新型CDDO-Me类似物的合成及抗肿瘤活性

以齐墩果酸(OA)为起始原料,经9步反应合成了C环含有α,β-不饱和酮结构的2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-酸甲酯(CDDO-Me)活性类似物1,再将不同的脂肪羧酸和芳杂环羧酸分别与其C-3位羟基酯化,设计、合成了新型CDDO-Me类似物(2a~2e),并进一步将C-1位溴代,得到化合物3a~3e。采用MTT法测定了目标化合物对肺癌细胞A549、肝癌细胞HepG2以及肺上皮细胞BEAS-2B的增殖抑制活性。结果表明,目标化合物对HepG2细胞和A549细胞的增殖均显示了不同程度的抑制,其中化合物3b和3c的抑制活性最强［IC₅₀=(6.13±1.16)μmol/L,IC₅₀=(5.49±1.03)μmol/L］,优于先导物1,与CDDO-Me相当。此外,目标化合物对正常细胞BEAS-2B的抑制活性显著小于对上述两种肿瘤细胞的抑制活性,显示了较高的肿瘤细胞选择性,其中3e对HepG2的选择性最高,其抑制作用是正常细胞的10倍,值得进一步研究。     

硫化氢供体型ADT-OH衍生物的合成及其活性

二硫杂环化合物5-对羟基苯基-3H-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)是一种缓释硫化氢供体,并具有一定的神经保护作用。为了研究其构效关系,对其芳环进行改造,合成了17个Y类化合物(Y₁~Y₁₇),其结构均经 ¹H NMR、¹³C NMR 和HR-MS确证,其中6个化合物(Y₄,Y₁₃~Y₁₇)结构是全新的。采用MTT法评价了该类化合物对谷氨酸诱导损伤的HT-22海马神经元细胞生存率的影响,结果发现,这些化合物在1~100 μmol/L浓度范围内具有很强的神经保护作用,其中化合物Y₁~Y₉,Y₁₁在全部测试浓度内均能非常显著地提高受损神经元的生存率(P<0.01),特别是化合物Y₁,Y₄,Y₆~Y₉,Y₁₁在1~10 μmol/L浓度范围内活性比ADT-OH强,值得进一步研究。     

类查尔酮Nrf2激活剂的合成及ARE诱导活性

对先导化合物CPUY191001结构进行改造,以期得到活性更好的ARE-Nrf2激活剂。通过羟醛缩合反应合成17个目标化合物,采用MTT法测试目标化合物的抗增殖活性,并利用荧光素酶报告基因实验考察目标化合物对ARE的诱导活性。MTT数据显示,该系列化合物几乎无细胞毒性(IC₅₀>50 μmol/L),活性测试结果表明,大部分类查尔酮衍生物对ARE具有一定的诱导活性,其中化合物2,3,10活性较优,且具有浓度依赖性。化合物2,3,10在抗炎与肿瘤预防治疗药物的研究领域中具有一定的应用前景,值得进一步研究。     

4-(N-芳基)胺基-6-长链烷氧基取代蝶啶类化合物的合成及其抗肿瘤活性

采用具有喹唑啉为母核的抗肿瘤药物作为先导化合物,利用生物电子等排原理,设计并合成一系列4-(N-芳基)胺基-6-长链烷氧基取代蝶啶类化合物7a~7l,并利用MTT法测试其对A549、KG1a和HGC-27肿瘤细胞的增殖抑制作用。以3-氨基吡嗪-2-羧酸甲酯为起始底物,通过6步反应合成12种目标化合物(7a~7l)并确证其结构(¹H NMR、¹³C NMR、MS)。生物活性试验表明,蝶啶4位为2-氯-5-硝基苯胺基取代时,其活性均高于其他苯胺基取代的产物。化合物7b对A549的活性(IC₅₀=11.55 μmol/L)与阳性对照物吉非替尼(IC₅₀=5.95 μmol/L)十分接近;化合物7k对3组细胞的IC₅₀均十分接近对照物吉非替尼。由于筛选出的化合物均有2-氯-5-硝基苯胺基片段,可以此结构为基础进行深入研究。     

