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如何防止药物丢失英语作文Title: Preventing Medication Loss: Strategies and Importance。
In today's fast-paced world, the loss of medication has become a concerning issue. Whether it's due to negligence, forgetfulness, or even theft, the consequences of medication loss can be severe. Therefore, it's crucial to implement effective strategies to prevent such losses. In this essay, we will explore various methods to safeguard medication and emphasize the importance of doing so.One of the most common reasons for medication loss is forgetfulness. People often misplace their medication or forget where they last placed it. To address this issue, individuals can establish a routine for taking medication and designate a specific place to store it. This could be a medicine cabinet, a drawer, or a pill organizer. By consistently storing medication in the same location, individuals are less likely to misplace it.Moreover, labeling medication containers can help prevent loss. Clearly marking the name of the medication, dosage instructions, and the patient's name can make it easier to identify and retrieve lost medication. Additionally, storing medication in its original packaging with the prescription label intact can provide important information in case of loss.Another effective strategy is to keep track of medication inventory. This involves regularly checking the quantity of medication on hand and replenishing supplies as needed. By monitoring inventory levels, individuals can identify any discrepancies or potential losses early on and take appropriate action.Furthermore, securing medication in a safe and accessible location is essential for preventing theft. This is especially important in shared living spaces or environments where there may be unauthorized access to medication. Investing in lockable storage containers or cabinets can help deter theft and protect valuablemedication.In addition to these practical measures, raising awareness about the importance of medication security is crucial. Education campaigns can inform individuals about the risks associated with medication loss and the steps they can take to prevent it. Healthcare professionals, community organizations, and government agencies can collaborate to disseminate information and promote responsible medication management.The consequences of medication loss can be significant, both for individuals and society as a whole. For individuals, losing medication can disrupt treatment plans, lead to missed doses, and jeopardize health outcomes. In cases where medication is lost or stolen, individuals may also incur financial costs to replace it. From a broader perspective, medication loss contributes to healthcare inefficiencies and strains healthcare resources.Moreover, medication loss can have serious implications for public health and safety. Certain medications, such asopioids and controlled substances, are particularly vulnerable to diversion and misuse when lost or stolen. This not only poses risks to individuals but also fuels substance abuse epidemics and undermines efforts to combat drug-related harm.In conclusion, preventing medication loss is essential for ensuring optimal health outcomes and promoting public safety. By implementing strategies such as establishing routines, labeling medication, monitoring inventory, securing storage, and raising awareness, individuals and communities can mitigate the risks associated with medication loss. Through collective efforts and responsible medication management, we can safeguard valuable resources and improve the well-being of individuals and society as a whole.。
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Patient: Mr. Smith。
他汀类药物治疗早期脑梗死的疗效观察衡水市第五人民医院，河北衡水053000【摘要】目的：研究他汀类药物治疗早期脑梗死的方法及疗效。
方法：将从2009年1月-2011年12月到本院神经内科住院治疗的92例早期脑梗死患者随机平均分为观察组及治疗组，给予观察组患者阿司匹林进行治疗；给予治疗组阿司匹林治疗的基础上，再加入辛伐他汀进行治疗。
比较两组患者的治疗效果，比较治疗后患者的神经功能缺损情况。
结果：治疗组患者的治疗总有效率、神经功能缺损情况均优于观察组患者，两组患者在治疗效果、神经功能缺损情况比较差异具有统计学意义(p<0.05)。
结论：采用他汀类药物对早期脑梗死患者进行治疗，能有效改善患者的神经功能，治疗效果显著，值得广泛推广。
【关键词】他汀类药物；早期脑梗死；神经功能缺损【中图分类号】r743.33【文献标识码】a文章编号：1004-7484（2012）-05-0729-02【abstract】objective：to study the statin treatment method and the curative effect of early cerebral infarction.methods：from 2009january -2011december to the institute of neurology hospital treatment of 92 patients with early acute cerebral infarction were randomly divided into observation group and treatment group，the observation group were given aspirin therapy；treatment group on the basis of aspirin therapy，adding simvastatin paring the two groups of patients with treatment，compared to patients after the treatment of nerve function defect.results：the treatment group patients treated with total efficiency，neurological deficits were superior to that in the observation group，two groups of patients in therapeutic effect，neurological deficit is the difference was statistically significant (p<0.05).conclusion：the use of statin drugs on early cerebral infarction patients were treated，can effectively improve the neurological function，obvious curative effect，and is worthy of popularization.【key words】statin；cerebral infarction；neural function defect在临床上，脑梗死是一种较为常见的心脑血管疾病，而且发病率呈逐年上升的趋势，其致残率及病死率均很高［1］，因此预防及治疗早期脑梗死对提高患者的治疗效果及预后有重要意义。
• 142•国际脑血管病杂志202丨年 2 月第 29 卷第 2 期Int J Cerebrovasc Dis, February 2021，Vol. 29, No. 2•综述•依折麦布预防缺血性卒中谭燕张健中山大学附属第一医院神经内科，广东省重大神经疾病诊治研究重点实验室，国家临床重点专科和国家重点学科，广州510080通信作者：张健，Email:zhjian55@【摘要】血脂异常是卒中高危因素，降低低密度脂蛋内胆固醇（low-density lipoprotein chesterol,L D L-C)水平可降低缺血性卒中发病风险。
他汀类药物和PC SK9抑制剂均可有效降低L D L-C水平，但有些患者不能耐受他汀类药物，而P C SK9抑制剂则价格昂贵。
动物实验显示，依折麦布可通过激活腺苷酸活化蛋內激酶（AMP-activated protein kinase, AMPK)信号通路减轻氧化应激和内质网应激反应,抑制细胞凋亡，增加自噬，从而保护神经组织。
临床研究表明，依折麦布可在他汀类药物治疗基础上进一步降低L D L-C水平，降低急性冠状动脉综合征患者的缺血性卒中风险，且没有明显不良反应。
但是，对于年龄為75岁、L D L-C升高且没有冠心病的老年人，依折麦布则不能降低卒中发生率。
目前，依折麦布用于缺血性卒中二级预防的相关研究较少，其作用尚需大样本随机对照试验进一步证实。
【关键词】卒中；脑缺血;依折麦布；降血脂药;抗胆固醇血症药基金项目：国家重点研发计划项目（20丨7丫?(：1307501);广东省自然科学基金（20丨7人0303丨3575);广东省自然科学基金（2017A030310523);华南神经疾病早期干预及功能修复研究国际合作基地(2015B050501003);广东省神经系统重大疾病诊治.T程技术研究中心；广东省神经系统重大疾病诊治转化医学创新平台；广东省神经系统疾病临床医学研究中心DOl ： 10.3760/cm a.j.issn. 1673-4165.2021.02.011Ezetimibe in the prevention o f ischemic strokeTan Yan, Zhang JianDepartment o f Neurology, the First Affiliated Hospital o f Sun Yat-sen University; Guangdong Provincial KeyLaboratory for Diagnosis and Treatment o f Major Neurological Diseases, National Key Clinical Specialty andKey Discipline o f Neurology, Guangzhou, 510080, ChinaCorresponding author: Zhang Jian Email:******************n【Abstract】Dyslipidemia is a risk factor for stroke, and reducing low-density lipoprotein cholesterol(LDL-C) levels can decrease the risk o f ischemic stroke. Both statins and PCSK9 inhibitors can effectivelyreduce LDL-C levels, but som e patients cannot tolerate statins, and PCSK9 inhibitors are expensive. Animalexperiments have shown that ezetimibe can reduce oxidative stress and endoplasmic reticulum stressresponse, inhibit cell apoptosis, increase autophagy, and protect nerve tissue by activating AMP activatedprotein kinase (AMPK) signaling pathway. Clinical studies have shown that ezetimibe can further reduceLDL-C levels on the basis o f statin therapy, and reduce the risk o f ischemic stroke in patients with acutecoronary syndromes, and there is no obvious adverse reaction. However, ezetimibe cannot reduce theincidence o f stroke in elderly people who are ^75years old, have elevated LDL-C and do not have coronaryheart disease. At present, there are few studies on the use o f ezetimibe for secondary prevention o f ischemicstroke, and its effect needs to be further confirmed by large randomized controlled trials.【Key w ord s】Stroke; Brain ischemia; Ezetimibe; Hypolipidemic agents; Anticholesteremic agentsFund programs ： National Key R&D Program o f China (2017YFC1307501); Guangdong Natural ScienceFoundation o f China (2017A030310523, 2017A030313575 ); South China International Cooperation Base forEarly Intervention and Functional Rehabilitation o f Neurological Diseases (2015b05001003); GuangdongEngineering and Technology Research Center for Diagnosis and Treatment o f Major Nervous SystemDiseases; Guangdong Translational Medicine Innovation Platform for Diagnosis and Treatment o f Major国际脑血管病杂志2021 年 2 月第 29 卷第 2 期Int J Cerebrovasc Dis，February 2021, Vol. 29, No. 2•143•Nervous System Diseases; Guangdong Clinical Medicine Research Center for Nervous System DiseasesDOI ： 10.3760/cm a.j.issn. 1673^ 165.2021.02.011卒中是全世界范围内继缺血性心脏病之后的第 二大死亡原因，但在中国已成为首位死亡原因[|]。
