含1,2-苯并噻嗪结构的［1,3,4］噻二唑并［3,2-a］［1,3,5］三嗪衍生物的合成及其抗肿瘤活性

以吡罗昔康合成中间体(CAS:35511-15-0)为原料,利用活性拼接等药物设计原理,设计并合成了9个结构新颖的目标化合物,其结构经¹H NMR、MS等表征。通过测定对胰腺癌细胞Capan-1、白血病细胞L1210和人肝癌细胞SMMC-7721的抑制活性,评价目标化合物的体外抗肿瘤活性。结果表明,化合物6f(IC₅₀=2.4±0.5 μmol/L)对胰腺癌细胞Capan-1表现出较好的抑制活性;化合物6h(IC₅₀=5.4±0.2 μmol/L)对白血病细胞L1210表现出较好的抑制活性;化合物6g(IC₅₀=3.8±0.2 μmol/L)对人肝癌细胞SMMC-7721表现出较好的抑制活性。初步的抗肿瘤活性实验结果表明,将吡罗昔康3位的侧链替代为噻二唑并三嗪侧链,对提高该类化合物的抗肿瘤活性有一定的作用。     

含1,2-苯并噻嗪结构的咪唑并［1,2-b］［1,3,4］三氮唑衍生物的合成及其抗肿瘤活性

以吡罗昔康甲基物为原料,利用生物电子等排等药物设计原理,合成8个结构新颖的三氮唑化合物,其结构经¹H NMR、MS表征。通过测定对胰腺癌细胞Capan-1和白血病细胞L1210的抑制活性,评价目标化合物的体外抗肿瘤活性。结果表明,化合物6b(IC₅₀=3.6±0.5 μmol/L)对胰腺癌细胞Capan-1表现出较好的抑制活性;化合物6a(IC₅₀=1.8±0.2 μmol/L)对白血病细胞L1210表现出较好的抑制活性。初步的抗肿瘤活性实验结果表明,咪唑并三氮唑侧链的引入,对提高该类化合物的抗肿瘤活性有一定的作用。     

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。     

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。     

甘草黄酮类化合物对CDK1的抑制活性及体内外抗肝癌活性

探讨甘草黄酮类化合物对细胞周期依赖性蛋白激酶(CDK1)的抑制活性及抑制肝肿瘤细胞Bel-7402活性。采用CDK1和CCK-8试剂盒分别测试甘草黄酮类化合物对CDK1的抑制活性和对肝癌Bel-7402细胞的体外增殖抑制活性。构建肝癌Bel-7402裸鼠皮下肿瘤模型,并将小鼠随机分为3组:灌胃给药组、阳性药物组和空白对照组,连续灌胃给药18 d,每隔1天记录实验小鼠的体重、肿瘤大小变化。结果表明,甘草黄酮类化合物对CDK1/cyclin B均展现出了抑制活性,尤其是异甘草素对CDK1/cyclinB的抑制活性(IC₅₀=0.05±0.005 μmol/L)是阳性药物夫拉平度(IC₅₀=0.29±0.230 μmol/L)的近6倍;通过分子对接研究发现,异甘草素在CDK1中能够与氨基酸残基K33、E81、L83、S84、D86、D149形成6个氢键,而阳性药物夫拉平度仅与氨基酸残基E81、L83、S84、Q132、D149形成5个氢键;体外抗肿瘤活性研究表明,甘草黄酮类化合物对Bel-7402有较强的抑制作用,其中异甘草素对Bel-7402(IC₅₀=0.7±0.11 mol/L)展现出了最强的抑制活性,是阳性药物夫拉平度(2.4±0.34)mol/L的3倍。动物体内研究表明,异甘草素的LD₅₀为4.38 mg/kg,并能够有效抑制肝癌Bel-7402细胞的增长。     