新型熊果酸衍生物与查耳酮缀合物的合成及其抗肿瘤活性初步评价

以天然产物熊果酸为先导化合物,将查耳酮通过酯化反应拼接到熊果酸衍生物得到10个熊果酸衍生物-查耳酮缀合物,其结构均通过¹H NMR,¹³C NMR和HRMS加以确认。初步的生物活性结果表明,这些缀合物对CNE2、KB、MCF-7、A549和HepG2细胞均有抑制活性。特别是对MCF-7细胞的抑制活性强于熊果酸和临床上应用的药物他莫昔芬,其中化合物11e(IC₅₀=4.7 μmol/L)的抗乳腺癌活性最强,是他莫昔芬(IC₅₀=15.2 μmol/L)的近3倍;同时,这些缀合物对正常的MCF-10A和VERO细胞没有毒性,安全性较他莫昔芬高。     

3-苯基-3-吡咯基戊烷类化合物的合成及体外生物活性

以非开环甾体类维生素D受体(VDR)激动剂LG190155为先导物,通过结构改造设计合成了一系列3-苯基-3-吡咯基戊烷类化合物。通过测定目标化合物对HL-60细胞的促分化能力间接测定其对VDR的激动能力。结果表明,化合物13a,13c,13d,13h,13i,13j表现出较好的HL-60促分化活性(EC₅₀<50 μmol/L),提示这6个化合物具有较好的VDR激动能力。其中以化合物13j的促分化活性最高(EC₅₀=0.10 μmol/L),且优于先导化合物LG190155。采用MTT法评价目标化合物对VDR高表达的肿瘤细胞(人前列腺癌细胞PC-3、人乳腺癌细胞MCF-7、人结肠癌细胞Caco-2、人肝癌细胞HepG2)和人肝正常细胞(L02)的增殖抑制活性。结果表明,化合物13a在HepG2细胞株中的增殖抑制活性最好(IC₅₀=0.11 μmol/L),且对普通肝细胞L02的抑制作用较低(IC₅₀=15.24 μmol/L),说明化合物13a对肝肿瘤细胞具有一定选择性。此外还发现所合成化合物的促分化活性与抑制增殖活性成正相关。     

罗丹宁衍生物的合成及抗肿瘤活性

在罗丹宁衍生物WL-276的基础上设计并合成一系列新的罗丹宁衍生物,并对这些化合物的抗肿瘤活性进行测定。以氨基酸为原料,经环合和缩合反应,合成了化合物Ⅱ_1-4,然后分别与硫化氢供体ADT-OH偶联得到化合物Ⅲ_1-4,共合成了8个目标化合物,其中4个未见报道,其结构均经¹H NMR、IR和HR-MS确证。然后用MTT法筛选其抗肿瘤活性。初步研究表明,化合物Ⅱ_1,3,4和Ⅲ_1-4对HepG2肿瘤细胞和DU145肿瘤细胞的增殖均具有较强的抑制作用,且化合物Ⅲ的活性比Ⅱ强;化合物Ⅲ_2,4对HepG2细胞和化合物Ⅲ_1,2,4对DU145细胞的抗增殖活性均高于阳性对照5-氟尿嘧啶。     

4-苯基-吡咯并［2,3-d］嘧啶类JAK2激酶抑制剂的设计、合成和抗肿瘤活性

以JAK2激酶抑制剂鲁索替尼(ruxolitinib)为先导化合物,应用分子杂交的药物设计原理,通过结构修饰改造,设计、合成了一系列新的4-苯基-吡咯并［2,3-d］嘧啶类衍生物并进行初步的体外活性评价。以4,6-二羟基嘧啶为起始原料,依次通过Vilsmeier-Haack反应、S_NAr取代、成环、脱水、Suzuki偶联、酰基化等多步反应最终合成得到12个目标化合物(12a~12l),其结构经¹H NMR、¹³C NMR、HRMS确证。对目标化合物进行体外JAK2激酶活性、GM-CSF诱导的TF-1细胞活性测试,结果表明,部分化合物(12b、12e和12h)具有一定程度的JAK2抑制活性;采用MTT法测试目标化合物对JAK2非依赖性A549细胞的抗增殖能力,结果显示,该类化合物A549细胞表现出良好的增殖抑制活性,尤其是化合物12c(IC₅₀=0.12 μmol/L)活性最强,表明该类化合物具有潜在的研究开发价值。     

