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91.
D. J. Trezise A. D. Michel C. B. A. Grahames B. S. Khakh A. Surprenant P. P. A. Humphrey 《Naunyn-Schmiedeberg's archives of pharmacology》1995,351(6):603-609
The effects of the putative selective P2X purinoceptor agonist, ,-methylene-l-adenosine 5-triphosphate (me-l-ATP), were determined at rat neuronal and smooth muscle P2X purinoceptors.Me-l-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 M. In contrast, the archetypal P2X purinoceptor agonist, , methylene ATP (meATP;1–100 M), produced concentration-related depolarisation responses with a mean EC50 value of 10.8 M. The depolarising effects of meATP were not attenuated by me-l-ATP (100 M). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 M), but not me-l.-ATP (1–300 M), evoked rapid ( < 20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, me-d-ATP and meATP competed with high affinity for [3H]Lx meATP binding sites, with mean pIC50 values of 7.7 and 8.3, respectively. However, me-l-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 M (mean pIC50 value 4.1).In prostatic segments of the rat vas deferens, me-l-ATP (1–100 M) and meATP (0.3–100 M) each produced concentration-related contractile responses with mean EC50 values of 17.1 and 3.6 M, respectively. Me-l-ATP (1–10 M) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [3H]meATP exhibited high affinity for me-l-ATP, meATP and me-d-ATP with mean PIC50 values of 7.7, 8.4 and 7.3, respectively.These results indicate that me-l-ATP exhibits neither agonist nor antagonist properties at P2X purinoceptors on rat vagal neurones and possesses only very low affinity for [3H]meATP binding sites in rat brain. In contrast, me-l-ATP is a potent, high affinity agonist at smooth muscle P2X purinoceptors of the rat vas deferens. This selective agonist action of me-l-ATP suggests that P2X purinoceptors in smooth muscle and neurones are different and represent distinct P2X purinoceptor subtypes. 相似文献
92.
Susumu Furukawa Tomoyo Matsubara Toshihir Ino Keijiro Yabuta Yoshimi Umezawa Toshikazu Motohashi 《European journal of pediatrics》1994,153(9):663-667
We compared the efficacy of oral administration of pentoxifylline (PTX) and intravenous infusions of gamma globulin (IVGG) combination therapy with that of IVGG in reducing the frequency of coronary-artery lesions (CAL) in children with Kawasaki disease (KD), in a randomized trial. All patients with KD received acetylsalicylic acid (30 mg/kg per day), until the 30th day, after the onset of fever, followed by daily acetylsalicylic acid at a dose of 3-5 mg/kg per day there-after, and intravenous IVGG, 200 mg/kg per day, for 5 consecutive days. In addition, patients randomly assigned to PTX and IVGG combination therapy groups received oral PTX at a dosage of 10 mg/kg per day (low-dose) or 20 mg/kg per day (high-dose), in three divided doses until the 30th day. Patients with KD were all free from CAL prior to treatment. We assessed the presence of CAL by two-dimensional echocardiography which was also done prior to treatment and then twice a week after hospital admission. We detected CAL in 3 of 18 patients (16.7%) in the IVGG therapy group, as compared with 2 of 18 patients (11.1%) in the low-dose PTX and IVGG combination therapy group. There were no significant differences between the two groups. In the next study, we detected CAL in 3 of 21 patients (14.3%) in the IVGG therapy group, as compared with none of 22 patients (0%) in the high-dose PTX and IVGG combination therapy group (2 = 6.4, P < 0.02). No adverse side-effects were observed in 79 patients with KD. 相似文献
93.
目的 了解保存时间及温度对补体活性的影响。方法:用单向琼脂扩散法和非离心单管法对不同温度和时间下标本的C_3含量及CH50进行测定。结果与结论:血清补体C_5含量在室温下24h、4C下4dC、-10C和-20C下8d内无显著变化;CH50在室温下12h、4C下24h,-10C和-20C下8d内CH50无明显变化。 相似文献
94.
McCormick B 《The breast journal》1999,5(5):330-334
▪ Abstract: Local control in the breast after breast-conserving surgery and radiation for the treatment of early invasive breast carcinoma has long been viewed as important to the patient to avoid later need for mastectomy. Now several studies support the hypothesis that local control is related to and impacts upon a patient's survival as well. The factors that predict for local control with this treatment are reviewed. The recent studies that support the link between local breast failure and distant disease are also discussed. ▪ 相似文献
95.
Giuseppe Caliendo Ferdinando Fiorino Paolo Grieco Elisa Perissutti Vincenzo Santagada Rosaria Meli Giuseppina Mattace Raso Angelina Zanesco Gilberto De Nucci 《European journal of medicinal chemistry》1999,34(12):1043
Two sets of benzotriazinone and benzoyltriazole derivatives were prepared and tested for local anaesthetic activity in comparison with lidocaine. Several of the prepared compounds exhibited a fairly good activity comparable or superior to that of lidocaine. The presence of a benzotriazinone or a benzoyltriazole moiety as an aromatic system was quite profitable for both the intensity and duration of activity. The acute toxicity in mice of the four most potent compounds of the series was also assessed. Compound 1b, which has an anaesthetic activity comparable to that of lidocaine, was also characterized by a more favourable therapeutic index. All compounds were tested in vitro to evaluate their negative chronotropic action in isolated rat right atria. 相似文献
96.
