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In vitro anti‐LPS dose determination of ketorolac tromethamine and in vivo safety of repeated dosing in healthy horses 
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下载免费PDF全文 A. W. Bianco G. E. Moore B. R. Cooper S. D. Taylor 《Journal of veterinary pharmacology and therapeutics》2018,41(1):98-104
Flunixin meglumine (FM) is a commonly used Nonsteroidal anti‐inflammatory drug (NSAID) in horses, but clinical efficacy is often unsatisfactory. Ketorolac tromethamine (KT) demonstrates superior efficacy compared to other NSAIDs in humans, but its anti‐inflammatory effects have not been investigated in the horse. Safety of repeated dosing of KT has not been evaluated. The first objective was to conduct a dose determination study to verify that a previously described dosage of KT would inhibit Lipopolysaccharide (LPS)‐induced eicosanoid production in vitro, and to compare KT effects of this inhibition to those of FM. Then, a randomized crossover study was performed using nine healthy horses to evaluate plasma concentrations of KT and FM following IV administration. Administered dosages of KT and FM were 0.5 mg/kg and 1.1 mg/kg, respectively. Safety following six repeated doses of KT was assessed. Ketorolac tromethamine and FM suppressed LPS‐induced Thromboxane B2 (TXB2) and Prostaglandin E2 (PGE2) production in vitro for up to 12 hr. Intravenous administration produced plasma concentrations of KT and FM similar to previous reports. No adverse effects were observed. A KT dosage of 0.5 mg/kg IV inhibited LPS‐induced eicosanoids in vitro, and repeated dosing for up to 3 days appears safe in healthy horses. Investigation of in vivo anti‐inflammatory and analgesic effects of KT is warranted. 相似文献
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临床上大部分抗血小板药物存在继发性出血等副作用,亟需寻找一种安全有效的抗血小板药物。二磷酸腺苷(ADP)和花生四烯酸(AA)是介导血小板聚集的主要物质,文章探讨成纤维细胞生长因子-21(FGF-21)是否抑制ADP或AA诱导大鼠血小板聚集和活化。将大鼠分为正常对照组、正常鼠血小板活化组、阿司匹林干预后血小板活化组、FGF-21高、中、低剂量干预后血小板活化组。给药干预后提取各组血小板,分别用ADP或AA处理,观察处理后血小板聚集情况以及P选择素和血栓素(TXB2)表达水平。与正常对照组相比,正常鼠血小板经ADP或AA处理活化后,血小板聚集率显著升高,血浆中P选择素和TXB2含量明显上升;与正常鼠血小板经ADP或AA处理活化后相比,经阿司匹林和FGF-21干预后分别经ADP或AA处理活化后的血小板聚集率显著下降,血浆中P选择素和TXB2含量显著下降;FGF-21干预组经ADP或AA活化后,血小板聚集率、P选择素和TXB2含量下降水平呈明显剂量依赖性。目前国内外尚未发现FGF-21对血小板聚集与活化作用的相关报道,研究首次证明FGF-21具有抑制ADP和AA诱导血小板聚集和活化作用及明显的抗血凝作用,填补FGF-21在抗血凝研究领域空白,为开发安全有效的抗血凝药物提供理论依据。 相似文献
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通过人工建立血栓闭塞性脉管炎大鼠模型，结合病理学切片结果，利用荧光定量PCR和ELISA方法检测病变组织中的Icam-1、Vcam-1和血清中的血栓素B2（TXB2）、抗内皮细胞抗体（AECA）的含量。结果表明清髓愈疽丹能够通过有效地降低Icam-1、Vcam—1、TXB2、AECA的含量，抑制淋巴细胞、白细胞的浸润和血小板的黏附聚集，阻止血液高凝状态的形成；延缓损伤内皮处免疫复合物的形成，从而减轻痛变部位的炎症与损伤，因此能抑制血栓的形成，对TAO有确实的疗效。 相似文献
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An isolated non-working trout heart, cannulated through the coronary artery and perfused with oxygenated saline with a coronary
pressure head of 3.0 kPa has been used in this study. Effects on the coronar resistance of catecholamines, thromboxanes (TXs)
and prostacyclin (PGI2) were analyzed. The effects of PGI2 and TXs in presence of noradrenaline were also evaluated. Both adrenaline and noradrenaline vasoconstrict the trout coronary
system, noradrenaline being more potent than adrenaline. TXA2 induces 45% vasoconstriction at 10−6M, while TXB2 at the same concentration is a slight vasodilator. PGI2 acts as a weak vasodilator (about 20% decrease in resistance at 10−6M). In presence of 10−7M noradrenaline, 10−8M TXA2 reduces the vasoconstriction induced by the catecholamine alone from 60% to about 15%. Under similar conditions, 10−9M PGI2 potentiates the vasoconstrictive response induced by noradrenaline while a much higher PGI2 concentration (10−6M) completely abolishes the vasoconstriction. The β-receptor antagonist propranolol induces vasoconstriction, and 10−9M PGI2 in presence of propranolol further increases the vasoconstriction. The α-receptor antagonist phentolamine induces vasodilation
and 10−9M PGI2 does not affect coronary resistance induced by phentolamine. These results imply a possible interaction between noradrenaline