Prescribing InformationDUPHASTONTabletsName of the medicinal productDuphaston 10mg film-coated tabletsQualitative and Quantitative CompositionDydrogesterone film-coated tablets contain 10 mg dydrogesterone per tablet. Pharmaceutical FormA round, biconvex, scored, white coloured film-coated tablet, one side bearing the inscription , the other side bearing the inscription ‘155’ on either side of the break markThe score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.IndicationsProgesterone deficienciesTreatment of progesterone deficiencies such as:-Treatment of dysmenorrhoea-Treatment of endometriosis-Treatment of secondary amenorrhoea-Treatment of irregular cycles-Treatment of dysfunctional uterine bleeding-Treatment of pre-menstrual syndrome.-Treatment of threatened and habitual abortion, associated with proven progesterone deficiency-Treatment of infertility due to luteal insufficiencyDosage and administrationDysmenorrhoea : 10 mg twice daily from day 5 to day 25 of thecycle.Endometriosis : 10 mg two or three times daily from day 5 today 25 of the cycle or continuously. Dysfunctional bleeding : 10 mg twice daily for five to seven days.(to arrest bleeding)Dysfunctional bleeding : 10 mg twice daily from day 11 to day 25 of the (to prevent bleeding) cycle.Amenorrhoea : an oestrogen once daily from day 1 to day 25 ofthe cycle, together with 10 mg dydrogesteronetwice daily from day 11 to day 25 of the cycle. Pre-menstrual syndrome : 10 mg twice daily from day 11 to day 25 of the cycle.Irregular cycles : 10 mg twice daily from day 11 to day 25 of the cycle.Threatened abortion : 40 mg at once, then 10 mg every eight hoursuntil symptoms remit.Habitual abortion : 10 mg twice daily until the twentieth week ofpregnancy. Infertility due to luteal : 10 mg daily from day 14 to 25 of the cycle. Insufficiency Treatment should be maintained for at least sixconsecutive cycles. It is advisable to continuetreatment for the first few months of pregnancyas described under 'Habitual abortion'. Duphaston is not recommended for use in children below age 18 due toinsufficient data on safety and efficacy.ContraindicationsHypersensitivity to the active substance or to any of the excipients.Known or suspected progestogen dependent neoplasms.Undiagnosed vaginal bleedingSpecial warnings and precautions for useBefore initiating treatment with dydrogesterone for abnormal bleeding, the etiology for the bleeding should be clarified.Treatment with dydrogesterone has infrequently been associated with alterations in liver function, sometimes accompanied by clinical symptoms. Thus, dydrogesterone should be used with caution in patients with acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal. In cases of severe hepatic impairment treatment should be discontinued.Breakthrough bleeding may occur in a few patients.Conditions which need supervisionIf any of the following conditions are present, have occurred previously, and/orhave been aggravated during pregnancy or previous hormone treatment, thepatient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Trademark, in particular:1. Porphyria2. DepressionOther conditionsPatients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.Interaction with other medicinal products and other forms of interactionNo interaction studies have been performed.Pregnancy and lactationIt is estimated that altogether roughly 35 million women have been treated with dydrogesterone. Although the number of pregnancies is difficult to estimate, as an approximation it can be assumed that in utero foetuses were exposed to dydrogesterone in around 9 million pregnancies1. From spontaneous surveillance systems to date, there is no evidence that dydrogesterone can not be used during pregnancy.No other relevant epidemiological data on dydrogesterone are available.However, a recent US case-control study investigating 502 cases with hypospadias and 1286 healthy controls suggested at least a 2-fold increased risk of second/third degree hypospadias among boys born by mothers who took progestogens (predominantly progesterone) shortly prior or during early pregnancy (OR 2.2, 95% CI 1.0-5.0). The causality is unclear as the indication for progesterone in pregnancy may be potential risk factors for hypospadias. For dydrogesterone, the risk of hypospadias is unknown.Animal studies have been conducted, however, are insufficient with respect to pregnancy, embryonal /fetal, or postnatal development due to major difference in metabolism between rats and humans (for details see section “preclinical safety data”. The potential risk for humans is unknown.Limited animal safety data suggest that dydrogesterone has delaying effects on partuition, which is consistent with its progestogenic activity.Dydrogesterone is excreted in the milk of nursing mothers. A risk to the suckling child cannot be excluded. Dydrogesterone should not be used during breast-feeding.There is no evidence that dydrogesterone decreases fertility at therapeutic dose.Effects on ability to drive and use machinesDydrogesterone has no or negligible influence on the ability to drive and use machines.1This high exposure in pregnancy is due to the fact that dydrogesterone has pregnancy related indications inlarge parts of the world.Undesirable effectsThe undesirable effects reported in clinical trials and/or in post marketing experience following dydrogesterone therapy are:MedDRA system organ class Common>1/100, <1/10Uncommon>1/1,000,<1/100Rare>1/10,000,<1/1,000Very rare<1/10,000 incl.isolated reportsBlood and the lymphatic system disorders Haemolytic anaemiaImmune systemdisordersHypersensitivityNervous system disorders Migraines/ headacheHepatobiliary disorders hepaticfunctionabnormal (withjaundice,asthenia ormalaise, andabdominal pain)Skin and subcutaneous tissue disorders Dermatitisallergic (e.g.rash, pruritus,urticaria)AngioedemaReproductive system and breast disorders Metrorrhagia Breastpain/tendernessGeneraldisorders andadministrationsite conditionsOedemaOther adverse reactions obtained from the market with unknown frequency in association with dydrogesterone treatment:Neoplasms benign, malignant and unspecified (incl. cysts and polyps)Increase in size of progestogen dependent neoplasms (e.g.meningioma) (see section 4.3). Psychiatric disordersDepressed moodReproductive system and breast disordersBreast swellingOverdoseLimited data are available with regard to overdose in humans. Dydrogesterone was well tolerated after oral dosing (maximum daily dose taken to date in humans 360 mg). No reports of ill-effects from overdose have been recorded. If a large overdose is discovered within two or three hours and treatment seems desirable, gastric lavage is recommended. There are no specific antidotes and treatment should be symptomatic. Aforementioned information is also applicable for overdosing in children. Pharmacological propertiesPharmacodynamic propertiesPharmacotherapeutic group: Genito Urinary system and sex hormones,ATC code: G03DB01Dydrogesterone is an orally-active progestogen which produces a complete secretory endometrium in an oestrogen-primed uterus thereby providing protection