三七皂苷Rg1对脑缺血再灌注损伤的保护作用

目的 探讨三七皂苷Rg1对大鼠局灶性脑缺血再灌注损伤后大脑皮质中BDNFmRNA表达的影响.方法 ♂SD大鼠36只随机分为脑缺血再灌注模型组、三七皂苷Rg1组和尼莫地平组,采用线栓法制作模型,各组分别于术后1、3、5 d随机取4只大鼠处死后,取出脑组织,经石蜡包埋切片,片厚5μm.用地高辛标记的寡聚核苷酸探针进行原位杂交实验,用HPIAS-100高清晰度彩色病理图文报告分析系统测量分析大鼠大脑皮质的BDNFmRNA的含量和阳性神经元数目的变化.结果 在脑缺血再灌注后不同的时间段上,与模型组比较,三七皂苷Rg1均能增加大脑皮质的BDNFmRNA含量及其阳性神经元的数量.用药3 d时,三七皂苷Rg1的作用达到高峰,且其作用在各时间段上均强于尼莫地平;5 d后,虽然BDNFmRNA的含量及阳性神经元的数量有一定程度的下降,但仍与三七皂苷Rg1组1 d时的表达水平相当,且三七皂苷Rg1组5 d时的表达水平仍强于模型组1 d和3 d时表达的水平及尼莫地平组1 d时的水平.结论 三七皂苷Rg1通过上调大鼠脑缺血再灌注损伤后,大脑皮质BDNFmRNA的含量和阳性神经元的数量,可发挥其治疗作用,疗效强于阳性对照药尼莫地平.     

益脑活血胶囊对脑缺血的保护作用

目的研究益脑活血胶囊对脑缺血的保护作用。方法使用小白鼠断头形成急性脑缺血模型,观察断头后张口喘气的时间;利用结扎大鼠双侧颈总动脉形成脑缺血模型,观察益脑活血胶囊对脑含水量和毛细血管通透性的影响。结果益脑活血胶囊能明显延长断头小鼠张口喘气时间;明显降低脑含水量、毛细血管通透性。结论益脑活血胶囊可通过改善微循环、降低毛细血管通透性、增加脑血流量起到对脑缺血的保护作用。     

吡拉格雷钠对局灶性脑缺血再灌注大鼠微循环和内皮功能的影响

目的：研究抗脑缺血药物吡拉格雷钠对局灶性脑缺血大鼠脑微血管血流量以及血管内皮功能的影响。方法采用改良的线栓法,建立大鼠大脑中动脉栓塞（ NCAO）脑缺血再灌注模型,以激光多普勒血流仪监测各给药组对大鼠脑微循环血流的影响,并采用酶联免疫ELISA法检测大鼠血浆中血管假vWF、TN、EPCR水平。结果吡拉格雷钠各给药组均使NCAO大鼠脑微循环血流量明显升高,并显著性降低vWF、TN、EPCR在大鼠血浆中含量。结论吡拉格雷钠能够明显改善NCAO大鼠脑微循环血流量并且对vWF、TN、EPCR均有抑制作用,对血管内皮细胞有明显的保护作用。     

三七总皂苷鼻腔给药的药代动力学与药效学

目的研究三七总皂苷鼻腔用粉雾剂以混悬液形式给药后在大鼠体内的药代动力学过程及对心脑血管疾病的保护作用。方法HPLC测定三七总皂苷混悬液大鼠鼻腔给药后血样中人参皂苷Rg1的浓度，考察药物在体内的动力学过程，并计算其绝对生物利用度；结扎SD大鼠的左冠状动脉建立急性缺血性心肌梗死模型，夹闭沙鼠的双侧颈总动脉建立脑缺血再灌注模型，考察三七总皂苷混悬液对心脑血管疾病的保护作用。结果三七总皂苷混悬液鼻腔给药后，Rg1在大鼠体内的过程符合二室模型，其绝对生物利用度为103.56％；对大鼠急性缺血性心肌梗死及沙鼠脑缺血再灌注所引起的脑水肿和脑卒中症状均具有明显的缓解作用，且呈剂量依赖性，剂量越高，保护作用越强。结论药代动力学和药效学结果证明，三七总皂苷鼻腔给药制剂具有很好的开发前景。     

中药育发液对肾上腺素致小鼠耳廓微循环障碍的影响研究

目的：研究中药育发液对肾上腺素致小鼠耳廓微循环障碍的影响。方法：以101育发液为阳性药,建立肾上腺素致小鼠耳廓微循环障碍动物模型,研究中药育发液对肾上腺素致小鼠耳廓微循环障碍的影响。结果：与空白组比较（75%乙醇组）,中药育发液高、中、低剂量组均能显著改善肾上腺素所致微循环障碍,并显著超过了给药前水平。结论：中药育发液可显著增加小鼠耳廓微循环的血流量,对局部的微循环障碍有明显的改善作用。     