Arezo Nahavandi Ahmad Reza Dehpour Ali Reza Mani Homayoun Homayounfar Ali Abdoli 《European journal of pharmacology》1999,370(3):1170
In this study the effect of nitric oxide (NO) synthesis inhibition on ethanol-induced gastric damage was evaluated in bile duct-ligated, sham-operated and unoperated rats. The animals were injected intraperitoneally with saline,
-arginine (200 mg/kg) or NG-nitro-
-arginine methylester (
-NAME) in doses of 5, 15 and 30 mg/kg, 30 min before ethanol administration. The animals were killed 1 h after ethanol administration and their stomachs were removed for measurement of gastric mucosal damage. The results showed that
-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated and unoperated rats, while in bile duct-ligated animals,
-NAME decreased and
-arginine enhanced the potentiation of ethanol-induced gastric mucosal damage. The plasma level of nitrite and nitrate was also measured and was significantly higher in bile duct-ligated rats than in control groups. The results suggest that inhibition of NO synthase with
-NAME has different effects on ethanol-induced gastric damage in cholestatic groups and in normal rats and that these effects can be explained by overproduction of NO in bile duct-ligated animals. 相似文献
97.
胰原性区域性门脉高压症血流动力学的临床研究 总被引:2,自引:0,他引:2
目的:研究胰原性区域性门脉高压症静脉血流动力学改变。方法:利用彩色多普勒及直接测量法测量血流动力学及脾静脉压力。结果:门静脉、肠系膜上静脉的血管直径、平均流速在两组间无差异。实验组脾静脉直径扩张,流速降低且静脉压力明显升高(P<0.05)。结论:胰原疾病可导致区域性门脉高压,正确的治疗方法是行脾脏切除术。 相似文献
98.
M. Gerlach P. Riederer 《Journal of neural transmission (Vienna, Austria : 1996)》1996,103(8-9):987-1041
Summary Animal models are an important aid in experimental medical science because they enable one to study the pathogenetic mechanisms and the therapeutic principles of treating the functional disturbances (symptoms) of human diseases. Once the causative mechanism is understood, animal models are also helpful in the development of therapeutic approaches exploiting this understanding. On the basis of experimental and clinical findings. Parkinson's disease (PD) became the first neurological disease to be treated palliatively by neurotransmitter replacement therapy.The pathological hallmark of PD is a specific degeneration of nigral and other pigmented brainstem nuclei, with a characteristic inclusion, the Lewy body, in remaining nerve cells. There is now a lot of evidence that degeneration of the dopaminergic nigral neurones and the resulting striatal dopamine-deficiency syndrome are responsible for its classic motor symptoms akinesia and bradykinesia. PD is one of many human diseases which do not appear to have spontaneously arisen in animals. The characteristic features of the disease can however be more or less faithfully imitated in animals through the administration of various neurotoxic agents and drugs disturbing the dopaminergic neurotransmission.The cause of chronic nigral cell death in PD and the underlying mechanisms remain elusive. The partial elucidation of the processes underlie the selective action of neurotoxic substances such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has however revealed possible molecular mechanisms that give rise to neuronal death. Accordingly, hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD.The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of PD. The currently most important animal models (e.g. the reserpine model, neuroleptic-induced catalepsy, tremor models, experimentally-induced degeneration of nigro-striatal dopaminergic neurons with 6-OHDA, methamphetamine, MPTP, MPP+, tetrahydroisoquinolines, -carbolines, and iron) critically reviewed next, and are compared with the characteristic features of the disease in man. 相似文献
99.
Raghavan Krishnaswamy S. Gray David B. Scholz Thomas H. Nemeth Gregory A. Hussain Munir A. 《Pharmaceutical research》1996,13(12):1815-1820
Purpose. The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development.
Methods. The pKa was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples.
Results. The pKa for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH of maximum stability is in the range of 4 to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is BAC2 which involves -lactam ring opening. The -lactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the k
OH controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced basicity of the -lactam nitrogen making it a good leaving group.
Conclusions. The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible. 相似文献
100.
Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines 总被引:2,自引:0,他引:2
A. E. Wakeling A. J. Barker D. H. Davies D. S. Brown L. R. Green S. A. Cartlidge J. R. Woodburn 《Breast cancer research and treatment》1996,38(1):67-73
Summary Since the mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor (EGFR), and EGFR is commonly overexpressed in solid human tumours, inhibitors of receptor tyrosine kinase activity (RTK) could prove to be effective antitumour agents. Screening of a compound library using an EGF-RTK enzyme prepared from human tumour derived A431 cells identified a series of potent (IC50<1µM) enzyme inhibitors. These inhibitors are quinazolines bearing a variety of substituted anilines at the 4-position. The most potent 4-anilinoquinazolines (IC50 20nM) have small non-polar meta substituents on the aniline ring, and are competitive with ATP and non-competitive with substrate. The growth inhibitory activity of these agents was assessed in vitro using KB cells (human oral squamous tumour) grown in the absence or presence of EGF. A selected compound, 4-(3-chloroanilino)quinazoline (CAQ), inhibited EGF-stimulated growth in a concentration dependent manner and complete blockade was observed at concentrations (1–10 µM) which had no effect on basal growth. Selectivity of growth inhibition by CAQ was further exemplified in IGF1-stimulated KB cells where no effect was detected at concentrations which completely blocked EGF-stimulated growth. Similarly, CAQ blocked TGF-stimulated growth in MCF-7 human breast cancer cells without affecting insulin-stimulated growth. These studies define a novel class of EGF-RTK inhibitors which are also potent and selective inhibitors of EGF-stimulated human tumour cell growthin vitro.
Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb. 相似文献