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131.
We investigated the cellular events linked to the induction of cannabinoid behavioural sensitization. In sensitized rats, autoradiographic binding studies with [3H]CP-55,940 showed a significant increase in cannabinoid receptor binding, specifically in the cerebellum, with no changes in the other brain areas where basal CB1-receptor expression is observed. In vitro autoradiography of CP-55,940-stimulated [35S]GTP gamma S binding provided a picture of cannabinoid receptor-mediated G protein activation. Basal [35S]GTP gamma S binding was not affected, whereas sensitized rats showed a significant increase of net [35S]GTP gamma S binding in the caudate putamen and cerebellum. Autoradiographic studies suggested that only these two areas had altered receptor functionality. We therefore focused our intracellular investigations only there, first surveying the responsiveness of the cAMP system to cannabinoids. CP-55,940 was unable to inhibit forskolin-induced cAMP accumulation in the cerebellum of sensitized animals, but no difference was observed between groups in the caudate putamen. Finally, we surveyed the levels of CREB and AP-1 binding activity, in the same two areas and found no difference in sensitized rats. The intracellular picture in sensitized rats suggests that besides the cAMP cascade, other signalling pathways may participate in the development of cannabinoid sensitization. 相似文献
132.
Chiou WL 《Journal of pharmacokinetics and pharmacodynamics》2001,28(1):3-6
In the literature, the meanings of the terms oral absorption and oral bioavailability of drugs vary greatly. Absorption has been considered to take place at the mucosal membrane of the gastrointestinal (GI) tract. It has also been defined as the process from the site of drug administration to the site of measurement. In the latter definition, the extent of oral absorption depends on the extent of first-pass elimination in the gut wall and liver even though a drug may be completely absorbed from the GI tract. Moreover, these two terms have also been used interchangeably. Inconsistency in the definition of these two terms has led to varying interpretations of these terms among students, researchers and laymen, and such an inconsistency seems undesirable. Apparently because of these inconsistencies, improper correlations between the Caco-2 permeability or intestinal permeability and the oral bioavailability of drugs subject to extensive first-pass effect may have occurred. It is suggested that absorption be defined as movement of drug across the outer mucosal membranes of the GI tract, while bioavailability be defined as availability of drug to the general circulation or site of pharmacological actions. Since transit times (this may range from about 1 min to several hours) across enterocytes, liver, lungs, and the peripheral venous sampling tissue are virtually unknown for all drugs, this factor alone would favor the use of oral bioavailability rate rather than oral absorption rate in all routine studies. 相似文献
133.
Tsukamoto Y Kato Y Ura M Horii I Ishitsuka H Kusuhara H Sugiyama Y 《Pharmaceutical research》2001,18(8):1190-1202
Purpose. To identify the factors governing the dose-limiting toxicity in the gastrointestine (GI) and the antitumor activity after oral administration of capecitabine, a triple prodrug of 5-FU, in humans.
Method. The enzyme kinetic parameters for each of the four enzymes involved in the activation of capecitabine to 5-FU and its elimination were measured experimentally in vitro to construct a physiologically based pharmacokinetic model. Sensitivity analysis for each parameter was performed to identify the parameters affecting tissue 5-FU concentrations.
Results. The sensitivity analysis demonstrated that (i) the dihydropyrimidine dehydrogenase (DPD) activity in the liver largely determines the 5-FU AUC in the systemic circulation, (ii) the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (dThdPase) and DPD in the tumor tissues, as well as the blood flow rate in tumor tissues with saturation of DPD activity resulting in 5-FU accumulation, and (iii) the metabolic enzyme activity in the GI and the DPD activity in liver are the major determinants influencing exposure to 5-FU in the GI. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other 5-FU-related anticancer agents, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges.
Conclusions. It was revealed that the most important factors that determine the selective production of 5-FU in tumor tissue after capecitabine administration are tumor-specific activation by dThdPase, the nonlinear elimination of 5-FU by DPD in tumor tissue, and the blood flow rate in tumors. 相似文献
134.
公立医院持续健康发展的重要一环就是科学把握积累与分配的关系。公立医院需要通过积累扩大再生产,但同样需要按生产要素进行合理分配。积累与分配比例应为业务收支结余(不含人员经费和修购基金)的4∶6,潍坊市的做法为这一"黄金分割"提供了实证。 相似文献
135.
目的结合新近发现的冠心病危险因素,总结青年人急性心肌梗死(AMI)的临床特点,探讨早发AMI的可能机制。方法回顾性对照分析青年组(≤40岁,37例)和中老年组(≥50岁, 105例)两组AMI患者与非冠心病患者的危险因素和促发因素的暴露率,并行冠脉造影检查。结果两组AMI患者危险因素分布存在差异,青年组表现为吸烟、血脂异常、家族史、C反应蛋白(CRP)、血浆纤维蛋白原(Fig)暴露率明显增多,中老年组为高血压、吸烟、血脂异常、糖尿病、CRP、Fig、同型半胱氨酸(P<0.05);青年组危险因素聚集率并不比中老年组高,但其发生AMI前多有明确的促发因素,且促发因素有聚集倾向,促发因素聚集与青年人AMI的发生存在明显剂量反应关系。结论青年人早发AMI可能与促发因素聚集有关,多种促发因素同时存在通过心肌缺血叠加效应导致动脉粥样硬化(As)患者和非As患者发生AMI。 相似文献
136.