for estrogen induced increased risk for endometrium hyperplasia and/or carcinogenesis. It is indicated in all cases of endogenous progesterone deficiency. Dydrogesterone has no estrogenic, no androgenic, no thermogenic, no anabolic and no corticoid activity. Pharmacokinetic propertiesAfter oral administration of labeled dydrogesterone on average 63% of the dose is excreted into the urine. Within 72 hours excretion is complete. Dydrogesterone is completely metabolized. The main metabolite of dydrogesterone is 20α-dihydrodydrogesterone (DHD) and is present in the urine predominantly as the glucuronic acid conjugate. A common feature of all metabolites characterized is the retention of the 4,6diene-3-one configuration of the parent compound and the absence of 17α-hydroxylation. This explains the lack of estrogenic and androgenic effects of dydrogesterone.After oral administration of dydrogesterone, plasma concentrations of DHD are substantially higher as compared to the parent drug. The AUC and C max ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. Dydrogesterone is rapidly absorbed. The T max values of dydrogesterone and DHD vary between 0.5 and 2.5 hours.Mean terminal half lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively.Dydrogesterone is not excreted in urine as pregnanediol, like progesterone. Analysis of endogenous progesterone production based on pregnanediol excretion therefore remains possible.Preclinical safety dataReceptor binding studies and functional activity studies revealed antiandrogenic potency of progesterone, dydrogesterone and its metabolite dihydrodydrogesterone (DHD). The antiandrogenic potency of dydrogesterone and its metabolite DHD is probably noticeably weaker than that of progesterone. With regard to antiandrogenic effects mediated by inhibition of 5α-reductase type II, an important enzyme for differentiation of the maleexternal genitalia, progesterone is as potent as the synthetic enzyme inhibitor finasteride, whereas dydrogesterone and DHD are inactive.The overall potential to act as antiandrogenic endocrine disruptors may be rated as highest for Progesterone, lower for Dydrogesterone and lowest for DHD. Embryofoetal developmental studies were conducted in rats and rabbits using high dosages of dydrogesterone. No structural adverse effects were recorded in the foetal offspring. In a subsequent peripostnatal developmental study pregnant rats were treated with similar dosages of dydrogesterone during the period of gestation, and pups were raised. There were occasions of hypospadias in the male offspring but only at the highest dose. The next lower dose of dydrogesterone showed a sufficient safety margin in rat plasma exposure (>80 fold) compared to the estimated exposure at the maximum human daily dose of 60 mg. However, due to major species differences in metabolism between rats and humans, no adequate margin of exposure could be determined for the main human metabolite dihydrodydrogesterone.Limited animal safety data suggest that dydrogesterone has delaying effects on parturition, which is consistent with its progestogenic activity.Dydrogesterone has been used in several animal models and has been proven to be an entity with low toxicity, not having mutagenic or carcinogenic properties. Pharmaceutical particularsList of excipientsLactose monohydrate, methylhydroxypropylcellulose, maize starch, colloidal anhydrous silica, magnesium stearate, Opadry Y-1-7000 whiteIncompatibilitiesNone knownShelf-life5 years.Special precautions for storageDo not store above 30˚C. Keep in a dry place.Keep the blister in the outer carton, in order to protect from moisture.Nature and contents of container- Blister strips of aluminium foil and PVC film, coated with PVDCof 20 tabletsSpecial precautions for disposalAny unused product or waste material should be disposed of in accordance with local requirements.Manufacturer: Solvay PharmaceuticalsImporter: Perrigo Israel Agencies Ltd.22.2.2010 The format of this leaflet was determined by the Ministry of Health and its content was checked and approved by it in February 2010.。
有利于骨愈合。
但是细菌对抗生素的抵抗力变得越来越强，因此更有必要进行抗生素骨水泥的进一步研究。
目前，虽然研究不断深入，但是对于抗生素骨水泥毒副作用的了解不够深入。
怎样才能有效选择不同感染病例的抗生素？如何确定最适剂量抗生素？如何做到抗生素浓度释放最佳控制，同时又能降低抗生素对局部和全身的毒性反应？如何把有效性和安全性达到最佳平衡,这些都是需要我们今后需要进一步研究,需要着重解决的问题。
参考文献［1］林鹏，蔡锦方,李宗玉，等•改良Papmeau植骨术与抗生素磷酸钙骨水泥局部应用治疗牵张成骨并发Ceirny H型骨髓炎的比 较研究［J］.现代生物医学进展,2017,31(13):2486.[2]沈骏，于晓雯,付士平，等•应用负压封闭引流技术结合负载万古霉素硫酸钙治疗慢性骨髓炎的疗效评价[J].上海医学，2011,34(3):224.[3] Buchholz HW,Elson RA,Heinert K.Antibiotlc.-loaded acryliccement(Current concepts[J].Clin Orthop,1984,190(96.-10& [4] Buchholz HW,Elson RA,Engelbrecht E,et al.Management ofdeep infection of total hip replacement[J].J Bone Joint Surg Br, 1981,63-B(3)：342-353.[5] Ostermann PA,Selingson D,Henry SL.Local antibiotic therapyfor severe open fractures:a review of1085cansecutive eases[J].Bone Jiont Surg,1995,77(1)：93.[6]吕厚山，马迪，丁海明•三种抗生素骨水泥抗菌和机械强度的研究•中华外科杂志,1998,36(Suppl)：50-52.(收稿日期：2020-0N-10)阿托伐他汀对难治性肾病综合征患者血脂及颈动脉内膜-中膜厚度影响杨建兵杨玉凤刘迎九肾病综合征是加速动脉粥样硬化的危险因素。
CHINA MEDICINE AND PHARMACY Vol.11 No.10 May 20211阿利西尤单抗联用他汀类药物对急性冠脉综合征患者血脂水平的影响叶韬华1，2 王慧勇1 柏 慧1 潘秀娣1 杜一鹏1 岑惠玲1 卜 彤1 曾昭华1▲1.广州医科大学附属第一医院心血管内科，广东广州 510120；2.广东省肇庆市端州区华佗医院内科，广东肇庆 526060[摘要] 目的 在急性冠脉综合征（ACS）患者中，研究观察阿利西尤单抗联用他汀类药物降脂治疗的效果，及低密度脂蛋白胆固醇（LDL-C）治疗达标率。
方法 选取广州医科大学附属第一医院心血管内科2020年4—7月入组的ACS 需要二次介入手术，且LDL-C ＞1.8 mmol/L 的32例患者，观察期为3个月。
根据既往是否已使用他汀类药物及对阿利西尤单抗接受情况分组，初用他汀组（n =12）即本次ACS 入院前未服用他汀类药物，入院后开始使用他汀类药物（阿托伐他汀钙片20 mg/d，或瑞舒伐他汀钙片10 mg/d）治疗；他汀加倍量组（n =9）即在原来他汀治疗基础上，改为加倍剂量他汀治疗；联用阿利西尤单抗组（n =11）即在原来他汀类药物治疗基础上，加用阿利西尤单抗75 mg，皮下注射，2周一次。
观察每组血脂（总胆固醇、甘油三酯、高密度脂蛋白胆固醇、LDL-C）、肝功能（丙氨酸氨基转移酶、谷氨酰转肽酶）、肾功能（肌酐）及外周血象（白细胞、血小板）等生化指标。
其中联用阿利西尤单抗组复查抽血，在下一针阿利西尤单抗注射液注射前一天。
以第一次入院时生化指标为分组治疗前指标；以按计划3个月后，二次介入治疗入院时，生化指标为分组治疗后指标。
并观察LDL-C 的治疗达标率。
结果 三个治疗组均能降低血清总胆固醇浓度和LDL-C 浓度。
初用他汀组、他汀加倍量组、联用阿利西尤单抗组治疗后总胆固醇降幅分别为34.65%（P ＜0.01）、7.94%（P ＞0.05）、52.88%（P ＜0.01）；LDL-C 降幅分别为40.93%（P ＜0.01）、8.17%（P ＞0.05）、72.38%（P ＜0.01）。
五加生化胶囊联合卡前列素氨丁三醇注射液治疗产后出血的临床疗效发布时间：2021-06-17T16:28:46.623Z 来源：《世界复合医学》2021年4期作者：郭仁秋[导读] 目的对五加生化胶囊联合卡前列素氨丁三醇注射液治疗产后出血的临床疗效展开研究郭仁秋黑龙江省大庆市第五医院 163714【摘要】目的对五加生化胶囊联合卡前列素氨丁三醇注射液治疗产后出血的临床疗效展开研究。
方法选取我院2020年9月-2021年2月期间收治的132例产后出血患者为研究对象，并采取随机平均法分为两组，各66例。
对照组患者采取常规卡前列素氨丁三醇注射液进行治疗，而观察组则在此基础上用五加生化胶囊对患者进行治疗，对临床治疗效果对比分析。
结果同对照组相比，观察组促进宫缩的有效率更高、患者出血量更少，止血时间更短，对比具有统计学意义（P＜0.05）。
结论对产后出血患者采用五加生化胶囊和拉前列素氨丁三醇注射液联合治疗的方式进行治疗可以在很大程度上减少出血量、缩短止血时间，及时有效的促进宫缩，值得推广。
【关键词】五加生化胶囊；卡前列素氨丁三醇；产后出血；临床疗效[Abstract] Objective To study the clinical effect of Wujia biochemical capsule combined with captopril aminobutanol injection in the treatment of postpartum hemorrhage. Methods 132 patients with postpartum hemorrhage were selected from September 2020 to February 2021 in our hospital. The patients were divided into two groups, 66 cases each. The control group was treated with conventional carboprostin aminobutyrol injection, while the observation group treated the patients with Wujia biochemical Capsule on this basis, and compared the clinical treatment effect. Results compared with the control group, the observation group had higher efficiency in promoting uterine contraction, less bleeding and shorter hemostasis time (P < 0.05). Conclusion the combination of Wujia biochemical capsule and alprostatin trianol injection can reduce the bleeding volume, shorten the hemostasis time and promote uterine contraction in time and effectively.[Key words] Wujia biochemical capsule; carbrostatin trianol; postpartum hemorrhage; clinical effect分娩往往伴随着很高的生命健康风险，产后出血是分娩过程中最常见的一种并发症【1】，当产妇产后24小时内出血量超过500毫升就存在一定生命危险，产后出血是造成分娩死亡的一大诱因，因此一旦出现大出血征兆，必须即使对出血量进行控制。
