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991.
Martin C. Michel Gertraud Hanft Gerhard Gross 《Naunyn-Schmiedeberg's archives of pharmacology》1990,341(4):385-387
Summary We used novel highly subtype-selective antagonists to study whether 1A- and/or 1B-adrenoceptors mediate the stimulation of inositol phosphate generation by noradrenaline in rat cerebral cortex. Phentolamine (10 M) and prazosin (100 nM) completely abolished the stimulated inositol phosphate generation. The 1A-selective antagonists 5-methyl-urapidil (100 nM) and (+)– and (–)-niguldipine (10 nM) caused only weak inhibition or none at all although these concentrations occupied 1A-adrenoceptors almost completely. In contrast, pretreatment with the irreversible 1B-selective chloroethylclonidine reduced the noradrenaline-stimulated inositol phosphate generation by 76 ± 8%. These data demonstrate that 1B-adrenoceptors couple to inositol phosphate generation; the signal transduction system of 1A-adrenoceptors remains unclear.
Send offprint requests to G. Gross at the above address 相似文献
992.
Allan M. Lefer Nobuo Aoki Donna Mulloy 《Naunyn-Schmiedeberg's archives of pharmacology》1990,341(3):246-250
Summary Defibrotide is known to enhance prostacyclin (PGI2) release from the vascular endothelium. We investigated the vasoactive effects of defibrotide in isolated rat hearts perfused at constant flow subjected to ischaemia and reperfusion. Defibrotide at 10–7 or 100 g/ml did not exert any direct vasoactive effect on normal rats hearts. However, ischaemia and reperfusion resulted in an impaired vasodilation to acetylcholine, an endothelium-dependent vasodilator. In contrast, the vasodilator response to the endothelium-independent dilator, nitroglycerin, was unaffected. Defibrotide, at 10–7 or 100 g/ml, markedly restored the vasodilation to acetylcholine 10–7 nmol/l to 1 mol/l (P < 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 g/1). Haemoglobin (150 nmol/l) inhibited the dilation to acetylcholine in response to defibrotide. However, no evidence of (PGI2) release was observed with acetylcholine-induced vasodilation in the presence or absence of defibrotide. Additionally, 10–100 g/ml of defibrotide did not significantly decrease superoxide radicals generated by a xanthine-xanthine oxidase synthetic system under conditions in which superoxide dismutase was effective. Thus, defibrotide appears to exert an endothelium-protective effect preserving endothelium-derived relaxing factor (EDRF) without directly scavenging free signals.Supported in part by Research Grant No. HL-25575 from the National Heart, Lung and Blood Institute of the NIH
Send offprint requests to A. M. Lefer at the above address 相似文献
993.
Summary Uridine 5-triphosphate- (UTP-) and adenosine 5-triphosphate-(ATP) induced vasoconstriction was studied in the rabbit basilar artery. The arteries were incubated and perfused at a constant rate of flow. Vasoconstriction was measured as an increase in perfusion pressure.Serotonin, histamine and noradrenaline caused concentration-dependent vasoconstriction, with potency decreasing in that order. Of the nucleotides tested, UTP, UDP, UMP, CTP, ATP, ADP, adenosine 5-O-(3-thio)triphosphate (ATPS), and ,-imido adenosine 5-triphosphate (AMP-PNP) elicited concentration-dependent vasoconstriction, whereas AMP, 2-methylthio-ATP, , -methylene-ATP and ,-methylene-ATP up to 10–3 mol/l caused no or only a very small increase in perfusion pressure. The order of potency of the pyrimidine nucleotides was: UTP = UDP UMP = CTP; that of the purine nucleotides was: ATPS > AMP-PNP > ATP > ADP > 2-methylthio-ATP = , -methylene-ATP = ,-methylene-ATP. The vasoconstrictor effects of UTP and ATP were not or only to a minor degree influenced by: phentolamine; a mixture of atropine, diphenhydramine and methysergide; indometacin; nordihydroguaiaretic acid; denervation by 6-hydroxydopamine; or mechanical removal of endothelium. Prolonged exposure to ,-methylene-ATP elicited only a very small vasoconstriction and did not change the constrictor effects of UTP or ATP. Prolonged exposure to ATPS elicited marked vasoconstriction; subsequently, responses to ATP were reduced whereas those to UTP were, if anything, slightly enhanced. Reactive blue 2 reduced neither the UTP- nor the ATP-induced vasoconstriction. ATP 10–3 mol/l elicited marked additional vasoconstriction after precontraction with UTP 10–3 mol/l, whereas UTP elicited only a very small additional vasoconstriction when its concentration was doubled from 10–3 to 2 × 10–3 mol/l.It is concluded that, in the rabbit basilar artery, the vasoconstrictor response to UTP is mediated by a pyrimidine nucleotide receptor which is distinct from the P2-purinoceptor, and that the vasoconstrictor response to ATP is mediated by a P2-receptor which is distinct from the known P2-subtypes.Send offprint requests to I. v. Kügelgen at the above address 相似文献
994.
