LIPID EMULSIONS OF PALMITOYLRHIZOXIN: EFFECTS OF COMPOSITION ON LIPOLYSIS AND BIODISTRIBUTION

Four types of lipid emulsion for highly lipophilic antitumour agent RS-1541 (13-O-palmitoylrhizoxin) with mean particle diameters of 200--260 nm were prepared using soybean oil (SOY) or dioctanoyldecanoylglycerol (ODO) for the oil phase and lecithin (LEC) or polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) for surfactants. The lipolysis rate of HCO-60-emulsified emulsions by lipoprotein lipase was much slower than that of LEC-emulsified emulsions. Particle sizes of emulsions incubated in plasma with the lipase for six hours were 75%, 79%, 101%, and 93% of initial values for SOY/LEC, ODO/LEC, SOY/HCO-60, and ODO/HCO-60 emulsions, respectively, showing an apparent size decrease for LEC-emulsified emulsions. In rats, uptake clearance values of SOY/LEC and ODO/LEC emulsions of RS-1541 in the reticuloendothelial system (RES) were 81·2 and 135·3 mL h⁻¹, respectively, and AUC values were 4·0 and 1·3 μ g h mL⁻¹, respectively. In contrast, RES uptake clearances of HCO-60 emulsions of RS-1541 were considerably lower (4·2 mL h⁻¹ for SOY/HCO-60; 2·2 mL h⁻¹ for ODO/HCO-60), resulting in high AUC values (35·4 μ g h mL⁻¹ for SOY/HCO-60; 63·9 μ g h mL⁻¹ for ODO/HCO-60). The concentrations of RS-1541 in tumour tissues after an intravenous administration of ODO/HCO-60 emulsions of RS-1541 to mice bearing solid tumour M5076 sarcoma were about ten times higher than those after the administration of SOY/LEC emulsions. These results indicate that HCO-60 emulsions, compared with conventional LEC emulsions, are more stable to lipoprotein lipase and show low uptakes by RES organs, long circulations in the plasma, and high distributions in tumours. Thus, these sterically stabilized emulsions could show potential as effective carriers for highly lipophilic antitumour agents to enhance the drug delivery in tumours.     

EFFECTS OF ANAESTHESIA ON THE REMOVAL FROM PLASMA OF INTRAVENOUSLY INJECTED CHYLOMICRON-LIKE LIPID EMULSIONS IN RATS AND MICE

1. In order to find an anaesthesia with minimum perturbation to the metabolism of chylomicrons, the effects of seven different anaesthetic agents on clearance from plasma of chylomicron-like emulsions were compared. 2. Avertin, urethane, fentanyl, and a ketamine/xylazine mixture all slowed the removal from plasma of emulsion triolein and cholesteryl oleate. The steroid anaesthetic althesin slowed the clearance of emulsion cholesteryl oleate without affecting the removal from plasma of emulsion triolein. Nembutal when injected intravenously at a hypnotic dose did not affect the clearance of emulsion triolein or cholesteryl oleate, whereas at the anaesthetic dose, nembutal slowed the clearance rate of both labelled lipids. 3. Except for althesin, which did not affect the plasma clearance of triolein, fractional clearance rates of emulsion triolein and cholesteryl oleate calculated from blood samples taken during 12 min after injection were significantly slower in the anaesthetized groups compared with controls. However, with avertin, althesin, nembutal and ketamine/xylazine, amounts of radiolabelled triolein and cholesteryl oleate remaining in plasma 25 and 30 min after injection were comparable with the control. Radioactive lipids in plasma remained much higher in rats treated with urethane and fentanyl-fluanisonium even 30 min after injection. 4. Avertin was simple to administer and produced a suitable depth of anaesthesia for minor surgery, tail vein injections and blood sampling, whereas althesin and the ketamine/xylazine mixture required supplementary doses to maintain anaesthesia towards the end of the experiment. We concluded that anaesthesia is best avoided for studies of chylomicron clearance. Avertin is the preferred agent if anaesthesia must be used, for example in newborn rats or in mice.     

