四-(对氨基苯基)钴卟啉-NO配合物的合成及NO释放效能和生物学活性

合成并结构表征meso-5,10,15,20-四(对氨基苯基)钴卟啉-NO配合物(TAPP-Co-NO)作为NO供体. 采用重氮化和偶合反应检测TAPP-Co-NO体外NO的释放效果. 选取家兔离体胸主动脉环测TAPP-Co-NO对家兔离体胸主动脉环舒张作用. 大鼠随机分为两组, 实验组静脉给予0.5 mL二甲基亚砜和TAPP-Co-NO混合液, 对照组静脉给予等量二甲基亚砜, 观察两组大鼠收缩压、舒张压和心率的变化. TAPP-Co-NO的释放效率为63.17%. TAPP-Co-NO能使甲氧胺引起家兔离体胸主动脉收缩的量效关系曲线非平行地右移, 最大反应(E_max)压低(P＜0.01), 压低百分率为55.7%. 实验组大鼠血压在用药后第5 s时开始下降, 第10 s时下降幅度达最大, 以后逐渐回升, 第60 s时接近用药前水平; 对照组大鼠, 血压水平在用药前后没有统计学差异; 实验组和对照组大鼠的心率在用药前后均无统计学差异. 结果表明, TAPP-Co-NO有较高的释放效率, 能明显抑制甲氧胺对家兔离体胸主动脉的收缩, 具有瞬间降压作用.     

(S)-萘普生-1,4-二氢吡啶类化合物的合成与生物活性

以(S)-萘普生为原料制得的(S)-萘普生氯甲酯与1,4-二氢吡啶-3,5-二羧酸单酯在无水K₂CO₃存在下于DMF中反应得到的粗产品经梯度结晶或柱层析纯化得标题化合物. 合成的7种目标化合物收率21%～73%, 经¹H NMR, IR, MS确证了结构. 家兔离体血管平滑肌收缩试验研究表明, 大部分目标化合物对苯肾上腺素诱导的血管收缩有松弛作用.     

O2-2,4-二硝基苯基偶氮二醇盐类化合物的设计、合成及抗肿瘤活性

以O2-2,4-二硝基苯基偶氮二醇盐(PABA/NO)为先导化合物,选择适当的仲胺作为偶氮二醇盐中相应的胺片段,并用碳氮键取代苯环5位的碳氧酯键,设计合成了化合物2a,2b和4a~4j,以期获得活性更强且稳定性好的抗肿瘤药物.目标化合物经1H NMR,13C NMR及HRMS进行了结构确证.生物活性测试结果表明,目标化合物可不同程度地抑制结肠癌HCT-116细胞的增殖,其中化合物4h的活性最强(IC50=7.945±0.421 μmol/L),优于PABA/NO(IC50=12.134±0.675 μmol/L).NO释放实验结果表明,此类化合物的NO释放量与细胞毒性呈正相关.化合物4h在HCT-116细胞中释放NO的量最多,约是正常细胞的2倍.此外,化合物4h在大鼠血浆中的体外稳定性显著优于PABA/NO,值得进一步研究.     

O~2-2,4-二硝基苯基偶氮鎓二醇盐类化合物的设计、合成及抗肿瘤活性

以O~2-2,4-二硝基苯基偶氮鎓二醇盐(PABA/NO)为先导化合物,选择适当的仲胺作为偶氮鎓二醇盐中相应的胺片段,并用碳氮键取代苯环5位的碳氧酯键,设计合成了化合物2a,2b和4a~4j,以期获得活性更强且稳定性好的抗肿瘤药物.目标化合物经~1H NMR,~(13)C NMR及HRMS进行了结构确证.生物活性测试结果表明,目标化合物可不同程度地抑制结肠癌HCT-116细胞的增殖,其中化合物4h的活性最强(IC50=7.945±0.421μmol/L),优于PABA/NO(IC50=12.134±0.675μmol/L).NO释放实验结果表明,此类化合物的NO释放量与细胞毒性呈正相关.化合物4h在HCT-116细胞中释放NO的量最多,约是正常细胞的2倍.此外,化合物4h在大鼠血浆中的体外稳定性显著优于PABA/NO,值得进一步研究.     

