脑益嗪抗运动病时大鼠血浆PG和小脑Na~ K~ ATPase图像分析定量研究

为探讨脑益嗪抗运动病作用机理，采用放射免疫方法和计算机图像分析系统，对运动病组（ＭＳＧ）和脑益嗪药物预防组（ＣＰＧ）大鼠血浆ＴＸＢ２、６ＫｅｔｏＰＧＦ１α和小脑毛细血管内皮细胞Ｎａ＋Ｋ＋ＡＴＰａｓｅ进行定量测量和分析研究。结果表明ＣＰＧ大鼠血浆ＴＸＢ２和６ＫｅｔｏＰＧＦ１α显著低于ＭＳＧ（ｐ＜００５），而小脑毛细血管内皮细胞Ｎａ＋Ｋ＋ＡＴＰａｓｅ活性则明显高于ＭＳＧ（ｐ＜００１）。作者认为，血浆ＴＸＢ２和６ＫｅｔｏＰＧＦ１α降低，与脑益嗪阻断血小板和血管内皮细胞Ｃａ２＋内流有关。脑内Ｎａ＋Ｋ＋ＡＴＰａｓｅ活性升高，可能是因为脑益嗪扩张脑血管、增加脑血流，阻滞Ｃａ２＋内流的结果。这些变化可视为脑益嗪抗运动病作用的重要机理。     

中药脑血宝制剂对凝血和血小板聚集率的影响

目的和方法:本研究在体内、体外实验的基础上,通过测定血浆中活化的部分凝血活酶时间(APTT)、凝血酶原时间(PT)、抗凝血酶III(AT-Ⅲ)活性、凝血酶时间(TT)、纤维蛋白原(Fng)、纤溶酶原(Plg)的变化以及血浆中血小板聚集率来观察脑血宝制剂对血液凝固过程不同阶段和血小板聚集率的影响,分析其抗血栓作用的机制。结果:脑血宝预防组,血浆中APTT、PT均比血栓组延长(P＜0.05,P＜0.01),AT-Ⅲ的活性高于血栓组(P＜0.05,P＜0.01),Fng含量低于血栓组,TT延长,Fng和TT呈负性相关关系,血小板聚集率明显低于血栓组(P＜0.05,P＜0.01)。结论:脑血宝制剂对凝血的多个环节均有抑制作用,从而对抗血栓的形成。     

应用光—色素法血栓生成模型研究榄香烯乳剂的抗血栓作用

应用光—色素法在大鼠肠系膜微静脉建立活体血栓生成模型，研究了在急性静脉注射条件下榄香烯乳剂的抗血栓作用。榄香烯乳剂用药组与生理盐水对照组相比，可以明显减缓血栓生长速度，延长血栓栓塞时间，表明榄香烯乳剂对血栓形成有一定的抑制作用。     

应用光-化学法血栓生成模型研究急慢性疗法下阿司匹林的抗血栓作用

采用光—化学法在大鼠肠系膜微静脉建立活体血栓生成模型，研究了在急性（一次用药）与慢性（每日给药，一周）条件下阿司匹林的抗血栓作用。慢性阿司匹林用药组与生理盐水对照组相比，可以明显减缓血栓生长速度，延长血栓栓塞时间，表明阿司匹林对血栓形成有一定的抑制作用。而急性用药组的抗栓作用并不明显     

全蝎提取液对家兔实验性动脉血栓的影响

目的:研究全蝎提取液对家兔实验性动脉血栓的影响。方法:采用双氧水(H2O2)损伤家兔颈总动脉复制血栓模型,观察全蝎提取液的抗血栓作用。结果:全蝎提取液能明显减轻兔血栓重量(P<0.01),使血浆6-酮-前列腺素1a(6-keto-PGF1a)含量明显升高(P<0.01),明显降低血栓烷B2(TXB2)含量(P<0.05),全蝎组的APTT、PT和TT较盐水对照组明显延长。结论:全蝎提取液有明显的抗动脉血栓形成作用,其作用机理可能与抗凝、抑制血小板活化和增加内皮细胞抗血栓能力有关。     