Methyl Xestospongoate类似物的设计、合成和抗肿瘤活性

设计、合成了52个Methyl Xestospongoate类似物并初步研究了其抗肿瘤活性。以炔基甲酯和二炔为原料,经过Cadiot-Chodkiewitz偶联和Sonogashira偶联反应合成了52个Methyl Xestospongoate类似物4(a~m)-7(a~m),并利用¹H NMR、¹³C NMR和HREI-MS法确定其结构,采用CCK-8法测定了部分化合物的体外抗肿瘤活性。结果显示化合物6k对A549和P-388肿瘤细胞的增殖具有较强的抑制活性,其IC₅₀分别为9.36和9.62 μmol/L。     

GFDA2唑并［5,4-d］嘧啶类化合物的设计、合成及其抗肿瘤活性

为了寻找具有更好抗肿瘤活性的化合物,设计合成了一系列GFDA2唑并［5,4-d］嘧啶类衍生物。以盐酸乙脒为起始原料,合成了13个化合物8a~8m;目标化合物结构经IR、¹H NMR、EI-MS和元素分析确证;采用MTT法先后对目标化合物进行了人脐静脉内皮细胞(HUVEC)的抗肿瘤血管生成抑制活性测试和3株肿瘤细胞(A549、HepG2、U251)的体外抗肿瘤活性测试;结果表明,化合物8c、8d、8g、8i和8l对HUVEC和3株不同肿瘤细胞表现出明显的增殖抑制活性;化合物8l对A549、HepG2和U251的抑制活性略优于阳性对照药舒尼替尼,值得进一步研究。     

Value of D-Dimers in patients with acute aortic dissection

Objective: To evaluatel the value of D-dimers in patients with acute aortic dissection (AAD). Methods: This study consisted of 16 patients with AAD and 27 non-AAD patients. Serum D-dimets were measured by Sta-Liatest D-DI immunoturbidimetric assay. Results: D-dimer level was higher (P ＜ 0.001) in patients with AAD(7.91 ± 5.52 μg/ml) than that in non- AAD group(1.57±1.24 μg/ml). D-dimer was positive (＞0.4 μg/ml) in all patients with AAD and in 10 control group patients (37%). Among patients with acute AAD, D-dimers tended to be higher in Stanford A than in Stanford B (8.67 ± 4.31 μg/ml vs. 3.24±1.27 μg/ml, P ＜0.01). D-dimer values tended to be higher in more extended disease(3.84 ± 1.65 μg/ml, 8.57 ± 3.58 μg/ml and 11.87 ± 5.69 μg/ml in thoracic aorta, thoracic and abdominal aorta, thoracic and abdominal aorta and iliacal arteries, respectively, P ＜ 0.05 for both 8.57 ± 3.58 and 11.87 ± 5.69 vs. 3.84 ± 1.65 ). Including the control group into the analysis, we found a sensitivity of 100%, a negative predictive value of 100%, and a specificity of 66% and a positive predictive value of 64% for D-dimer in diagnosis of AAD in our patients with suspected AAD. Conclusion: D-dimer was elevated in patients with AAD. A negative D-dimer test result could be useful in excluding AAD.     