人参皂苷Rg1对大鼠脑缺血再灌注损伤细胞凋亡的影响

目的:研究人参皂苷Rg1对大鼠脑缺血再灌注损伤时细胞凋亡的影响。方法:采用大鼠右侧大脑中动脉阻断(middle cerebral artery occulusion,MCAO)局灶性脑缺血再灌注模型,缺血前给予人参皂苷Rg1 25、501、00 mg.kg-1灌胃,7 d。末次给药1h后制备MCAO模型,缺血2 h,再灌注22 h后,分别用Longa’s法T、TC染色法评价大鼠的神经功能状态及脑梗死面积;用TUNEL法测定缺血再灌后神经细胞凋亡的程度;用Western blot法测定大脑缺血侧脑组织中与凋亡相关基因Caspase-3、Bcl-2的蛋白表达。结果:人参皂苷Rg1(50、100 mg.kg-1)可明显减少MCAO再灌注后脑梗死面积,改善神经功能症状,与模型组比较具有显着性差异(P<0.05或P<0.01);脑缺血2 h再灌22 h后,模型组大鼠缺血侧细胞凋亡程度、Caspase-3蛋白表达明显增加,同时Bcl-2的蛋白表达降低。给予人参皂苷Rg1(50,100mg.kg-1)后,缺血侧细胞凋亡程度、Caspase-3蛋白表达降低,而Bcl-2的蛋白表达增加,与模型组相比具有统计学意义(P<0.01或P<0.05)。结论:人参皂苷Rg1对大鼠脑缺血再灌注损伤引起的细胞凋亡具有明显的保护作用,其机理可能与人参皂苷Rg1影响Caspase-3、Bcl-2的表达有关。     

珠子参水提物对小鼠耳廓微循环的影响

目的：观察珠子参水提物对耳廓微循环的影响。方法：采用耳廓微循环观察法检测珠子参水提物对正常和血瘀模型小鼠耳廓微循环的影响。结果：珠子参水提物能明显增加耳廓微血管管径及毛细血管开放数目,能有效改善肾上腺素所致的耳廓微循环障碍。结论：珠子参水提物具有改善小鼠耳廓微循环作用。     

桃红四物汤不同提取部位对血虚血瘀模型大鼠微循环的影响

目的观察桃红四物汤不同提取部位对血虚血瘀模型大鼠微循环的影响。方法采用皮下注射乙酰苯肼及腹腔注射环磷酰胺的方法复制大鼠血虚血瘀模型,观察桃红四物汤不同提取部位对模型动物耳廓微循环血流量、微血管血流速度和管径的影响。结果桃红四物汤水提组能明显加快模型动物微动脉和微静脉血流速度,增加微循环血流量,与模型组比较具有显著性差异（P〈0．01）,但对微动脉和微静脉血管管径未见明显影响。多糖组和醇提组具有明显扩张模型动物微血管、增加傲血管管径,显著加快微动脉和微静脉的血流速度以及提升模型动物微循环血流量的作用,与模型组比较均具有显著性差异（P〈0．01）。水提醇沉上清部分,虽较模型组也有明显扩张微血管的作用（P〈0．01）,但仅见微动脉血流速度较模型组有明显加快（P〈0．01）,而对微静脉血流速度影响不明显,微循环血流量增加也不及多糖组,与多糖组比较具有统计学差异（P〈0．05）。结论桃红四物汤不同提取部位均能显著增加血虚血瘀模型动物微循环血流量,改善微循环,但不同提取部位在改善微循环的作用方式上有所不同。推测认为,多糖可能为桃红四物汤补血活血的物质基础。     

激光散斑成像法测定灯盏花素对大鼠脑血流量的影响

目的:考察灯盏花素对大鼠脑血流量的影响。方法:通过激光散斑成像方法测定灯盏花素对正常大鼠脑血流量的影响,并对大鼠脑血流的不同区域进行了计算分析。结果:正常大鼠腹腔注射灯盏花素100mg.kg-1后,大鼠的脑血管(包括大小动脉和静脉)的形态无明显变化;大鼠脑动脉的血流量迅速增加,最高可增加一倍左右,并维持在一个相对较高的水平;给药10min后,微循环区的血流量显著增加,最高可增加原血流量的50%～60%左右。结论:灯盏花素能显著改善正常大鼠大脑动脉及微循环区的血流量,其机制可能与其松弛毛细血管前后括约肌,减少血流阻力及改善血液的流变性等作用有关。     

依昔苯酮的药效学研究

目的：观察依昔苯酮（exifonel,Exf)对实验动物的药效学作用。方法：双线结扎大鼠双侧颈总动脉,检验急性不完全性脑缺血大鼠的脂指数,脑含水量;比色测定大鼠脑内伊文思蓝含量;观察Exf对大鼠脑毛细血管通透性的影响;跳台试验观察Exf对小鼠学习记忆的影响。结果：Exf能明显减轻大鼠实验性脑缺血所引起的脑指数,脑含水量和脑毛细血管通透性增高的病理改变。并增强小鼠学习记忆功能。结论：Exf具有增加脑血流量,降低脑毛细血管通透性和提高学习记忆的功能。     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro

[6,7-³H] Estrone (E) and [6,7-³H]estradiol-17 (E₂) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E₂ were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (mol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E₂, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E₂, respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate.Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10³–10⁴ have been found for potent, 10² for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.Paper presented at the Satellite Symposium of the European Society of Toxicology, Rome, March 29, 1983     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.