Structure-activity relationships of quaternary protoberberine alkaloids having an antimalarial activity

Seventeen quaternary protoberberine alkaloids related to berberine 1 were tested for antimalarial activity in vitro against Plasmodium falciparum and structure-activity relationships are proposed. The activity of the protoberberine alkaloids was influenced by the type of the oxygen substituents on rings A, C and D and the position of the oxygen functions on ring D. The position of the oxygen functions on ring D and the type of the oxygen substituents at the C-13 position (ring C) strongly influenced the activity. Shifting the oxygen functions at C-9 and C-10 to C-10 and C-11 on ring D resulted in a significant increase in the activity. Compounds bearing a methylenedioxy function at C-2 and C-3 (ring A) or C-9 and C-10 (ring D) showed higher activity than those which have methoxy groups at the same positions. Introduction of a methoxy group into the C-1 position (ring A) decreased the activity. Replacement of a hydroxy group at C-2 or C-3 (ring A) by a methoxy group led to a reduction in the activity. Displacement of a hydroxy function at C-13 (ring C) by the oxygen substituents such as OMe, OEt, OCOOEt, and OCON(Me)₂ reduced the activity. In the same replacement at C-9 (ring D), the activity depended upon the type of the oxygen function. Six protoberberines displayed more potent activity than berberine 1. The activity decreased in the order: 10, 11, 17 and 18 > 7 and 8 > 1.     

肿瘤可溶性抗原实验研究

目的　探讨肿瘤可溶性抗原免疫原性,为肿瘤疫苗的研制和肿瘤免疫治疗提供实验依据。方法　提取卵巢癌细胞的可溶性成分作为肿瘤可溶性抗原(tumorsolubleantigen,TSA),单独用TSA或联合IL-2,CD-3单抗诱导外周血单个核细胞(PBMC),检测PBMC活化、增殖、分泌细胞因子以及活化的细胞对肿瘤的杀伤特性。结果　TSA能刺激正常人PBMC增殖和分泌细胞因子(TNF,IFN)。用TSA联合IL-2和抗CD3单抗诱导正常人PBMC产生杀瘤性效应细胞,对TSA来源的肿瘤细胞具有选择性杀伤作用,证实TSA具有免疫原性。肿瘤细胞提取物中细胞多肽是主要活性成分,但细胞膜成分也具有免疫活性。结论　用该实验方法提取TSA具有免疫原性,可用于肿瘤疫苗的研制和肿瘤过继免疫治疗,该实验方法和结果可为检测和评价肿瘤提取物是否具有免疫原性提供参考。     

Degradation of methyl and ethyl mercury into inorganic mercury by oxygen free radical-producing systems: Involvement of hydroxyl radical

Degradation of methyl mercury (MeHg) and ethyl Hg (EtHg) with oxygen free radicals was studied in vitro by using three well-known hydroxyl radical (OH)-producing systems, namely Cu²⁺-ascorbate, xanthine oxidase (XOD)-hypoxanthine (HPX)-Fe(III)EDTA and hydrogen peroxide (H₂O₂)-ultraviolet light B. For this purpose, the direct determination method for inorganic Hg was employed. MeHg and EtHg were readily degraded by these three systems, though the amounts of inorganic Hg generated from MeHg were one half to one third those from EtHg. Degradation activity of XOD-HPX-Fe(III)EDTA system was inhibited by Superoxide dismutase, catalase and the OH scavengers and stimulated by H₂O₂. Deletion of the OH formation promoter Fe(III)EDTA from XOD-HPX-Fe(III)EDTA system resulted in the decreased degradation of MeHg and EtHg, which was enhanced by further addition of the iron chelator diethylenetriamine pentaacetic acid. In all these cases, a good correlation was observed between alkyl Hg degradation and deoxyribose oxidation determining OH. By contrast, their degradation appeared to be unrelated to either Superoxide anion production or H₂O₂ production alone. We further confirmed that H₂O₂ (below 2 mM) itself did not cause significant degradation of MeHg and EtHg. These results suggested that OH, but not and H₂O₂, might be the oxygen free radical mainly responsible for the degradation of MeHg and EtHg.     

Comparison of renal function and psychomotor performance in workers exposed to elemental mercury

Summary Renal function and psychomotor performance (eye-hand coordination, arm-hand steadiness) of a group of 43 workers exposed to mercury vapor were examined. Their mean age and average duration of exposure to mercury were 38 and 5 years, respectively. The results were compared with those obtained in a matched group of 47 control workers. Increased proteinuria and albuminuria were found slightly more prevalent in the Hg-exposed group than in the control workers. These results are in agreement with those found during a previous study carried out in another group of workers also exposed to elemental mercury (Bucket et al. 1980). The scores of the psychomotor tests were less satisfactory in the Hg workers than in the control workers, the arm-hand steadiness test being more discriminative than the eye-hand coordination test. Preclinical changes in psychomotor function can be detected independently of the presence of signs of renal dysfunction. No clear-cut relationships were found between the prevalence of abnormal psychomotor scores and the level of mercury in blood (HgB) or in urine (HgU). Increased prevalences of abnormal psychomotor scores seem however to occur for HgB between 1 and 2 g/100 ml and for HgU between 50 and 100 g/g creatinine. Therefore, a biologic threshold limit value of 50 g/g creatinine is proposed for urinary mercury to prevent the development of preclinical effects on the central nervous system. A similar critical HgU level based on renal dysfunction prevalences has been suggested in a previous study.This study was supported by a grant from the Commission of the European Communities     

Mercury-induced necrosis of murine renal cell carcinoma

Administration of the nephrotoxic agent, bichloride of mercury (HgCl₂), to BALB/c mice bearing subcapsular renal tumor transplants induced early preferential necrosis of the tumor cells compared with mercury-treated normal kidney tubular cells and untreated control tumors. The principle is established that a selective proximal tubular poison is also toxic for a tumor of the same cellular origin.     