Research of combined liver-kidney transplantation model in rats

Objective： To set up a simple and reliable rat model of combined liver-kidney transplantation. Methods： SD rats served as both donors and recipients. 4℃ sodium lactate Ringer＇s was infused from portal veins to donated livers,and from abdominal aorta to donated kidneys, respectively. Anastomosis of the portal vein and the inferior vena cava （IVC） inferior to the right kidney between the graft and the recipient was performed by a double cuff method, then the superior hepatic vena cava with suture. A patch of donated renal artery was anastomosed to the recipient abdominal aorta. The urethra and bile duct were reconstructed with a simple inside bracket. Results： Among 65 cases of combined liver-kidney transplantation, the success rate in the late 40 cases was 77.5%. The function of the grafted liver and kidney remained normal. Conclusion： This rat model of combined liver-kidney transplantation can be established in common laboratory conditions with high success rate and meet the needs of renal transplantation experiment.     

APPLICATION OF LORNOXICAM TO PATIENT-CONTROLLED ANALGESIA IN PATIENTS UNDERGOING ABDOMINAL SURGERIES

FOR anesthesiologis s ,treatingpostoperativepainhas alwaysbeen a problem.Althoughopioidshave been provedtobe effective,theirsideeffectscouldnotbeignored.With thedevelopmentofscienceand pharmacology,many drugs with aspectsof satisfactoryanalgesicefficacyand couldbe welltoleratedby patientshave been developed.And lornoxicamisone of them, which isa non-steroidalanti-inflammatorydrug (NSAID ), with analgesic, anti-infl-ammatory,andantipyreticproperties.Itseliminationhalf-time(3 to 5 hours) isle…     

Acupuncture Combined with Spinal Tui Na for Treatment of Primary Dysmenorrhea in 30 Cases

Objective: To observe the therapeutic effects in acupunture treatment of primary dysmenorrhea combined with spinal Tui Na, and study its mechanism. Methods: Thirty cases of the treatment group were treated by acupuncture combined with spinal Tui Na, and thirty cases in the control group were treated by routine acupuncture. Results: The total effective rate was 93.3% in the treatment group, and 73.3% in the control group, with a significant difference between the two groups (P<0.05). Conclusions: Acupuncture combined with spinal Tui Na has good prospects for treatment of primary dysmenorrhea.     

Luo Lingjie's Experience in Treating Chronic Nephropathy

In treating chronic nephropathy,Luo Lingjie,a chief physician,pays attention to regulating the balance between yin and yang,treating infection if present,and removing pathogenic factors.He prescribes gentle drugs and uses carefully strongly warming-tonifying ones,emphasizes the importance of persuading the patient to persist in treatment with medication and nurse one's health for recuperation,and is good at combined use of TCM and western medicine therapy and brings the merits of various therapies into full play,with obvious theraoeutic effects.     

Dr.Zhang Ren's Experience in the Acupuncture Treatment of Different Diseases with the Same Therapeutic Principle

Dr.Zhang Ren,the chief physician,is the chairman of Shanghai Acupuncture and Moxibustion Association.Having been engaged in medicine for about 40 years,he is experienced in treating various intractable diseases.In his long years of clinical practice,he advocates taking the TCM differentiation as the basis to seek for the acupuncture method for treatment of modern intractable diseases.The author of this essay had the fortune to follow Dr.Zhang in study.The following is a summary of Dr.Zhang's experience in the acupuncture treatment for different intractable diseases with the same therapeutic principle.     