去氢骆驼蓬碱静脉注射乳剂在动物体内的药代动力学

目的：研究去氢骆驼蓬碱（harmine,HAR）静脉注射乳剂在大鼠体内的药动学和小鼠体内的组织分布。方法：HPLC法测定血药浓度,计算药动学参数;用放射性同位素示踪法测定给药后各脏器组织的分布特征。结果：iv给药,药动学过程可用三室开放模型拟合;乳剂的组织分布能力强于水溶液。iv或ig乳剂,³H-HAR定向于肝、淋巴器官分布。乳剂的LD₅₀大于水溶液。结论：将HAR制成静脉注射乳剂可改变HAR体内过程,降低其神经系统毒副作用。     

鳗鱼油精对大鼠血脂和血液粘度的影响

用鳗鱼油精喂高脂大鼠，连续５ｗ。２５５．４ｍｇ／ｋｇ和５１０．８ｍｇ／’ｋｇ的剂显著降低血清总胆固醇，甘油三酯和低密度脂蛋白水平。１２７．７ｍｇ／ｋｇ的剂量作用不显著。３个剂量ＴＣ的降低率分别是１３．３％，、３７．１％和４８．７％；ＴＧ的降低率是９．５％，１２．９％和２５．２％；ＬＤＬ的降低率是５．１％，４７．４％和６２．２％。     

EFFECTS OF ADRENALINE AND NORADRENALINE ON CLEARANCE OF TRIACYLGLYCEROL-RICH LIPOPROTEINS FROM PLASMA: STUDIES WITH CHYLOMICRON-LIKE LIPID EMULSIONS IN RATS

1. Adrenaline was infused intravenously in rats during the clearance from plasma of an injected lipid emulsion designed to model chylomicrons and the triacylglycerol-rich plasma lipoproteins. The clearance rates of emulsion radiolabelled triolein (TO) and cholesteryl oleate (CO) were both increased, suggesting that hydrolysis of lipoprotein triglycerides and clearance of remnants from plasma were increased. The distribution of radiolabels in tissues showed more TO in skeletal and cardiac muscle after adrenaline, while more CO was found in liver compared with controls. Lesser amounts of both labels were found in the spleens of treated rats. 2. In a similar experiment with noradrenaline, the clearance rate of emulsion CO was decreased. The removal of CO was retarded more than that of emulsion TO, which was not significantly affected, and CO label recovered in liver was significantly decreased, suggesting that the removal of remnants from plasma was slowed after noradrenaline. In experiments in which noradrenaline was infused continuously for 1 week the clearances of emulsion CO and TO were both reduced. 3. Our findings suggest possible connections between plasma catecholamines and the development of arteriosclerosis, in view of the atherogenicity of remnants of the triacylglycerol-rich plasma lipoproteins. Yet to be established is whether the linkage we have found between lipoprotein clearance, adrenaline and noradrenaline contributes to the atherogenic effects of chronic stress and for the protective effects of exercise.     

水飞蓟总黄酮与Fenofibrate合用对大鼠高血脂症的影响

以Silymarin和Fenofibrate配成的复方能显著地降低高血脂症大鼠血清TC、LDL-c和VLDL-c,提高HDL-c的血浓度,使高血脂症大鼠血清脂蛋白的相互比值恢复到接近正常水平。肝脏TC和TG的含量下降。结果证明复方既保留了Silymarin降脂保肝的作用,又有增多HDL-c的功能,可缓解Fenofibrate引起肝脏肿大等不良反应,其降脂性质优于单方Silymarin或Fenofibrate,说明两药有增强作用。     

福康片对大鼠吗啡药代动力学的影响

目的··:研究福康片戒毒药物对大鼠吗啡药代动力学的影响。方法··:用放射免疫法 (RIA)测定了大鼠单独皮下注射 (sc)盐酸吗啡 (A组 )和合并灌胃 (ig)福康片 (B组 )后吗啡的血药浓度 ,计算两组吗啡药代动力学参数。结果··:两组吗啡药代动力学模型均符合二室模型一级吸收。B组吗啡血药浓度明显低于A组。合用福康片后 ,大鼠吗啡的t1/2ka由0.078h增加到0.164h ;Cmax由3971.143μg·L -1减少到2248.474μg·L -1 ;AUC由每小时11337.584μg·L-1 减少到8005.219μg·L-1;t1/2β 由4.091h减少到3.615h ;CL由每小时0.529L·kg-1 增加到0.750L·kg-1。结论··:福康片可降低吗啡的吸收速率及血液中的吗啡浓度     