大鼠软脑膜微血栓模型的建立及抗血栓药物的实验观察

以建立一个筛选抗血栓药物的体内微血栓模型为主要目的,本实验采用显微操作仪和微量注射技术,将二磷酸腺苷(ADP)溶液(1×10~(-2)M,5×10~(-2)M)微量注射到大鼠软脑膜微血管表面,在微血管中定位、定量诱发出白色的血小板性附壁血栓。通过对血栓形成过程的定量分析,观察几种体外血小板聚集抑制剂(阿斯匹林、654-2、川芎嗪)对血栓形成的影响。结果表明:在不损伤血管壁的条件下,单纯ADP(2μl/次)对微静脉的血栓诱发率达85%,病理切片结果发现血栓体主要由血小板构成。三种血小板聚集抑制剂均表现有不同程度的抗血栓作用。以上结果提示该微血栓模型在研究抗血栓药物及血栓形成机制方面可能有一定的实用价值。     

脑益嗪抗运动病时大鼠血浆PG和小脑Na^＋—K^＋—ATPase图？…

为探讨脑益嗪抗运动病作用机理，采用放射免疫方法和计算机图像分析系统，对运动病组和脑佃嗪药物预防组大鼠血浆ＴＸＢ２，６－Ｋｅｔｏ－ＰＧＦ１α和小脑毛细血管内皮＾＋－Ｋ＾＋－ＡＴＰａｓｅ进行定量测量和分析研究。结果表明ＣＰＧ大鼠血浆ＴＸＢ２和６－Ｋｅｔｏ－ＰＧＦ１α显著低于ＭＳＧ，而小脑毛细血管内皮细胞Ｎａ＾＋－Ｋ＾＋－ＡＴＰａｓｅ活性则明显高于。     

新一代高效特异抗凝药物—水蛭素

概述了水蛭素的组成与结构，药理学及药代动力学特征，抗凝，抗血栓活性与作用，天然水蛭素提取和进行重组或人工合成水蛭素的方法，认为水蛭素是一种很有希望的防治血栓新药     

右旋糖酐对体外人工血栓的影响

近年来,对右旋糖酐抗血栓作用机制的研究主要集中在两方面,即右旋糖酐在体内通过干扰Ⅷ因子中Ristocetin辅助因子而抑制血小板粘附、凝聚功能,使血栓不容易形成或形成易溶解的松散血栓,这种作用只有体内输注后才能发生。另一方面主要通过右旋糖酐体内输注或体外直接加入血中加速凝块溶解的研究认为其抗血栓作用不是血小板因素,而是在右旋糖酐存在下形成粗糙的     

764-3对牛主动脉内皮细胞PGI_2释放影响初探

血管内皮细胞既可通过合成分泌PGI_2、血栓调节蛋白(Thrombo-modulin)、t-PA等起抗血栓作用,又能通过合成分泌vWF、PAI等起促血栓形成的作用。因此,血管内皮细胞在止血血栓中的作用越来越受到人们注意,血管内皮细胞研究已成为止血血栓研究的重要方面。PGI_2是由内皮细胞合成的一种强的血管扩张剂和血小板聚集抑制物质,与TXA_2的作用相反。PGI_2与TXA_2之间活性的平衡是控制正常止血机制、防治血栓形     

Gastric histamine content and gastric ulcer formation in cold/restraint stressed rats: Effects of cinnarizine and flunarizine

The effects of the calcium channel blockers cinnarizine (20 mg/kg p.o.) and flunarizine (10 mg/kg p.o.) on gastric and small intestine histamine content and ulcer formation were determined in cold/restraint stressed rats (4°C for 3 h). The effects of cimetidine (100 mg/kg p.o.) were studied for comparison. After the stress, a significant increase (+27%) in gastric histamine content concomitant with gastric ulceration was observed. Pretreatment with cinnarizine or flunarizine restored histamine to the control value and reduced both the incidence (–22% and –44% respectively) and the severity (-nearly 35%) of gastric ulcers. Neither marked changes in histamine content nor mucosal lesions were detected in the small intestine. The effects of cinnarizine and flunarizine resembled those of cimetidine. The obtained data suggest a possible relation between the decrease in the elevated histamine content in stressed rats and the protection against ulcer formation exerted by cinnarizine and flunarizine.     

