蛇床子素在兔体内药物代谢动力学

目的研究蛇床子素在兔体内的药物代谢动力学。方法用高效液相色谱法,以丹皮酚为内标,以甲醇-水(80∶20)为流动相,测定兔血液中蛇床子素(iv,10 mg·kg^-1)的含量。采用3P87程序计算药物代谢动力学参数。结果蛇床子素iv药代动力学符合二房室开放模型,T_1/2α=5.81 min,T_1/2β=42.2 min,K21=0.036 0·min^-1,K₁₂=0.045 0·min^-1,K₁₀=0.054 0·min^-1,AUC=235 mg·min·L^-1,CLs=0.043 0 L·min^-1·kg^-1,V_C=0.780 L·kg^-1。结论蛇床子素在兔体内分布及消除较快     

常咯啉在实验性心律失常狗的药代动力学-药效动力学分析

用Harris冠脉结扎法诱发的心律失常狗研究常咯啉药代动力学-药效动力学。7只狗按83.33μg·kg^-1·min^-1静脉滴注60min,在给药期间和停药后不同时间记录ECG及测定血药浓度。C-T数据用药代程序计算药代参数;药效数据用药代-药效同步分析模型计算药效动力学参数,K₁₀, T_1/2,Vd,Cl分别为0.0087min^-1,78.03min,40.55ml·kg^-1和0.421ml·kg^-1·min^-1;K_eO和Ce(50)分别为0.0048min^-1和2.01μg·ml^-1.     

生物降解型左旋18-甲基炔诺酮微球在大鼠的药代动力学

用放射免疫法研究了左旋18-甲基炔诺酮(LNG)微球和LNG微晶在大鼠的药代动力学。大鼠单次imLNG微晶35mg·kg^-1后4.88h.血药峰值达67.66nmol·L^-1,MRT为10.16d,T_{<0.32nmol·L^-1}为41.50d;而单次imLNG微球20.4,41.1和83.3mg·kg^-1后,血药分别于6,4.67和4.33h达峰浓度15.19,33.61和38.55nmol·L^-1,MRT分别为69.23,65.12和63.25d,T_{<0.3nmol·L^-1}分别为167.81,169.73和167.23d。可见LNG微球在大鼠的MRT和T_{<0.32nmol·L^-1}分别约为LNG微晶的6.6和4.2倍,提示该微球具有明显的缓释长效作用,且初始血药峰值明显低于肌注LNG微晶。     

Pharmacokinetic modelling of microencapsulated metronidazole

The aim of present study is to develop a pharmacokinetic model for microencapsulated metronidazole to predict drug absorption pattern in healthy human and validate this model internally.  Metronidazole was microencapsulated into ethylcellulose shells followed by the conversion of these microcapsules into tablets.  Dissolution study of tablets was conducted in 450 mL double distilled water, 0.1 mol·L⁻¹ HCl and phosphate buffer (pH 6.8) maintained at (37 ± 0.5) ℃ using USP apparatus II at 50, 100 and 150 r·min⁻¹.  Three metronidazole tablets (T₁: fast release, T₂: moderate release, T₃: slow release and reference) were administered to twenty four healthy human volunteers and serial blood samples were collected for 12 hours followed by their analysis using RP-HPLC.  Drug release data were analyzed by various model dependent and independent approaches.  Drug absorbed (%) was determined by Wagner-Nelson method from plasma concentration profile.  Internal predictability was checked from C_max and AUC.  Optimum dissolution profile was observed in double distilled water and 50 r·min⁻¹.  A good level A correlation was observed between drug dissolution and absorption profiles (correlation coefficient, R² = 0.900 9, 0.942 6, 0.901 5 and 0.932 for T₁, T₂, T₃ and reference, respectively).  Internal    predictability was found less than 10%.  Good correlation coefficients and low prediction errors elaborate the validity of this mathematical in-vitro in-vivo correlation model as a predictive tool for the determination of  pharmacokinetics from dissolution data.     

