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61.
L. J. Schaaf B. R. Dobbs I. R. Edwards D. G. Perrier 《European journal of clinical pharmacology》1988,34(5):439-443
Summary The disposition kinetics of a new 5-fluorouracil prodrug, 5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-deoxy-5-fluorouridine (5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">dFUR (2 and 4 g · m–2) on separate days.Plasma concentrations of 5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l · min–1) but no apparent change in renal clearance (0.32 to 0.29 l · min–1) or steady-state apparent volume of distribution (19.8 to 20.4 l).The mechanism for dose-dependence of 5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding. 相似文献
62.
G. Molderings J. Likungu H. R. Zerkowski M. Gothert 《Naunyn-Schmiedeberg's archives of pharmacology》1988,337(4):408-414
Summary Spirally cut strips of human saphenous veins preincubated with 3H-noradrenaline were superfused in the presence of corticosterone and, unless stated otherwise, of cocaine or desipramine. Tritium overflow was stimulated electrically (2 Hz). Adrenaline (in the presence of rauwolscine), isoprenaline and the preferential content/g3475x60v51903p1/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">2-adrenoceptor agonist procaterol concentration-dependently increased the electrically evoked tritium overflow. Prenalterol, a content/g3475x60v51903p1/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor agonist with moderate preference for content/g3475x60v51903p1/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">1-adrenoceptors, was ineffective. The concentration-response curve of isoprenaline was shifted to the right by the nonselective content/g3475x60v51903p1/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor antagonist propranolol and by the preferential content/g3475x60v51903p1/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">2-adrenoceptor antagonist ICI 118,551, but was not affected by the content/g3475x60v51903p1/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">1-selective antagonist atenolol. In experiments on strips preexposed to adrenaline 10 nmol/l (i. e. a concentration higher than that which normally occurs in vivo) for 32 min in the absence of cocaine or desipramine, the electrically evoked 3H overflow was not affected 12 and 44 min after withdrawal of adrenaline, irrespective of whether propranolol was absent or present in the superfusion fluid. — In veins incubated with 3H-adrenaline, a considerable amount of the radioactivity was accumulated. During subsequent superfusion with 3H-adrenaline-free solution, electrical stimulation induced tritium overflow in a tetrodotoxin-sensitive manner. Propranolol failed to modify the evoked tritium overflow. — It is concluded that the sympathetic nerve fibres of the human saphenous vein are endowed with facilitatory presynaptic content/g3475x60v51903p1/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">2-adrenoceptors. These receptors do not seem to play a substantial role in a local adrenaline (previously taken up)-mediated positive feedback loop regulating noradrenergic transmission, at least under the present in vitro conditions.This study was supported by a grant of the Deutsche Forschungsgemeinschaft
Send offprint requests to M. Göthert 相似文献
63.
S. -L. Brown D. S. Charney S. W. Woods G. R. Heninger J. Tallman 《Psychopharmacology》1988,94(1):24-28
Lymphocyte beta adrenergic receptor binding using [125I]CNP was determined in patients with panic disorder (N=4) or agoraphobia with panic attacks (N=17) and age- and sex-matched healthy subjects (N=22). The patients showed a significantly lower number of content/wu4260l3781wn4j4/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenergic receptor binding sites and a significantly higher affinity of binding than healthy subjects. A past or present history of major depression in the patients did not alter these findings. These results are consistent with a growing body of knowledge implicating noradrenergic dysfunction in the pathophysiology of panic anxiety. 相似文献
64.
Five aliphatic 5content/l6444461378u1m1u/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-esters of 5-iodo-2content/l6444461378u1m1u/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">deoxyuridine (IDU) were synthesized via an acid chloride alcoholysis reaction. The solubility in pH 7.4 phosphate buffer, lipophilicity as determined by partition experiments in octanol/pH 7.4 buffer, and cytotoxicity of these potential prodrugs were evaluated. The esters showed a 43- to 250-fold increase in lipophilicity and a 1.6- to 14-fold decrease in aqueous solubility relative to IDU. At a concentration of 50 µM, all esters showed reduced cytotoxicity toward uninfected Vero cells relative to IDU. 相似文献
65.
An avidin–biotin enzyme-linked immunosorbent assay (ELISA) is described for content/h1v517777n768x1l/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">h-endorphin (content/h1v517777n768x1l/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">h-EP). Microtiter plates coated with commercially available antibodies were used together with content/h1v517777n768x1l/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">h-EP tracer derivatives that were biotinylated in positions 24, 28, and 29 via a C6 spacer arm. Nonspecific binding of biotinylated derivatives to the microtiter plates was blocked with a mixture of 1% casein and 10% ethanolamine in 0.1 M NaHCO3. A sequential saturation procedure using a high-affinity antiserum in combination with an avidin–alkaline phosphatase complex matched the sensitivity of reported radioimmunoassays (RIAs), with a detection limit of 0.5 fmol/assay. The intra- and interassay coefficients of variation were 5 and 12%, respectively. Results obtained by ELISA and RIA showed good correlations (r = 0.95). The content/h1v517777n768x1l/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-EP concentration in extracted rat plasma after high-performance liquid chromatographic (HPLC) fractionation was determined by this method to be 1600 fmol/ml. 相似文献
66.