安心颗粒对急诊经皮冠状动脉介入术后生活质量影响的研究

目的：评价使用安心颗粒对急诊经皮冠状动脉介入术（PPCI）术后生活质量的影响.方法：将160例接受PPCI的急性ST段抬高型心肌梗死患者随机分为安心颗粒组（术前顿服安心颗粒8.8g,术后安心颗粒4.4 g/次,每日2次）和对照组（仅接受基础药物治疗）.所有患者均服用阿司匹林、氯吡格雷和阿托伐他汀.分别在入院时、出院前1d、出院后180 d时,应用心肌梗死多维度量表（MIDAS）、中文版SF-36评价量表对患者生活质量评分.并观察术后30 d以内的出血并发症、血小板减少症发生情况.结果：入院时和出院前1d,两组患者的心肌梗死MIDAS、SF-36量表评分比较无差异（P＞0.05）;出院后180 d时,与对照组比较,安心颗粒组MIDAS、SF-36评分明显减低（P＜0.05）;组内与入院时比较,两组出院前1d、出院后180 d时,MIDAS、SF-36评分均降低（P＜0.05）.两组患者在随访期间均无大量出血、少量出血、重度和极重度血小板减少症发生,安心颗粒组有4例、对照组有7例发生不明显出血（P＞0.05）.两组发生轻度血小板减少症的患者数比较无差异（P＞0.05）.结论：PPCI使用安心颗粒,能改善急性ST段抬高型心肌梗死患者的生活质量,且不增加出血风险.     

The comparative studies of the influences of Urapidil and Nicardipine on sino-atrial node function, atrio-ventricular node function and hemodynamics

Objective:To investigate the influences of urapidil and nicardipine on rabbit sinus function,atrio-ventricular node function and hemodynamics.Methods:Thirty-two Angora's rabbits were selected and randomly divided into four groups.U1 group:urapidil 0.25 mg/kg;U2 group:urapidil 0.5 mg/kg;N1 group:nicardipine 10 μg/kg;N2 group:nicardipine 20 μg/kg.All these medicine were administrated within 30 seconds.Measurements were taken before and after the administration of urapidil or nicardipine for the following data:mean blood pressure(MAP),heart rate(HR),sino-atrial conduction time(SACT),maximal sinoatrial recovery time(SNRTmax)corrected sinus node recovery time(CSNRT),index of sinus node recovery time(SNRTI),Wenckebach A-V conduction frequency (WB),and P-R interval.Results:Significant MAP and HR changes were identified in all of the four groups before and after administration of both urapidil and nicardipine.No significant changes could be found in the rest of the parameters.Intergroup analysis showed that SACT and CSNRT of N1 and N2 groups were shorter than those of the U2 group(P＜0.01);the MAP decreased(P＜0.01)and the HR increased drastically(P＜0.01).Conclusions:Neither urapidil(0.25 mg/kg,0.5 mg/kg)nor nicardipine(10μg/kg,20μg/kg)has any significant influence on rabbit sinus function or rabbit atrio-ventricular node function.Nicardipine could be a better choice than urapidil for parafunctional sinus node patients.     

猪肺磷脂注射液联合经鼻持续气道正压通气对呼吸衰竭早产儿的临床疗效及肌酸激酶同工酶活性的影响

目的 探讨猪肺磷脂注射液联合经鼻持续气道正压通气(NCPAP)对呼吸衰竭早产儿的临床疗效及肌酸激酶同工酶活性(CK-MB)的影响.方法 选取呼吸衰竭早产儿80例,分为观察组和对照组各40例.对照组采用NCPAP给氧治疗,观察组给予NCPAP给氧联合猪肺磷脂气管内给药.观察两组患儿治疗前及治疗12h、24 h后PaO2、PaCO2、血氧饱和度(SaO2)、pH的变化情况,检测治疗前及治疗5d后血清CK-MB水平;评估两组患儿的临床治疗效果.结果 两组患儿PaO2、PaCO2、SaO2、pH比较,差异均有统计学意义(P＜0.05),其中观察组治疗后的PaO2、SaO2、pH均高于对照组,PaCO2则低于对照组.两组的PaO2、SaO2、pH均随观察时间延长而升高(P＜0.05),PaCO2均随观察时间的延长而降低(P＜0.05).观察组治疗有效率为87.5％,显著高于对照组的70.0％ (P ＜0.05).治疗5d后两组患儿血清CK-MB水平均较前降低(P＜0.05),且观察组明显低于对照组(P＜0.05).结论 猪肺磷脂注射液气管内给药联合NCPAP可以显著降低呼吸衰竭早产儿CK-MB的含量,提高治疗有效率,起到很好的呼吸循环支持作用.