中性盐和碱性盐胁迫对黑果枸杞种子萌发及幼苗生长的影响

在中性盐(NaCl)和碱性盐(Na₂CO₃)胁迫下,对采自河西走廊黑河中游的黑果枸杞进行种子萌发及幼苗生长试验,测定了发芽率(G_r)、发芽势(G_v)、发芽指数(G_I)、活力指数(V_I)和相对盐害率及幼苗的组织含水量、可溶性蛋白质含量、叶绿素含量、电导率、丙二醛含量和POD含量等指标。结果表明,黑果枸杞种子萌发的NaCl、Na₂CO₃浓度的临界值分别是50 mmol·L^-1和2.5 mmol·L^-1,极限值分别是300 mmol·L^-1和100 mmol·L^-1;在NaCl和Na₂CO₃胁迫下,发芽率分别为69.17%和71.67%;幼苗组织含水量分别由对照的88.97%降低到56.17%、70.27%;可溶性蛋白质含量最大值分别为7.09%、7.73%;叶绿素含量分别由对照的1.27 mg·g^-1降到0.78 mg·g^-1、0.92 mg·g^-1;电导率分别由对照的25.63%增加到64.77%、74.8%;丙二醛含量分别由对照的1.5 μmol·g^-1增加到6.9、6.5 μmol·g^-1;POD活性分别由对照的380.4 U·g^-1·min^-1降低到139.2 U·g^-1·min^-1、192.7 U·g^-1·min^-1。黑果枸杞是盐生植物,低浓度的盐促进萌发,高浓度的抑制萌发;碱性盐更适合其生长;黑果枸杞幼苗在盐胁迫下的生理响应及生态适应综合表现出黑果枸杞更适于碱性盐生长。     

间硝苯地平在Beagle犬体内的药代动力学

目的用反相高效液相色谱法研究间硝苯地平(m-nifedipine，m-Nif)在Beagle犬体内的药代动力学特征。方法正交设计优化色谱分离条件，Beagle犬分别iv给予m-Nif 0.288 mg·kg^-1和ig m-Nif 1.152，3.456，10.370 mg·kg^-1。用反相高效液相色谱法分析血浆中原型药物浓度，血浆药物浓度-时间数据用3P97药代动力学软件分析。结果Beagle犬iv m-Nif，其体内过程符合二室模型，T_1/2β为116.8 min；ig给予m-Nif 后在Beagle犬体内的代谢符合一室模型，其中低剂量(1.152 mg·kg^-1)组C_max为20 μg·L^-1， T_1/2(k_e)为147 min；中剂量(3.456 mg·kg^-1)组C_max为36 μg·L^-1，T_1/2(k_e) 为122 min；高剂量(10.37 mg·kg^-1)组C_max为69 μg·L^-1，T_1/2(k_e)为144 min。结论Beagle犬ig和iv m-Nif 后，血浆中药物消除迅速，口服绝对生物利用度较低。     

HIV感染者中唐草片对洛匹那韦药动学的影响

目的 探讨唐草片对洛匹那韦在HIV感染者中的药动学的影响。方法 入组单纯服用含洛匹那韦的高效抗逆(反)转录病毒治疗方案的患者,达稳态后采血,然后联合服用唐草片2周后采血。采血时间点为：服用洛匹那韦前(0 h)、后0.5,1.0,2.0,3.0,4.0,6.0,8.0,10.0和12.0 h的样本,液相色谱串联质谱检测血浆中洛匹那韦浓度,并采用DAS 2.1.1软件计算药动学参数。结果 入组16例HIV感染者,单纯服用洛匹那韦组合者中的洛匹那韦AUC_0-t为(100.12±57.72)mg·L^-1·h^-1, C_max为(13.24±8.35)mg·L^-1,T_max为(4.16±2.39)h,T_1/2为(9.62±7.57)h;同时服用唐草片后,洛匹那韦的AUC_0-t为(95.55± 58.50)mg·L^-1·h^-1,C_max为(12.36±7.26)mg·L^-1,T_max为(4.06±3.06)h,T_1/2为(9.20±7.18)h。2组之间各参数均无显著差异。结论 唐草片对HIV感染者中洛匹那韦的药动学参数无影响。     

溴泰君(W198)在大鼠和比格狗体内的药代动力学

目的研究溴泰君(W198)在大鼠和比格狗的药代动力学。方法采用HPLC紫外检测方法测定大鼠及比格狗注射W198后血清药物浓度。结果大鼠iv W198 10,20和40 mg·kg^-1 3个剂量的T_1/2β分别为6.60,7.36和6.77 h,AUC_0-24h分别为3.797,7.371和15.192 mg·h·L^-1,V_d分别为7.14,4.33和4.13 L·kg^-1,CL分别为2.83,2.60和2.71 L·(kg·h)^-1。大鼠im W198 20 mg·kg^-1后T_1/2β为11.61 h,AUC_0-24h为4.191 mg·h·L^-1,im的生物利用度为56.9%。比格狗iv W198 5 mg·kg^-1,T_1/2β为11.72 h,AUC_0-24h为12.646 mg·h·L^-1,V_d为0.70 L·kg^-1,CL为0.46 L·(kg·h)^-1。W198与人血浆蛋白的结合率平均为78.0%。结论W198 im的T_1/2β比iv的略长,其生物利用度为56.9%。在10～40 mg·kg^-1剂量内的吸收呈现一级动力学特征。     