右旋糖酐与氟碳乳剂稀释血液对心肌缺血时全血粘度与侧支循环影响的比较

用麻醉开胸狗对比观察了低分子右旋糖酐与氟碳乳剂稀释血液对急性心肌缺血时全血粘皮与侧支血流量变化的影响。结果表明,氟碳乳剂稀释血液除具有与右旋糖酐稀释血液相同的降低全血粘度、增加侧支血流量、提高缺血区心肌供血量/需血量比值等作用外,还可使血氧分压与活性氧明显增加,因而使缺血区心肌供氧量增加。     

前胡丙素对高血压大鼠血压及犬血管阻力的影响

目的　观察前胡丙素(pra C)的降压及对外周血管阻力的影响。方法　在肾型高血压大鼠模型与正常血压大鼠用尾容积法测血压。用RDB III型输液泵连接于麻醉杂种犬,以控制血流量与压力法直接测定锥动脉、冠脉左旋支、股动脉的阻力。结果　pra-C 20 mg·kg^-1·d^-1 ig给药3 0d对肾性高血压大鼠(RHR)降压峰值时间为6h ,从(213±10 )mmHg降至(144.0±1.5)mmHg,降低原水平30% ,持续至20h。pra-C分别以100 μg·kg^-1 及20 μg·kg^-1与pra-E 20 μg·kg^-1iv可降低上述血管的阻力,减慢心率,降低阻力呈剂量相关。结论　pra-C有降压作用,降低犬外周动脉阻力,增加小鼠耐缺氧时间。     

EFFECTS OF CENTRAL SEROTONIN NERVE LESIONS ON BLOOD PRESSURE IN NORMOTENSIVE AND HYPERTENSIVE RATS

1 Separate ascending and descending pathways of serotonin (5-hy-droxytryptamine, 5-HT) nerves in the rat central nervous system have been selectively lesioned by Idealized intracerebral administration of 5,7-dihydroxytryptamine (5,7-DHT) after pretreatment with desipramine (DMI). 2 Bilateral injections of 5,7-DHT into the medial forebrain bundle or the cervical spinal cord caused extensive losses of 5-HT and tryptophan hydroxylase in the anterior hypothalamus and thoracic spinal cord, respectively, without affecting noradrenaline (NA) levels. 3 The hypothalamic lesions caused only a slight, transient reduction of systolic blood pressure in normotensive rats. 4 A more pronounced and sustained hypotension occurred in normotensive rats but not in hypertensive rats after the spinal lesions.     

EFFECTS OF SELENIUM DIOXIDE ON BLOOD AND FEMORAL BONE MARROW OF RATS

This study was undertaken to investigate the effects of selenium dioxide (SeO₂) on rat blood and femoral bone-marrow oxidant mechanisms. Treatment with SeO₂, 67 mu g Se/kg ip daily for 14 d, significantly decreased lipid peroxidation and the concentrations of Fe in serum and bone marrow. The concentrations of Se in serum and bone-marrow cells were significantly increased after SeO₂ treatment. The activities of glutathione peroxidase (GPx) in blood and bone-marrow cells were markedly increased. The levels of oxyhemoglobin in blood were significantly increased, while the concentrations of methemoglobin were decreased after SeO₂ administration. The fragility of erythrocytes membranes was significantly decreased in SeO₂-treated rats compared to controls. Data suggest that treatment with a low dose of SeO₂ may provide antioxidant nutrients to blood and bone marrow.     