MSCT用于他汀类药物治疗冠状动脉非钙化斑块疗效评估的可行性研究曹中华;高锋;高毅;康陈波;刘岩【摘要】Objective:To discuss the feasibility on therapeutic evaluation of non-calcified coronary plaques with statins by mul-ti-slice spiral computed tomography (MSCT). Methods:Select 60 cases of confirmed non-calcified coronary plaque,treated with single statin. Selective coronary angiography (SCA) and MSCT examination performed before treatment and 1 year after treat-ment to evaluate arterial stenosis,MSCT examination evaluated the luminal stenosis (SE) and the cross-sectional area (S),na-ture and patch area,patch CT density values change in the location of plaques. Detected the serum total cholesterol (TC), triglyceride (TG),low density lipoprotein (LDL-C),high density lipoprotein (HDL-C). Results:TC、TG、LDL-C of post treatment were less than prior treatment (P<0.05),HDL-C of post treatment was higher than prior treatment (P<0.05). Coronary artery stenosis segment had 127 with SCA inspection of prior treatment,114 with MSCT inspection of prior treatment,the diagnosis co-incidence rate were93.70%,102 with SCA inspection of after treatment,93 with MSCT inspection of after treatment,the diagno-sis coincidence rate were91.18%,the difference was not statistically significant (P>0.05). Coronary artery plaque had 114 with MSCT inspection of prior treatment,93 with MSCT inspection of prior treatment,the drop rate were 22.84%. SE,S,nature and patch area of post treatment were less than prior treatment(P<0.05),patch CT density values of after treatment was higher than prior treatment (P<0.05). Conclusion:Statins have definice efficacy in the treatment of non-calcified plaques of the coro-nary arteries. MSCT can assess the changes of non-calcified coronary plaques after statins therapy quantitatively ,effective moni-toring method is feasible.%目的:探讨MSCT用于他汀类药物治疗冠状动脉非钙化斑块疗效评估的可行性.方法:选取确诊的冠状动脉非钙化斑块患者60例,给予单一的他汀类药物治疗,在治疗前、治疗1年时行选择性冠状动脉造影检查(SCA)及MSCT检查,评价动脉血管狭窄情况.MSCT检查同时评价斑块所在位置管腔狭窄度(SE)及截面积(S)、斑块性质及面积、斑块CT密度值变化,检测治疗前后血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)变化.结果:患者治疗后TC、TG、LDL-C较治疗前明显下降,HDL-C较治疗前明显升高(均P<0.05).以SCA为金标准,冠状动脉狭窄节段治疗前SCA检出114个,诊断符合率89.76%(114/127);治疗1年后MSCT检出93个,诊断符合率91.18%(93/102).SCA检查冠状动脉狭窄节段的诊断符合率治疗前后比较差异无统计学意义(P>0.05).MSCT显示治疗前114个非钙化斑块,治疗1年后斑块数下降至93个,下降率为22.84%,治疗后冠状动脉管腔SE、S、斑块面积均较治疗前明显下降(P<0.05),斑块密度值较治疗前升高(P<0.05).结论:他汀类药物治疗冠状动脉非钙化斑块疗效肯定.MSCT可清晰显示斑块治疗前后变化,同时可进行准确的量化评估,是一种可行的监测方法.【期刊名称】《中国中西医结合影像学杂志》【年(卷),期】2017(015)004【总页数】3页(P416-418)【关键词】体层摄影术,X线计算机;他汀类;冠状动脉疾病;斑块,动脉粥样硬化性;治疗结果【作者】曹中华;高锋;高毅;康陈波;刘岩【作者单位】河南省濮阳市安阳地区医院放射科,河南安阳 455000;河南省濮阳市安阳地区医院放射科,河南安阳 455000;河南省濮阳市安阳地区医院放射科,河南安阳 455000;河南省濮阳市安阳地区医院放射科,河南安阳 455000;河南省濮阳市安阳地区医院放射科,河南安阳 455000【正文语种】中文冠状动脉粥样硬化性心脏病是全球常见病，病理基础是冠状动脉粥样硬化性改变，可表现为稳定性斑块及不稳定性斑块，钙化斑块相对稳定，未钙化斑块稳定性较差，易脱落形成血栓，导致脑中风。
卡前列素氨丁三醇注射液治疗宫缩乏力性产后出血的临床治疗效果发布时间：2021-07-19T05:12:25.183Z 来源：《健康世界》2021年6期作者：曹廷娜[导读] 目的探讨分析对宫缩乏力性产后出血患者采用卡前列素氨丁三醇注射液进行治疗的临床应用效果。
四川省广安市邻水安康医院 638500摘要：目的探讨分析对宫缩乏力性产后出血患者采用卡前列素氨丁三醇注射液进行治疗的临床应用效果。
方法此次研究对象选自本院2018年12月到2020年12月期间期间收治的宫缩乏力性产后出血患者，共计124例，按照对其采用的治疗方法进行平均分组：分别是观察组62例和对照组62例。
其中接受常规治疗的患者为对照组，接受卡前列素氨丁三醇注射液进行治疗的患者为观察组。
比较两组患者的临床治疗效果以及产后出血量。
结果观察组患者的治疗效果明显好于对照组患者，（P<0.05）；观察组患者的产后出血量明显低于对照组患者，（P<0.05）。
结论根据本次研究的结果可以确认，对宫缩乏力性产后出血患者采用卡前列素氨丁三醇注射液进行治疗可以取得更好的治疗效果，还可以有效的降低患者的产后出血量，是一种安全有效的治疗方式，具有推广价值。
关键词：宫缩乏力性产后出血；卡前列素氨丁三醇注射液；治療效果；对比分析Abstract：Objective To investigate the clinical effect of captoprietin trianol injection in the treatment of postpartum hemorrhage with uterine asthenia.Methods 124 patients with uterine asthenia postpartum hemorrhage were selected from the period from December 2018 to December 2020.According to the treatment methods，the subjects were divided into 62 cases in observation group and 62 in control group.The patients who received routine treatment were the control group，and the patients who received the treatment with carboprost aminobutanol injection were the observation group.The clinical treatment effect and postpartum hemorrhage were compared between the two groups.Results the treatment effect of the observation group was better than that of the control group（P < 0.05）；The postpartum hemorrhage of the observation group was significantly lower than that of the control group（P < 0.05）.Conclusion according to the results of this study，it can be confirmed that the treatment of postpartum hemorrhage patients with uterine asthenia can achieve better therapeutic effect by using captoprietin trianol injection，and can effectively reduce the amount of postpartum hemorrhage.It is a safe and effective treatment formula and has the promotion value.Keywords：postpartum hemorrhage due to uterine contraction and asthenia；Carbrostatin aminobutyrol injection；The therapeutic effect；comparative analysis产后出血属于产科在临床上最为常见也是最为严重的一种并发症，是导致孕产妇死亡的最主要原因。
中国当代医药2021年1月第28卷第1期CHINA MODERN MEDICINE Vol.28No.1January 2021·临床研究·肝硬化门静脉高压症合并食管胃底曲张破裂出血是临床常见的急危重症,有较高的致死率,食管胃底静脉曲张破裂出血是肝硬化门静脉高压症最常见的死亡原因[1-2]。
当前临床治疗肝硬化食管胃底静脉曲张破裂出血的主要方法为内科药物治疗,最新临床研究显示[3-5],生长抑素及类似物奥曲肽为肝硬化门静脉高压症合并食管胃底曲张破裂出血患者治疗提供一种新思路。
本研究对三种血管活性药物(奥曲肽、生长抑素和垂体后叶素)在肝硬化食管胃底静脉曲张破裂出血治疗的临床效果进行探究,现报道如下。
三种血管活性药物治疗肝硬化致食管胃底静脉曲张破裂出血的临床效果席艳辽宁省凌源市中心医院合理用药办公室,辽宁凌源122500[摘要]目的探究奥曲肽、生长抑素和垂体后叶素三种血管活性药物治疗肝硬化食管胃底静脉曲张破裂出血的临床效果及不良反应,并分析不同药物治疗方案的经济性。
方法2017年7月~2019年12月,按照三种血管活性药物(奥曲肽、生长抑素和垂体后叶素)分别选取辽宁省凌源市中心医院治疗的20例肝硬化致食管胃底静脉曲张破裂出血患者,三种血管活性药物对应三种不同用药方法,对不同用药方法的临床效果、不良反应及药物经济性进行综合比较分析。
结果生长抑素组及奥曲肽组的临床治疗总有效率高于垂体后叶素组,差异有统计学意义(P <0.05);在用药期,生长抑素组及奥曲肽组未见明显不良反应,垂体后叶素组出现腹痛及大便次数增多症状7例,1例在治疗期因疼痛难忍而停药,1例发生呕吐恶心症状,1例出现头晕、头痛症状。
生长抑素组及奥曲肽组的药费高于垂体后叶素组,差异有统计学意义(P <0.05)。
结论在肝硬化食管胃底静脉曲张破裂出血患者治疗中,奥曲肽、生长抑素较垂体后叶素有更好的临床效果,更低用药不良反应,但垂体后叶素有价格优势,建议临床根据患者的实际综合考虑用药方案。
瑞舒伐他汀、阿托伐他汀对脑梗死病人静脉溶栓效果-风险的影响刘宁宁; 董瑞芳; 史方堃【期刊名称】《《中西医结合心脑血管病杂志》》【年(卷),期】2019(017)021【总页数】4页(P3403-3406)【关键词】脑梗死; 静脉溶栓; 瑞舒伐他汀; 阿托伐他汀; 血脂; 超敏C反应蛋白; 神经功能【作者】刘宁宁; 董瑞芳; 史方堃【作者单位】沧州市中心医院脑科医院河北沧州 061000【正文语种】中文【中图分类】R743; R255.2脑梗死是临床常见脑血管病变，系由各类原因所致脑组织血液循环障碍引起的脑组织缺血、缺氧及坏死表现，病人伴不同程度神经功能缺失，依据发病机制可分为脑栓塞、腔隙性脑梗死及脑血栓形成，其中脑血栓形成最为常见，占全部脑梗死的60%[1]。
目前早期溶栓促进梗死脑组织再通，恢复缺血脑组织灌注是治疗脑梗死的常用手段[2]。
近年来研究发现，他汀类药物用于脑卒中急性期可改善病人预后，促进病人神经功能恢复，降低其死亡风险，同时可强化溶栓药物效果[3]。
但由于分子结构的差异，不同他汀类药物药代动力学及药效均存在一定的差别，其中瑞舒伐他汀对3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制效果最强，其次为辛伐他汀、阿托伐他汀等[4]。
基于此，本研究探讨瑞舒伐他汀、阿托伐他汀对脑梗死病人静脉溶栓效果及风险的影响，现报道如下。
1 资料与方法1．1 临床资料选择2014年12月—2016年12月我院收治的120例脑梗死病人作为研究对象。
纳入标准：符合全国脑血管学术会议通过的脑梗死诊断标准[4]，经影像学检查证实；年龄>18岁；存在持续性脑功能损害体征，时间超过0.5 h，美国国立卫生研究院卒中量表(NIHSS)评分≥4分；梗死时间≤6 h；病人或家属已签署知情同意书。
排除标准：近3个月内有心肌梗死、脑梗死史或头颅外伤史者；影像学检查见颅内出血者；近期有外科大手术史者；发病前48 h应用肝素抗凝者；无法控制高血压或高血糖者；合并严重肝肾功能障碍者；合并全身感染性疾病者；有出血倾向疾病者；短暂性脑缺血发作者；对他汀类药物成分过敏者；合并恶性肿瘤且预计生存期低于3个月者；妊娠、哺乳期女性；依从性差无法配合治疗者。
阿托伐他汀在改善高血压合并高血脂患者管内功能中的临床应用探讨摘要：探讨阿托伐他汀在改善高血压合并高血脂患者管内功能中的临床应用探讨，高血压合并高血脂在临床较为常见，为世界重大卫生问题，与单纯高血压和正常人群比较，高血压合并高血脂患者除血脂和血压升高外，白介素-1、超反应蛋白、白细胞介素-6等炎症因子也呈显著升高表现，故采用阿托伐他汀治疗，可将上述炎症因子的水平显著降低，使患者的炎症状态明显改善，进而减少了并发症的发生率，显著改善了患者的生存质量。
关键词：阿托伐他汀；高血压合并高血脂【中图分类号】r544.1 【文献标识码】a 【文章编号】1674-7526(2012)04-0107-02高血压合并高血脂在临床较为常见，为世界重大卫生问题，是病发冠心病、脑卒中的重要危险因素。
目前，随着物质生活水平的巨大进步，公众饮食结构发生了较大的改变，加之人口步入老龄化及其它多因素的影响，其病发率在逐年升高，对人类身心健康均造成严重威胁[1-4]。
但发病机制尚不十分明确，有文献报道，高血压合并高血脂疾病发生和发展中血管内皮损伤所致的炎症反应可能为参于的重要因素。
故选择一种有效方式行针对性治疗对改善患者预后具有非常重要的临床意义[5-6]。
1 高血压合并高血脂病理机制分析炎症除在创伤和感染的病理生理过程中存在外，随着研究的深入，显示其与心血管病也有着密切相关性，如高血压、心肌病、动脉粥样硬化等的病理过程中均有炎症参与[7-9]。
炎症因子包括细胞因子、趋化因子、转化生长因子、黏附因子和急性期反应蛋白等，是指炎症过程中炎症反应由细胞产生和分泌的物质参与，如冠心病、动脉粥样硬化等。
为临床针对高血压血管壁的病理过程进行治疗提供了依据。
2 阿托伐他汀作用机制分析研究表明，他汀类药物除可降低血脂外，还对动脉粥样斑块有缩小、稳定作用，显著改善了血管弹性。
这一作用与他汀类的降胆固醇作用相关，可使高血压血管壁的病理过程得到改变[10-13]。
第一次作业1.定义：情报检索语言是根据情报检索的需要而创制的人工语言，专门用于各种手工的和计算机化的情报检索系统，表达文献主题概念和检索课题概念。
类型：情报检索语言可分为分类检索语言、主题检索语言和代码检索语言三大语系，此外，还有一种引证关系追溯法，按其作用来看，也可以说是情报检索语言的一种类型。
2. 具有直接性、专指性、灵活性的优点。
3.文献数据库类型：（1）题录数据库（2）文摘数据库（3）图书馆馆藏目录数据库（4）全文数据库（5）光盘数据库（6）多媒体数据库（7）网络数据库4.检索式：(作者单位:重庆医科大学) and (第一作者:文明)题录：超小型Fe3O4纳米的磁学性能测定作者：文明(1); 柏玮(2); 李少林(2); 李建(3); 李必波(4); 李强(3); 张志伟(1) 作者单位：(1)重庆医科大学附属第一医院放射科,重庆400016; (2)重庆医科大学基础医学院放射医学教研室,重庆400016; (3)西南大学物理学院,重庆400715; (4)重庆医科大学药学院,重庆400016出处：西南师范大学学报?自然科学版2007; 32(6) : 15-18相关链接：主题相关5.检索式：(缺省[智能]:糖尿病肾病) and (缺省[智能]:醛糖还原酶抑制剂预防)题录：醛糖还原酶抑制剂对糖尿病大鼠肾小球蛋白激酶C活性的影响作者：杨君作者单位：海军总医院肾内科100037出处：海军总医院学报2003.03.30; 16(1) : 11-13相关链接：参考文献主题相关6.检索式：(缺省[智能]:肿瘤) and (缺省:奥沙利铂or 草酸铂or 乐沙定or 草铂)题录：草酸铂联合不同方法静脉输注5-氟尿嘧啶治疗晚期消化道肿瘤的观察及护理作者：黄宗琼; 何敏; 许辉琼; 易琼作者单位：四川大学华西医院肿瘤二病房,四川成都610041出处：华西医学2008; 23(2) : 375-376相关链接：主题相关7.检索式：(缺省[智能]:视盘) and (主题词:血管炎)题录：中药为主治疗视盘血管炎作者：温树东; 李勋赤; 李长海作者单位：广州中山医科大学中山医科中心510060出处：中国中医眼科杂志1999.08.11; 9(3) : 153-154相关链接：参考文献主题相关第二次作业1.检索式：(机构=南京医科大学)*(题名或关键词=流行病学)*全部期刊*年=2000-2010命中文献数：共找到189条题录：BL教学模式在流行病学教学中的应用胡志斌彭志行沈红兵南京医科大学流行病与卫生统计学系,江苏南京210029摘要:在流行病学的教学中分别应用PBL教学模式和传统教学模式教学．并对教学效果进行量化比较。
