1—（4—胺乙酰胺基）苄基四氢异喹啉类化合物的合成及其心血管活性

研究发现某些异喹啉类化合物具有较好的心血管活性，Ｎ胺乙酰基取代的苄基四氢异喹啉化合物对二氢吡啶（ＤＨＰ）受体有较好的亲和力〔１〕．据报道〔２〕化合物１（２乙胺基乙酰胺基３，４二甲氧基）苄基异喹啉具有较强的抗心律失常作用，毒性远低于利多卡因．...     

2—芳氧乙基四氢异喹啉类化合物的合成

为寻找主要作用于钙或钾通道的新型心血管药物，在已有研究基础上，结合一些钙拮抗剂和钾通道调控剂的结构特征，设计合成了１３个Ｎ－芳氧乙基取代的苄基／萘甲基四氢异喹啉化合物（Ⅱ１￣Ⅱ１３）。初步药理试验结果表明：化合物（Ⅱ３）和（Ⅱ４）对高钾诱导的血管收缩抑制作用与粉防己碱相当，化合物（Ⅱ５）抑制磷脂酶Ａ２活性较强，化合物（Ⅱ３，Ⅱ４，Ⅱ６，Ⅱ７）对肿瘤多药抗药性的逆转活性均超过阳性对照品维拉帕米。     

6-(4'-取代酰胺基苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集作用

目的：６（４′取代苯基）４,５二氢３（２Ｈ）哒嗪酮类化合物的合成及抗血小板聚集活性的研究。方法：通过付克反应、碳链延长、水解和环合反应得到两个关键中间体,然后通过酰化反应制得各种酰胺化合物;参考Ｂｏｒｎ比浊法测定目标化合物的抗血小板聚集活性。结果：设计合成了２４个６（４′取代酰胺基苯基）４,５二氢３（２Ｈ）哒嗪酮类化合物,２２个为首次报道;所有化合物在体外对ＡＤＰ诱导的兔血小板聚集均有不同程度的抑制作用,第ＩＩ类化合物的抑制作用强于第Ｉ类化合物,其中Ｉ１,Ｉ３,ＩＩ１,Ｉ３,ＩＩ４,Ｉ６和ＩＩ９的抑制作用均强于对照药ＣＩ９３０,其中Ｉ１和ＩＩ３的抑制作用最强,其ＩＣ５０约为ＣＩ９３０的１／１０。结论：其中一些化合物显示较强的抗血小板聚集活性,值得进一步研究。     

6-(4-取代-1-哌嗪乙酰胺基)-3，4-二氢-2(1H)-喹啉酮类化合物的合成及正性肌力作用初探

设计并合成了１０个６（４取代１哌嗪乙酰胺基）３,４二氢２（１Ｈ）喹啉酮类化合物,其结构经元素分析、红外光谱和核磁共振氢谱确证．初步药理实验表明：６（４苄基１哌嗪乙酰胺基）３,４二氢２（１Ｈ）喹啉酮具有较明显的正性肌力及扩血管作用．     

1-(4-烃氧基)苄基四氢异喹啉类化合物及相关化合物的合成与生物活性

以有心血管活性的异喹啉生物碱为先导物,设计合成了15个3,4-二氢(II_1,2)和1,2,3,4-四氢-(4-烃氧基)苄基四氢异喹啉化合物(II_3～15)。药理实验表明:大部分化合物有舒张血管条作用,其中化合物II₉对低钾诱导的血管收缩有较强的抑制作用,而对高钾诱导的血管收缩无作用,对硝酸乌头碱诱发的大鼠室性心律失常有明显保护作用。     

α-乙酰氨基-β-〔4-(1,2-二氢-2-氧代喹啉)〕丙酸乙酯的选择性硫代反应

分别以五硫化二磷和对甲氧苯基硫代硫化磷为硫化试剂与α乙酰氨基β〔４（１，２二氢２氧代喹啉）〕丙酸乙酯进行选择性硫代反应，均得到了目标产物α乙酰氨基β〔４（１，２二氢２硫代喹啉）〕丙酸乙酯，再进一步水解得α乙酰氨基β〔４（１，２二氢２硫代喹啉）〕丙酸，这两个化合物尚未见文献报道，并对酰胺的硫代反应机制进行了探讨．     