苯甲酰胺类衍生物的合成及扩血管活性

报道了22个苯甲酰胺类衍生物的合成,其中大多数化合物有不同程度的扩血管活性,化合物H_1,11,17,E_1,3对去甲肾上腺素[NE](10^-7mol·L^-1)引起的大鼠主动脉条收缩的抑制作用明显优于先导物N-(4-甲氧基苯甲酰基)-N′-肉桂基哌嗪,化合物H_7,15,E₇对85.7mmpL·L^-1KCl引起的大鼠主动脉条收缩有明显的抑制作用,进一步钾通道实验表明E1可能为ATP敏感型钾通道开放剂。并初步分析了此类化合物的构效关系。     

辽东楤本化学成分的研究

从辽东楤本(Aralia elata)的根皮中分得8个化合物,利用理化和光谱方法鉴定分别为胡萝卜甙-6’-棕榈酸酯(6’-O-palmitoyl-β-sitosterol-3-O-β-D-glucoside,A₅)、罗盘草甙A(silphioside A,A₉)、楤木皂甙A甲酯(araloside A methyl ester,A₁₀)、竹节人参甙I_b(chikusetusaponin I_b,A₁₁)、楤木皂甙A(araloside A,A₁₂)、楤木皂甙C(araloside C,A₁₅、楤木皂甙G(araloside G,A₁₆)、无梗五加甙D(acanthoside D,B₁)。化合物A₅,A₉,A₁₁和B₁为首次从该植物中分得,A₁₀为新天然产物,A₁₆为新化合物命名为楤木皂甙G,归属了化合物A₉,A₁₅的¹³C-NMR化学位移。     

硝酸甘油和尼可地尔对缺血区冠脉循环作用的比较

采用实验性冠脉狭窄犬模型,冠脉内恒流灌注硝酸甘油和尼可地尔(均为1μg·kg~(-1)·min~(-1)).发现硝酸甘油有两种作用:灌注5min时能扩张冠脉狭窄段(R_L)及狭窄远端小动脉(R_s),增加冠脉血流量(CBF),改善心肌缺血;但灌注10min后.却引起R_L的增加、CBF的减少,使冠状静脉全血粘度(Hb)、血细胞比容(Hct)增加。加重心肌缺血和恶化冠脉循环。尼可地尔能持久和缓和地扩张冠脉.使R_S降低,CBF增加,降低冠状静脉的Hb、Hct.改善缺血区冠脉循环。     

巴曲酶对急性心肌缺血犬冠脉节段阻力和流量的影响

犬冠状动脉定量狭窄造成急性心肌缺血,观察巴曲酶(batroxobin)对冠脉循环及血流动力学的影响。结果显示,batroxobin可剂量依赖性地增加缺血心脏冠脉血流量,2BU·kg^-1(0.1BU·kg^-1·min^-1)iv后40min,缺血犬冠脉流量比盐水对照组增加12%,此时小冠脉阻力由4.1±0.5降至3.2±0.5mmHg·min·ml^-1,而大冠脉阻力无明显变化;给药后120min,上述作用仍然持续,且冠脉总阻力降低13%,左室压上升及下降最大速率与盐水对照组相比分别增大14%和16%。结果表明,batroXobin在冠脉低灌流状态下仍可降低小冠脉阻力,增加冠脉流量,这可能是其改善缺血犬冠状循环及心脏功能的机理之一。     

Dilatation of coronary stenosis as the salutary effect of nitroglycerin in relief of myocardial ischemia in the dog

To clarify the role of coronary responses to nitroglycerin (NTG) in relieving myocardial ischemia, we examined the effects of NTG in canine models of dynamic and fixed coronary stenoses. Application of coronary stenosis in the proximal left circumflex artery decreased resting coronary blood flow by approximately 40% and caused a significant depression of left ventricular (LV) dP/dt. During fixed coronary stenosis created with an externally applied constrictor device, intravenous NTG, 5 micrograms/kg, reduced mean aortic pressure by 12 +/- 1.1 mm Hg (mean +/- SEM, p less than 0.01) and coronary blood flow by 9 +/- 1.0% (p less than 0.01) but did not affect stenosis resistance and LV dP/dt. During dynamic coronary stenosis produced with an intraluminal microballoon occluder, intravenous NTG caused a marked increase in coronary blood flow by 40 +/- 8.3% (p less than 0.01) and a decrease in stenosis resistance by 62 +/- 9.3% (p less than 0.01), as compared with postocclusion values, concomitant with a significant improvement in LV dP/dt. Intracoronary infusion of NTG, 1.0 microgram/kg/min, had few systemic and coronary hemodynamic effects during fixed coronary stenosis, whereas intracoronary NTG increased coronary blood flow and reduced stenosis resistance, depending on its dose, during dynamic coronary stenosis. These results indicate that NTG is capable of increasing coronary blood flow and alleviating myocardial ischemia due to direct stenosis-dilating effects related to the vasomobility of the coronary stenosis.     