Cardiovascular PharmacologyStatin post-treatment provides protection against simulated ischemia in bovine pulmonary arterial endothelial cellsXing Wu a ,b ,Daowei Lin a ,c ,Guofu Li a ,d ,Zhiyi Zuo a ,⁎aDepartment of Anesthesiology,University of Virginia,Charlottesville,VA 22908,USAbDepartment of Cardiology,First Af filiated Hospital,Sun Yat-Sen University,Guangzhou 510080,Guangdone,China cDepartment of Anesthesiology,Sun-Yat-Sen Memorial Hospital,Sun-Yat-Sen University,Guangzhou 510120,Guangdone,China dIntensive Care Unit,Shengjing Hospital,China Medical University,Shenyang 110004,Liaoning,Chinaa b s t r a c ta r t i c l e i n f o Article history:Received 3September 2009Received in revised form 2March 2010Accepted 18March 2010Available online 31March 2010Keywords:StatinPostconditioning Endothelial cells Protein kinase BStatins,inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)reductase,can have protective effects in various organs.We determined whether application of statins after a detrimental insult protected endothelial cells.Bovine pulmonary arterial endothelial cells (BPAEC)were subjected to a 5-h oxygen –glucose deprivation (OGD)and a 1-h simulated reperfusion.Simvastatin or atorvastatin alone or plus mevalonate (the immediate product of the reaction mediated by HMG-CoA reductase),geranylgeranyl pyrophosphate (GGPP,a product downstream of mevalonate),Ly294002(a protein kinase B/Akt inhibitor),U0126[an extracellular signal-regulated kinase (ERK)pathway inhibitor]or diphenyleneiodonium [a nicotinamide adenine dinucleotide phosphate (NADPH)oxidase inhibitor]were added to cells immediately after the OGD for 1h.Simvastatin and atorvastatin dose-dependently reduced the OGD and simulated reperfusion-induced lactate dehydrogenase (LDH)release from primary BPAEC and BPAEC between passage 4and 15.This effect was inhibited by mevalonate,GGPP and Ly294002and was not affected by U0126.Consistent with those results,simvastatin and atorvastatin increased the expression of phospho-Akt/activated Akt,and did not change the expression of phospho-ERK/activated ERK after the OGD and simulated reperfusion.The OGD and simulated reperfusion-induced LDH release and superoxide production,as measured by the dihydroethidium fluorescent intensity,were inhibited by diphenyleneiodonium.These results suggest that statin post-treatment reduces OGD and simulated reperfusion-induced cell injury.This effect may be mediated by inhibiting HMG-CoA reductase and the subsequent inhibition of small GTPases.GTPase activation depends on GGPP generation and contributes to the formation of NADPH oxidase complex that produces superoxide.The statin post-treatment-induced protection may also involve activated Akt.©2010Elsevier B.V.All rights reserved.1.IntroductionStatins are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)reductase.They are widely used in clinic to reduce blood cholesterol levels and,therefore,to decrease risks for cardiovascular diseases.Statins also have pleiotropic effects that are unrelated to its cholesterol lowering results (Davignon,2004).For example,statins can be used to reduce osteoporosis and tumor growth and to improve ventricular function in patients with heart failure (Davignon,2004;Miida et al.,2004).Several studies have shown that statins can induce a preconditioning effect (Domoki et al.,2009;Gu et al.,2008;Lazar et al.,2003),a phenomenon in which a prior application of a stimulus or drug reduces injury caused by a subsequent insult.This statin-inducedpreconditioning effect is inhibited by mevalonate,the immediate product of the reaction mediated by HMG-CoA reductase and the precursor molecule for both sterol (including cholesterol)and nonsterol (isoprenoid)biosynthesis (Domoki et al.,2009).The term postconditioning is initially used to describe a phenomenon of protection by applying a modi fied reperfusion sequence [3to 5cycles of a brief episode of ischemia (10–30s)and reperfusion (10–30s)]to the tissues or organs that just suffer a prolonged episode of ischemia (Zhao et al.,2003).Subsequently,it has been shown that postconditioning effect can be induced not only by the application of brief episodes of ischemia (ischemic postconditioning)but also by the use of drugs in various organs including brain and heart (Lee et al.,2008;Weihrauch et al.,2005).Endothelial cells are an important component for all organs and systems.They form a unique barrier to prevent free access of chemicals and cells in the blood to the vascular smooth muscle cells and parenchymal cells of organs.Endothelial cells also release various molecules,such as nitric oxide,to affect the functions of other cells (Nathan and Xie,1994).Thus,it is critical to maintain the structural and functional integrity of endothelial cells;however,many insults canEuropean Journal of Pharmacology 636(2010)114–120⁎Corresponding author.Department of Anesthesiology,University of Virginia Health System,1Hospital Drive,PO Box 800710,Charlottesville,Virginia 22908-0710,USA.Tel.:+14349242283;fax:+14349242105.E-mail address:zz3c@ (Z.Zuo).0014-2999/$–see front matter ©2010Elsevier B.V.All rights reserved.doi:10.1016/j.ejphar.2010.03.028Contents lists available at ScienceDirectEuropean Journal of Pharmacologyj o u r n a l h o me p a g e :w w w.e l sev i e r.c om /l oc a te /e j p h a rthreaten this integrity.For example,ischemia can injure endothelial cells.One potential approach that can be used clinically to protect endothelial cells is by a postconditioning/post-treatment mechanism induced by drugs.Thus,we hypothesize that statins can induce a postconditioning effect in endothelial cells.We tested this hypothesis with statins(simvasatin and atorvastatin)in the bovine pulmonary arterial endothelial cells(BPAEC),and used oxygen–glucose depriva-tion(OGD)to simulate ischemia in vitro.We also determined whether statin-induced postconditioning effects were mediated by inhibiting the HMG-CoA reductase and by activating the phosphoinositide3-kinase(PI3K)/protein kinase B(Akt)or extracellular signal-regulated kinase(ERK),two kinases that have been shown to mediate protection induced by various preconditioning and postconditioning stimuli in many organs(Raphael et al.,2006;Zuo et al.,2006).2.Materials and methods2.1.ReagentsSimvastatin and Ly294002were purchased from Calbiochem(San Diego,CA).Atorvastatin was kindly provided as a gift by Pfizer(New York,NY).Mevalonate,geranylgeranyl pyrophosphate(GGPP),dihy-droethidium,U0126,diphenyleneiodonium and the anti-glyceraldehyde 3-phosphate dehydrogenase(GAPDH)antibody(catalogue number: G9545)were obtained from Sigma(St.Louis,MO).The Lactate dehydrogenase(LDH)kit was purchased from Clontech Laboratory (Mountain View,CA).The anti-phospho-ERK antibody(catalogue number:sc-7383)and anti-ERK(catalogue number:sc-93)antibody were from Santa Cruz Biotechnology,Inc.(Santa Cruz,CA).The anti-phospho-Akt antibody(anti-Ser473)(catalogue number:9271)and the anti-Akt antibody(catalogue number:9272)were obtained from Cell Signaling Technology,Inc.