低效价肝素对兔主动脉壁摄取~(125)Ⅰ-胆固醇的影响

低效价肝素(38 U/mg)50 mg/kg,给家兔iv,可抑制兔主动脉壁摄取~(125)I—CH,在第12h,抑制率为53%,对已被去甲肾上腺素损伤的动脉内皮,肝素仍可降低主动脉壁~(125)I-CH的摄取量,抑制率为34.6%。iv~(125)I-CH 50μCi/kg 12 h后,备组血中~(125)I-CH的cpm无显著差异。但动脉壁与血中cpm的比值差异非常显著,一次iv后,肝素降低动脉内皮通透性的作用可持续24h以上。     

内吗啡肽及其类似物对心血管系统的作用

目的研究内吗啡肽(EMs)及其类似物对心血管系统的影响，初步探讨其作用机理。方法测定EMs及其类似物对大鼠平均动脉压和后肢血管阻力、蟾蜍肠系膜微动脉内径、兔离体胸主动脉条张力的影响。结果EMs及其类似物剂量依赖(10^-9-10^-6mol·L^-1，iv)且Nx敏感地降低麻醉大鼠平均动脉压、后肢血管灌流压和扩张蟾蜍肠系膜微动脉。EMs对去内皮兔离体胸主动脉条张力无影响；但剂量依赖地显著降低完整内皮胸主动脉条张力并被Nx和L-NNA阻断。结论EMs及其类似物通过降低外周阻力而显著降低动脉血压，其作用与血管内皮细胞释放NO有关。     

7-甲氧基-4′-羟基-3′-二乙胺甲基异黄酮(MHDF)对大鼠血流动力学和主动脉的作用

本实验观察了MHDF对整体大鼠血流动力学和离体大鼠胸主动脉的作用。结果表明iv MHDF(3～12.8 mg/kg)能降低大鼠左心室±dp/dt_max,V_max,V_pm和LVSP,延长T-dp/dt_max,减慢心率。MHDF还能舒张大鼠胸主动脉,ED₅₀为6.5×10^-6mol/L;非竞争拮抗NA和CaCl₂致主脉收缩,pD₂′为3.11±0.21和3.73±0.07;抑制高K⁺致主动脉收缩,IC₅₀为1.76×10^-5mol/L。提示MHDF对血管的作用与α受体阻断剂不同,而可能与钙拮抗有关。     

抗疟药咯萘啶在兔体内的药代动力学

本文报道抗疟药咯萘啶iv,im和ig给药后在兔体内的药代动力学。用NONLIN程序对血药—时间数据进行拟合。一次快速iv 6 mg/kg后的血药—时间过程符合线性三室开模型。药代动力学参数(±SD):t 1/2_β为59±10h;V_c2.418±0.287L/kg;V_d(ss),29±6 L/kg;总清除率Cl_T为0.442±0.131 L/kg·h。Im和ig给药后的动力学过程以线性二室开模型描述。im 6 mg/kg,吸收速率常数K_a为33.5±21.8 h^-1,t 1/2_β为52±8 h,吸收完全。Ig 30或60 mg/kg后的k_a为2.41±1.26 h^-1,t 1/2_β为55±5 h,吸收程度为34.6%。咯萘啶在血中呈不均一分布,im后1～96 h,球/浆浓度比为3～6。     

蒿甲醚在兔体内的药代动力学

本文报道蒿甲醚在兔体内的药代动力学。静脉输注蒿甲醚脂肪乳剂(蒿甲醚80mg/kg)后,血药时间数据用NONLIN程序拟合曲线,符合线性二室开模型。药代动力学参数的平均(SD)为:t1/2(α和β)分别为0.144(0.077)h和0.896(0.371)h;k₂₁,k₁₀和k₁₂分别为1.235(0.705),4.143(1.370)和1.140(0.951)h^-1;V_c,V_d(area)和V_d(ss)分别为0.609(0.119),2.985(0.787)和1.054(0.202)L/kg;清除率为2.401(0.339)L·kg^-1·h。肌内注射油剂250mg/kg或125mg/kg,血药时间数据按矩量法计算,得吸收速率常数(Ka)为0.0377(0.0119)h^-1;吸收程度为36.14(18.39)%。     

