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11.
Coeliac haemodynamic effects of endothelin-1, endothelin-3, proendothelin-1 [1-38] and proendothelin-3 [1-41] in conscious rats. 下载免费PDF全文
S. M. Gardiner P. A. Kemp A. M. Compton T. Bennett 《British journal of pharmacology》1992,106(2):483-488
1. Conscious, chronically-instrumented, Long Evans rats were given bolus doses of endothelin-1, endothelin-3 (both at 0.01 and 0.1 nmol kg-1), proendothelin-1 [1-38] and proendothelin-3 [1-41] (both 0.1 and 1 nmol kg-1) in order to compare their effects on coeliac haemodynamics, because it has been reported that, in conscious dogs, endothelin-1 has paradoxical, prolonged hyperaemic vasodilator effects in this vascular bed. Measurements were made also of mesenteric and hindquarters haemodynamics for comparison. In a separate experiment, endothelin-1 (0.1 nmol kg-1) was given before and 20 min after the onset of an infusion of mecamylamine (50 mumol kg h-1) to ensure that the responses measured were not confounded by rapid reflex changes in autonomic activity. 2. None of the peptides caused any increases in coeliac flow or any sustained rises in coeliac vascular conductance, although such changes were clear-cut in the hindquarters vascular bed following the higher dose of endothelin-1 and endothelin-3. In animals treated with mecamylamine the regional haemodynamic effects of the higher dose endothelin-1 were not different from those in animals with intact baroreflexes. 3. Although the lower dose of both endothelin-1 and endothelin-3 caused less marked coeliac, than mesenteric vasoconstriction, this difference was not apparent with the higher dose of the peptides, or with proendothelin-1 [1-38]. However, proendothelin-3 [1-41] had less marked coeliac and hindquarters vasoconstrictor effects than proendothelin-1 [1-38], in spite of both peptides causing similar changes in mesenteric haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
12.
R Dixon AM Hughes K Nairn M Sellers JV Kemp RA Yates 《Cephalalgia : an international journal of headache》1998,18(7):468-475
Zolmitriptan (ZomigTM ) is a 5HT1B/1D agonist which has the ability to cross the intact blood-brain barrier to access central as well as peripheral receptors. Because of the potential for central nervous system side effects, this randomized, double-blind, placebo-controlled, 6-period crossover study evaluated the effects of 2.5 and 5 mg doses of zolmitriptan on psychomotor performance and investigated any pharmacodynamic or pharmacokinetic interaction with diazepam. Twelve healthy volunteers received the following "treatments" as single doses: zolmitriptan 2.5 mg, zolmitriptan 5 mg, diazepam 10 mg, zolmitriptan 2.5 mg+diazepam 10 mg, zolmitriptan 5 mg+diazepam 10 mg and placebo. Pre-dose and at 1, 4, 8, and 24 h post-dose, the following validated battery of psychomotor tests was performed: Bond-Lader visual analogue scales (calmness, contentedness, and alertness factors), critical flicker fusion test, choice reaction time (recognition, motor, and total reaction times), finger-tapping test, number cancellation test and digit symbol substitution test. Plasma concentrations of zolmitriptan, its active metabolite, and diazepam and its active metabolites were measured at the same timepoints. Zolmitriptan 2.5 and 5 mg had no effect on psychomotor function when given alone. In contrast, diazepam 10 mg had profound effects, consistent with its sedative properties, but there was no synergism on concomitant administration of either dose of zolmitriptan. Plasma concentrations of zolmitriptan, diazepam, and their respective active metabolites were similar when the two drugs were given alone or in combination. 相似文献
13.
Inhibition of the haemodynamic effects of angiotensin II in conscious rats by AT2-receptor antagonists given after the AT1-receptor antagonist, EXP 3174. 下载免费PDF全文
R. E. Widdop S. M. Gardiner P. A. Kemp T. Bennett 《British journal of pharmacology》1992,107(3):873-880
1. Conscious, Long Evans rats (n = 10), chronically instrumented for the measurement of regional haemodynamics, were studied on 3 consecutive experimental days to assess responses to angiotensin II (AII) (125 pmol kg-1, i.v.) and noradrenaline (1 nmol kg-1, i.v.) in the absence and presence of the AT2-receptor antagonist, PD 123319 (10 mg kg-1, i.v.) (day 1), the AT1-receptor antagonist, EXP 3174 (1 mg kg-1, i.v.) (day 2), and PD 123319 (10 mg kg-1, i.v.) given 24 h after EXP 3174 (day 3). 2. In naive rats (day 1), PD 123319 did not antagonize the haemodynamic effects of AII or noradrenaline. EXP 3174 (day 2) caused a marked, prolonged blockade of the haemodynamic effects of AII but not those of noradrenaline. Twenty four h after administration of EXP 3174 (day 3) there was still significant attenuation of the haemodynamic effects of AII. However, administration of PD 123319 at this time caused a further inhibition (lasting 1 h) of the effects of AII but not those of noradrenaline. 3. An identical 3 day protocol was used in a separate group of rats (n = 6) in which the AT2-receptor antagonist, PD 123177, was given instead of PD 123319, and the results were essentially the same, i.e., PD 123177 significantly attenuated the haemodynamic effects of AII but only when given 24 h after EXP 3174.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
14.
