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1.
G. G. C. Hwa M. Avoli A. Oliver J. G. Villemure 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1991,83(2):329-339
Summary Intracellular and extracellular recordings were made from human neocortical slices of the temporal lobe maintained in vitro. The slices were treated with bicuculline methiodide to reduce synaptic inhibition mediated by tha gamma-aminobutyric acid A (GABAA) receptor. Spontaneously occurring epileptiform activity was never observed in over 60 slices examined. All epileptiform discharges were elicited by single-shock stimuli delivered in the underlying white matter or within the cortical layers. Intracellularly, the stimulus-induced epileptiform discharge resembled the paroxysmal depolarization shift (PDS). This potential was observed in neurons located between 200 and 2200 m from the pia. It was characterized by a 100–1800 ms long depolarization which triggered burst firing of action potentials, and was at times followed by an afterdischarge. Simultaneous intracellular and extracellular recordings showed that each PDS was reflected by the synchronous discharge of a neuronal aggregate. The voltage behaviour of the PDS and its preceding EPSP was analyzed in cells that were injected with the lidocaine derivative QX-314. The amplitudes of the PDS depolarizing envelope measured at its peak and during its falling phase both behaved as a monotonic function of the membrane potential by increasing in amplitude during hyperpolarization. In addition, the PDS peak amplitude showed a much greater rate of increase than the early EPSP peak amplitude, thus suggesting that the synaptic conductance underlying the PDS was much greater. Perfusion of the neocortical slices with the N-Methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-phosphonovaleric acid (APV) reduced both the duration and the amplitude of the paroxysmal field discharge in a dose related fashion. The effects of APV were reflected intracellularly by an attenuation of the PDS's late phase and a blockade of the afterdischarge. Similar findings were also obtained by using the NMDA receptor antagonist 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid. These data indicate that reduction or blockade of the GABAA receptor is sufficient to elicit epileptiform discharges in the human neocortex maintained in vitro. Mechanisms dependent upon the NMDA receptor contribute to this type of epileptiform response mainly by prolonging the stimulus-induced depolarizing potential and the associated burst of firing. 相似文献
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《Journal of pharmaceutical sciences》2021,110(9):3118-3128
Nitrosamine-contaminated medicinal products have raised safety concerns towards the use of various drugs, not only valsartan and all tetrazole-containing angiotensin II receptor blockers, but also ranitidine, metformin, and other medicines, many of which have been recalled and prone to shortage. At any stages, from drug substance synthesis throughout each product's lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions. Consequently, drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products in the market. This review encompasses various critical elements contributing to successful control measures against current and upcoming nitrosamine issues, ranging from accumulated knowledge of their toxicity concerns and potential root causes, precise risk evaluation, as well as suitable analytical techniques with sufficient sensitivity for impurity determination. With all these tools equipped, the impact of nitrosamine contamination in pharmaceuticals should be mitigated. An evaluation aid to tackle challenges in risk identification, as well as suitable industry-friendly analytical techniques to determine nitrosamines and other mutagenic impurities, are among unmet needs that will significantly simplify the risk assessment process. 相似文献
4.
目的:研究大鼠耳蜗螺旋神经节神经元A型γ-氨基丁酸受体(Gamma-aminobutyric acid receptor GABAAR)和N—甲基—D—天门冬氨酸受体(N-methyl D-aspartat receptor,NMDAR)亚单位的表达及意义。
方法:原代培养大鼠螺旋神经节神经元,采用RT-PCR检测大鼠螺旋神经节神经元GABAAR和NMDAR亚单位的mRNA表达。
结果:大鼠螺旋神经节神经元mRNA表达GABAAR亚单位有α1-6,β1-3,γ1-3,且在α亚单位族中, α1,α3表达较高,差别无统计学意义(P>0.05), α1,α3的表达量与其余亚单位表达量以及其余GABAAR亚单位之间表达量的差异有统计学意义(P<0.05),各亚单位表达量大小排列顺序是:α1/α3>α6>α5>α4>α2。β亚单位族中,β亚单位族中各亚单位表达量两两比较差异有统计学意义,表达量排列顺序β1>β3>β2(P<0.05);γ亚单位族中各亚单位表达量两两比较差别有统计学意义(P<0.05),表达量排列顺序是γ2>γ1>γ3;NMDAR表达的亚单位有NR1,NR2A,NR2B,NR2C,NR2D,NR3A,NR3B,其中NR1亚单位的表达最高(P<0.05)。
结论:大鼠螺旋节神经元mRNA上表达GABAAR的主要亚单位α1-6,β1-3,γ1-3和NMDAR NR1,NR2-D,NR3A-B亚单位. 相似文献
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Facilitation and Feedback in the Hypothalamo-Pituitary-Adrenal Axis during Food Restriction in Rats 总被引:1,自引:0,他引:1
Sylvia Garcia-Belenguer Charles Oliver‡ Pierre Morméde† 《Journal of neuroendocrinology》1993,5(6):663-668
After 4 weeks of food restriction to 50% of ad libitum intake in rats, plasma corticosterone levels were increased, without any change in adrenal weight, and with no evidence of sympathetic nervous system activation (as measured by Tyrosine Hydroxylase and Phenylethanolamine N-Methyl Transferase activities in the adrenal gland). Plasma corticosterone levels were normalized with the addition of 35% of the calories as sugar. The adrenocortical axis activity was therefore investigated in more detail (nycthemeral cycle of corticosterone levels, ACTH and corticosterone response to a CRF challenge) in ad libitum fed rats and in animals fed 85% or 50% of the intake of the control animals, just before switching the lights off in order to maintain the diurnal rhythm of food intake. Food restriction to 85% did not change mean plasma corticosterone levels but sharpened the peak of corticosterone measured in the evening, indicating that the adrenocortical axis is more sensitive to the endogenous signals responsible for its diurnal cycle of activity. Indeed, the ACTH response to CRF was also increased. A 50% food restriction regimen increased mean corticosterone levels and attenuated the day/night difference, with high corticosterone levels maintained throughout the day. However, the ACTH response to CRF was not different from that measured in ad libitum fed rats, but the corticosterone response was lower, confirming that the adrenal gland is hyposensitive to ACTH. The results are discussed in terms of the balance between inhibiting/activating mechanisms and endocrine/neural influences at each level of the hypothalamo-hypophyso-adrenal axis, depending on the level of food deprivation. 相似文献
7.
