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81.
Interactions between imidazoline compounds and sulphonylureas in the regulation of insulin secretion
Mirna Mourtada Colin A Brown Stephen A Smith Valerie Piercy Susan L F Chan Noel G Morgan 《British journal of pharmacology》1997,121(4):799-805
- Imidazoline α2-antagonist drugs such as efaroxan have been shown to increase the insulin secretory response to sulphonylureas from rat pancreatic B-cells. We have investigated whether this reflects binding to an islet imidazoline receptor or whether α2-adrenoceptor antagonism is involved.
- Administration of (±)-efaroxan or glibenclamide to Wistar rats was associated with a transient increase in plasma insulin. When both drugs were administered together, the resultant increase in insulin levels was much greater than that obtained with either drug alone.
- Use of the resolved enantiomers of efaroxan revealed that the ability of the compound to enhance the insulin secretory response to glibenclamide resided only in the α2-selective-(+)-enantiomer; the imidazoline receptor-selective-(−)-enantiomer was ineffective.
- In vitro, (+)-efaroxan increased the insulin secretory response to glibenclamide in rat freshly isolated and cultured islets of Langerhans, whereas (−)-efaroxan was inactive. By contrast, (+)-efaroxan did not potentiate glucose-induced insulin secretion but (−)-efaroxan induced a marked increase in insulin secretion from islets incubated in the presence of 6 mM glucose.
- Incubation of rat islets under conditions designed to minimize the extent of α2-adrenoceptor signalling (by receptor blockade with phenoxybenzamine; receptor down-regulation or treatment with pertussis toxin) abolished the capacity of (+)-and (±)-efaroxan to enhance the insulin secretory response to glibenclamide. However, these manoeuvres did not alter the ability of (±)-efaroxan to potentiate glucose-induced insulin secretion.
- The results indicate that the enantiomers of efaroxan exert differential effects on insulin secretion which may result from binding to effector sites having opposite stereoselectivity. Binding of (−)-efaroxan (presumably to imidazoline receptors) results in potentiation of glucose-induced insulin secretion, whereas interaction of (+)-efaroxan with a second site leads to selective enhancement of sulphonylurea-induced insulin release.
82.
In this review the state of the art of treating patients with epilepsy in the nineties in the Netherlands is presented. It describes general strategies for treatment with antiepileptic drugs and the history of development of the classical anticonvulsant drugs. Eight new drugs, including vigabatrin, lamotrigine, felbamate, oxcarbazepine, gabapentin, tiagabine, levetiracetam and topiramate are discussed. A review of their pharmacological and clinical properties is presented. Dutch experience with these drugs is included. 相似文献
83.
论述了中药材“地区习惯用药”的由来与含义,近现代和历史上的“地区习惯用药”的实例以及产生“地区习惯用药”的原因,随品种性质判明而渐趋分化等。最后提出应该积极研究,促其分化,按其本质分类处理的建议。 相似文献
84.
Electrophysiological effects of dridocainide on isolated canine,guinea-pig and human cardiac tissues
C. Pankucsi P. P. Nánási M. Hegedüs A. Kovács G. Szénási K. Szemerédi 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(5):520-528
The cellular electrophysiological effects of dridocainide (EGIS-3966), a novel class I antiarrhythmic agent, was studied using conventional microelectrode techniques in canine cardiac Purkinje fibres and papillary muscle preparations obtained from humans and guinea-pigs. In each preparation, dridocainide (0.6–2 mol/l) decreased the maximum velocity of action potential upstroke (Vmax) in a frequency-dependent manner, although marked differences were observed in its effects in Purkinje fibre and ventricular muscle preparations. In canine Purkinje fibres, action potential duration measured at 50% and 90% of repolarization was decreased, while action potential duration measured at 10% of repolarization was increased by dridocainide. In addition, the plateau of the action potential was depressed by the drug. These changes in action potential configuration were not observed in guinea pig or human papillary muscles. The offset kinetics of the dridocainide-induced V
max block were different in Purkinje fibres and in ventricular muscle: the slow time constant of recovery of V
max was estimated to be 2.5 s in dog Purkinje fibre and 5–6 s in human and guinea-pig papillary muscle. In guinea-pig papillary muscle, the rate of onset of the V
max block was 0.15 and 0.2 per action potential in the presence of 0.6 and 2 mol/l dridocainide, respectively. Dridocainide also decreased the force of contraction in this preparation. On the basis of the present results, dridocainide appears to posess mixed class LC and LA properties, with LC predominance in human and guinea-pig ventricular muscle. Present results also indicate that results of conventional classification of class I drugs may depend on the parameters chosen, as well as on the preparation selected. 相似文献
85.