P A Brennan G T Gardiner J McHugh 《The British journal of oral & maxillofacial surgery》1991,29(3):176-179
The bovine derived polypeptide, aprotinin, inhibits the activation of certain chemical mediators of acute inflammation. These mediators are responsible for causing pain and swelling in traumatised tissue. The properties of aprotinin were assessed in patients requiring surgical removal of third molars, a procedure which often results in considerable postoperative pain and swelling. A double blind clinical trial compared the effects of local infiltration of 1 ml of saline on one side of the mouth and aprotinin (10,000 international units) on the other, in patients requiring extraction of both mandibular third molars. Pain scores were assessed with a visual analogue scale, and swelling was subjectively assessed. The results, when analysed statistically, showed that aprotinin significantly reduced postoperative pain and swelling on the side of the mouth on which it was used, as compared to the control side (0.01% significance). 相似文献
15.
16.
Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents 总被引:4,自引:0,他引:4
J E Arrowsmith S F Campbell P E Cross J K Stubbs R A Burges D G Gardiner K J Blackburn 《Journal of medicinal chemistry》1986,29(9):1696-1702
A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen. 相似文献
17.
Summary— Experiments were designed to determine whether or not indapamide, an antihypertensive agent with vasodilator properties, inhibits endothelium-dependent contractions. Rings of aortae with and without endothelium from spontaneously hypertensive rats (SHR) were suspended in conventional organ chambers for the measurement of isometric force. Acetylcholine and adenosine diphosphate-β-S in the presence of a nitric oxide synthase inhibitor, caused endothelium-dependent contractions, which were inhibited by indapamide. The compound (10−4 M) also slightly reduced the contractions of rings without endothelium evoked by U-46,619, which activates thromboxane-endoperoxide receptors. These results demonstrate that indapamide inhibits endothelium-dependent contractions in the SHR aorta, and suggest that the inhibition is due, at least in part, to the action of the drug on the hypertensive vascular smooth muscle. 相似文献
18.
19.
Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. 总被引:12,自引:0,他引:12 下载免费PDF全文
A. W. Stitt Y. M. Li T. A. Gardiner R. Bucala D. B. Archer H. Vlassara 《The American journal of pathology》1997,150(2):523-531
Advanced glycation end products (AGEs), formed from the nonenzymatic glycation of proteins and lipids with reducing sugars, have been implicated in many diabetic complications; however, their role in diabetic retinopathy remains largely unknown. Recent studies suggest that the cellular actions of AGEs may be mediated by AGE-specific receptors (AGE-R). We have examined the immunolocalization of AGEs and AGE-R components R1 and R2 in the retinal vasculature at 2, 4, and 8 months after STZ-induced diabetes as well as in nondiabetic rats infused with AGE bovine serum albumin for 2 weeks. Using polyclonal or monoclonal anti-AGE antibodies and polyclonal antibodies to recombinant AGE-R1 and AGE-R2, immunoreactivity (IR) was examined in the complete retinal vascular tree after isolation by trypsin digestion. After 2, 4, and 8 months of diabetes, there was a gradual increase in AGE IR in basement membrane. At 8 months, pericytes, smooth muscle cells, and endothelial cells of the retinal vessels showed dense intracellular AGE IR. AGE epitopes stained most intensely within pericytes and smooth muscle cells but less in basement membrane of AGE-infused rats compared with the diabetic group. Retinas from normal or bovine-serum-albumin-infused rats were largely negative for AGE IR. AGE-R1 and -R2 co-localized strongly with AGEs of vascular endothelial cells, pericytes, and smooth muscle cells of either normal, diabetic, or AGE-infused rat retinas, and this distribution did not vary with each condition. The data indicate that AGEs accumulate as a function of diabetes duration first within the basement membrane and then intracellularly, co-localizing with cellular AGE-Rs. Significant AGE deposits appear within the pericytes after long-term diabetes or acute challenge with AGE infusion conditions associated with pericyte damage. Co-localization of AGEs and AGE-Rs in retinal cells points to possible interactions of pathogenic significance. 相似文献
20.
F V Elmslie A J Vivian H Gardiner C Hall A P Mowat R M Winter 《Journal of medical genetics》1995,32(4):264-268
Alagille syndrome (AGS) is one of the major forms of chronic liver disease in childhood with severe morbidity and a mortality of 10 to 20%. It is characterised by cholestasis of variable severity with paucity of interlobular bile ducts and anomalies of the cardiovascular system, skeleton, eyes, and face. Previous studies suggest a wide variation in the expression of the disease and a high incidence of new mutations. To determine more accurately the rate of new mutations and to develop criteria for detecting the disorder in parents we systematically investigated parents in 14 families with an affected child. Clinical examination was supplemented by liver function tests, echocardiography, radiographic examination of the spine and forearm, ophthalmological assessment, and chromosome analysis. Six parents had typical anomalies in two or more systems pointing to the presence of autosomal dominant inheritance. Systematic screening of parents for the features defined in this study should improve the accuracy of genetic counselling. 相似文献