medications can be helpful for managing knee OA in the short-term but are less effective for long-term management. Additionally, more prolonged use significantly increases the risk of serious associated side effects that are not too uncommon. Diseasemodifying osteoarthritis drugs are being researched as a treatment modality to potentially halt or slow disease progression but data at this time is limited and continued studies are being conducted to further investigate their effectiveness. Intra-articular injectables are also implemented to manage knee OA ranging from corticosteroids to hyaluronans to more recently plateletrich plasma and even stem cells while several other injection therapies are presently being studied. The goal of developing new treatment strategies for knee OA is to prolong the need for total knee arthroplasty which should be utilized only if other strategies have failed. High tibial osteotomy and unicompartmental knee arthroplasty are potential alternatives if only a single compartment is involved with more data supporting unicompartmental knee arthroplasty as a good treatment option in this scenario. Arthroscopy has been commonly used for many years to treat knee OA to address degenerative articular cartilage and menisci, however, several high-quality studies have shown that it is not a very effective treatment for the majority of cases and should generally not be considered when managing knee OA. Improving the management of knee OA requires a multi-faceted treatment approach along with continuing to broaden our understanding of this complex disease so that therapeutic advancements can continue to be developed with the goal of preventing further disease progression and even potentially reversing the degenerative process.

Comparison of intra-articular injection of parecoxib vs oral administration of celecoxib for the clinical efficacy in the treatment of early knee osteoarthritis

BACKGROUND Non-steroid anti-inflammatory drugs(NSAIDs)have played a crucial role in the treatment of osteoarthritis,especially in the early stages.However,the cardiovascular risk and adverse gastrointestinal reactions of oral NSAIDs in elderly people cannot be underestimated.Intra-articular injection of NSAIDs may be a new attempt for early knee osteoarthritis treatment.Parecoxib may be a suitable drug for intra-articular injection.AIM To observe the clinical efficacy of the intra-articular injection of parecoxib for early knee osteoarthritis.METHODS Early knee osteoarthritis patients(n=110)were retrospectively analyzed.These patients were divided into three groups:Basic treatment+oral glucosamine(group A,n=37),oral celecoxib+basic treatment+oral glucosamine(group B,n=37),and intra-articular injection of parecoxib+basic treatment+oral glucosamine(group C,n=36).Intra-articular injection of parecoxib was performed once every 2 wk at a dose of 40 mg each time,for three times total.The three groups were compared in terms of visual analogue scale(VAS)scores,Hospital for Special Surgery(HSS)scores and patient satisfaction before and after treatment.The levels of inflammatory cytokines in the synovial fluid were detected in the three groups before and after treatment.RESULTS All patients were followed up for an average of 15.5±2.7 mo.The clinical efficacy was estimated by VAS and HSS scores at 12 mo after treatment.Inflammatory cytokine levels in the synovial fluid were evaluated at 3 mo after treatment.VAS and HSS scores were significantly improved in each group compared with before(P<0.001).There were significant differences among the three groups in VAS and HSS scores(P<0.001).The clinical efficacy of group C was superior to that of groups A and B(P<0.001),while group B outperformed group A in this respect(P<0.001).The patient satisfaction was the highest in group C(P<0.001).After treatment,the levels of tumor necrosis factorα(TNF-α)and interleukin(IL)-6 in the synovial fluid decreased in each group compared with before(P<0.001),while the levels of IL-10 increased(P<0.001).The three groups differed significantly in the levels of TNF-a,IL-6 and IL-10 in the synovial fluid after treatment(P<0.001).CONCLUSION For patients with early knee osteoarthritis,intra-articular injection of parecoxib could effectively improve clinical symptoms.This method may be a reliable alternative for early knee osteoarthritis.

Design,Synthesis and in vitro Evaluation of a New Class of Novel Cyclooxygenase-2 Inhibitors:3,4-diaryl-3-pyrrolin-2-ones

design, synthesis and in vivo evaluation of a new class of COX-2 inhibitors 3, 4-diaryl-3-pyrrolin-2-ones are reported.

Effectiveness of therapeutic barium enema for diverticular hemorrhage

AIM:To evaluate the effectiveness of barium impaction therapy for patients with colonic diverticular bleeding.METHODS:We reviewed the clinical charts of patients in whom therapeutic barium enema was performed for the control of diverticular bleeding between August2010 and March 2012 at Yokohama Rosai Hospital.Twenty patients were included in the review,consisting of 14 men and 6 women.The median age of the patients was 73.5 years.The duration of the followup period ranged from 1 to 19 mo(median:9.8 mo).Among the 20 patients were 11 patients who required the procedure for re-bleeding during hospitalization,6patients who required it for re-bleeding that developed after the patient left the hospital,and 3 patients who required the procedure for the prevention of rebleeding.Barium(concentration:150 w%/v%)was administered per the rectum,and the leading edge of the contrast medium was followed up to the cecum by fluoroscopy.After confirmation that the ascending colon and cecum were filled with barium,the enema tube was withdrawn,and the patient’s position was changed every 20 min for 3 h.RESULTS:Twelve patients remained free of rebleeding during the follow-up period(range:1-19mo)after the therapeutic barium enema,including 9men and 3 women with a median age of 72.0 years.Re-bleeding occurred in 8 patients including 5 men and 3 women with a median age of 68.5 years:4developed early re-bleeding,defined as re-bleeding that occurs within one week after the procedure,and the remaining 4 developed late re-bleeding.The DFI(disease-free interval)decreased 0.4 for 12 mo.Only one patient developed a complication from therapeutic barium enema(colonic perforation).CONCLUSION:Therapeutic barium enema is effective for the control of diverticular hemorrhage in cases where the active bleeding site cannot be identified by colonoscopy.