EFFECTS OF ADRENORECEPTOR ANTAGONISTS AND AGONISTS ON CLEARANCE OF EMULSION MODELS OF TRIACYLGLYCEROL-RICH LIPOPROTEINS FROM PLASMA IN RATS

1. We previously found that adrenaline and noradrenaline exert essentially opposite effects on clearance from plasma of chylomicron-like emulsions injected intravenously in rats, suggesting mechanisms that may be implicated in the atherogenic effects of chronic stress and hypertension and conversely in the protective effect of regular exercise. 2. The mechanisms underlying the effects of adrenaline and noradrenaline have now been investigated. Chronic adrenergic blockade with either the alpha 1-receptor antagonist doxazosin or the beta-receptor antagonist propranolol slowed the clearance of labelled emulsion lipids from plasma of normal Wistar rats. The results with doxazosin were unexpected in view of its capacity to decrease plasma triglycerides in patients. 3. In spontaneously hypertensive rats (SHR) the clearance of triolein (TO) was very slow compared with normal Wistar rats. Emulsion TO clearance provides a measure of lipolysis by lipoprotein lipase, and a defect in clearance indicates either defective enzyme action or poor perfusion of capillary beds rich in enzyme. Defective enzyme activity in SHR was excluded, suggesting redistribution of blood flow away from skeletal muscle and adipose tissue. In SHR the TO clearance from injected chylomicron-like emulsions was improved by blockade with doxazosin compared with control untreated SHR. 4. The beta 2-adrenoreceptor agonist Fenoterol was infused intravenously during clearance of an injected lipid emulsion. Clearance of radiolabelled cholesteryl oleate (CO) was clearly slowed while there was a lesser reduction of TO clearance rate. Emulsion CO clearance provides a measure of the uptake of lipoprotein remnants by the liver, and a defect in clearance of CO indicates either defective ligand (apolipoprotein E)-receptor interaction or decreased perfusion of the splanchnic bed. Isoprenaline, a non-selective beta-adrenergic agonist, gave similar results. Both compounds reduced mean arterial pressure by about 20-40 mm Hg at the doses employed, indicating that the beta 1 (cardiac) effect of the isoprenaline was insufficient to offset its vasodilatatory effect on skeletal muscle arterioles (beta 2). 5. The alpha-agonist phenylephrine, at a dose which moderately raised mean arterial pressure, slowed clearance of both TO and CO for the first 12 min after injection of emulsion but at later time points clearances caught up with the controls. 6. Administration of a mixture of isoprenaline and phenylephrine produced definite enhancement of both TO clearance and CO clearance. The effect of the mixture was opposite to the effects of of either agonist alone, demonstrating clearly that direct effects on lipoprotein lipase activity or receptor mediated processes were not involved.(ABSTRACT TRUNCATED AT 400 WORDS)     

氟碳乳剂的心血管作用

本文报道氟碳乳剂(FCE)对正常及失血性低血压动物的血流动力学作用及小鼠耐缺O₂能力的影响。麻醉狗,静注氟碳乳剂0.1 ml/kg,即刻引起血压急骤下降。重复注射出现快速耐受性。麻醉大鼠输注.FCE 30 ml/kg,血压和心率稍有降低,而麻醉猫和兔输注FCE 10 ml/kg,无降压反应。正常兔输注FCE后,对左心室压和心肌收缩性无明显变化。猫和狗,在失血性低容期时,平均动脉压、左室内压,心搏出量、心输出量和心肌收缩性均降低,补充FCE后,上述各项指标得以恢复。静注FCE可延长小鼠在常压缺氧下的存活时间。     

复方褐胶胶囊对大鼠胃排空及小肠推进功能的作用

本文用放射性核素方法研究自制中药复方褐藻胶胶囊（ｃｏｍｐｏｕｎｄ ａｌｇｉｎ ｃａｐｓｕｌｅ, ＣＡＣ）,对大鼠胃排空率和小肠推进比的影响。结果 ＣＡＣ组大鼠胃排空率和小肠推进比分别为 ８７． ７％± ３． ４３％和 ８０． ７％±６．４％,明显高于对照组６７％±４．１８％和６２．５％±６．４９％。提示ＣＡＣ对大鼠胃排空和小肠推进功能有显著的促进作用。     