and prostanoids (TXs and PGI2) in the vasomotion of trout coronary system. 相似文献
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WU Jian-mei CHEN Xiao-na GUO Zheng-xiang JI Xiao-wei SHI Qiao-ya YIN Hong-ping SHEN Li RU Hai-long LIN Guo-hua LIU Chuan-fei LIU Cui-qing 《园艺学报》2012,28(6):1103-1108
AIM: To investigate the role of Rho kinase in diabetic vascular endothelial dysfunction. METHODS: SD rats, genetic db/db diabetic model and high-fat diet-induced obese mice were used in this study. The thoracic aorta of the rats or mice were isolated and suspended in organ bath or myograph for measurement of the changes in isometric tensions. The levels of phosphorylated endothelial nitric oxide synthase(eNOS) were determined by Western blotting. Thromboxane B2(TXB2),prostaglandin F2α(PGF2α) and thromboxane receptor (TP receptor) activators in artery were measured by ELISA. RESULTS: Endothelium-dependent vasorelaxation was attenuated by TP receptor activation, which was ameliorated by Rho kinase inhibitors. The improved endothelium-dependent vasorelaxation by inhibition of Rho kinase was abolished by pretreatment with the inhibitor of eNOS. Consistently, the level of phosphorylated eNOS was inhibited by TP receptor activation, which was reversed by inhibition of Rho kinase. The endothelium-dependent vasorelaxation was also improved by Rho kinase inhibitors in diabetic and obese animals. The levels of TXB2 and PGF2α in the arteries were increased in diabetic animals compared with the controls. CONCLUSION: Rho kinase plays a role in diabetic endothelial dysfunction, which may be related to TP receptor activation and eNOS inhibition. 相似文献
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为考察油菜籽粕芥子碱氯化盐的降压作用及其对血管内皮因子的影响,采用动脉插管方式记录新西兰大耳白兔的收缩压、舒张压、平均动脉压研究芥子碱氯化盐的降压作用,酶联免疫吸附测定法（ELISA）检测血清中前列环素（PGI2）、血栓素A2（TXA2）、内皮素-1(ET-1)的水平,硝酸还原酶法检测血清中NO的水平。结果表明:芥子碱氯化盐在0.025~12.5 mg/kg浓度范围能够显著降低实验动物收缩压、舒张压及平均压;随其浓度增加,降压率上升,维持时间延长。ELISA实验结果表明芥子碱氯化盐对实验动物血清中PGI2、ET-1水平作用不显著,2.4 mg/kg与9.6 mg/kg芥子碱氯化盐能够显著降低血清中TXA2的水平。上述结果说明油菜籽粕芥子碱氯化盐具有显著的降压作用,其降压机制可能是通过抑制血管收缩因子TXA2的水平实现的。 相似文献
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Alejandro M. S. Mayer Mary L. Hall Michael Holland Cristina De Castro Antonio Molinaro Monica Aldulescu Jeffrey Frenkel Lauren Ottenhoff David Rowley Jan Powell 《Marine drugs》2014,12(4):1732-1756
Although human exposure to Gram-negative Vibrio vulnificus (V. vulnificus) lipopolysaccharide (LPS) has been reported to result in septic shock, its impact on the central nervous system’s innate immunity remains undetermined. The purpose of this study was to determine whether V. vulnificus MO6-24/O LPS might activate rat microglia in vitro and stimulate the release of superoxide anion (O2−), a reactive oxygen species known to cause oxidative stress and neuronal injury in vivo. Brain microglia were isolated from neonatal rats, and then treated with either V. vulnificus MO6-24/O LPS or Escherichia coli O26:B6 LPS for 17 hours in vitro. O2− was determined by cytochrome C reduction, and matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatinase zymography. Generation of cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), IL-6, and transforming growth factor-beta 1 (TGF-β1), chemokines macrophage inflammatory protein (MIP-1α)/chemokine (C-C motif) ligand 3 (CCL3), MIP-2/chemokine (C-X-C motif) ligand 2 (CXCL2), monocyte chemotactic protein-1 (MCP-1)/CCL2, and cytokine-induced neutrophil chemoattractant-2alpha/beta (CINC-2α/β)/CXCL3, and brain-derived neurotrophic factor (BDNF), were determined by specific immunoassays. Priming of rat microglia by V. vulnificus MO6-24/O LPS in vitro yielded a bell-shaped dose-response curve for PMA (phorbol 12-myristate 13-acetate)-stimulated O2− generation: (1) 0.1–1 ng/mL V. vulnificus LPS enhanced O2− generation significantly but with limited inflammatory mediator generation; (2) 10–100 ng/mL V. vulnificus LPS maximized O2− generation with concomitant release of thromboxane B2 (TXB2), matrix metalloproteinase-9 (MMP-9), and several cytokines and chemokines; (3) 1000–100,000 ng/mL V. vulnificus LPS, with the exception