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74.
EMD56431对麻醉犬血流动力学的作用 总被引:1,自引:0,他引:1
采用静脉注射和灌胃的方式给予犬EMD56431,在麻醉开胸状态下,分别在颈内动脉、股动脉、主动脉或冠状动脉左旋支及左心室插管或放置各种型号的探头,同步检测心输出量(CO),冠脉流量(CF),脑血流量(CBF)和股动脉血流量(FF),左室收缩压(LVSP),左室压上升和下降速率(±dp/dtmax),左室舒末压(LVEDP),收缩压(SAP),舒张压(DAP),平均动脉压(MAP),心电图(ECG)等指标,并计算出心率(HR),心脏指数(CI)和外周阻力(TPR).结果经静脉注射EMD5643125,50,100μg/kg均可对麻醉犬产生剂量依赖性的降压作用,同时减慢HR,增加CF,降低TPR和±dp/dtmax,除静脉注射100μg/kg EMD56431外,其余对心功能,器官血流量,ECG无明显影响;灌胃给予EMD 56431200μg/kg也具有明显而持久的降压作用,降压时未见反射性HR加快.静注和灌胃EMD56431产生的效应相当.结果提示EMD56431对麻醉犬有明显而持久的降压作用,且该药生物利用度较高,具有广阔的临床开发前景. 相似文献
75.
The calcium sensitizer and PDEIII inhibitor EMD82571 caused exencephaly, micrognathia, agnathia and facial cleft in 58% of fetuses. In pursue of mechanisms and to define adverse outcome pathways pregnant Wistar rats were dosed daily with either EMD82571 (50 or 150 mg/kg/day) or retinoic acid (12 mg/kg/day) on gestational days 6–11 and 6–17, respectively. Hypothesis driven and whole genome microarray experiments were performed with whole embryo, maternal liver, embryonic liver and malformed bone at gestational days 12 and 20. This revealed regulation of genes critically involved in osteogenesis, odontogenesis, differentiation and development and extracellular matrix. Importantly, repression of osteocalcin and members of TGF-β/BMP signaling hampered osteo- and odontogenesis. Furthermore, EMD82571 impaired neurulation by inhibiting mid hinge point formation to cause neural tube defects. Taken collectively, a molecular rationale for the observed teratogenicity induced by EMD82571 is presented that links molecular initiating events with AOPs. 相似文献
76.
《Expert opinion on therapeutic patents》2013,23(4):439-440
Whilst considerable advances have been made in the treatment of depression, particularly with the advent of the selective serotonin re-uptake inhibitors (SSRIs), current drug treatments are unsatisfactory for several reasons. In particular, they fail to treat approximately 30% of patients, and they are slow in onset, requiring 3 - 8 weeks for efficacy. Consequently, the search for new antidepressants is now focussed on providing solutions to these problems. This review surveys the antidepressant patent literature for the years 1995 - 1997 in the context of these issues. Progress has been made, particularly with combinations of SSRIs and 5-HT autoreceptor ligands. Initially this has been achieved by combining individual drugs with single modes of action, but single compounds with multiple activities have also been patented. There has also been extensive patent activity suggesting that agonists at postsynaptic 5-HT1A and 5-HT2C receptors and antagonists at presynaptic 5-HT1B autoreceptors possess antidepressant potential. While the major focus of research has been the enhancement of serotonergic neurotransmission, attention is now turning to other mechanisms of action. In particular, growing interest in the role of corticotrophin-releasing factor (CRF) in stress-related disorders, and recent clinical trials with the substance P antagonist, MK-869, has seen a rapid expansion in patent activity around CRF and tachykinin receptor antagonists for the treatment of depression. 相似文献
77.
H Grobecker M F Roizen D M Jacobowitz I J Kopin 《European journal of pharmacology》1977,46(2):125-133
The effects of repeated high doses of the adrenergic neuron blocking drug guanethidine or a hexahydropyrazinoindole compound (2-guanyl-1,2,3,10,10a, hexahydro-1,2,a-pyrazinoindole, EMD 21192) (30 mg/kg i.p., 21.5 mg/kg i.p. respectively, equimolar doses) on sympathoadrenal activity were investigated in normotensive adult rats. During treatment for 5 weeks with either guanethidine or EMD 21192 the systemic blood pressure fell steadily. Noradrenaline content in the heart and vas deferens were decreased markedly by guanethidine and to a much less degree by EMD 21192. EMD 21192 markedly lowers the catecholamine content of the adrenal medulla, presumably as a result of inhibition of dopamine-beta-hydroxylase. The plasma catecholamine concentrations reflected the different sites of action of the drugs in the sympathoadrenal system, i.e. guanethidine mainly reduced circulating norepinephrine and dopamine-beta-hydroxylase by more than 50%, whereas EMD 21192 decreased considerably by the total catecholamines (mainly epinephrine) without altering significantly in the plasma norepinephrine. Disappearance or reduction of fluorescent nerve endings in the iris and the heart and a decrease of the intensity of fluorescence in chromaffin cells of the adrenal gland caused by the drugs were consistent with the biochemical alteration. Whereas the repeated doses of guanethidine caused degeneration of sympathetic nerves, destruction of adrenergic neurons was not found after prolonged treatment with EMD 21192. 相似文献
78.