月见草油乳剂的生理药物动力学模型探讨

本文考察了大鼠按9ml/kg静注2号月见草油乳剂后,血浆、心、肝、脾、肺、肾、胃肠道、脑、肌肉中γ-亚麻酸浓度变化;大鼠静注一负荷剂量4.5ml/kg 1号月见草油乳剂后,再以4.5ml/kg·h静脉输注至稳态,测定γ-亚麻酸组织-血浆表观分配系数。在此基础上,进一步设计了一个血流限速生理药物动力学模型,在IBM微型计算机上用MAXSIM程序模拟γ-亚麻酸在大鼠体内的分布与清除,模型包括肝、肾、胃肠道、肌肉和血浆。离心过滤法测得γ-亚麻酸血浆中游离分数为0.459。     

侧脑室注射内吗啡肽-1对麻醉大鼠血压的影响

目的　观察侧脑室注射内吗啡肽-1(EM-1)对麻醉大鼠血压的影响,并初步探讨其作用机理。方法　侧脑室埋植导管给药,颈动脉插管测血压。结果　icv EM-1剂量依赖、纳洛酮敏感地降低麻醉大鼠的血压。icv或iv酚妥拉明、普萘洛尔和iv L-NNA对EM-1引起的血压降低反应无影响;给予阿托品(icv 25 μg·kg^-1 ;或iv 50 μg·kg^-1)和切断双侧迷走神经减弱EM-1引起的血压降低反应。结论　icv EM-1可引起麻醉大鼠血压降低;此效应由阿片受体介导,有中枢M受体的参与,通过兴奋迷走神经所致     

可乐定透皮剂对清醒大鼠血压的影响

用尾袖法测定了可乐定透皮贴片(3、6、12μg/片)对清醒大鼠0—30h血压的作用。大鼠贴片后0.5—2h出现明显降压作用,持续时间为8—20h。每鼠12μg可乐定ig的大鼠,ig后0.5h出现明显降压作用,持续时间为2h。用空白贴片观察的大鼠未出现降压作用。可乐定贴片含药剂量的大小与降压作用百分率之间有一定关系。     

EFFECTS OF CELERY EXTRACT AND 3-N-BUTYLPHTHALIDE ON LIPID LEVELS IN GENETICALLY HYPERCHOLESTEROLAEMIC (RICO) RATS

1. Aqueous celery extract was administered intraperitoneally to genetically hypercholesterolaemic (RICO) and normochol-esterolaemic (RAIF) rats via Alzet osmotic pumps over a 13 day period. 2. The serum cholesterol concentration of the celery extract-treated RICO rats was found to be significantly lower (P<0.05) than the control rats. Aqueous celery extract was effective in preventing the rise of cholesterol level in the RICO rats. However, no such observation was seen in the RAIF rats. The serum triglyceride level was unchanged in both strains of rats. 3. When 3-n-butylphthalide (BuPh), a unique component in celery, was administered in the same manner to the RICO and RAIF rats, it did not produce significant changes in the serum and liver lipid profiles of these rats. The activities of hepatic 3-hydroxy-3-methylglutaryl CoA reductase in both strains of rats were also not significantly different from their respective controls. 4. Together with our recently reported thin-layer chroma-tography findings that BuPh was not detected in the aqueous celery extract, this study suggests that the effect of celery extract on serum cholesterol levels in the RICO rats could be attributed to chemical constituents other than BuPh.     

LONG-TERM ANGIOTENSIN II ANTAGONISM IN SPONTANEOUSLY HYPERTENSIVE RATS: EFFECTS ON BLOOD PRESSURE AND CARDIOVASCULAR AMPLIFIERS

1. The angiotensin II type 1 receptor antagonist, losartan, prevented the development of hypertension in spontaneously hypertensive rats (SHR). 2. Losartan also prevented the development of left ventricular hypertrophy and vascular amplifier abnormalities. 3. Part of the hypotensive effect induced by long-term treatment with losartan persisted for a long time after the withdrawal of treatment. 4. The results support the hypothesis that angiotensin II contributes to the development of hypertension and cardiovascular hypertrophy in SHR.