咖啡酸和阿魏酸及其类似物对内皮素-1生物效应的拮抗作用

目的：对咖啡酸和阿魏酸以及两者化学衍生物肉桂酰胺类似物Ｎ３（５甲基异吓恶唑）基３，４二羟基肉桂酰胺（化合物１）和Ｎ４安替比林基４羟基３甲氧基肉桂酰胺（化合物２）拮抗内皮素１（ＥＴ１）的缩血管及致血管平滑肌细胞增殖效应进行了初步研究。方法：用这四种化合物对ＥＴ１缩血管及致血管平滑肌细胞增殖作用的拮抗效应拮抗进行了研究。结果：咖啡酸和阿魏酸及其衍生物对ＥＴ１缩血管及致血管平滑肌细胞增殖效应有明显的拮抗作用，该作用具剂量依赖性，经药效动力学分析，阿魏酸及其衍生物的拮抗活性显著大于咖啡酸及其衍生物；这四种化合物能剂量依赖性地抑制ＥＴ１致血管平滑肌细胞增殖作用。结论：咖啡酸和阿魏酸及其衍生物为一类新的ＥＴ拮抗剂。     

吡酮酸类抗菌药物的研究 XII.6-氯-1-环丙基-7-(1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用

合成了１６个６氯１环丙基７（１哌嗪基）１，４二氢４氧代喹啉３羧酸及其类似物，并测定了抗菌活性，结果表明，化合物１１Ｃａ及１１Ｃｃ对金葡菌１５的活性是环丙沙星的４倍，对大肠杆菌２２和绿脓杆菌２９的活性与环丙沙星相当     

6-取代苯基-4,5-二氢-3(2H)-哒嗪酮衍生物的合成及其抑制血小板聚集活性

共合成了１４个６取代苯基４，５二氢３（２Ｈ）哒嗪酮衍生物（Ⅱ１～１４），除化合物（Ⅱ１０）外均未见文献报道．对这些化合物及中间体（Ｅ１～３）进行了ＡＤＰ诱导的家兔体外抑制血小板聚集实验，结果表明：（Ｅ１～３），（Ⅱ４），（Ⅱ９），（Ⅱ１１）及（Ⅱ１４）有较强的活性     

肉桂酰胺类似物的合成及其对内皮素1生物效应的拮抗作用

合成了肉桂酰胺类似物Ｎ３（５甲基异唑）基３，４二羟基肉桂酰胺（１）和Ｎ４安替比林基４羟基３甲氧基肉桂酰胺（２）．实验发现化合物（１），（２）对内皮素１（ＥＴ１）引起的缩血管和致血管平滑肌细胞有丝分裂效应具有显著的拮抗作用     

TOXIC AND CARCINOGENIC EFFECTS OF PARENTERAL AND PERCUTANEOUS ATP AND ITS IRON COMPLEX

ABSTRACT

The long term effects of percutaneous, subcutaneous and intraperitoneal administration of sodium–ATP (NaATP) and ferric iron–ATP (FeATP) were studied on an animal model. Both compounds induce a generalized lymphoadenitis which in the case of FeATP led to lymphomas. The analytical study of the involved target tissues showed intracellular composition changes that result from the impairment of the cell membrane permeability. The morbidity and mortality rate were higher with FeATP which seems to be the result of two different, in intensity and duration, interactions with the cell plasma membrane. The influence of the changes in cellular calcium homeostasis, and its relationship with carcinogenesis and immuno response are discussed.     