R. R. Ruffolo C. F. Sauermelch R. N. Willette 《European journal of clinical pharmacology》1990,38(Z2):S112-S114
The effects of labetalol and carvedilol on local cutaneous microvascular perfusion and calculated local cutaneous microvascular resistance were investigated in anesthetized rats at submaximal doses that produced equivalent reductions in blood pressure and heart rate. Labetalol decreased cutaneous perfusion (– 25% ± 3%) without significantly affecting cutaneous vascular resistance ( – 6% ± 3%). In marked contrast, carvedilol dramatically increased cutaneous perfusion ( + 64% ± 9%) and significantly reduced cutaneous vascular resistance ( – 57% ± 3%). These results suggest that carvedilol and labetalol possess differences in the mechanisms by which they produce vasodilation in vivo. 相似文献
995.
H. Okuno Y. Kitao M. Takasu H. Kano K. Kunieda T. Seki Y. Shiozaki Y. Sameshima 《European journal of clinical pharmacology》1990,39(4):365-367
Summary The depressant effect of interferon- on drug metabolizing activity in the liver has been investigated in 12 patients with chronic active hepatitis B. 7-methoxy-coumarin (7-MC) O-demethylase and 7-ethoxycoumarin (7-EC) O-deethylase, in specimens obtained by liver biopsy, were measured before and after interferon treatment. 7-MC and 7-EC O-dealkylase activity were significantly reduced after interferon treatment, from 13.4 to 9.24 nmol·g–1 liver·min–1, and from 3.22 to 2.16 nmol·g–1 liver·min–1, respectively. The magnitude of the fall varied widely between individual patients. The study provides the first direct evidence that interferon- can impair the activity of drug metabolizing enzymes in the human liver. 相似文献
996.
We studied central mechanisms of antidepressants that affect feeding behavior in rats. The tricyclic compounds amitriptyline, doxepin and imipramine significantly induced feeding after their infusion into the third cerebral ventricle in the light phase, but the tricyclic, desipramine, and the dicyclic zimelidine, did not. Drinking was not affected by any compound tested. The relative order of potency in eliciting feeding was: amitriptyline and doxepin > imipramine > desipramine and zimelidine. To clarify the involvement of neuronal histamine in antidepressant-induced feeding, alpha-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase, was intraperitoneally administered before infusion of amitriptyline. FMH attenuated the amitriptyline's effect. Bilateral microinfusion of amitriptyline into the ventromedial hypothalamus or the paraventricular nucleus verified that these are loci for the modulation of feeding by amitriptyline. In the lateral hypothalamus, amitriptyline was less effective. These findings indicate that tricyclic antidepressants directly facilitate feeding, which is, at least in part, mediated by histamine in the hypothalamus. 相似文献
997.
The present experiments investigated changes in -adrenoceptor binding and noradrenaline stores in mouse cerebral cortex after single treatments with drugs which bind to the GABAA receptor but which attenuate the actions of GABA. Neither the GABA antagonist, securinine, nor the picrotoxin/Cl– channel ligand, picrotoxin, affected noradrenaline levels or -adrenoceptor binding. However, both the benzodiazepine inverse agonist, DMCM, and pentylenetetrazole increased noradrenaline levels 24 h after injection. Only pentylenetetrazol modified -adrenoceptor binding: there was a significant increase in receptor number 4 days after injection, but a significant decrease after 7 days. The anxiogenic, proconvulsant drug, yohimbine, was without effect. The changes induced by DMCM and pentylenetetrazole do not seem to be related to the behavioural effects of these drugs or to their affinity for binding to benzodiazepine receptors. The possibility that these compounds have actions in addition to those at the GABAA receptor is discussed. 相似文献
998.