Short- and long-term treatment with folic acid suppresses thrombus formation in atherogenic mice in vivo

In the present study, we examined the effects of short- and long-term treatment with folic acid (FA) on thrombus formation in vivo in atherogenic mice to explore a novel agent for the prevention of atherothrombotic disease. Apolipoprotein E and low-density lipoprotein receptor double deficient (ApoE^−/−LDLR^−/−) mice were orally administrated a single bolus of FA (20 mg/kg) or fed an atherogenic diet with or without FA (0.02, 0.5, and 1.5 mg/kg) for 12 weeks. Thrombus formation and endothelial function were assessed in vivo using the He–Ne laser-induced carotid artery thrombus formation test and the flow-mediated vasodilation method. Platelet reactivity was assessed ex vivo using haemostatometry. Short-term treatment with FA markedly increased plasma folate levels and significantly suppressed laser-induced thrombus formation in apoE^−/−LDLR^−/− mice. Short-term treatment with FA suppressed platelet reactivity in apoE^−/−LDLR^−/− mice, but FA treatment did not affect endothelial function or plasma homocysteine levels. Long-term treatment with FA increased plasma folate levels dose-dependently. Thrombus formation and endothelial dysfunction were suppressed by treatment with 0.5 and 1.5 mg/kg of FA, respectively, but not with 0.02 mg/kg of FA, whereas platelet reactivity was not altered by treatment with any dose of FA. Long-term treatment with all doses of FA decreased the plasma homocysteine levels in apoE^−/−LDLR^−/− mice, although this result was not consistent with its anti-thrombotic action. In conclusion, our data showed that short- and long-term treatment with FA could suppress in vivo thrombus formation in an atherogenic setting, independent of its hypohomocysteinemic action.     

Inhibition of Radiation-Induced Oxidative Damage in the Lung Tissue: May Acetylsalicylic Acid Have a Positive Role?

The lung is relatively sensitive to irradiation. It is shown that acetylsalicylic acid (ASA) might reduce oxidative injury and that it has a place in protection from cancer. The aim of this study is to evaluate the potential radioprotective effects of ASA. Whole-body irradiation (6 Gy, single dose) was applied to the rats. Glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels in the lung tissue were measured. Control (C), Radiation (R), Radiation?+?ASA (R?+?ASA; received irradiation and 25 mg/kg of ASA intraperitoneally (i.p.)), and Radiation?+?Amifostine (R?+?WR-2721; received irradiation and 200 mg/kg of WR-2721 i.p.) groups were used. The MPO levels decreased statistically significantly in the group administered ASA. Histopathologically, a radioprotective effect of ASA was more evident in the R?+?ASA group. ASA is an agent which has not been used as a radioprotector in the clinic yet, and it is worth supporting with more advanced studies.     

Antiplatelet mechanism of an herbal mixture prepared from the extracts of <Emphasis Type="Italic">Phyllostachys pubescens</Emphasis> leaves and <Emphasis Type="Italic">Prunus mume</Emphasis> fruits

Background

Bamboo (Phyllostachys pubescens) leaves and Japanese apricot (Mume fructus) fruit are traditionally recognized to be safe herbs broadly used for food and medicinal purposes in Southeast Asia. Our group previously explored their antiplatelet effects. This study was designed to confirm inhibition effects of PM21 (a 2:1 mixture of bamboo leaf extract and Japanese apricot fruit extract) on platelet aggregation and evaluate its potency to use as an herbal remedy to prevent and/or treat the diseases caused by platelet aggregation and thrombus formation.

Methods

Washed platelets were prepared and platelet aggregation was induced by adding 5 μg/mL collagen. Anti-platelet effects of PM21 (75 mg/kg, 150 mg/kg, and 300 mg/kg for ex vivo and in vivo assays, and 50, 100, 200 μg/mL for in vitro assays) were evaluated. In ex vivo assays, PM21 was orally administered to rats daily after overnight fasting for 3 days and blood was collected 1 h after the final treatment. In vivo antithrombotic effect of PM21 was observed from a carrageenan induced mouse tail thrombosis model.

Results

In ex vivo assay, PM21 inhibited platelet aggregation significantly. PM21 showed a strong antithrombotic effect by reducing significantly the length of mouse tail thrombus. PM21 increased intracellular cAMP level and reduced the release of ATP, TXA₂, and serotonin. PM21 also reduced intracellular concentration of calcium ion, fibrinogen binding to integrin α_IIbβ₃, and phosphorylation of ERK2, p38, PLCγ2, and PI3 K.

Conclusions

PM21 showed remarkable inhibitory effects on platelet aggregation and thrombus formation. Its inhibitory function seems to influence on GPVI binding to its ligand and subsequent initiation of a signaling cascade that involves activation of effector proteins and secretion of effector molecules, such as ATP, TXA₂, serotonin, and Ca²⁺. PM21 also appears to exert its anti-platelet effect by deactivation of ERKs activation pathway as well as inhibition of fibrinogen binding to integrin α_IIbβ₃.