of TXB2, yielded both attenuated O2− production, and a progressive decrease in MMP-9, cytokines and chemokines investigated. Thus concentration-dependent treatment of neonatal brain microglia with V. vulnificus MO6-24/O LPS resulted in a significant rise in O2− production, followed by a progressive decrease in O2− release, with concomitant release of lactic dehydrogenase (LDH), and generation of TXB2, MMP-9, cytokines and chemokines. We hypothesize that the inflammatory mediators investigated may be cytotoxic to microglia in vitro, by an as yet undetermined autocrine mechanism. Although V. vulnificus LPS was less potent than E. coli LPS in vitro, inflammatory mediator release by the former was clearly more efficacious. Finally, we hypothesize that should V. vulnificus LPS gain entry into the CNS, it would be possible that microglia might become activated, resulting in high levels of O2− as well as neuroinflammatory TXB2, MMP-9, cytokines and chemokines. 相似文献
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DINO M. BRADLEY STEVEN F. SWAIM DANA M. VAUGHN ROBERT D. POWERS JOHN A. MCGUIRE† GREGORY A. REINHART‡ JOHN BURR‡ RICK A. SWENSON‡ 《Veterinary dermatology》1996,7(4):203-208
Abstract Twenty-six Alaskan sled dogs were used to study the biochemical and histopathological changes which occur when dog paws are exposed to cold temperatures and physical stress. They were separated into a running group of 20 dogs and a control group of six non-running dogs. Over 2 1/2 days, the running group ran in their natural environment for 170 miles and environmental parameters were recorded. Following the run, an 8-mm díameter skin biopsy specimen was taken from the lateral aspect of the right fore and hind paws of the running and non-running dogs. The skin was evaluated for histopathological changes and the présence of 2, 3-dinor thromboxane B2 (2, 3-dinor TxB2). No significant histopathological changes were noted in any of the biopsy specimens. Based on measured elevation of 2, 3-dinor TxB2, the forepaws experienced more physical stress than the hind paws. Wet snow at higher environmental temperatures caused more paw stress than hard crusted snow at lower environmental temperatures. Resumen Se emplearon veintiséis perros trineo de Alaska para estudiar las alteraciones bioquimicas e histopatológicas ocurridas durante la exposición de las patas a las bajas temperaturas y al estrés fisico. Se dividieron entre un grupo de 20 perros corredores y un grupo control de seis perros no corredores. Durante dos días y medio el grupo de corredores corrió en su ambiente natural 170 millas. Durante la carrera se tomó una biopsia por punch de 8 mm del aspecto lateral de la pata derecha delantera y trasera de los perros corredores y no corredores. Se evaluaron las alteraciones histopatológicas cutáneas y la presencia de tromboxano B2 2, 3-dinor (2, 3-dinor TxB2). No se observaron alteraciones histopatológicas significativas en ninguna de las muestras de biopsia. Según la elevación detectada en 2.3-dinor TxB2, las patas delanteras sufrieron un estrés fisico mayor que las traseras. La nieve húmeda en temperaturas ambientales elevadas causó un estrés mayor que la nieve dura en temperaturas ambientales más bajas. [Bradley, D.M., Swaim, S.F., Vaughn, D.M., Powers, R.D., McGuire, J.A., Reinhart, G.A., Burr, J., Swenson, R.A. Biochemical and histopathological evaluation of changes in sled dog paw skin associated with physical stress and cold temperatures. (Estudio bioquimico e histopatologico de las alteraciones en las patas de perros de trineo asociadas al estrés fisico y por las bajas temperaturas). Veterinary Dermatology 1996; 7 : 203–208.] Résumé Vingt six chiens de traineau de l'Alaska fürent utilisés dans une étude évaluant les modifications biochimiques et histologiques survenant lorsque les pattes sont exposées à des températures froides et des stress physiques. lls fürent divisés en un groupe de vingt chiens de course et un groupe de six chiens ne courant pas. Après deux jours et demi, le groupe de course avait parcouru 170 miles dans son environnement