(Danvers,MA).2.2.Cell cultureThe bovine pulmonary arterial endothelial cell(BPAEC)was isolated and characterized as described earlier(Zuo and Johns,1997).The cells were cultured in a T75flask containing12ml of culture media composed of Dulbecco's Modified Eagle's Medium(DMEM)(containing 1000mg/l D-glucose,L-glutamine and pyridoxine HCl),110mg/l sodium pyruvate,10%heat inactivated fetal bovine serum,90µg/ml thymidine, 100U/ml penicillin and100µg/ml streptomycin.The cells were kept in a humidified atmosphere of95%air–5%CO2at37°C.The medium was changed three times per week.When the cells were70–80%confluent, they were exposed to0.05%trypsin-EDTA solution and sub-cultured in a newflask.Experiments were performed on BPAECs at passages4to15.Primary BPAEC cultures were used in some experiments.These cells were harvested and sorted byflow cytometry as described earlier(Zuo and Johns,1997).Cultures with N98%endothelial cells as identified by staining with acetylated low density lipoprotein coupled with1,1′-dioctadecyl-3,3,3′,3′-tetramethylindo-carbocyanine perchlorate were used in the studies.2.3.Exposure to oxygen–glucose deprivationThe cells were plated into6-well plates at a density of5×105cells/ ml(2ml/well)and cultured overnight(about17h).Glucose-free buffer contained154mM NaCl,5.6mM KCl,3.6mM NaHCO3,2.3mM CaCl2, and5.0mM HEPES.OGD buffer was prepared by bubbling the glucose-free buffer with100%N2for30min.Cells in the control group were washed with and incubated in glucose containing buffer(2g/l glucose) in a humidified atmosphere of95%air–5%CO2at37°C.OGD was applied by washing cells with the OGD buffer three times and then placing the cells in a2ml/well of this OGD buffer.These plates were immediately placed in an air-tight chamber(Billups-Rothenberg,CA)gassed with 100%N2for10min.The oxygen content in the outlet of the chamber was monitored with a Datex™infrared analyzer(Capnomac,Helsinki, Finland)and reached0%at3∼5min after the onset of gassing.After closure of the inlet and outlet of the chamber,the chamber was kept at 37°C for5h except for the time-course experiment.After confirming that the oxygen content in the chamber was0%at the end of the OGD period,the chamber was opened and glucose was added to make the final glucose concentration in the buffer at2g/l.The plates were then kept for1h in a humidified atmosphere of95%air–5%CO2at37°C.2.4.Application of statins and other chemicalsSimvastatin or atorvastatin was added to the incubation buffer at the beginning of the simulated reperfusion to make thefinal concentrations from0.5to10µM in the buffer.In some experiments,diphenyleneio-donium(20µM),GGPP(10,20and40µM),mevalonate(200and 500µM),Ly294002(10µM)or U0126(1µM)was added to the in-cubation buffer at the onset of the simulated reperfusion(the con-centrations in the brackets are thefinal concentrations in the incubation buffer).All of the incubations with these agents were for1h.ctate dehydrogenase assayLDH activity was determined using the LDH cytotoxicity detection kit,as we did before(Kim et al.,2009).Briefly,the incubation solution harvested from the6-well plates at the end of the experiments was centrifuged at13,000rpm for10min and100µl of the cell-free supernatant was transferred to96-well plates.The supernatant was incubated with the same amount of reaction mixture from the kit.LDH activity was determined by a colorimetric assay with the absorbance wavelength at492nm and the reference wavelength at655nm in a spectrophotometry(Bio-Rad Laboratories,Hercules,CA).Background absorbance from the cell-free buffer solution was subtracted from all absorbance measurements.After removal of the buffer from6-well plates,1%triton X-100lysing solution was applied to the remaining cells.The percentage of LDH released to incubation buffer in total LDH was calculated:spontaneously released LDH in the buffer/(spontane-ously released LDH in the buffer+intracellular LDH released by triton X-100).The LDH values from various treatment groups were then normalized by the mean values from the corresponding control cells in the same set of experiments.2.6.Superoxide production assayDihydroethidium is a cellular membrane-permeablefluorophore hydroethidine and was used to measure the superoxide production from the BPAEC.The method of measuring superoxide production was similar to a previously described method(Chen et al.,2008)with some modifications.Briefly,the cells were plated into6-well plates and grew overnight.They were then loaded with10µM dihydroethidium in basal DMEM for30min.After being washed with phosphate buffered saline, the cells were then subjected to OGD for5h and simulated reperfusion for1h.Aliquots(1.5ml)of the incubation buffers were taken for fluorescent intensity measurement on a spectrofluorometer(Instrument Photon Technology International,Birmingham,NJ)with excitation and emission set at470and610nm,respectively.2.7.Western blot analysisThe cells were grown in100-mm culture dishes and subjected to OGD and statin post-treatment as described above.The cells were harvested at 1h after the OGD and then homogenized in a lysis buffer containing 50mM Tris(pH7.4),140mM NaCl,1%Triton X-100,0.1%sodium dodecyl sulfate,30µM MG132and Roche's complete protease inhibitor mixture(Roche Applied Science,Indianapolis,IN).Homogenates were centrifuged at4°C for30min at13,000rpm.The supernatant was used115X.Wu et al./European Journal of Pharmacology636(2010)114–120for Western blotting.Thirty microgram proteins per lane were loaded for electrophoresis on a 10%polyacrylamide gel and then blotted onto a polyvinylidene di fluoride membrane.After blocking with Tris buffered saline containing 5%(w/v)bovine serum albumin and 0.1%Tween-20,the membranes were incubated with the following primary antibodies:anti-phospho-ERK antibody (1:1000),anti-ERK antibody (1:1000),anti-phospho-Akt antibody (1:1000),anti-Akt antibody (1:1000)or anti-GAPDH antibody (1:5000).Appropriate secondary antibodies were then used.Protein bands were visualized by the enhanced chemiluminescence method and detected and analyzed by Genomic and Proteomic Gel Documentation Systems from Syngene (Frederick,MD).The protein band intensities of ERK and Akt were normalized by the corresponding band intensities of GAPDH.The results from cells under various experimental conditions were then normalized by those of the corresponding control cells.2.8.Statistical analysisData of LDH release and superoxide production are expressed as mean±S.D.(n ≥6for each experimental condition).Results were analyzed by one-way analysis of variance followed by the Tukey test for post hoc analysis after con firmation of normal distribution of the data or by Kruskal –Wallis analysis of variance on ranks followed by the Dunn's test when the data are not normally distributed.Western blotting results are also presented as mean ±S.D.(n ≥4for each experimental condition).Results were analyzed by one-way repeated measurement analysis of variance or one-way repeated measurement analysis of variance on ranks followed by the Tukey test for post hoc analysis.A P value b 0.05was considered statistically signi ficant.3.Results3.1.Statins induced a postconditioning effect in the BPAECTo identify a condition that could cause signi ficant cell injury,we performed a time-course experiment.Different lengths of OGD caused a time-dependent LDH release,a parameter often used to re flect cell injury.Five-hour OGD followed by 1-h simulated reperfusion caused a signi ficant LDH release from cells (Fig.1).Thus,we chose this condition for other experiments.Post-treatment with statins dose-dependently reduced the OGD and simulated reperfusion-induced BPAEC injury (Fig.2).Post-treatment with 0.5,1,2or 4µM simvastatin or 2or 4µM atorvastatin statistically signi ficantly reduced the OGD –and reperfusion-induced LDH release (Fig.2).Consistent with the results from BPAEC at passages 4to 15,OGD and reperfusion also induced cell injury of primary BPAEC cultures and this injury was reduced by simvastatin or atorvastatin post-treatment (Fig.3).3.2.HMG-CoA reductase inhibition may be involved in the statin-induced postconditioning effectTo determine whether the cell protection induced by statins was related to their inhibition of HMG-CoA reductase,we