有氧运动训练对D-半乳糖诱导的亚急性衰老大鼠血管老化的影响

目的探讨游泳运动对大鼠血管抗衰老的影响。方法 30只健康雄性SD大鼠(180~220g)随机分为3组:溶剂对照组(n=10),D-半乳糖组(n=10)和有氧运动+D-半乳糖组(运动组,n=10)。D-半乳糖组和运动组大鼠每日颈部皮下注射D-半乳糖(125 mg/kg),溶剂对照组大鼠每日颈部皮下注射同体积生理盐水,且运动组大鼠每日进行60 min的无负重游泳运动训练,持续8周。以血浆总一氧化氮合成酶(T-NOS)活力,一氧化氮(NO),内皮素(ET)和NO/ET平衡建立血管衰老指标评价体系,并测量主动脉组织超氧化物歧化酶、谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)和丙二醛(MDA)含量。结果与溶剂对照组相比,D-半乳糖组大鼠主动脉MDA和血浆ET含量显著升高,而GSH-Px、SOD活力、血浆NO含量和NO/ET比值显著下降。与D-半乳糖组相比,运动组大鼠主动脉MDA含量和T-NOS活力显著下降,GSHPx、SOD、T-NOS活力、NO含量和NO/ET比值显著升高(P0.05),且与对照组相比上述各项指标无显著差异。结论 D-半乳糖皮下注射可诱导大鼠主动脉脂质过氧化反应,血浆NO/ET失衡;适宜的有氧运动能显著增加大鼠血管的抗氧化能力,减少脂质过氧化反应,改善NO/ET失衡,预防血管衰老。     

N-4-羟基苯基维甲酰胺与呋咱氮氧化物偶联物的合成及抗肿瘤活性研究

为了寻找治疗乳腺癌的药物, 将N-4-羟基苯基维甲酰胺(4-HPR)以乙酸为连接基团通过酯键或酰胺键与NO供体呋咱氮氧化物缀合, 合成了NO供体型维甲酸类化合物, 共11个新的目标化合物, 其结构经IR, MS, ¹H NMR和元素分析表征, 总收率为8.8%～12.9%. 对目标物进行体外抗乳腺癌活性测试, 结果表明, 所有目标物均具有不同程度的抗肿瘤活性, 其中8g抗肿瘤活性和对照药阿霉素相当.     

N-[(S)-脯氨酰]羟胺的合成及催化直接不对称羟醛反应研究

(S)-脯氨酸用苯甲氧羰酰氯保护氨基后用混合酸酐法与羟胺偶合, 给出N-[N-苯甲氧羰酰-(S)-脯氨酰]羟胺, 催化氢解脱去保护基得标题化合物. 该化合物对映选择性催化直接羟醛反应, 产率最高达到90.0%, 对映体过量最高达89.5%.     

新型二氢吡啶类钙拮抗剂化合物的合成与生物活性

以1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸单甲酯(1)或双乙烯酮为原料,设计合成了16个未见文献报道的二氢吡啶类钙拮抗剂化合物4a～4l及9a～9d,利用IR,1HNMR,ESI-MS和元素分析对目标化合物的结构进行表征.离体大鼠胸主动脉血管环收缩实验表明,化合物4e,4g～4j对KCl所致的血管环收缩有明显的舒张作用,其生物活性均强于阳性对照苯磺酸左旋氨氯地平.     

给药硝酸镨后大鼠尿液和血清的核磁共振代谢组学研究

采用基于核磁共振的代谢组学方法,分析了腹腔注射给药2,10和50 mg/kg体重剂量硝酸镨(Pr(NO3)3) 168 h内Wistar大鼠尿液和血清的核磁共振氢谱.由尿液及血清中内源性代谢物如柠檬酸、琥珀酸、α-酮戊二酸、肌酸酐、N-氧三甲胺、氨基酸、乳酸、牛磺酸及葡萄糖等的浓度变化,并结合大鼠血清指标研究了轻稀土化合物Pr(NO3)3在大鼠体内的急性生物效应.结果表明,Pr(NO3)3急性毒性的靶向器官为肝脏和肾脏,但以肝脏为主,且呈现明显的剂量-反应关系.低、中剂量组的Pr(NO3)3会通过改变大鼠体内酶代谢而造成肝脏线粒体中的能量代谢(脂肪、糖代谢)紊乱;同时,Pr(NO3)3还会影响肾脏的正常功能,改变肾脏中渗透质的平衡,影响肾脏对氨基酸的重吸收和利用.     

黄酮糖苷Parkinsonin B的全合成

天然黄酮碳糖苷化合物特有的稳定性和显著的生物活性, 使其化学合成成为当今糖化学领域的研究热点之一. 本工作立体专一性地全合成了天然黄酮碳苷Parkinsonin B. 通过控制物质的量比, 首先高选择性合成了2-羟基-4,6-二甲氧基苯乙酮(3), 并与糖给体O-(2,3,4,6-四-O-苄基-α-D-葡萄糖基)三氯乙酰亚胺酯(7)发生立体专一性糖基化反应得到碳糖苷化合物8, 化合物8经查耳酮路线进而合成黄酮碳苷Parkinsonin B (1). 经IR, MS, ¹H NMR及元素分析证实了产物及中间体的结构, 同时讨论了全合成反应的主要影响因素, 并对其¹H NMR解析进行了探讨.     