Ketoprofen,peginterferon 2a and ribavirin for genotype 1 chronic hepatitis C:A phaseⅡ study

AIM:To evaluate the safety of adding ketoprofen to pegylated-interferon(PEG-IFN)with or without ribavirin and the effect on viral kinetics,STAT1 activity and expression of 2'-5'-oligoadenylate synthetase (2'-5'OAS)in genotype 1 chronic hepatitis C in a phaseⅡstudy. METHODS:Forty-five patients were studied:fifteen were randomized to PEG-IFN plus ribavirin(PR),16 to PEGIFN plus ketoprofen and 14 to PR and ketoprofen.Themolecular study of IFN-dependent signal transduction was conducted in 9 patients from each group. RESULTS:The combination of ketoprofen and PEG- IFN with or without ribavirin was safe and well tolerated.An early activation of STAT1 was observed in ke-toprofen-treated patients,but this activation was less sustained over time.Conversely,ketoprofen plus PEG- IFN and ribavirin induced an early and sustained increase of 2'-5'OAS transcription starting 24 h after the first dose until the 36th wk.These data are consistent with the clinical results,showing a better sustained virological response and a lower relapse rate in patients receiving ketoprofen plus PEG-IFN and ribavirin. CONCLUSION:The addition of ketoprofen to the standard therapy of chronic hepatitis C should be explored in larger randomized clinical studies.

非甾体抗炎药相关性上消化道出血的临床及胃镜特征观察

目的探讨非甾体抗炎药相关性上消化道出血的临床及胃镜特征。方法选择我院收治的50例非甾体抗炎药相关性上消化道出血患者为观察组,将同期580例溃疡、黏膜糜烂出血的患者作为对照组。统计观察组对非甾体抗炎药的应用情况。比较两组患者的临床及胃镜特征。结果应用非甾体抗炎药防治心脑血管疾病服药27例,主要为阿司匹林;治疗关节痛10例,包括双氯芬酸钠、吲哚美辛、布洛芬;治疗感冒等8例,服用感冒胶囊(含扑热息痛)及氨基比林;服用2种或2种以上非甾体抗炎药5例。观察组临床特征中无消化系统症状、年龄≥60岁、血红蛋白≥10 g/L、住院时间<14 d、存活的占比均高于对照组(P<0.05);胃镜检查过程中病变性质的糜烂性、多发、胃部、Hp阳性发生率高于对照组(P<0.05)。结论非甾体抗炎药相关性上消化道出血患者典型消化道症状相对较少,以年龄≥60岁Hp阳性患者高发,且患者的血红蛋白影响较小,停药后可较快痊愈;胃镜检查特征表现为黏膜糜烂、浅表溃疡以及出血症状。临床上应采取相应的措施避免及减少患者非甾体抗炎药相关性上消化道出血的发生。

A tribute to Dr.Frank I Tovey on his 90th birthday

This paper pays a tribute to Dr.Frank I Tovey on his 90th birthday which happens on September 1,2011,and briefly describes the major findings in his research career and contributions as follows.The geographical prevalence of duodenal ulceration is related to staple diets.Unrefined wheat and maize,soya,certain pulses and millets are associated with a low prevalence while refined wheat,maize and rice,yams,cassava and green banana with a high prevalence.Predominant foodstuffs from low prevalence areas are ulceroprotective in rat peptic ulcer models.The protective activity lies in the lipid fraction present in these foodstuffs.The lipid fraction also promotes ulcer healing,is active both orally and intramuscularly and is ulceroprotective against nonsteroidal anti-inflammatory drugs(NSAIDs).The phospholipids and phytosterols present in the lipid have been identified to be responsible for this protective activity.The combination of phospholipids and phytosterols may be of value in the prevention and treatment of duodenal ulceration and protection against the ulcerogenic effect of NSAIDs.

美洛昔康联合阿仑膦酸钠对膝骨性关节炎合并骨质疏松的临床研究

目的探讨美洛昔康联合阿仑膦酸钠对膝骨性关节炎合并骨质疏松患者的临床疗效。方法 64例Kellgren-Lawrence 2-3级的膝骨性关节炎合并骨质疏松患者随机分为试验组32例和对照组32例。试验组口服美洛昔康片,每次15 mg,每天3次,连用3个月;口服阿仑膦酸钠片,每次70 mg,每3天1次,连用1个月。对照组仅口服美洛昔康片。比较2组患者的临床疗效、疼痛、僵硬程度、日常活动难度及生存质量。结果治疗后,试验组有效率(96.9%)显著高于对照组(78.1%,P<0.05)。试验组疼痛程度较治疗前显著降低(P<0.05)。试验组的僵硬程度、日常活动难度及生存质量变化情况均显著优于对照组(P<0.05)。结论美洛昔康联合阿仑膦酸钠治疗膝骨性关节炎合并骨质疏松,不仅明显减轻患者疼痛、改善关节僵硬情况,而且可以提高患者生存质量。

吲哚美辛新剂型研究进展

吲哚美辛属于非甾体类抗炎药(NSAIDs),是环氧酶抑制剂之一。普通制剂具有生物利用度低、毒副作用大等不足。而脂质体、纳米粒等药物传递系统不仅能够改善吲哚美辛的溶解度、提高生物利用度,而且还具有靶向性,能增加吲哚美辛在病灶区域的浓度、增强疗效、降低系统毒性。因此开发吲哚美辛新剂型是对其研究的一个重要方向。本文通过文献检索对国内外吲哚美辛新剂型的研究进展进行了综述。