口服二巯基丁二酸的毒性和对铅、铜、锑、锶、铊、钷的促排作用

小鼠一次灌胃二巯基丁二酸(DMSA)混悬剂的LD₅₀为6g/kg,大白鼠为4g/kg。正常狗每天灌DMSA0.5g/kg共6周(5天/周)给药后食量减少,呕吐,体重减轻。血象、血糖、心电图、肝功能和肾功能均无显著变化。解剖一狗见十二脂肠有少量充血。灌服0.2g/kg组无明显症状。兔一次灌服DMSA后半小时,血中SH含量达高峰,5小时内血中SH浓度已明显下降。小鼠皮下注射²¹⁰Pb-醋酸铅后以骨和肾²¹⁰Pb含量最高。静注二巯基丁二酸钠(Na-DMS)或灌服DMSA可排除体内吸收²¹⁰Pb,二者均非常显著降低骨和肾中²¹⁰Pb。兔皮下注射硫酸铜后,DMSA可明显促进尿铜的排泄。加服NaHCO₃或枸橼酸钠可加强DMSA的排铜作用。小鼠分别肌注¹²⁵Sb-吐酒石、⁹⁰Sr-硝酸锶、²⁰⁴Tl-硫酸亚铊和¹⁴⁷Pm-硝酸钷后立即灌胃DMSA和NaHCO₃,DMSA明显增加放射性金属在尿中排泄。促使¹²⁵Sb排泄增加6倍、⁹⁰Sr 2倍、²⁰⁴Tl 11倍和可提高¹⁴⁷Pm 12倍。血和大多组织中放射性都有降低。上述结果提示口服DMSA可用于金属中毒治疗。DMSA比Na-DMS稳定低毒,值得继续研究。     

四氢巴马汀等单胺排空作用的比较

利血平(1.5mg/kg,ip)单独给药后24h能显著降低大鼠脑内NA(—60%)和DA(—75%)。预先给予dl-THP(60mg/kg)能使脑内NA和DA进一步下降,分别为正常对照组的15和5%,与单给利血平组有显著性差别。dl-THP同样亦能协同利血平排空5HT的作用。相反,预先给予丁苯那嗪(50mg/kg)则部分拮抗利血平的排空作用。此外,dl-THP与利血平不同,对Na⁺K⁺-ATP酶和Mg²⁺-ATP酶活性无显著影响。l-或d-THP在10^-4mol/L的较高浓度下能诱发豚鼠输精管节律性收缩,并不被多种受体阻断剂拮抗。在体研究表明,dl-THP在较大剂量下与利血平相似,降低犬鼠体温。     

烟浪丁的抗心律失常作用

NICO 100 mg/kg iv,可明显对抗乌头碱和BaCl₂诱发大鼠及氯仿-肾上腺素引起兔的心律失常;降低CaCl₂所致的大鼠室颤率;提高豚鼠心脏哇巴因中毒时的耐量。50 mg/kg iv,也可预防结扎大鼠左冠状动脉引起的心律失常。50～100 mg/kg ip,能降低氯仿或ACh—CaCl₂引起的小鼠室颤率或房颤(扑)率。NICO可减慢豚鼠心率,且可拮抗异丙肾上腺素的正性变率作用。     