采用体内药物累积法测定小鼠 ip 白血康后的体内过程和药动学参数,白血康在小鼠体内的过程符合二室开放模型,模型方程为:体存率%=87.1711e~(-1.0952t) 138.1771e~(-0.0272t),t_(1/2)α=0.6328h,t_1/2β=25.48h,k_(21):0.6821h~(-1),k_(12)=0.3966h~(-1),k_(10)=0.0437h~(-1),Vc=3.55L/kg. 相似文献
137.
We investigated the effect of vinconate on ischemia-induced calcium accumulation in the gerbil brain. The animals were allowed to survive for 7 days after 10 min of ischemia. Abnormal calcium accumulation was evaluated in the gerbil brain after ischemia. Following 10 min ischemia, abnormal calcium accumulation was found in the neocortex, the striatum, the hippocampus, the thalamus, the substantia nigra and the inferior colliculus. Intraperitoneal administration of vinconate (100 mg/kg) immediately after 10 min of ischemia significantly reduced the areas of abnormal calcium accumulation only in the striatum. However, the application of vinconate (100 and 300 mg/kg) 10 min before ischemia dose-dependently decreased the areas of abnormal calcium accumulation in the striatum, the thalamus and the substantia nigra. Morphological observation revealed neuronal damage in the identical sites of the abnormal calcium accumulation. Furthermore, a autoradiographic study using 14C-vinconate showed that this drug easily penetrates the blood-brain barrier and especially localizes in the striatum and the thalamus after 5 min ischemia. The result suggests that vinconate reduces the areas of abnormal calcium accumulation in the postischemic gerbil brain. This effect seems to be mediated via the height distribution in the brain following ischemia. 相似文献
138.
老年迟发性硬膜下积液的CT分析 总被引:1,自引:0,他引:1
目的 探讨老年迟发性硬膜下积液CT表现。方法 回顾性分析28例老年迟发性硬膜下积液的CT资料。结果 15例表现为颅骨内板下新月型水样密度影,8例表现为大脑镰旁弧型水样密度影,5例上述两种类型均有表现。属单纯性硬膜下积液15例,临床症状轻;复合型硬膜下积液13例,临床症状多样。结论 老年迟发性硬膜下积液的CT表现有其特征性,结合病史及病程可作出正确诊断。 相似文献
139.
几种不同钙化合物对大鼠铝、铅代谢的影响 总被引:2,自引:0,他引:2
目的 : 观察不同钙化合物对大鼠铝、铅代谢的影响。方法 : 将幼年 Sprague-Dawley大鼠 3 0只 (雌雄性各半 ) ,分成柠檬酸钙 +铝 +铅组、醋酸钙 +铝 +铅组和碳酸钙 +铝 +铅组等三组。各组动物分别用不同形式的钙化合物通过灌胃给予等剂量钙元素 ,共四周。实验结束后 ,用电感耦合等离子体原子发射光谱法 (ICP-AES)分别测定全血、肝、肾、股骨和大脑中铝和铅的含量。结果 : (1 )大鼠摄入醋酸钙和柠檬酸钙后对铅的表观吸收率高于碳酸钙组的大鼠。 (2 )摄入柠檬酸钙和醋酸钙的大鼠的组织中铝和铅水平高于摄入碳酸钙的大鼠 ,且大脑和骨骼中尤为明显。结论 : (1 )长期摄入柠檬酸钙和醋酸钙有增加铅吸收的危险 ,并可使铅和铝蓄积在骨骼和大脑。(2 )碳酸钙可能比柠檬酸钙和醋酸钙更有利于铝从肾排出。 相似文献
140.
Selective neuronal vulnerability following transient cerebral ischemia in the gerbil: distribution and time course 总被引:4,自引:0,他引:4
An important feature of ischemic brain damage is the selective vulnerability of specific neuronal populations. We studied the distribution and time course of neuronal damage following transient cerebral ischemia in the gerbil, using light microscopy and 45Ca autoradiography. Following 5 min of ischemia, selective neuronal damage determined by abnormal 45Ca accumulation was recognized only in the hippocampal CA1 subfield and part of the inferior colliculus. Ischemia for 10 to 15 min caused extensive neuronal injury in the 3rd and 5th layers of neocortex, the striatum, the septum, the whole hippocampus, the thalamus, the medial geniculate body, the substantia nigra, and the inferior colliculus. Progression of the damage was rapid in the medial geniculate body and the inferior colliculus, moderate in the neocortex, striatum, septum, thalamus, and the substantia nigra, and was delayed in the hippocampal CA1 sector. However, the delayed damage of the hippocampus occurred earlier when the ischemia period was prolonged. Histological observation revealed neuronal loss in the identical sites of the 45Ca accumulation. This study revealed that the distribution and time course of selective neuronal damage by ischemia proceeded with different order of susceptibility and different speed of progression. 相似文献