used mevalo-nate,the immediate product of the reaction mediated by HMG-CoA reductase,and GGPP,an isoprenoid metabolite that is downstream of mevalonate and is necessary for geranylgeranylation/activation of small GTPases (Merla et al.,2007a;Rikitake and Liao,2005).Mevalonate at 500µM and GGPP at 20and 40µM abolished the protection induced by post-treatment with simvastatin or atorvasta-tin,while 40µM GGPP alone did not affect the endothelial cell survival after the OGD and simulated reperfusion (Fig.4).Since overproduction of reactive oxygen species,such as super-oxide,is an important mechanism for ischemia –reperfusion injury (Gwag et al.,2001),we determined whether statin post-treatment could reduce superoxide production after OGD.As shown in Fig.5,OGD and reperfusion signi ficantly increased superoxide production and this increase was inhibited by post-treatment with simvastatin and atorvastatin.Consistent with the LDH release data,the inhibition of superoxide production by statin postconditioning was abolished by GGPP (Fig.5).The OGD and reperfusion-induced superoxide production and cell injury were also inhibited by diphenyleneiodo-nium,an inhibitor of flavoenzymes that include nicotinamide adenine dinucleotide phosphate (NADPH)oxidase (Fig.6).3.3.Akt but not ERK may be involved in the statin-induced postconditioning effectAs shown in Fig.7,Ly294002,an inhibitor of Akt,attenuated the statin post-treatment-induced protection.However,the ERK inhibitor U0126did not affect the protective effects of statin post-treatment.Neither Ly294002nor U0126affected cell injury in cells subjectedtoFig.1.Time-course experiment.Bovine pulmonary arterial endothelial cells were exposed to or not exposed to various lengths of oxygen –glucose deprivation (OGD)and 1-h simulated reperfusion.Results are means±S.D.(n =6–24).*P b 0.05compared withcontrol.Fig.2.Statin postconditioning effect.Bovine pulmonary arterial endothelial cells were exposed to or not exposed to a 5-h oxygen –glucose deprivation (OGD)and 1-h simulated reperfusion.The cells were posttreated with or without various concentrations of simvastatin or atorvastatin for 1h immediately after the OGD.Results are means±S.D.(n =12to 41for panel A and 29to 45for panel B).*P b 0.05compared with control.^P b 0.05compared with OGD only.116X.Wu et al./European Journal of Pharmacology 636(2010)114–120OGD and reperfusion alone (Fig.7).Consistent with these inhibitor results,simvastatin and atorvastatin increased the expression of phospho-Akt/activated Akt,but did not change the expression of phospho-ERK/activated ERK after the OGD and simulated reperfusion.Simvastatin and atorvastatin did not change the expression of total Akt and ERK (Figs.8and 9).4.DiscussionStatins are a commonly used class of drugs that can reduce blood cholesterol level via inhibition of HMG-CoA reductase.Statins also have many other effects (Davignon,2004;Miida et al.,2004).For example,statins can induce a preconditioning effect in various organs (Domoki et al.,2009;Gu et al.,2008;Lazar et al.,2003).Recently,it has been shown that application of statins after brain ischemia improves neurological outcome (Prinz et al.,2008;Sugiura et al.,2007).We show here that post-treatment of endothelial cells,a cell type that exists in all organs and systems,with simvastatin and atorvastatin reduces OGD and reperfusion-induced cell injury.These protective effects can be induced at concentrations as low as 0.5µM simvastatin and 2µM atorvastatin.Although these concentrations are much higher than the blood concentrations of these statins in healthy volunteers when they take clinical relevant dosages,these concentra-tions are close to the blood concentrations of these statins (especially in the case of simvastatin)in critical ill patients who take statins and also may be taking drugs that are cytochrome P450inhibitors (Hermann et al.,2004;Kruger et al.,2009).Because of the concern that cultured cells with multiple passages can have endogenous changes,we con firm the statin post-treatment-induced protection in the primary endothelial cell cultures.The inhibition of HMG-CoA reductase by statins reduces mevalo-nate production,which then attenuates cholesterol synthesis via the inhibition of the prenylation pathway.Mevalonate is also a substratefor GGPP production via a series of reactions.GGPP can then be used to geranylgeranylate/activate GTPases,such as Rho A and Rac (Chen et al.,2008;Merla et al.,2007a;Rikitake and Liao,2005).Thus,statins can lead to the inhibition of GTPase activity.In our study,mevalonate dose-dependently reversed the statin post-treatment-induced pro-tection,suggesting that this protection was mediated by theinhibitionFig. 3.Statin postconditioning effect in primary cultures.Primary cultures of bovine pulmonary arterial endothelial cells were exposed to or not exposed to a 5-h oxygen –glucose deprivation (OGD)and 1-h simulated reperfusion.The cells were posttreated with or without 1or 2µM simvastatin or 2or 4µM atorvastatin for 1h immediately after the OGD.Results are means±S.D.(n =18to 54for panel A and 18to 54for panel B).*P b 0.05compared with control.^P b 0.05compared with OGDonly.Fig.4.Inhibition of statin post-treatment-induced protection by mevalonate and geranylger-anyl pyrophosphate (GGPP).Bovine pulmonary arterial endothelial cells were exposed to or not exposed to a 5-h oxygen –glucose deprivation (OGD)and 1-h simulated reperfusion.The cells were posttreated with or without 2µM simvastatin or 4µM atorvastatin in the presence or absence of various concentrations of mevalonate or GGPP for 1h immediately after the OGD.Results are means±S.D.(n =15to 47for panel A,18to 47for panel B,12to 45for panel C and 12to 45for panel D).*P b 0.05compared with control.^P b 0.05compared with OGD only.#P b 0.05compared with OGD+statin post-treatment.117X.Wu et al./European Journal of Pharmacology 636(2010)114–120of HMG-CoA reductase.Our results also showed that GGPP dose-dependently abolished the statin post-treatment-induced protection,suggesting that this protective effect may not be through the reduction of cholesterol production and may be through the inhibition of geranylgeranylation/activation of small GTPases.Rac is a small GTPase and is a necessary component of NADPH oxidase complex that facilitates superoxide production (Hordijk,2006).Our results showed that OGD and reperfusion induced a signi ficant increase of superoxide production.Statin post-treatment attenuated this increased superoxide production.These results,along with the results showing that statin post-treatment reduced OGD and reperfu-sion-induced cell injury,suggest that the increased superoxideproduction may participate in the mechanisms of cell injury under this experimental condition.This idea is strongly supported by our results that diphenyleneiodoium,a NADPH oxidase inhibitor,reduced OGD and reperfusion-induced superoxide production and cell injury.Together,these results suggest that statins inhibit HMG-CoA reductase,which then reduces the production of GGPP.The reduced GGPP level decreases the activation of GTPases,which leads to the inhibition of NADPH oxidase activity.This series of reactions ultimately results in a decreased superoxide production and cell protection.Small GTPases,such as Rho A,can inhibit PI3K/Akt pathway,an intracellular survival pathway (Merla et al.,2007a ).Since statins can lead to inhibition of GTPases (Chen et al.,2008;Merla et al.,2007a;Rikitake and Liao,2005),statins may activate the PI3K/Akt pathway.Consistent with this idea,application of statins has been shown to increase PI3K/Akt activity (Merla et al.,2007b;Nakata et al.,2007)and this effect may be a mechanism for the statin-induced protection.Our study showed that Ly294002,an Akt inhibitor,abolished simvastatin and atorvastatin post-treatment-induced protection in the endothe-lial cells.Simvastatin and atorvastatin increased the expression of phospho-Akt.These results strongly suggest the involvement of Akt in this protection.However,ERK1/2,protein kinases that may be involved in protection induced by various preconditioning stimuli (Dirnagl et al.,2003;Zuo et al.,2006)and can also be activated by application of statins (Anger et al.,2008;Merla et al.,2007b ),may not be involved in the statin post-treatment-induced protection in the endothelial cells because U0126,an ERK1/2inhibitor,did not inhibit the protective effect of statins,and simvastatin and atorvastatin did not change the expression ofphospho-ERK.Fig.5.Inhibition of superoxide production after oxygen –glucose deprivation (OGD)and simulated reperfusion by statin post-treatment.Bovine pulmonary arterial endothelial cells were exposed to or not exposed to a 5-h OGD and 1-h simulated reperfusion.The cells were posttreated with or without 2µM simvastatin or 4µM atorvastatin in the presence or absence of 20µM GGPP for 1h immediately after the OGD.Results are means ±S.D.