Pharmacokinetics and tissue distribution study of clevidipine and its primary metabolite H152/81 in rats

This present study was designed to investigate the pharmacokinetic profiles and tissue distribution characteristics of clevidipine and its primary metabolite H152/81 in rats following a single intravenous administration of clevidipine butyrate injectable emulsion. For this study, a sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was established and validated for the simultaneous quantitation of clevidipine and H152/81 in rat whole blood and various tissues. A Hedera ODS‐2 column with two gradient elution programs was employed for the troubleshooting of matrix effect on the detection of analytes among different biological samples. The experimental data showed that clevidipine represented quick elimination from blood with a half‐life of about 4.3 min and rapid distribution in all of the investigated tissues after administration; the highest concentration of clevidipine was found in the heart whereas the lowest concentration was detected in the liver. In addition, clevidipine was almost undetectable in most tissues except for heart and brain at 90 min post‐dosing, suggesting that there was no apparent long‐term accumulation in rat tissues. For H152/81, the peak concentration of 3714 ± 319 ng/mL occurred at 0.129 ± 0.048 h, the half‐life was 10.08 ± 1.45 h and area under the concentration–time curve was 42091 ± 3812 ng h/mL after drug administration. In addition, H152/81 was found at significant concentration levels in all tissues, in descending order of lung, kidney, heart, liver, spleen and brain at each time point. The results of current study offer useful clues for better understanding the distribution and metabolism of clevidipine butyrate injectable emulsion in vivo.     

丙泊酚复合司可林在精神病患者无抽搐电休克的应用

目的对丙泊酚复合司可林在精神病患者无抽搐电休克中的应用效果进行分析和总结。方法随机选择江西省新余市第二医院于2014年7月—2016年7月收治的精神科患者140例,均采用无抽搐电休克治疗。所有患者均给予丙泊酚与司可林行麻醉,观察麻醉效果。结果血氧饱和度及血压在给药后、电刺激时及清醒后差异不显著,但电刺激时的心率明显快于给药前,而给药后及清醒后的心率与给药前相比,无显著差异。本组共11例发生不良反应,但程度较轻微,停药后可自行消失,未作特殊处理。结论在精神病患者无抽搐电休克治疗中应用丙泊酚与司可林,心率、血压及血氧饱和度的变化较小,有效性高、安全性好,值得推广。     

急性镉中毒大鼠致死时重要器官镉的分布

分别通过静脉和呼吸道急性镉染毒，探讨了急性镉中毒大鼠致死时，血液，心、肝、肾、脑、肺的镉分布。８０只Ｗｉｓｔａｒ大鼠分为对照组和染毒组，氯化镉进行急性染毒，在心肌收缩功能降低为染毒前的５０％及心跳停止时，取器官标本，用原子吸收分光光度计测定镉含量。实验结果提示，急性镉中毒时，血液、心脏的镉含量早期升高缓慢，后期升高较快，肝脏镉含量呈线性快速升高；而肾脏镉含量经呼吸道染毒时与肝脏类似，经静脉染毒时，     

舒芬太尼不同浓度对气管插管全麻患者插管反应的抑制效果比较

目的比较舒芬太尼不同靶控浓度对气管插管全麻患者插管反应的抑制效果。方法抽取清远市中医院2014年7月—2015年6月78例气管插管全麻患者,根据舒芬太尼血浆靶控浓度将该78例患者分为低质量浓度组(0.4 ng/m L)和高质量浓度组(0.6 ng/m L),两组各39例。比较两组麻醉诱导前(T1)、气管插管时(T2)、插管后1 min(T3)、插管后3 min(T4)和插管后5 min(T5)的平均动脉压(MAP)、心率(HR)指标。结果低质量浓度组患者血压心率较为平稳,各时点MAP、HR相比较差异无统计学意义(P0.05);高质量浓度组患者血压心率变化幅度较大,T3、T4时点MAP、HR较T1、T2、T3均明显较低,差异具有统计学意义(P0.05);低质量浓度组T3、T4时点MAP、HR较高浓度组明显较高,具有统计学意义(P0.05)。结论不同浓度舒芬太尼对行气管插管全麻患者的插管反应抑制效果不同,质量浓度维持在0.4 ng/m L具有较好的稳定血压心率作用,有利于达到理想的插管反应抑制效果。     

Kinetic distribution of paeoniflorin in cortex of normal and cerebral ischemia-reperfusion rats after intravenous administration of Paeoniae Radix extract

The time course of paeoniflorin in the cortex of normal and cerebral ischemia-reperfusion rats, following intravenous administration of Paeoniae Radix extract at a dose of 60 mg/kg of paeoniflorin, was determined using high-performance liquid chromatographic (HPLC) assay. The results showed that paeoniflorin could penetrate through the blood-brain barrier to reach the cortex, and that the injuries of ischemia-reperfusion could play an important role in pharmacokinetic process of paeoniflorin in the cortex after intravenous administration of Paeoniae Radix extract. The cortex concentrations of paeoniflorin in cerebral ischemia-reperfusion rats were lower 5 min after dosing and declined more slowly than that in normal control.     