Hellawell K 《Drug and alcohol review》1995,14(3):317-322
Illicit drugs have become a major global problem in recent decades following considerable recent political change, including the collapse of communism and the formation of international super-states to increase trade. Despite increasing collaboration between law enforcement authorities in different countries, illicit drug problems appear likely to increase in the future because of the vast profits available, continuing (and increasing) demand and more permissive attitudes concerning drugs among young people. While rejecting legalization or decriminalization, the search for more effective responses by law enforcement authorities and the community generally must be stepped up. Police services continue to play an important role restricting the availability of illicit drugs but increasing emphasis needs to be given to reducing demand, including more available and more effective preventive drug education in schools. Police also need to work with harm reduction approaches devised to reduce the negative consequences of drug use for those who continue to use illicit drugs. New measures proposed in Britain are outlined. These stress the importance of a multi-sectoral approach operating at both national and local levels with the objective of reducing drug-related crime, reducing the acceptability and availability of illicit drugs and reducing the harmful consequences of illicit drug use. Harm reduction requires a commitment for close collaboration between police and drug treatment services to maximize the effectiveness of needle-exchange schemes and other harm reduction approaches. Cautioning, now commonly used in Britain for selected minor drug offences, has a number of benefits including reducing criminal justice costs. Greater emphasis must be placed on diversion schemes involving close links between police and drug treatment services. Future progress requires firm commitments to providing adequate and effective drug treatment services, conducting research to develop and evaluate more effective diversion schemes, improving collaboration between sectors and effective leadership. In addition to the major costs of illicit drug use to the community, the huge cost to individuals must remain a major focus driving the search for more effective responses to the problems resulting from illicit drugs. 相似文献
86.
Harm reduction in the developing world 总被引:1,自引:0,他引:1
Samarasinghe D 《Drug and alcohol review》1995,14(3):305-309
This paper examines harm reduction from the perspective of poor countries. In considering which elements of the broad approach are suitable for adaptation and adoption by poor countries, there is a need to examine critically the arguments put forth in support of it and which, if any, of these are supported by evidence. There are also significant indirect influences that the approach is likely to have on how drug use is understood and interpreted by wider society. The likely impact of these on areas other than simply services directed to drug users needs to be assessed. There are some features regarding harm caused by alcohol and other drug use that are specific to poor countries. Most important among these is that levels of use which are not deemed to be harmful in rich societies cause grave harm through diverting meagre resources away from survival needs in the poor world. Alcohol, as well as other drugs, tends in deprived settings to cause dependence and other problems much earlier in people's drinking careers and at much lower levels of consumption than in rich countries. 相似文献
87.
A new type of ultra-short acting -blocker which might prove advantageous in treating acute arrhythmias was designed, synthesized and investigated. Based on the soft drug inactive metabolite approach, the inactive phenylacetic acid metabolite of both metoprolol and atenolol was reactivated by esterification with sulfur-containing aliphatic alcohols. Since the sulfur-containing moieties are labile to the ubiquitous esterases, the new compounds should be inactivated by a one step enzymatic cleavage back to the inactive phenylacetic acid derivative. Pharmacological and pharmacokinetic profiles of the new compounds were evaluated in rats and rabbits. Isoproterenol-induced tachycardia was inhibited with short-term infusion of each compound. This tachycardia blocking effect rapidly disappeared upon termination of infusion, while -blocking activity was 2–4-fold longer after comparable doses of the short-acting -blocker, esmolol. The rapid recovery from the -receptor blockade is believed due to fast hydrolysis of the soft drugs in the body. This is supported from in vitro results showing the tl/2 of esmolol is about 10-fold longer than the new soft drugs in rat, rabbit, dog and human blood. Hydrolysis studies in phosphate buffered solutions indicated that the esters are labile to base-catalyzed hydrolysis. However, the relative t1/2 values measured in biological media compared to phosphate buffered solution clearly support rapid enzymatic cleavage of the soft drugs. Interestingly, one of the soft -blockers, the sulfonyl ester derivative, showed a unique property of exhibiting good -receptor blocking activity without significant hypotensive action. 相似文献
88.