苦参碱及氧化苦参碱的药代动力学与药效动力学

以QTc延长率为效应指标,用药代动力学-药效动力学结合模型对苦参碱、氧化苦参碱iv后在免体内的处置和效应动力学作定量分析,两药的血浓时程均符合二房室模型,两药的效应与效应室浓度之间的关系均符合S形E_max模型。两药彼此的药动学和药效学性质均有明显差异,但它们各自的劳动学和药效学性质在所用剂量范围内均为非剂量依赖性。     

LIVER ALCOHOL AND ALDEHYDE DEHYDROGENASE: INHIBITION AND POTENTIATION BY HISTAMINE AGONISTS AND ANTAGONISTS

1. The in vitro effects of histamine, some other Hi- and H₂-receptor agonists and some antagonists were studied on the specific activities and kinetics of rat liver alcohol dehydrogenase (ADH), and cytoplasmic and mitochondrial liver aldehyde dehydrogenase (ALDH). 2. Histamine (H₁- and H₂-agonist) non-competitively inhibited ADH and ALDH, 2-(2-aminoethyl) pyridine (Hi-receptor agonist) non-competitively inhibited ADH. There were no changes of cytoplasmic and mitochondrial liver ALDH activities in the presence of 2-(2-aminoethyl) pyridine. 3. Betazole (H₂-receptor agonist) produced a competitive inhibition of mitochondrial ALDH but not of ADH or cytoplasmic ALDH. 4. Diphenhydramine (H₁-receptor antagonist) non-competitively inhibited ADH at a lower concentration. It stimulated mitochondrial ALDH activity without changes in cytoplasmic ALDH from control values. 5. Burimamide (H₂-receptor antagonist) produced a biphasic and dose-dependent stimulation and non-competitive inhibition of ADH and it non-competitively inhibited ALDH in both cytoplasmic and mitochondrial fractions. Metiamide (H₂-receptor antagonist) non-competitively inhibited all ADH and ALDH of both liver fraction studied. 6. It is concluded that liver ADH and ALDH activity can be altered by compounds which affect both Hi- and H₂-histamine receptors and that these compounds may cause an in vivo potentiation and/or reduction of the toxic effect of ethanol.     

TOXICOKINETICS AND EFFECTS OF FIBROUS AND NONFIBROUS PARTICLES

Chronic inhalation of fibrous and nonfibrous particles by rats at high concentrations results in lung tumor formation if the particles are poorly soluble in the lung. Even rather benign nonfibrous particles such as TiO 2 produce this result. One significant change during a chronic inhalation exposure of poorly soluble particles of low cytotoxicity (PSP) is an impairment of normal clearance mechanisms in the alveolar region of the lung in rats, resulting in a continued buildup to high lung burdens accompanied by chronic alveolar inflammation, fibrosis, and mutational events. Since these are obviously high-dose effects, questions about their extrapolation to humans exposed to much lower concentrations have been raised. Results of key studies reported for chronic inhalation of PSP in rats indicate that mechanisms of PSP-induced lung tumors at high doses do not operate at low dose levels. Furthermore, the existence of two thresholds can be postulated: One is a dosimetric threshold for the endpoint alveolar macrophage-mediated clearance, which is related to lung particle overload. The other is a mechanistic threshold for the endpoint mutation, which is determined by the level of antioxidant defenses to counter-balance reactive oxidant species released by activated inflammatory cells. A no-observed-adverse-effect level (NOAEL) could therefore be based on avoiding alteration of the toxicokinetic of the particles such that the lung burdens stay below the dosimetric threshold. The suggestion that PSP-associated organic compounds (e.g., diesel particulate matter) contribute to the lung tumor responses in rats observed in chronic inhalation studies is not supported by experimental data from in vivo studies. It can be concluded that high-dose rat lung tumors due to PSP should not be used for low-dose extrapolations, and no significant contribution to human lung cancer risk can be predicted from levels of PSP below lung overload. With respect to the pulmonary toxicokinetics of inhaled fibrous particles, the biopersistence of long fibers (>20 µm) which cannot be phagocytized by alveolar macrophages is a key parameter related to long-term carcinogenic effects. Long fibers with a very low biopersistence should not be considered as carcinogenic. Since the clearance kinetics of fibers can generally be described by a biphasic or multiphasic pattern - fast initial and slow final phase - it is essential that the slow phase of the retention kinetics of fibers longer than 20 µm is considered in a biopersistence assay. Based on the results of such assay, fibers can be classified into one of two categories: a biopersistent fiber that cannot be dissolved in the lung within an acceptable time period; or a biosoluble fiber when even long nonphagocytizable fibers will be disappearing rapidly from the lung. However, in addition to biopersistence, it should be mandatory to evaluate fiber toxicity in an appropriate assay relative to a fiber whose long-term effects are well known. Moreover, for organic fibers it is likely that different rules may have to be established for characterization of their toxic and carcinogenic potential.     