Effect of water extracts of aloe and some herbs in decreasing blood ethanol concentration in rats. II

Oral administration of ethanol to rats at a dose of 3 g/kg decreased alcohol dehydrogenase (ADH) activity and metabolism of lactate to pyruvate in the liver. The effects of water extracts of Aloe and some other herbs on blood ethanol concentration and on ADH activity in liver cytosol were examined. The water extracts of these herbs caused a faster elimination of ethanol from blood of normal rats when administered orally 30 min before oral administration of ethanol. The rapid elimination of ethanol seems to be due to a protection of ADH activity and the supply of nicotinamide dinucleotide, both of which are reduced by high ethanol concentration. The effects of ethanol in decreasing the enzyme activities relating to its own metabolism occur when high concentrations of ethanol pass through the liver, and thus may primarily appear during the absorption of alcohol from the gastrointestinal tract, when portal concentration of ethanol are very high.     

Increased transport of theophylline into gastrointestinal lumen and gastrointestinal dialysis by activated charcoal in rats with hepatic cirrhosis

The characteristics of exsorption and/or excretion of theophylline into the small intestinal lumen in rats with hepatic cirrhosis (HC rats) induced by carbon tetrachloride were investigated by an in situ single-pass perfusion technique. The serum concentrations of theophylline after i.v. administration of aminophylline (10 mg/kg) in the HC rats were significantly higher than those in normal rats during the experimental period. Moreover, the exsorption of theophylline from blood into the intestinal lumen was significantly increased in the HC rats compared with the normal rats. Treatments with oral activated charcoal reduced the serum theophylline levels in the HC rats. Consequently, gastrointestinal dialysis by oral administration of activated charcoal may be a useful method to remove poisonous drugs from the blood in patients with hepatic failure (including cirrhosis), which decreases the systemic clearance.     

Epinine Kinetics and Plasma Catecholamine Changes Following Oral Administration of the Prodrug Ibopamine in Patients with Chronic Heart Failure

Abstract

Epinine plasma levels, and Epinine - induced plasma Catecholamine changes were investigated in nine patients with chronic heart failure (NYHA class I and II), following oral administration of Ibopamine 100 mg. Norepinephrine, Epinephrine, Dopamine, and Epinine plasma levels were monitored for up to four hours after the drug administration. Arterial pressure and heart rate were recorded, too. Epinine plasma levels were lower than previously estimated, the maximal individual level ranging from 2792 to 7228 pg/mL. Both Norepinephrine and Epinephrine showed a very small decrease (less than 18%) after Ibopamine administration. No changes were shown in arterial pressure and heart rate. Previous assessment of Epinine pharmacokinetics is likely to be reviewed extensively owing to possible overestimation by assay methods used in former studies. Epinine - induced plasma Catecholamine changes may be mediated by (i) the claimed hemodynamic effect of the drug, and/or (ii) by the complex interrelationships between Epinine itself and both adrenergic and dopaminergic receptors.     

Antihypertensive Effect of Galegine from Biebersteinia heterostemon in Rats

The aerial part of Biebersteinia heterostemon Maxim. (Geraniaceae Biebersteiniaceae) known as ming jian na bao in Chinese, has been traditionally used in Tibetan folk medicine for treatment of diabetes and hypertension. The aim of the present study was to evaluate the effects of galegine obtained from an ethanol extract of the entire Biebersteinia heterostemon plant on the rat’s cardiovascular system in order to characterize its contributions as an antihypertensive agent. The antihypertensive effect of galegine was investigated in pentobarbital-anesthetized hypertensive rats at three dose levels based on the LD₅₀ of galegine. Meanwhile a positive control group received dimaprit with the same procedure. Dimaprit infusion induced a significant hypotension which declined by an average margin of 20%. Simultaneously, single administration of galegine at the doses of 2.5, 5, and 10 mg/kg by intraperitoneal injection induced an immediate and dose-dependent decrease in mean arterial blood pressure (MABP) by an average margin of 40% with a rapid increase in heart rate (HR). We demonstrated that galegine is effective in reducing blood pressure in anesthetized hypertensive rats with rapid onset and a dose-related duration of the effects. The results indicate that galegine was the bioactive compound which can be used as a pharmacophore to design new hypertensive agents.