     

Bothrojaracin, a Bothrops jararaca snake venom-derived (pro)thrombin inhibitor, as an anti-thrombotic molecule

Bothrojaracin (BJC) is a selective and potent thrombin inhibitor (KD = 0.6 nM) which also binds to prothrombin on proexosite I (KD = 175 nM). Incubation of BJC with human or rat plasma produced a band that co-migrates with purified prothrombin-BJC complex. We further analyzed the in vivo anti-thrombotic effect of BJC on a venous thrombosis model in rats that combines stasis and hypercoagulability. The administration of 1 mg/kg (i.v.) doses of BJC decreased thrombus weight by approximately 95%. Evaluation of the in vivo effect of BJC in mice using a pulmonary thromboembolism model induced by thrombin showed that BJC protects 100% of mice from death. Altogether, our data show that BJC is a potent anti-thrombotic agent that could further help the development of new prothrombin-directed drugs.     

Clinical evaluation of platelet antagonists on the ex vivo inhibitory effects of platelet aggregation

It is necessary in clinical to establish the effects of new substances for the primary and secondary prevention of thrombotic illnesses. We measured maximum aggregation after addition of collagen (F.C. 1.7 micrograms/ml) or ADP (F.C. 1.7 mumol/l) in 41 patients without drug treatment, 91 with ticlopidine, 22 with aspirin (ASA); 82-750 mg, 13 with ASA 81 mg, 20 with ticlopidine 100 mg and ASA 81 mg, 13 with cilostazol, 25 with flurbiprofen, 19 with nifedipine and evaluated the ex vivo effect of platelet antagonists. ASA inhibited remarkably collagen-induced platelet aggregation compared with other drugs, but there was significant (p less than 0.01 for 0.5 mumol/l ADP; p less than 0.02 for 1.0 mumol/l ADP) increase of primary aggregation induced by low dose of ADP in 14 healthy volunteers. While ticlopidine only significantly reduced ADP-induced platelet aggregation and we couldn't find dose dependency of ticlopidine (100-300 mg/day) on inhibitory effects of ADP or collagen-induced platelet aggregation. Our results indicate that the administration of one tablet of aspirin for pediatrics (aspirin 81 mg/tab) together with ticlopidine 100 mg is suitable for reduction of platelet aggregation.     

The effect of 5-lipoxygenase inhibition on Ascaris antigen (Ag)-induced responses in atopic monkeys

The effects of two 5-lipoxygenase (5LO) inhibitors, ZD2138 or Zileuton, on acute, inflammatory responses to aerosolizedAscaris suum (Ag) were determined in atopicMacaca fascicularis monkeys. Monkeys (n=6 each group) were dosed with vehicle, 3 or 10 mg/kg ZD2138, or 30 mg/kg Zileuton (p.o.). Both ZD2138 or Zileuton significantly inhibited ex vivo LTB₄ production in Ca²⁺ ionophore-stimulated whole blood from these same monkeys (n=6 each group) by 45.5% (3 mg/kg ZD2138), 82.5% (10 mg/kg ZD2138) and 84.3% (30 mg/kg Zileuton). ZD2138 (10 mg/kg) reduced bronchoalveolar lavage (BAL) LTE₄ levels (65.1% inhibition), BAL neutrophils (88.9% inhibition), and IL-6 (54.0% inhibition) 4h post Ag. Zileuton inhibited these responses and also reduced BAL levels of IL-8 (73.4% inhibition). A second study was performed to evaluate the effects of ZD2138 on chronic Ag-induced responses. Treatment with ZD2138 did not prevent pulmonary inflammation or the development of airway hyperresponsiveness (AHR). Based upon these results, 5LO inhibition significantly reduced ex vivo LTB₄ and in vivo LTE₄ production as well as several acute inflammatory responses to Ag in the lung. However, ZD2138 did not inhibit more chronic responses following multiple Ag exposure.accepted by M.J. Parnham     

Characteristics of the antihistamine effect of TAK-427, a novel imidazopyridazine derivative