IQ23 对豚鼠心室肌细胞钙通道和CHO H10细胞异源表达的钙通道α1亚单位的作用 总被引:1,自引:0,他引:1
应用膜片钳全细胞记录技术, 观察了具有正性肌力作用的苄基异喹啉衍化物IQ23,即1-〔对甲氧苄基-2-(N-苄基, N-甲基)〕-6,7-二甲氧基异喹啉盐酸盐,对豚鼠心室肌分离细胞的Ca2+通道, 以及CHO H10细胞表达的Ca2+通道α1亚单位的作用. 结果显示, 当豚鼠心室肌细胞从保持电位(Vh)-50 mV除极至测试电位(Vt)0 mV时, IQ23 3, 10 μmol·L-1分别使Ca2+电流(ICa)由对照的(0.47±0.23) nA增至(0.57±0.23)和(0.79±0.31) nA (P<0.05). 在CHO H10细胞Vt 为20 mV时, IQ23 10 μmol·L-1电压依赖性的增强Ba2+电流(IBa), IBa从(0.45±0.10) nA增至(0.67±0.20) nA (Vh=-80 mV), 或从(0.43±0.08) nA增至(0.60±0.14) nA (Vh=-40 mV). IQ23 10和30 μmol·L-1还分别使电流-电压曲线的峰值和失活曲线的半失活电位向负膜电位方向移动. 实验结果表明, IQ23通过作用于通道的α1亚单位, 对心肌L型Ca2+通道产生电压依赖性激动作用, 此作用为其正性肌力效应提供了部分解释. 相似文献
8.
Asymmetry in D-2 binding in female rat striata 总被引:1,自引:0,他引:1
An asymmetry in D-2 receptor densities (Bmax) measured by [3H]N-methyl spiperone binding was found in striata from female Sprague-Dawley rats. The D-2 Bmax on the right side was on average 40% greater than the D-2 Bmax on the left side. This asymmetry is greater in magnitude and opposite in direction to that reported for males and is independent of directional preference exhibited during nocturnal circling. 相似文献
9.
In the present study, Memantine (MN) an uncompetitive N-methyl-d-aspartate (NMDA) open channel blocker has been investigated for its suitable therapeutic time-window on the basis of its influence on behavioural and biochemical changes in rats subjected to transient focal ischemia. MN (20 mg/kg, ip) was administered at pre, during and post ischemic state and the extent of neuroprotection was compared to ascertain its therapeutic time-window in stroke treatment. Neuroprotective effect was assessed by measuring glutamate, glutamine synthetase, glutathione, Na+K+ATPase, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD), lactate and pyruvate levels. Middle cerebral artery occlusion produced neurological deficits, anxiogenic behaviour, histological changes, increased glutamate levels along with depletion of Na+K+ATPase, energy stores such as ATP, NAD, lactate, and antioxidant glutathione. MN significantly restored glutamate, glutamine synthetase, Na+K+ATPase and lactate levels on preischemic administration. In addition, MN reversed the altered neurological and behavioural paradigms significantly and prevented the neurodegeneration on preischemic treatment. However, it failed to exert any effect on energy metabolite (ATP and NAD) levels irrespective of the treatment phase. Based on the present data, it is summarized that the suitable therapeutic time window of MN is preischemic phase in stroke and it possesses only a subjective role in reversing ischemic brain biochemical alterations preferentially in favor of neuronal homeostasis. 相似文献
10.
Donovan BT Bakshi T Galbraith SE Nixon CJ Payne LA Martens SF 《Journal of pharmacological and toxicological methods》2011,64(3):269-276