Effects of nitroglycerin on the coronary microcirculation in normal and ischemic myocardium.

Nitroglycerin dilates conduit coronary vessels and only transiently increases flow, however the effects of nitroglycerin in the microcirculation of normal myocardium and during myocardial ischemia have not been assessed. The goal of this investigation was to determine the effects of steady-state levels of nitroglycerin on the microcirculation of normal and ischemic myocardium. Microvessels on the left ventricle were viewed using stroboscopic epi-illumination in anesthetized, open-chest dogs. Myocardial perfusion was measured with radioactive microspheres. Aortic pressure and heart rate were kept constant by an aortic snare and left atrial pacing. Microvessel diameters were measured under control conditions and during steady-state infusion of nitroglycerin (n = 11, 0.01-100 micrograms kg-1 min-1, i.v.). Nitroglycerin selectively dilated arteries from 201 to 386 microns, but had no effect on large arterioles less than 200 microns. Total coronary vascular resistance remained constant except at the highest dose. When mean coronary pressure was decreased to 35 mm Hg, small arterioles less than 100 microns dilated. Diameters of larger arterioles decreased. Nitroglycerin (10 micrograms kg-1 min-1, i.v., n = 8) selectively dilated microvessels greater than 200 microns in the region distal to the stenosis, although myocardial perfusion was not affected. Thus, nitroglycerin altered the distribution of microvascular resistance without altering overall resistance. We conclude that steady-state infusion of nitroglycerin selectively dilates coronary arterial microvessels greater than 200 microns. During decreased perfusion pressure, recruitable vasodilation in response to nitroglycerin is due to dilation of microvessels greater than 200 microns.     

生脉输液对麻醉犬血流动力学及心肌耗氧量的影响

目的研究生脉输液对麻醉犬血流动力学及心肌耗氧量的影响。方法将杂种犬36只,随机分为6组(每组6只):对照组、阳性药组(硝酸甘油注射液组和生脉注射液组)、生脉输液高、中、低三个剂量组。人工呼吸下开胸,观察用药前后不同时间点麻醉犬的冠脉流量(CBF)、心输出量(CO)、冠脉阻力(CAVR)、总外周阻力(TPVR)、心搏出量(SV)、心搏指数(SI)、心脏指数(CI)、左室作功(LVSW)、心肌血流量(MBF)、心肌耗氧指数(MOCI)、耗氧量(VO2)、心肌氧利用率(MOUR)等指标的变化。结果与对照组比较,生脉输液(200,100 mg生药.kg-1)能显著增加麻醉犬冠状动脉和主动脉的血流量、增加心肌血流量,降低总外周血管阻力和冠状动脉阻力,提高心搏出量和心肌氧利用率。结论生脉输液对麻醉犬血流动力学参数有改善作用,具有良好的抗心肌缺血作用。     

Vasodilator responses of coronary conduit and resistance arteries to continuous nitroglycerin infusion in humans: a Doppler guide wire study

To examine the responses of coronary conduit and resistance arteries to the continuous i.v. administration of nitroglycerin in 15 patients with atypical chest pain, we measured coronary blood flow velocity in the left anterior descending coronary artery using a Doppler guide wire and the lumen diameter and cross-sectional area by quantitative coronary angiography. Systolic flow, diastolic flow, total coronary flow, and coronary vascular resistance were calculated. Stepwise increases in dose of nitroglycerin resulted in significant dose-dependent decrease in mean aortic pressure (p < 0.01) and increase in lumen diameter (p < 0.05). After nitroglycerin administration of 0.5 microg/kg/min, systolic flow decreased significantly by 89.9+/-15.7% (p < 0.01), and diastolic flow increased significantly by 74.2+/-37.1% (p < 0.05). Total coronary flow did not change significantly with the various doses of nitroglycerin. However, coronary vascular resistance decreased significantly at concentrations greater than 0.5 microg/kg/min nitroglycerin. Continuous nitroglycerin infusion did not reduce either diastolic or total coronary blood flow despite a significant reduction in coronary perfusion pressure. These results indicate that subendocardial blood flow might be maintained during continuous i.v. infusion of nitroglycerin within the clinical dose range.     