(n =18–34).*P b 0.05compared with control.^P b 0.05compared with OGD only.#P b 0.05compared with OGD +simvastatin post-treatment.&P b 0.05compared with OGD+atorvastatinpost-treatment.Fig.6.Inhibition of oxygen –glucose deprivation (OGD)and simulated reperfusion-induced superoxide production and cell injury by diphenyleneiodonium (DPI).Bovine pulmonary arterial endothelial cells were exposed to or not exposed to a 5-h OGD and 1-h simulated reperfusion.The cells were incubated with or without 20µM diphenyleneiodonium for 1h immediately after the OGD.Results are means±S.D.(n =19to 34for panel A and 11to 26for panel B).*P b 0.05compared with control.^P b 0.05compared with OGDonly.Fig.7.Involvement of Akt in statin postconditioning effect.Bovine pulmonary arterial endothelial cells were injured by a 5-h oxygen –glucose deprivation (OGD)and 1-h simulated reperfusion.They were posttreated with or without 2µM simvastatin or 4µM atorvastatin in the presence or absence of 10µM Ly294002or 1µM U0126for 1h immediately after the OGD.Results are mean±S.D.(n =28to 62for panel A and 10to 54for panel B).*P b 0.05compared with control.^P b 0.05compared with OGD only.#P b 0.05compared with OGD+simvastatin post-treatment.&P b 0.05compared with OGD+atorvastatin post-treatment.118X.Wu et al./European Journal of Pharmacology 636(2010)114–120Our findings may have a broad implication.Post-treatment/postconditioning may be more clinically practicable than precondition-ing because post-treatment eliminates the need to predicate the occurrence of detrimental insults,such as ischemia,for its application.Endothelial cells are ubiquitous in all organs and tissues and are a necessary component as a physical barrier to prevent free access of chemicals and cells in the blood to the vascular smooth muscle cells and parenchymal cells of organs.Thus,it is critically important to maintain the functional and structural integrity of endothelial cells under various physiological and pathophysiological conditions.In summary,we have shown for the first time that post-treatment with simvastatin and atorvastatin induces protection against OGD and simulated reperfusion in endothelial cells.This effect may be mediated by inhibition of HMG-CoA reductase and the production of GGPP,which leads to inhibition of GTPases and decreased superoxide production.PI3K/Akt,but not ERk1/2,may also be involved in the statin post-treatment-induced protection in the endothelial cells.AcknowledgementThis study was supported by grants (R01GM065211and R01NS045983to Z Zuo)from the National Institute of Health,Bethesda,MD,by a grant from the International Anesthesia Research Society (2007Frontiers in Anesthesia Research Award to Z Zuo),Cleveland,OH,by a Grant-in-Aid from the American Heart Association Mid-Atlantic Af filiate (0755450U to Z Zuo),Baltimore,MD,and the Department of Anesthesiology,University of Virginia.ReferencesAnger,T.,El-Chafchak,J.,Habib,A.,Stumpf,C.,Weyand,M.,Daniel,W.G.,Hombach,V.,Hoeher,M.,Garlichs, C.D.,2008.Statins stimulate RGS-regulated ERK 1/2activation in human calci fied and stenotic aortic valves.Exp.Mol.Pathol.85,101–111.Chen,W.,Pendyala,S.,Natarajan,V.,Garcia,J.G.,Jacobson,J.R.,2008.Endothelial cellbarrier protection by simvastatin:GTPase regulation and NADPH oxidase inhibition.Am.J.Physiol.Lung Cell.Mol.Physiol.295,L575–L583.Davignon,J.,2004.Bene ficial cardiovascular pleiotropic effects of statins.Circulation109III39-43.Dirnagl,U.,Simon,R.P.,Hallenbeck,J.M.,2003.Ischemic tolerance and endogenousneuroprotection.Trends Neurosci.26,248–254.Domoki, F.,Kis, B.,Gaspar,T.,Snipes,J.A.,Parks,J.S.,Bari, F.,Busija, D.W.,2009.Rosuvastatin induces delayed preconditioning against oxygen –glucose deprivation in cultured cortical neurons.Am.J.Physiol.Cell Physiol.296,C97–C105.Gu,W.,Kehl, F.,Krolikowski,J.G.,Pagel,P.S.,Warltier, D.C.,Kersten,J.R.,2008.Simvastatin restores ischemic preconditioning in the presence of hyperglycemia through a nitric oxide-mediated mechanism.Anesthesiology 108,634–642.Gwag,B.J.,Won,S.J.,Kim,D.Y.,2001.Excitotoxicity,oxidative stress,and apoptosis inischemic neuronal death.In:Lin,C.S.(Ed.),New Concepts in Cerebral Ischemia.CRC Press,New York,pp.79–112.Hermann,M.,Asberg,A.,Christensen,H.,Holdaas,H.,Hartmann,A.,Reubsaet,J.L.,2004.Substantially elevated levels of atorvastatin and metabolites in cyclosporine-treated renal transplant recipients.Clin.Pharmacol.Ther.76,388–391.Hordijk,P.L.,2006.Regulation of NADPH oxidases:the role of Rac proteins.Circ.Res.98,453–462.Kim,J.A.,Li,L.,Zuo,Z.,2009.Iso flurane induces a postconditioning effect on bovinepulmonary arterial endothelial cells exposed to oxygen –glucose deprivation.Eur.J.Pharmacol.615,144–149.Kruger,P.S.,Freir,N.M.,Venkatesh,B.,Robertson,T.A.,Roberts,M.S.,Jones,M.,2009.Apreliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis.Intensive Care Med.35,717–721.Lazar,H.L.,Bao,Y.,Zhang,Y.,Bernard,S.A.,2003.Pretreatment with statins enhancesmyocardial protection during coronary revascularization.J.Thorac.Cardiovasc.Surg.125,1037–1042.Fig.8.Increase of the expression of phospho-Akt (p-Akt)by statins.Bovine pulmonary arterial endothelial cells were exposed to a 5-h oxygen –glucose deprivation (OGD)and 1-h simulated reperfusion.They were posttreated with or without 2µM simvastatin or 4µM atorvastatin for 1h immediately after the OGD.Cells were harvested for Western analysis of p-Akt (panel A)and total Akt (pane B).A representative Western blot is shown in the top panel and the graphic presentation of the p-Akt or total Akt protein abundance quanti fied by integrating the volume of autoradiograms from 8separate experiments is shown in the bottom panel.Values in graphs are expressed as fold changes over the control and are presented as the means ±S.D.^P b 0.05compared with OGD only.Ator:atorvastatin;Sim:simvastatin.Fig.9.No effects on the expression of phospho-extracellular signal-regulated kinase (ERK)(p-ERK)by statins.Bovine pulmonary arterial endothelial cells were exposed to a 5-h oxygen –glucose deprivation (OGD)and 1-h simulated reperfusion.They were posttreated with or without 2µM simvastatin or 4µM atorvastatin for 1h immediately after the OGD.Cells were harvested for Western analysis of p-ERK (panel A)and total ERK (pane B).A representative Western blot is shown in the top panel and the graphic presentation of the p-ERK or total ERK protein abundance quanti fied by integrating the volume of autoradiograms from 4separate experiments is shown in the bottom panel.Values in graphs are expressed as fold changes over the control and are presented as the means ±S.D.^P b 0.05compared with OGD only.Ator:atorvastatin;Sim:simvastatin.119X.Wu et al./European Journal of Pharmacology 636(2010)114–120。