单链尿激酶型纤溶酶原激活剂在兔及猕猴中的生物转化和药代动力学

目的：研究重组单链尿激酶型纤溶酶原激活剂(rh-sc-uPA)单链和代谢物双链(tc-uPA)的药代动力学和转化。方法：¹²⁵I标记结合生化反应及RP-HPLC测定血浆¹²⁵I-sc-uPA和¹²⁵I-tc-uPA浓度;平板溶圈法测定血浆溶纤组分浓度。结果：兔iv ¹²⁵I-sc-uPA后单链呈双指数消除,T_1/2α和T_1/2β分别为7和43 min,双链呈单指数消除T_1/2=9 min,约有38%单链转化为双链。猕猴静脉推注不同剂量rh-sc-uPA后血浆纤溶组分浓度呈单指数下降,T1/2分别为(6.3±1.8) min, (11.5±2.1) min和(12.3±2.9) min,CLS随剂量变慢。推注n-tc-uPA T_1/2=(13.7±2.7) min。结论：兔iv ¹²⁵I-sc-uPA后可检测到¹²⁵I-rh-sc-uPA与¹²⁵I-tc-uPA。猕猴iv rh-sc-uPA后血浆溶纤组分浓度呈非线性变化。     

注射用益气复脉（冻干）不同给药途径对心力衰竭大鼠的药效作用对比研究

目的 探讨注射用益气复脉（冻干）（YQFM）不同给药途径对心力衰竭大鼠的药效。方法 将70只经腹主动脉结扎造成心力衰竭模型的SD大鼠随机分为7组：模型组（ig＋尾iv 0.9%氯化钠注射液），YQFM尾iv低、高剂量组（ig 0.9%氯化钠注射液＋尾iv YQFM 464.3、928.6 mg·kg^-1，低剂量为临床等效剂量），益气复脉胶囊组（ig益气复脉胶囊246.3 mg·kg^-1＋尾iv 0.9%氯化钠注射液），YQFM ig组（ig YQFM 464.3 mg·kg^-1＋尾iv 0.9%氯化钠注射液），卡托普利片组（ig卡托普利片3.35 mg·kg^-1＋尾iv 0.9%氯化钠注射液），联合给药组（ig卡托普利片3.35 mg·kg^-1＋尾iv YQFM 464.3 mg·kg^-1），另取10只进行切口不进行结扎SD大鼠为假手术组（ig＋尾iv 0.9%氯化钠注射液）。分别于给药后1 h的第1、3、5、7、14天眼内眦取血，酶联免疫吸附试验（ELISA）法检测大鼠血清中心钠肽（ANP）、脑钠肽（BNP）、内皮素（ET）水平；连续给药14 d，给药结束后对各组大鼠进行心脏超声检测；取出心脏，HE染色后观察病理变化。结果 与模型组相比，给药后1 d，YQFM尾iv低、高剂量组及卡托普利片组和联合给药组血清ANP水平显著降低（P＜0.05、0.01），YQFM尾iv低、高剂量组和联合给药组血清BNP、ET水平显著降低（P＜ 0.05）；给药后7、14 d，各给药组血清ANP、BNP、ET水平显著降低（P＜0.05、0.001）；各给药组的左室短轴缩短率（LVFS）、左室射血分数（LVEF）、E峰与A峰的比值（E/A）均显著上升（P＜0.001）；各给药组心肌细胞病理变化有明显好转。与YQFM ig组相比，给药后1 d YQFM尾iv低、高剂量组和给药后14 dYQFM尾iv低剂量组血清ANP水平显著降低（P＜0.05）；给药后1、7 d YQFM尾iv低、高剂量组和给药后14 d YQFM尾iv低剂量组血清BNP水平显著降低（P＜0.05、0.01、0.001）；给药1 d YQFM尾iv低、高剂量组和给药7、14 d YQFM尾iv低剂量组血清ET水平显著降低（P＜0.05、0.001）； YQFM尾iv低、高剂量组的E/A均显著升高（P＜0.05、0.001）。结论 不同给药途径的YQFM均可以对心力衰竭大鼠发挥治疗作用，尾iv途径比ig途径治疗效果更好，也能更早发挥药效。     