Influence of nitroglycerin on the size of experimental myocardial infarction

Summary The effect of nitroglycerin (N.G.) on the size of myocardial infarction was studied in 12 open-chest dogs with chloralose-urethane anesthesia by means of epicardial ECG-mapping and compared with the influence of simple ligature of the same coronary artery branch. In order to identify the specific effect of N.G. on the heart and the coronary circulation without contribution of the peripheral circulation in 6 dogs aortic pressure was stabilized by a clamp placed around the descending aorta and heart rate was kept constant by atrial pacing.Nitroglycerin (0.5 mg/kg i.v.) infused during the occlusion period of 20 min resulted in a decrease of mean arterial pressure for 27 mm Hg (p<0.005) and left ventricular enddiastolic pressure for 2 mm Hg (p<0.05) indicating a diminishment in oxygen demand. Mean coronary blood flow was reduced to a similar extent (18%) as in the control infarction (22%). Compared to simple occlusion no significant alteration in the extent of ST-elevation in the epicardial electrogram was observed during N.G.-infusion even in the presence of hypotension. In the stabilized group with constant afterload (mean arterial pressure) and heart rate nitroglycerin induced a slight, but not significant decrease of the enddiastolic left ventricular pressure compared to the control group. However, coronary blood flow and ST-elevation were unaffected. Thus, neither in the unstabilized nor in the stabilized group the extent of myocardial injury after ligature of a coronary artery branch were influenced by nitroglycerin. Obviously the improvement in the oxygen demand during nitroglycerin is out balanced by the reduction in oxygen supply so that in effect myocardial infarction size is not altered by N.G. as estimated from epicardial ECG.With support of the Deutsche Forschungsgemeinschaft.     

Vasodilating effects of nicorandil and nitroglycerin in anaesthetized open-chest dogs

Vasodilating effects of intravenous administrations of nicorandil (SG-75) and nitroglycerin were analyzed in anaesthetized open-chest dogs by measuring simultaneously, and continuously, coronary (CBF), vertebral (VBF), renal (RBF) and aortic blood flow (AoF). Nicorandil 10-300 micrograms/kg i.v. and nitroglycerin 1-30 micrograms/kg i.v. decreased aortic blood pressure and increased CBF in a dose-dependent fashion. The doses of nicorandil and nitroglycerin which reduced coronary vascular resistance to about 60% of the predrug value were 100 micrograms/kg and 10 micrograms/kg, respectively. Nicorandil 100 micrograms/kg i.v. significantly increased AoF and heart rate, significantly decreased left ventricular end-diastolic pressure and did not significantly change VBF, RBF and left ventricular dP/dt. Nitroglycerin 10 micrograms/kg i.v. significantly increased VBF and heart rate, significantly decreased left ventricular end-diastolic pressure and produced an initial increase followed by a decrease in AoF and RBF. When compared with these doses of both drugs, the ratio of percent decrease in coronary vascular resistance to that in total peripheral resistance was over 1.0 in both drugs and the value of this ratio in nicorandil was significantly larger than that in nitroglycerin. The duration of increase in CBF produced by nicorandil 10-300 micrograms/kg i.v. was dose-dependent, but was not changed by nitroglycerin 1-30 micrograms/kg i.v. The results indicate that nicorandil and nitroglycerin dilate coronary vasculature more markedly than other vascular beds and that the potency of selective coronary vasodilatation and the duration of action are more significant in nicorandil than in nitroglycerin.     

保心胶囊对大鼠急性心肌缺血模型心电图及瘀血模型血液流变性的影响

观察四逆汤制剂———保心胶囊抗心肌缺血的药理效应。方法 :运用垂体后叶素造大鼠急性心肌缺血模型 ,运用皮下注射大剂量肾上腺素加冰水冷浴造大鼠瘀血模型 ,观察保心胶囊对大鼠急性心肌缺血模型心电图ST段和瘀血模型血液流变性等指标的影响。结果 :保心胶囊低、高二个剂量组与模型组相比 ,可显著改善缺血心电图ST段和低切变率的全血粘度 (P <0 0 5)。结论 :保心胶囊可有效降低血液粘度 ,改善冠脉循环 ,保护缺血心肌。