Sam C. Barranco Courtney M. Townsend Barbara Y. Ho Karen J. Reumont Steven K. Koester Pamella J. Ford 《Investigational new drugs》1990,8(Z1):S9-S18
A clone of human gastric cancer cells (AGS-6) and the parental line (AGS-P) from which it was isolated were used in cell survival studies to determine whether pretreatment for 24, 48 or 72h with -difluoromethylornithine (DFMO, 5mM) would increase the cell's sensitivity to 5-Fluorouracil (5FU), Adriamycin (Adria), 1-(2-chloroethyl)-3-(4-methyl cyclohexyl)-1-nitrosourea (MeCCNU), or Bleomycin (Bleo). Generally, the AGS parental cells were most sensitive to the anticancer agents after exposures to DFMO. However, there was no way to predict in advance from DFMO-induced changes in ornithine decarboxylase (ODC), polyamine or cell kinetics values, how long an exposure to DFMO was required before sensitization to an anticancer agent occurred. The degree of potentiation for a single drug was variable from time to time during exposure to DFMO, and broad differences in the sensitizations were demonstrated among the four anticancer drugs. The AGS-6 clone exhibited little or no increased sensitivity as a result of pretreatment with DFMO, even though the DFMO-induced reductions in ODC and polyamine values in these cells were similar to those produced in the more sensitive parental line. 相似文献
999.
The binding characteristics of valproic acid (VPA) and its pharmacologically active monounsaturated metabolite, E-2-VPA, to rat plasma proteins were compared. The plasma free fraction was determined by a rapid equilibrium procedure, which minimizes the interfering effects of nonesterified fatty acids liberated by in vitro lipolysis. Nonlinear binding behavior was observed with both compounds over their respective pharmacologic concentration range. Multiple binding-site models were invoked to explain the binding isotherm. The 2-unsaturated compound has a much higher affinity for the rat plasma proteins (mainly albumin) than its saturated precursor. The equilibrium association constants for the high- and intermediate-affinity sites were more than an order of magnitude higher with E-2-VPA than with VPA (104–106 versus 103
M
–1). This difference in binding affinity was also reflected by a lower plasma free fraction for E-2-VPA compared with VPA (<<10 versus >20% at total concentrations of less than 100 µg/ml). A more pronounced dose- and concentration-dependent variation in the distribution and clearance kinetics is predicted for the 2-unsaturated analogue compared to VPA. Also, the structural dependency in plasma protein binding observed with these branched-chain fatty acids may provide insights into the mechanism of interaction between fatty acyl molecules and albumin. 相似文献
1000.
The Liposome as a Model Membrane in Correlations of Partitioning with α-Adrenoceptor Agonist Activities 总被引:1,自引:0,他引:1
The apparent partition coefficients of a group of imidazoline -adrenoceptor agonists in liposome/buffer systems (Km) and in the n-octanol/buffer system (P) have been compared in quantitative structure–activity relationships (QSAR) employing biological activities and receptor binding affinities. A parabolic relationship between log K
m
and log P was found, and log K
m
was greater than log P for all liposome compositions. In liposomes, log K
m
decreased in the order, negatively charged > neutral > positively charged. Overall, hyper- and hypotensive activities of these drugs correlated better with log K
m
than with log P; however, poor correlations were obtained between partition coefficients and in vitro binding affinities. Linear correlations of log K
m
with hypotensive activities were obtained with negatively charged liposomes, whereas correlations with hypertensive activities were obtained using positively charged liposomes. Multiple regressions of biological activities with binding affinities showed positive correlations with hypotensive but not hypertensive activities with or without the inclusion of log K
m
or log P. Thus, the liposome represents a more selective model membrane system than a bulk oil phase for predicting the biological activities of imidazoline -adrenoceptor agonists. 相似文献