naturel, dont les paramètres fürent enregistrés. Après la course, des biopsies de 8 mm de díamètre fürent prises sur les faces latérales des pattes antérieure et postérieure droites des chiens d'attelage et de ceux qui étaient restés au repos. L'évaluation de l'état cutané s'est faite sur les modifications histologiques et la présence de 2, 3-dinor thromboxane B2 (2, 3-dinor TxB2). Aucune modification histologique significative n'a été notée dans aucune des biopsies réalisées. Jugé sur l'élévation du 2, 3 TxB2, les pattes antérieures subissent un stress physique supérieur aux pattes postérieures. La neige humide à temperatures plus élevées cause plus d'agression que la neige dure et crouteuse à des températures plus basses. [Bradley, D.M., Swaim, S.F., Vaughn, D.M., Powers, R.D., McGuire, J.A., Reinhart, G.A., Burr, J., Swenson, R.A. Biochemical and histopathological evaluation of changes in sled dog paw skin associated with physical stress and cold temperatures. (Evaluation des modifications biochimiques et histologiques induites par les stress physiques et le froid au niveau de la peau des pattes de chiens de traineau). Veterinary Dermatology 1996; 7 : 203–208.] Zusammenfassung Sechsundzwanzig Alaska-Schlittenhunde wurde für eine Studie über biochemische und histopathologische Veränderungen herangezogen, die an den Pfotenballen auftreten, wenn sie kalten Temperaturen und physischem Streß ausgesetzt sind. Die Hunde wurden in eine Renngruppe von 20 Hunden und eine Kontrollgruppe von sechs Nicht-Rennhunden eingeteilt. Über einen Zeitraum von zweieinhalb Tagen rannte die Renngruppe in lhrer natürlichen Umgebung 170 Mellen, wobei die Umgebungsparamenter aufgezeichnet wurden. Nach dem Rennen wurden Biopsien mit einem Durchmesser von 8 mm von der Lateralseite der rechten Vorder-und Hinterpfote bei den Renn-und Nichtrennhunden entnommen. Die Haut wurde auf histopathologische Veränderungen und die Anwesenheit von 2, 3-dinor-Thromboxan BA (2, 3-dinor TxB2) untersucht. Es wurden keine signifikanten histopathologischen Veränderungen bei einer der Biopsien festgestellt. Auf der Basis der gemessenen Erhöhung von 2, 3-dinor TxB2 erfuhren die Vorderpfoten mehr physischen Streß als die Hinterpfoten. Nasser Schnee und höhere Umgebungstemperaturen verursachten mehr Pfotenstreß als harter, verkrusteter Schnee bei niedrigeren Umgebungstemperaturen. [Bradley, D.M., Swaim, S.F., Vaughn, D.M., Powers, R.D., McGuire, J.A., Reinhart, G.A., Burr, J., Swenson, R.A. Biochemical and histopathological evaluation of changes in sled dog paw skin associated with physical stress and cold temperatures (Biochemische und histopathologische Untersuchung von Hautveränderungen an den Pfoten von Schlittenhunden in Verbindung mit physischem Streß und Kälte). Veterinary Dermatology 1996; 7 : 203–208.] 相似文献
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Andersen, P. Haubro, M. Hesselholt and N. Jarlev: Endotoxin and arachidonic acid metabolites in portal, hepatic and arterial blood of cattle with acute ruminai acidosis. Acta vet.scand.1994,35,223-234.– Ruminai acidosis was induced experimentally with 70 g barley / kg body weight in 2 rumen fistulated cows with chronic indwelling catheters in the portal vein, in a hepatic vein and the carotid artery. The cows were followed for 24 and 20h after the overfeeding and evaluated clinically and by clinical chemistry. The 2 cows exerted different responses to the treatment. Both cows showed signs of severe ruminai acidosis. Both cows had endotoxin in portal and hepatic vein blood, but only 1 of the cows convincingly developed a systemic endotoxaemia. A pre-hepatic release of the stable prostacyclin and thromboxane metabolites, 6-ketoprostaglandin Flα and thromboxane B2 was demonstrated in this cow. The results of the present study show that endotoxin and arachidonic acid metabolites of pre-hepatic origin may be factors involved in the pathogenesis of ruminai acidosis, and that investigation of the factors affecting translocation of ruminai endotoxin and subsequent clearing in the liver, will be of importance. 相似文献