氧代赖氨酸的抗癌及药理实验研究

氧代赖氨酸系我所抗菌素室从辽宁省大连地区土壤中分离得到的新种玫瑰录褐链霉菌(Streptomyces roseoviridofuscus n sp)所产生的抗菌素。经动物实验证明对多种实体瘤有效,本文继续报道以不同给药途径和给药方案对脑瘤-22小鼠的治疗作用。用氧代赖氨酸的总量为1～1.5g/kg,于按种后不同时间以腹腔、尾静脉、肌肉、口服给药,对脑瘤-22均有明显治疗作用,其抑制率为47～78%。氧代赖氨酸200～400 mg/kg静脉注射对狗的血象、肝、肾功能,心电图影响不明显,100 mg/kg剂量对猴也无毒性反应。以氚标记的氧代赖氨酸对实验小鼠进行研究,表明口服吸收良好。静脉注射或口服200mg/kg,均以肝放射性为高,瘤中放射性虽不高,但能维持48小时以上。放射性排出以肾脏为主,静脉注射后24小时从尿中排出约为63%。     

THE CHRONIC EFFECTS OF β-ADRENORECEPTOR ANTAGONISTS ON THE EFFLUX OF TRITIATED NORADRENALINE FROM SYMPATHETIC NERVES OF THE PITHED RAT

• 1 The effect of chronic administration of two β-adrenoreceptor blocking drugs, propranolol and timolol, on transmitter noradrenaline release from sympathetic nerves has been investigated in vivo using the pithed rat preparation.
• 2 Oral treatment for 4 weeks with either propranolol (46.3 mg/kg/day) or timolol (7.1 mg/kg/day) significantly raised the stimulation frequency threshold for release of radioactivity on stimulation of the whole spinal outflow of the pithed rat after i.v. injection of ³H-NA.
• 3 No differences in the stimulation-evoked rise in mean arterial pressure were observed between control or treated rats nor was the heart rate response to stimulation altered after timolol treatment. However, in propranolol treated rats the mean rises in heart rate were significantly higher with 3 and 30 Hz stimulation than in control rats.
• 4 Timolol treatment significantly increased the blood concentration and lowered the heart content of ³H-NA whilst propranolol treatment did not significantly change either blood or heart levels.
• 5 Log dose-response curves for mean rises in heart rate after i.v. isoprenaline were not shifted to the right in either propranolol or timolol treated pithed rats. With the lowest doses of isoprenaline (1 and 25 ng), the mean rises in heart rate in timolol treated rats were significantly greater than in the controls.
• 6 Thus chronic administration of propranolol or timolol decreased the stimulation-induced increase in plasma ³H-NA but this change in release was not related to reduced rises in blood pressure or heart rate.

     

The effect of ethanol on phenobarbitone and pentobarbitone absorption into rat blood and brain

Male rats administered [¹⁴C]phenobarbitone (50 mg/kg) or [¹⁴C]-pentobarbitone (30 mg/kg) simultaneously with either 15% ethanol (3 g/kg) or saline intraperitoneally were killed 5, 10 or 20 min after injection. The radioactivity in the blood, whole brain and different brain areas was measured. Phenobarbitone was absorbed more slowly into the blood and brain than pentobarbitone. Ethanol-treated rats had significantly higher phenobarbitone concentrations than the saline-treated controls in the blood, whole brain, cerebrum and cerebellum up to 10 min after injection. Pentobarbitone concentrations were not significantly altered by ethanol. Barbiturate concentrations in the cerebral cortex were lower than in other regions of the brain. The brain: blood barbiturate ratios were not appreciably changed by ethanol. It is concluded that ethanol (15%) given intraperitoneally aided the transport of phenobarbitone across the peritoneum and hence increased the rate of its absorption into the blood and brain.     