We examined the effect of the highly selective 5-hydroxytryptamine (5-HT)(2A) receptor antagonist 7-[4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl]-1H-indole-3-carbonitrile HCl (EMD 281014) in congenital learned helpless male rats in the forced swim test. The administration of EMD-281014 (0.3-30 mg/kg i.p.) to congenital learned helpless rats dose-dependently and significantly (at 10 and 30 mg/kg) decreased immobility and increased swimming compared to vehicle-treated animals. Thus, EMD 281014 produces effects in the forced swim test resembling those of antidepressants. 相似文献
79.
Beekman KW Colevas AD Cooney K Dipaola R Dunn RL Gross M Keller ET Pienta KJ Ryan CJ Smith D Hussain M 《Clinical genitourinary cancer》2006,4(4):299-302
Two randomized trials demonstrated an improvement in survival with docetaxel-based chemotherapy for patients with metastatic, androgenindependent prostate disease. However, the effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential. Cilengitide (EMD121974; NSC 707544), is a potent selective αvβ3 and αvβ5 integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities including endothelial cell proliferation and migration. Blocking the ligation of integrins by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In prostate cancer specifically, integrins are known to be involved in metastases with differential expression on tumor cells. Tumors and vascular endothelial cells produce factors, such as vascular endothelial growth factor and basic fibroblast growth factor, that promote neovascularization, which has been implicated in prostate cancer progression. Cilengitide has been shown to inhibit αvβ3- and αvβ5-mediated cell adhesion and block in vitro endothelial cell migration. In vivo experiments demonstrated that cilengitide inhibited cytokine-induced basic fibroblast growth factor- and vascular endothelial growth factor-mediated angiogenesis in a dose-dependent manner. Cilengitide also inhibited tumor growth in various in vivo systems. Two Cancer Therapy Evaluation Program-sponsored, multicenter, phase II trials are designed to evaluate the safety and efficacy of this agent in patients with androgen-independent prostate cancer. National Cancer Institute trial 6735 is evaluating cilengitide at 2000 mg in patients with nonmetastatic androgen-independent prostate cancer, and National Cancer Institute trial 6372 is evaluating 2 dose levels of cilengitide, 500 mg or 2000 mg, intravenously twice weekly in patients with metastatic prostate cancer. 相似文献
80.
Janne E. Reseland Sjur Reppe Aileen M. Larsen Heidi S. Berner Finn P. Reinholt Kaare M. Gautvik Ivan Slaby S. Petter Lyngstadaas 《European journal of oral sciences》2006,114(S1):205-211
Observations that amelogenins, in the form of enamel matrix derivative (EMD), have a stimulatory effect on mesenchymal cells and tissues, and on the regeneration of alveolar bone, justified investigations into the effect of EMD on bone-forming cells. The binding and uptake of EMD in primary osteoblastic cells was characterized, and the effect of EMD on osteoblast gene expression, protein secretion, and mineralization was compared with the effect of parathyroid hormone (PTH). Although no specific receptor(s) has yet been identified, EMD appeared to be taken up by osteoblasts through clathrin-coated pits via the interaction with clathrin adaptor protein complex AP-2, the major mechanism of cargo sorting into coated pits in mammalian cells. EMD had a positive effect on factors involved in mineralization in vitro , causing an increased alkaline phosphatase (ALP) activity in the medium as well an as increased expression of osteocalcin and collagen type 1. Several hundred genes are regulated by EMD in primary human osteoblasts. There appear to be similarities between the effects of EMD and PTH on human osteoblasts. The expression pattern of several mRNAs and proteins upon EMD stimulation also indicates a secondary osteoclast stimulatory effect, suggesting that the osteogenic effect of EMD in vivo , at least partly, involves stimulation of bone remodelling. 相似文献