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941.
Abdel-Rahman SM Johnson FK Manowitz N Holmes GB Kearns GL 《Journal of clinical pharmacology》2002,42(10):1089-1096
The pharmacokinetics of nizatidine following a single 5.0 mg/kg oral dose given as an extemporaneous liquid formulation in apple juice was examined in 12 healthy children (8.0 +/- 2.4 years, 30.7 +/- 8.4 kg). Nizatidine and N-desmethylnizatidine were quantitated by HPLC/MS from five post dose blood samples taken over a 12-hour period. The apparent terminal elimination rate constant for nizatidine in the pediatric subjects (0.58 +/- 0.8h(-1)) was virtually identical to that (0.54 +/- 0.13 h(-1)) previously reported from adult studies. When corrected for an estimated 30% reduction in nizatidine oral bioavailability observed in adults upon coingestion of the drug with other fruit/vegetable juices, nizatidine pharmacokinetic parameter estimates (e.g., Cmax, CL/F, Vss/F) in our pediatric subjects were similar to those previously reported in adults who were administered dimensionally similar (e.g., approximately 4 mg/kg) solid oral doses of the drug. Examination of the mean area under the curve (i.e., AUC0-infinity for nizatidine and N-desmethylnizatidine suggested an approximate 15% metabolic conversion of the parent drug. Finally, nizatidine plasma concentrations in pediatric patients following a single 5.0 mg/kg oral dose exceeded the EC50 value of the drug for gastric acid suppression determined from adult studies for approximately 6 hours. 相似文献
942.
A series of N-alkyl-N'-(phenethyl- and cyclohexenylethyl) guanidines and N(2)- and N(2), 4-substituted imidazolin-2-amine hydrochlorides with triazasterol-related structures was designed and synthesized as stable analogues to mimic high energy intermediates of ergosterol biosynthesis. The in vitro antifungal susceptibility tests with a standard panel of pathogenic fungi revealed moderate to strong antimycotic effects of the sixteen prepared compounds, in some cases comparable with the activity observed for itraconazole. 相似文献
943.
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947.
A training set of 27 propofol (2,6-diisopropylphenol) analogues was used to construct four-dimensional (4D) quantitative structure-activity relationship (QSAR) models for three screens of biological activity: loss of righting reflex (LORR) in tadpoles, enhancement of agonist activity at the gamma-aminobutyric acid type A (GABA(A)) receptor, and direct (agonist-independent) activation of the receptor. The three resulting 4D-QSAR models are almost identical in form, and all suggest three key ligand-receptor interaction sites. The formation of an intermolecular hydrogen bond involving the proton of the ligand -OH group is the most important binding interaction. A hydrophobic pocket binding interaction involving the six-substituent is the second most significant binding site, and a similar hydrophobic pocket binding interaction near the two-substituent is the third postulated binding site from the 4D-QSAR models. A test set of eight compounds was used to evaluate the tadpole LORR 4D-QSAR model. Those compounds highly congeneric to the training set compounds were accurately predicted. However, compounds exploring substituent sites and/or electronic structures different from the training set were less well-predicted. Overall, the results show a striking similarity between the models of the sites responsible for anesthesia and those mediating effects of the training set of propofol analogues on the GABA(A) receptor; it follows that the GABA(A) receptor is therefore the likely site of propofol's anesthetic action. 相似文献
948.
Previous studies have shown that amino acid residues in trans-membrane (TM) segments 1, 2 and 3 of the alpha subunit are critical for the enhancement of GABA(A) receptor function by inhaled anesthetics. In this study we used tryptophan (Trp) scanning mutagenesis between Ile 406 and Asn 417 in the alpha1 subunit to determine the effects of Trp substitution in the fourth transmembrane segment (TM4) on receptor gating and anesthetic modulation. Wild-type and mutant alpha1 subunits were transiently expressed in HEK 293 cells with wild-type beta2 and gamma2s subunits and GABA-activated currents were recorded using whole-cell voltage clamp. The potentiation by three inhaled anesthetics (isoflurane, halothane and chloroform) of responses elicited by a submaximal concentration of GABA were also examined.EC(50) values for GABA at the mutant receptors were in the range 4-60 microM (wild-type=20 microM), indicating that Trp substitution can alter the apparent affinity of the receptor for GABA positively or negatively, dependent on position. The variation of the calculated EC(50) value for GABA exhibited an interesting periodicity, with the cycle length for each repeat corresponding to approximately 3.6 amino acids. These data are consistent with an alpha-helical structure for the TM4 segment of the alpha subunit. Several of these Trp point mutations altered the ability of one or more of the three inhaled anesthetics to modulate receptor function; four of the 12 mutations abolished receptor modulation by one or more of the anesthetics tested. These data are consistent with a role for these residues at the extracellular end of TM4 in anesthetic modulation of GABA(A) receptors. 相似文献
949.
Hung JC Augustine SC Cheng KT Green RL Hopkins WM Laven DL Nelson BR Petry NA Ponto JA Quinton TM Swanson DP 《Journal of the American Pharmacists Association : JAPhA》2002,42(5):789-798
OBJECTIVES: To provide background information related to the development of the Nuclear Pharmacy Compounding Guidelines, to discuss regulatory complexities related to radiopharmaceutical compounding practice, and to summarize the gaps in the current compounding regulations for radiopharmaceuticals. DATA SOURCES: The Guidelines closely follow the provisions of section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the monographs and chapters related to pharmacy compounding in the United States Pharmacopeia (USP), and the recommended guidelines published by the American Society of Health-System Pharmacists. SUMMARY: The Food and Drug Administration Modernization Act (FDAMA) of 1997 established parameters under which the compounding of drug products is appropriate and lawful, but these criteria expressly do not apply to radiopharmaceuticals. The Nuclear Pharmacy Compounding Practice Committee, a group of nuclear pharmacists convened by the American Pharmaceutical Association, developed the Nuclear Pharmacy Compounding Guidelines to establish a set of principles and guidelines for good radiopharmaceutical compounding practice. The intent of the new document is to provide guidance on radiopharmaceutical compounding practices that have evolved over the last 2 decades and to place them in an appropriate regulatory framework in accordance with previous enforcement policies and guidelines issued by the U.S. Food and Drug Administration (FDA) regarding the exemption of certain pharmacy practices from enforcement of adulteration, misbranding, and new drug requirements. CONCLUSION: The Nuclear Pharmacy Compounding Guidelines, recently released by APhA, is the first official document that provides realistic and practical compounding guidance for nuclear pharmacists. Even though the United States Court of Appeals for the Ninth Circuit recently ruled section 503A of the FD&C Act to be invalid in its entirety, and the Supreme Court upheld that ruling, the compliance policy guides issued by FDA in March 1992 and revised in May 2002 maintain guiding principles on pharmacy compounding similar to those stated in section 503A of the FD&C Act. The Nuclear Pharmacy Compounding Practice Committee is optimistic that the practical information contained in the Guidelines will assist state boards of pharmacy, FDA, and the United States Pharmacopeial Convention in setting appropriate standards for nuclear pharmacy compounding practice that will ensure the continued availability of high-quality compounded radiopharmaceuticals at reasonable cost. 相似文献
950.