Cotinine determination by immunoassays may be influenced by other nicotine metabolites 总被引:1,自引:0,他引:1
Polyclonal rabbit anticotinine antiserum, which can be used for biomonitoring nicotine uptake by the determination of cotinine in body fluids, was checked by a competitive ELISA for its cross-reactivity with nine nicotine metabolites. The highest percentage of relative crossreactivity (about 30%) was observed with trans-3content/w1202211463l54w5/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-hydroxycotinine, a metabolite which is known to be excreted in 3-fold higher amounts than cotinine in the urine of human smokers. Therefore, it is possible that cotinine determinations performed by immunochemical methods — especially in urine — may yield overestimated cotinine concentrations. 相似文献
67.
Hexachloro-1,3-butadiene (HCBD) is more nephrotoxic to female than male rats. Metabolism of HCBD involves conjugation with glutathione followed by formation of the cysteine conjugate S-(pentachloro-1,3-butadienyl) cysteine (PCBD-CYS) and then the mercapturic acid N-acetyl-S-pentachloro-1,3-butadienyl-cysteine (PCBD-NAC). PCBD-NAC is also more nephrotoxic to female rats than male rats. The deacetylation of [14C]-PCBD-NAC to PCBD-CYS and the binding of radiolabelled metabolites to protein has been studied using renal cytosol preparations from male and female rats in vitro, since a sex-related difference in these reactions could explain the difference in nephrotoxicity found in vivo. PCBD-NAC was rapidly metabolised by renal cytosol. The rate of metabolism was similar with either male or female renal cytosol, and the major metabolite identified was PCBD-CYS. N-Acetylation of PCBD-CYS to PCBD-NAC was not detected in the presence of either male or female renal cytosol. Covalent binding of radioactivity from [14C]-PCBD-NAC to cytosolic protein could be detected after 5 min incubation, and although the extent of binding was similar for both male and female cytosol at early time periods, after 60 min incubation more binding was found in the presence of male cytosol. Covalent binding was largely prevented by aminooxyacetic acid, an inhibitor of cysteine conjugate content/n213751817337213/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-lyase, suggesting a role for this enzyme in the activation of HCBD. These results indicate that the sex differences in the nephrotoxicity of HCBD and PCBD-NAC in the rat are not attributable to differences in the rate of deacetylation of PCBD-NAC to give the proximate nephrotoxin PCBD-CYS.This work was supported by a fellowship from the European Science Foundation granted to I. S. P. 相似文献
68.
In order to clarify the etiology of a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats, the nephrotoxicity of p-dichlorobenzene (p-DCB) was investigated in a subchronic study. Groups of ten male and ten female Fischer 344 rats were dosed by gavage with 0 (controls), 75, 150, 300 or 600 mg p-DCB/kg/day in corn oil. Half of the animals were sacrificed after 4 weeks and the remainder after 13 weeks. Increased urinary LDH and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells were observed in male rats over the entire dose range investigated. Tubular single cell necrosis, dilated tubules with granular cast formation in the outer zone of the medulla, were evident in male rats after 4 and 13 weeks of treatment with doses of 150–600 mg/kg/day. In female rats there was no indication of a nephrotoxic action of p-DCB. The effects on the kidney, both in their morphological characteristics and the fact that they occur exclusively in male animals, correspond to the light hydrocarbon nephropathy observed as a result of short-term treatment with a number of aliphatic and cyclic hydrocarbons. The development of cortical renal tumors seems to be associated with this kind of kidney damage which is unique to male rats. The literature on this subject generally regards these renal effects as not predictive for man. 相似文献
69.
The ability of thiols to reduce 3content/t48jt274574gh5r2/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-azidothymidine (AZT) to 3content/t48jt274574gh5r2/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-aminothymidine has been investigated. Incubation with glutathione, dithiothreitol (DTT), or mercaptoethanol at pH 7.2 and 37°C leads to quantitative reduction of the azido moiety to an amine. The reaction is first order in AZT and first order in reducing agent (mono- or dithiol). The second-order rate constants are 2.77 × 10–3, 6.55 × 10–5, and 6.35 × 10–6
M
–l sec–1 for the dithiothreitol, glutathione, and mercaptoethanol reductions, respectively. The thiol reduction of alkyl azide to amine under mild conditions is a synthetic method particularly suitable for water-soluble azido compounds that are sensitive to catalytic hydrogenation. The potential for the mono- or dithiol-mediated reduction of alkyl azides under biological conditions must be considered when conducting studies of azido drugs. 相似文献
70.