Pharmacological Modification of Hypertensive Blood-Brain Barrier Opening

Abstract: Acute hypertension was induced by intravenous injection of adrenaline (20 μg/kg) or bicuculline (1.2 mg/kg) in conscious, unrestrained rats with indwelling catheters in aorta and a jugular vein. Three min. after the blood pressure increase, the rats were anaesthetized, and the brains perfused in situ for 1 min. to remove blood and tracers from cerebral vessels. Evans blue-albumin and ¹²⁵I labelled serum albumin were used as tracers of the blood-brain barrier function. Pretreatment with trifluoperazine, thioridazine, imidazole and desipramine significantly reduced the leakage of albumin into the brain compared to non-treated controls. Acute hypertension enhances pinocytosis activity in cerebral vessels. It is argued that the protective effect of the drugs mentioned may be mediated via an inhibition of the formation of pinocytotic vesicles.     

一种新静脉注射肝脏造影混悬制剂-TABAC-的药物代谢动力学研究

2,4,6三碘-3-乙酰胺基苯甲酸-N-环己胺甲酰氧基乙酯是一种新肝脏造影剂,简称TABAG。本文报道用同位素¹³¹Ⅰ标记TABAC并将其制成混悬制剂,在大白鼠体内进行药物代谢动力学研究。根据血药-时间曲线形状符合二室开放模型,其动力学关系式为C=5.51e^0.0538t+0.245e^-0.00221t 从动力学参数K₁₂与K₂₁值表明,正向转运速度比逆向转运速度大5.6倍。肝脏药量-时间曲线显示药物迅速进入肝脏,其摄取峰区域在注射后15分钟到2小时之间,与X线摄影结果相符合。24小时以后,肝脏含药量只剩注入量的8%,两天后降到注入量的3%左右。用药96小时后,该药71%以上由大小便排出。从各脏器内药量分布图表明,肝脏含药量比例最高。在摄取峰值时,肝内药量约占注入量的70%,肺、心、肾内含药量很少。说明药物可以迅速浓集在肝脏,从而初步证实利用肝脏网状内皮组织吞噬作用来设计肝脏造影剂的设想是成功的。这种设想及其新型制剂有助于制剂的定向发展。     

三尖杉酯碱的代谢

本文报告³H-三尖杉酯碱在正常及肿瘤鼠体内的吸收、分布和排泄。静脉注射³H-三尖杉酯碱后,大鼠血中放射性迅速降低,快、慢两相的生物半衰期分别为3.5分钟和50分钟。给大鼠静脉注射³H-三尖杉酯硷,注射后15分钟时,药物在各组织中的分布以肾脏为最高,肝、骨髓、肺、心脏、胃肠、脾、肌肉次之,睾丸、血及脑较低。两小时后各组织中的药物浓度均迅速下降,但骨髓的下降较慢,在所有组织中药物浓度居于首位。24小时后则在所测组织中药物浓度均降到相当低的水平。³H-三尖杉酯碱在肿瘤小鼠体内的分布情况与正常大鼠的分布趋势大致相仿。³H-三尖杉酯碱在静脉注射后24小时自大鼠体内排出的总放射性,在尿相当于注射剂量的30.2%,在粪相当于16.6%,其中原型药共占14.5%。此外胆汁也是一条重要排泄途径。静脉注射后24小时可自胆汁排出剂量的24.5%,其中原型药占17.1%。该硷口服给药可迅速吸收入血,但吸收不完全。     