Study of preclinical changes in workers exposed to inorganic mercury in chloralkali plants

Summary The aim of the present work was to clarify the question of preclinical changes of Hg intoxication (micromercurialism) in man. The study to detect these disorders was performed on 39 chloralkali plant workers who had been exposed to mercury for more than 7 years. The ambient air, urine and blood values of the last few years were determined in extensive measurements by various methods and related to one another. The average ambient air concentrations were clearly below the currently applicable threshold limit value (German MAK) of 0.1 mg/m³. For the purpose of clarifying the mentioned question of preclinical changes of intoxication, the exposed persons were subjected to psychomotor-function examinations and compared with a group of nonexposed persons. The blood pressure and pulse frequency values of both groups were also determined and compared with one another. No significant differences between the two groups of persons examined were detectable.Presented at the 18th Congress of the Deutsche Gesellschaft für Arbeitsmedizin in Frankfurt, 24th May 1978     

可溶性血管细胞黏附分子1在妊高征发病中的作用

目的　研究可溶性血管细胞黏附分子 1(solublevascularcelladhesionmolecule - 1,sVCAM - 1)在妊高征发病中的作用。方法　用酶联免疫吸附法 (ELISA)测定 6 7例孕妇血清中sVCAM - 1水平 ,其中正常妊娠组 15例 ,妊高征组 5 2例。结果　中、重度妊高征患者血中sV CAM - 1水平显著高于正常妊娠组 (P <0 .0 1) ;轻度妊高征患者与正常妊娠组相比 ,虽无统计学差异 ,但有升高趋势 ;妊高征组产后该指标下降 ,与正常妊娠组比较无显著性差异 (P >0 0 5 )。sVCAM - 1浓度与平均动脉压呈正相关 (r =0 .5 4 2 ,P <0 .0 1)。结论　妊高征患者血中sVCAM - 1水平升高 ,表明内皮细胞损伤在妊高征的发病中起重要作用。     

脐血干细胞对单纯疱疹性角膜炎患者免疫指标水平的影响

目的　探讨脐血干细胞结膜下注射对单纯疱疹性角膜炎 (herpessimplexkeratitis ,HSK)患者血T淋巴细胞 (T -lymphocytes ,T -LC)亚群和白细胞介素 -2 (interleukin -2 ,IL -2 )及可溶性IL -2受体 (SIL -2R)水平含量的影响。方法　将患者随机分为两组 ,治疗组 5 0例5 1只眼 ,结膜下注射脐血干细胞 3次 ;对照组 5 0例 5 2只眼 ,静脉滴注病毒唑 2周。检测两组患者血T -LC亚群、IL -2及SIL -2R水平含量 ,并与 5 0例健康志愿者作正常对照。结果　两组患者治疗前血T -LC亚群CD4 、CD8、CD4 /CD8及IL -2、SIL -2R水平含量均明显不同于正常者(P <0 0 5～ 0 0 1) ;治疗后治疗组上述指标明显较治疗前改善 (P <0 0 5～ 0 0 1) ,基本接近正常者 (P >0 0 5 ) ,而对照组治疗前后上述指标差异均无显著性 (P >0 0 5 ) ,与正常者差异有显著性 (P <0 0 5～ 0 0 1) ;两组治疗后上述指标间比较均差异有显著性 (P <0 0 5～ 0 0 1) ;临床效果治疗组明显优于对照组 (P <0 0 5～ 0 0 1) ,平均痊愈时间缩短 (P <0 0 1)、复发率降低 (P <0 0 5 )。结论　脐血干细胞结膜下注射治疗HSK疗效好 ,有明显调节患者血T -LC亚群、IL -2及SIL -2R水平作用     

卡介苗素注射液对儿童肾病综合征继发感染预防的初步探讨

目的 观察卡介苗素注射液对小儿单纯性肾病综合征(SNS)继发感染的影响。方法38例初治SNS患儿随机分卡介苗素治疗组(Ⅰ组,n=22)和单纯强的松对照组(Ⅱ组,n=16)。2组均采用强的松中程疗法,Ⅰ组在此基础上给卡介苗素0.5mg(1ml)肌肉注射,隔天一次,疗程3～6个月。观察治疗阶段患儿8周内缓解率、继发感染率、感染控制时间、复发率及用药前和用药3个月后血清、尿可溶性白介素2受体(sIL一2R)及血浆IgG、IgA、IgM的变化。结果 Ⅰ组和Ⅱ组8周内缓解率无显著差异,继发感染率和复发率Ⅰ组均显著低于Ⅱ组。感染后治愈天数Ⅰ组显著少于Ⅱ组[(5.0±1.6)d vs(8.0±2.0)d,P<0.05]。Ⅰ组感染后有6例出现病情反复,但感染控制后尿蛋白即消失,而Ⅱ组感染后有8例复发,感染控制后尿蛋白有5例仍阳性,需恢复激素用量才转阴。血清sIL-2R用药后Ⅰ组下降显著高于Ⅱ组,与正常组比已无显著差异,而Ⅱ组仍显著高于正常组。尿sIL-2R与血清sIL-2R一样也发生上述显著变化。血浆IgG用药后Ⅰ组上升显著高于Ⅱ组,与正常组比较已无显著差异。而Ⅱ组仍显著低于正常组。血浆IgA、IgM用药前后两组比较均无差别。结论卡介苗素在佐治SNS中具有预防和降低感染、减少和预防复发、避免反复大量应用激素的作用,此机制可能在于其降低SNS患儿血、尿sIL-2R水