珍珠母贝中糖胺聚糖的提取分离纯化

目的:对马氏珍珠母贝中提取、分离得到的糖胺聚糖(glycosam inog lycans,GAG)进行化学组分研究。方法:样品经还原、水解和乙酰化,采用气相色谱-质谱法定性测定。结果:测定出马氏珍珠母贝中经提取、分离得到的GAG中的3种主要成分,其骨架结构分别与(硫酸乙酰)肝素、(硫酸)软骨素和透明质酸相符。结论:马氏珍珠母贝中提取分离的糖胺聚糖中含有肝素、软骨素和透明质酸。     

HPLC和~1HNMR分析确定cis－A－和cis－B－羟甲芬太尼的组成和构型

羟甲芬太尼（１）是一个强效的镇痛剂和高亲和、高选择性的阿片μ受体激动剂。通过ＨＰＬＣ和１ＨＮＭＲ分析，ｃｉｓ－Ａ－ｌ被确定为由等量的ｃｉｓ－（＋）－（３Ｒ，４Ｓ，２＇Ｓ）－ｌ和：ｃｉｓ－（—）－（３Ｓ，４Ｒ，２＇Ｒ）－１组成的外消旋体，ｃｉｓ－Ｂ－ｌ被确定为由等量的ｃｉｓ－（—）－（３Ｒ，４Ｓ，２＇Ｒ）－１和ｃｉｓ－（＋）－（３Ｓ，４Ｒ，２＇Ｓ）－１组成的外消旋体。     

冰毒吸食者焦虑抑郁情绪和自我概念的测评及相关分析

目的:了解冰毒吸食者焦虑抑郁情绪和自我概念状况,探讨二者之间的关系,为临床心理干预提供依据。方法:采用抑郁自评量表(SDS),焦虑自评量表(SAS)和田纳西自我概念量表(TSCS)对36例强制戒毒的冰毒吸食者(研究组)和36例健康人群(对照组)进行调查,将结果进行统计学处理分析。结果:(1)研究组SDS,SAS评分明显高于对照组,差别具有统计学意义(P<0.01);(2)TSCS评分比较,研究组除自我批评因子分高于对照组外,其余各因子分均低于对照组,差异具有统计学意义(P<0.01);(3)TSCS与SAS和SDS之间具有高度相关性(r=0.411-0.462,P<0.01)。结论:冰毒吸食者焦虑抑郁情绪明显,表现为消极的自我概念;焦虑抑郁情绪影响自我概念。临床治疗中应关注戒毒者负性情绪和自我概念,采取有效措施帮助他们消除负性情绪,树立积极的自我概念,促进心理康复。     

顶头孢霉229与12的分生孢子及原生质体的形成和再生

头孢菌素产生菌顶头孢霉菌株229的沉没培养或斜面培养都可形成分生孢子,并可用普通滤纸将它们与菌丝及节孢子分开,但是它们成活率极低.这种成活的分生孢子的数量与培养基成分有关.菌丝培养基成分对制备顶头孢霉原生质体有显著影响.用一种MM培养基培养的菌丝,不经巯基化合物预处理,酶解(1%纤维素酶)3小时后,可得到大量原生质体.原生质体的再生频率为1.8～4.6%.与分生孢子形成的菌落相比,原生质体再生菌落的产抗生素能力显示出较大的变异性.本文还讨论了山梨醇与Nikkomycin对菌丝生长形态及原生质体形成的影响.