徐倍倍 《新疆医科大学学报》1999,22(4):285-287
目的:观察中药配合低能量氦-氖激光血管内照射为主治疗缺血性中风疗效。方法:治疗组:用中药配合低量氦-氖激光血管内照射为主治疗缺血性中风69例;对照组:用降纤酶、尼莫通治疗缺血性中风42 例。结果:治疗组基本痊愈48 例,显效8例,有效7例,无效5 例,恶化1 例,有效率为91.30% 。对照组基本痊愈20例,显效1例,有效9 例,无效11 例,恶化1例,有效率为71.43% 。经χ2 检验,χ2= 7.6,Ρ< 0.01,有显著差异。结论:治疗组中药配合低能量氦-氖激光血管内照射为主治疗缺血性中风综合疗效明显优于对照组用降纤酶和尼莫通治疗缺血性中风 相似文献
89.
RATIONALE AND OBJECTIVES: The authors evaluated the cardiac tolerability of paramagnetic contrast agents for magnetic resonance (MR) angiography in an in vitro model of ischemic rat heart. MATERIALS AND METHODS: The left anterior descending coronary artery was temporarily occluded in a perfused rat heart model to induce cardiac ischemia and reperfusion. A dose of 0.4 mL of gadobenate dimeglumine, of gadopentetate dimeglumine, or of D-mannitol was injected directly into the aorta both during the ischemia and during the reperfusion period. The left ventricular pressure and heart rate were recorded. RESULTS: Myocardial ischemia resulted in decreased cardiac activity, with a reduction in left ventricular pressure and heart rate. A further decrease in cardiac activity was temporarily induced by injection of contrast medium during both the ischemic and early reperfusion phases. Less marked responses were induced by a hyperosmolal solution of mannitol. CONCLUSION: These results suggest that the transient cardiac effects induced by bolus injection of paramagnetic contrast medium may be regarded as the combined effects of the osmotoxicity of the contrast medium solution and the chemotoxicity of the contrast medium molecule. 相似文献
90.
Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis 总被引:8,自引:4,他引:4
PURPOSE: To determine the modulation of sodium currents in hippocampal CA1 neurons by carbamazepine (CBZ) and valproate (VPA), before and after kindling epileptogenesis. METHODS: Voltage-dependent sodium current was measured in isolated hippocampal CA1 neurons, by using the whole-cell voltage-clamp technique. CBZ (15-100 microM) or VPA (0.5-5 mM) was applied by bath perfusion. Cells from fully kindled rats were compared with controls, 1 day and 5 weeks after the tenth generalized seizure. RESULTS: CBZ did not affect sodium current activation but selectively shifted the voltage dependence of steady-state inactivation to more hyperpolarized potentials. One day after the last kindled generalized seizure, the shift induced by 15 microM CBZ was 2.1+/-0.5 mV (mean +/- SEM; n = 20) compared with 4.3+/-0.3 mV (n = 16; p<0.001) in matched controls. The EC50 of the concentration-effect relation was 57+/-6 microM compared with 34+/-2 microM (p<0.01) in controls. Five weeks after kindling, these values had recovered to a level not different from control. VPA induces at a relatively high concentration a similar but smaller shift in voltage dependence of inactivation than does CBZ. After kindling, the shift induced by 2 mM VPA (2.8+/-0.6 mV; n = 19) was not different from controls (3.0+/-0.5 mV; n = 22). The EC50 for VPA was 2.6+/-0.3 mM compared with 2.5+/-0.4 mM in controls. CONCLUSIONS: Both CBZ and VPA selectively modulate the voltage dependence of sodium current steady-state inactivation and as a consequence reduce cellular excitability. The effect of CBZ was reduced immediately after kindling epileptogenesis, apparently by a reduced affinity of its receptor. In contrast, the shift induced by VPA was not different at any stage after kindling epileptogenesis. The change in CBZ sensitivity after kindling is related to epileptic activity rather than to the epileptic state, because it almost completely recovers in a period without seizures. 相似文献