OBJECTIVE AND DESIGN: The characteristics of the antihistamine effect of the new antiallergic compound TAK-427 were investigated. MATERIALS AND METHODS: In vitro binding assay of [(3)H] pyrilamine was performed using recombinant human histamine H(1) receptors (rhH(1)R). In vivo studies were performed in male ICR mice or Hartley guinea pigs. Drugs were administered orally 1 h before examinations. Determinations were made of histamine-induced skin reaction, ex vivo measured radioligand binding to brain and lung H(1) receptors, pentobarbital-induced sleeping time, passive cutaneous anaphylaxis (PCA) reaction, and antigen-induced itch-scratch responses (ISRs). RESULTS: TAK-427 inhibited ligand binding to rhH(1)R with an IC(50) value of 17.3 nmol/l. TAK-427 inhibited histamine-induced skin reactions in guinea pigs and mice with an ID(50) value of 0.884 and 0.450 mg/kg, p.o., respectively; significant inhibition associated with 10 mg/kg of TAK-427 was still observed 24 h after dosing in guinea pigs. TAK-427 showed as high selectivity for peripheral H(1) receptors as terfenadine and epinastine did, which was evaluated by ex vivo measured radioligand binding. Even at 300 mg/kg, TAK-427 did not affect pentobarbital-induced sleeping time in mice. TAK-427 significantly inhibited PCA in mice and guinea pigs, and also inhibited antigen-induced ISRs in guinea pigs. CONCLUSIONS: These results suggest that TAK-427 may have a long-lasting antihistamine activity with minimum sedative side effect and suppress acute phase allergic reactions.     

Ethanolic extract of Otostegia persica ameliorates bone loss in diabetic rats irrespective to its glucose lowering effect

The present study was conducted to investigate the effect of ethanolic extract of Otostegia persica on bone loss in streptozotocin (STZ)-treated diabetic rats. Forty male Wistar rats were randomly divided into five equal groups and treated as follows: group 1 (control); group 2 (STZ group), received STZ 50 mg/kg by a single IP injection; groups 3, 4, and 5 treated with STZ as mentioned above +200 mg/kg, 300 mg/kg, and 450 mg/kg of O. persica extract per day by oral gavage, respectively. On day 29, sera harvested and left femoral and tibiofibular bones were dissected for histomorphometric study, while right femoral and tibiofibular bones as well as L4 vertebrate were removed for determination of ash weight. Obvious hyperglycemia was seen in the STZ group as compared to the control. Administration of O. persica extract at the dosage of 300 mg/kg reversed the hyperglycemia. Alkaline phosphatase activity was markedly increased in all experimental groups as compared to control. Epiphyseal and metaphyseal trabecular width as well as epiphyseal bone area/tissue area significantly decreased in STZ group. O. persica extract at the dosage of 200 mg/kg reversed all these parameters to the control level. Marrow area/cortical area in rats treated with 450 mg/kg O. persica extract were highest among groups. No significant difference observed in osteoid thickness among different groups. Although the ash weights of both compact and cancellous bones in STZ group had no significant difference with control, ash weight of L4 vertebrate in rats treated with 300 and 450 mg/kg of extract was significantly lower than other groups. In conclusion, ethanolic extract of O. persica has bone protective effects in STZ-treated rats irrespective to its glucose lowering properties.     

Modification of Immune Response by Cinnarizine

Abstract

Effects of cinnarizine on immune response in mice were investigated. Mice were orally administered with cinnarizine and were immunized with sheep red blood cells (SRBC) intravenously. Numbers of plaque forming cells (PFC) to SRBC in spleen of these mice were assayed and delayed-type hypersensitivity (DTH) response to SRBC was measured. 1) PFC response in immunization with 5 × 10⁶ cells/mouse of SRBC was enhanced by administration of 25 mg/kg of cinnarizine, while the response in immunization with 5 × 10⁸ cells/mouse was suppressed by 25 to 200 mg/kg of cinnarizine. 2) From study on timing of administration, suppression of PFC response by 6.25 to 200 mg/kg of cinnarizine was observed at 24 hr. after the immunization. 3) 12.5 to 200 mg/kg of cinnarizine suppressed polyclonal B cell activation induced by lipopolysaccharide (LPS). 4) Colchicine induced suppressor T cell inactivation was prevented by administration of 50 mg/kg of cinnarizine and it was suggested that cinnarizine may induce suppressor T cells from the study of adoptive cell transfer system. 5) 50 mg/kg of cinnarizine showed the suppression of DTH response in expression phase, but not in induction phase. It was concluded that immune responses in mice were modified by cinnarizine.