A STUDY OF ANGIOTENSIN II RECEPTORS AFTER CHRONIC INHIBITION OF NITRIC OXIDE SYNTHASE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. Nitric oxide (NO) synthase inhibition, induces a sustained increase in blood pressure and amplifies the pressor response to infused angiotensin II (AngII). This study was designed to investigate the contribution of AngII receptors to the elevated blood pressure and enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR) chronically treated with N^G-nitro-l -arginine-methyl ester (l -NAME). 2. Two groups of 13 week old female SHR were housed four to a box. Group I rats received l -NAME for 7 days (2.5 mg/kg per day) in their drinking water. Group II rats received water only. Blood pressure was monitored daily by tail-cuff plethysmography. Plasma AngII was measured by radioimmunoassay. Aortic and uterine receptor binding was determined by saturation analysis using [¹²⁵I]-Sar⁸, Ile¹)AngII. Data was analysed using the computer program ligand. 3. Mean systolic blood pressure was significantly elevated in rats treated with l -NAME compared with the control group. Plasma AngII concentration was slightly decreased in rats treated with l -NAME compared with control. Densities of both aortic and uterine AngII receptors increased significantly following NO synthase inhibition. Receptor affinity in the aorta decreased in the l -NAME group compared with control. However, uterine AngII receptor affinity was unchanged. 4. We conclude that the increased blood pressure and enhanced pressor responsiveness that occurs with chronic inhibition of NO synthesis may result partly from increased vascular AngII receptor expression.     

Inhibition of heterolysosome formation and function in mouse kidneys by injection of mercuric chloride

Intravenous or intraperitoneal injections of mercuric chloride (5 mg Hg/kg) into mice resulted in an inhibition of proteolytic activity in isolated kidney heterolysosomes containing intravenously injected denatured (formaldehyde) ¹²⁵I-albumin but not in these particles from the liver. The inhibition occurred if the mercuric chloride was injected up to about 17 hr before injection of labeled protein. The proportion of particle-bound radioactivity which could be released by osmotic shock was substantially decreased in subcellular suspensions from mercury-injected mice. In some experiments therefore, digestive rates were normal in mercury-injected mice if proteolysis was measured in terms of the osmotically releasable radioactivity rather than in terms of the total particle-bound material. This suggest that mercury inhibited either endocytosis of labeled protein or heterolysosome formation. However, in most experiments in which digestion was measured in the presence and absence of mercaptoethanol, stimulation of proteolysis by mercaptoethanol was significantly greater in heterolysosomes from mercury-injected animals than in the controls. This suggests that mercury affected proteolytic activity within the organelles as well as heterolysosome formation.     

黄花夹竹桃次甙乙的药代动力学研究

本文研究[³H]标记的黄花夹竹桃次甙乙(Neriifolin简称次甙乙)在大鼠体内的药代动力学。静脉注射后[³H]-次甙乙在血浆中的消除半衰期(T_1/2β)为5天,分布容积(Vd)为15.3L/kg。药物的主要分布在肝脏、胆汁和胃肠道内。灌胃给药吸收迅速完全,30 min血药浓度即达高峰。无论静脉注射或灌胃后,放射性主要从粪中排出,尿中较少,排出形式主要是代谢产物。[³H]-次甙乙与血浆蛋白的结合为91.7%。结果表明:次甙乙在大鼠体内的药代动力学特点与一般亲脂性强心甙相似。     

苦参总黄酮抗心律失常的实验研究

苦参总黄酮自苦参根提得,约含0.3%。给小鼠尾静脉注射LD₅₀为103.1±7.66 g/kg。按Lawson氏法选择吸入氯仿产生心室纤颤阳性率达80%以上的小鼠(体重25～30 g),进行实验。静注苦参总黄酮后,对小鼠吸入氯仿所致心室纤颤有明显地对抗作用,其ED₅₀为28.9±1.1 g/kg,治疗指数为3.56。在同样条件下,硫酸奎尼丁的治疗指数为2.89。给家兔静注苦参总黄酮8 g和30 g/kg,30～60分钟后,能明显对抗氯仿-肾上腺素引起的心律失常。完全对抗率分别为40%和70%。给大鼠静注乌头碱引起心律失常,静注苦参总黄酮20～40g/kg,有明显地治疗作用。第一次治疗的有效率达63%,第二次治疗的有效率为84%。给麻醉大鼠静脉注射苦参总黄酮30 g/kg和60 g/kg,呈现明显地负性自律性作用,负性频率作用和负性传导作用。这些作用随剂量的增加而增强。它们可能是治疗心律失常的药理基础。