含芳杂环取代的马蹄金素衍生物的设计、合成及抗乙肝病毒活性

以马蹄金素(MTS)为先导化合物,设计、合成了11个新的含芳杂环取代的马蹄金素衍生物,其结构经NMR、ESI-MS确认。采用HepG2 2.2.15细胞为乙肝病毒载体,评价目标化合物的抗HBV活性。结果表明,化合物7a［IC₅₀=2.94 μmol/L,选择指数(SI)=146.39］和9a(IC₅₀=2.21 μmol/L,SI>250)对HBV DNA复制的抑制活性高于先导化合物MTS(IC₅₀=11.16 μmol/L,SI=10.78),且具有更高的SI,提示该化合物在治疗HBV感染时具有更高的安全性,具有潜在的研究开发价值。     

异甜菊醇衍生物的合成及抗肿瘤活性

对异甜菊醇C-环、D-环进行结构修饰与改造,同时将其C₁₉-COOH成酯,设计并合成了 9个未见文献报道的新化合物(5~13),所有目标化合物的结构均经ESI-MS,IR,¹H NMR确定。采用MTT法测试了目标化合物对HCT116,Huh7,SW620及HepG2等细胞的抗肿瘤活性。初步研究结果表明,化合物13表现出对人结肠癌HCT116细胞具有选择性抑制作用(IC₅₀=3.57 μmol/L),与阳性对照舒尼替尼(sunitininb)(IC₅₀=5.62 μmol/L)活性相当,化合物10对HCT116,Huh7,SW620均有较强抑制作用。     

3-(4′-苯甲酰基氨基-苯基)-香豆素衍生物的合成及体外降血糖活性

首先以对氨基苯乙酸和水杨醛类化合物为原料,通过Perkin缩合反应,再经盐酸酸化合成了3个3-芳基香豆素类化合物4a~4c;再与取代苯甲酰氯6a~6h通过酰胺化反应合成得到了10个3-(4′-苯甲酰基氨基-苯基)香豆素类化合物7a~7j。所有目标化合物的结构均经过¹H NMR,¹³C NMR,ESI-MS进行了确证。通过测定α-葡萄糖苷酶抑制活性和晚期糖基化终产物(AGEs)形成抑制活性评价了目标化合物的体外降血糖活性。结果表明化合物7f(IC₅₀=10.84±0.36 μmol/L)表现出较好的α-葡萄糖苷酶的抑制活性;化合物7g(IC₅₀=5.01±0.55 μmol/L)对AGEs形成抑制活性远高于阳性药氨基胍盐酸盐(AG,IC₅₀=290.31±7.32 μmol/L),这些结果为抗糖尿病药物的进一步研究提供了理论基础。     

4-(3-磺酰基苯基)氨基-6-甲酰基吡咯并［2,3-d］嘧啶类化合物的设计、合成与生物活性

以JAK2抑制剂baricitinib和fedratinib为先导化合物,运用分子杂交药物设计原理,设计并合成了17个以4-(3-磺酰基苯基)氨基-6-甲酰基吡咯并［2,3-d］嘧啶(3)为母核、结构新颖的目标化合物,并通过JAK2激酶和粒细胞-巨噬细胞集落刺激因子(GM-CSF)诱导的TF-1细胞对所合成的化合物进行了活性测试。结果显示,多数化合物具有JAK2抑制活性,其中化合物(31)表现出较好的JAK2激酶活性(IC₅₀=0.009 μmol/L)和GM-CSF诱导的TF-1细胞抑制活性(IC₅₀=0.136 μmol/L),表明该化合物具有潜在的研发价值。     

川芎嗪/查耳酮类杂合物的设计、合成及抗血小板聚集活性

基于药物设计的生物电子等排和拼合原理,设计、合成了一系列川芎嗪/查耳酮类杂合物(2~26),以期得到活性较强的抗血小板聚集药物。结果表明,目标化合物对二磷酸腺苷(ADP)和花生四烯酸(AA)诱导的血小板聚集均显示不同程度的抑制,其中化合物8活性最强,对ADP诱导的血小板聚集的抑制作用(IC₅₀=0.14 mmol/L)是川芎嗪的9.1倍,查耳酮的10.5倍;对AA诱导的血小板聚集的抑制作用(IC₅₀=0.09 mmol/L)是川芎嗪的8.8倍,查耳酮的10.0倍,且略优于阿司匹林(IC₅₀=0.15 mmol/L)。     

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.