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91.
The current algorithm for selecting a population pharmacokinetic/pharmacodynamic model is based on the well-established forward addition/backward elimination method. A central strength of this approach is the opportunity for a modeller to continuously examine the data and postulate new hypotheses to explain observed biases. This algorithm has served the modelling community well, but the model selection process has essentially remained unchanged for the last 30 years. During this time, more robust approaches to model selection have been made feasible by new technology and dramatic increases in computation speed. We review these methods, with emphasis on genetic algorithm approaches and discuss the role these methods may play in population pharmacokinetic/pharmacodynamic model selection. 相似文献
92.
Kashyap Patel Julie A Simpson Kevin T Batty Sophie Zaloumis Carl M Kirkpatrick 《British journal of clinical pharmacology》2015,79(1):97-107
Malaria remains a global public health concern and current treatment options are suboptimal in some clinical settings. For effective chemotherapy, antimalarial drug concentrations must be sufficient to remove completely all of the parasites in the infected host. Optimized dosing therefore requires a detailed understanding of the time course of antimalarial response, whilst simultaneously considering the parasite life cycle and host immune elimination. Recently, the World Health Organization (WHO) has recommended the development of mathematical models for understanding better antimalarial drug resistance and management. Other international groups have also suggested that mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) models can support the rationalization of antimalarial dosing strategies. At present, artemisinin-based combination therapy (ACT) is recommended as first line treatment of falciparum malaria for all patient groups. This review summarizes the PK–PD characterization of artemisinin derivatives and other partner drugs from both preclinical studies and human clinical trials. We outline the continuous and discrete time models that have been proposed to describe antimalarial activity on specific stages of the parasite life cycle. The translation of PK–PD predictions from animals to humans is considered, because preclinical studies can provide rich data for detailed mechanism-based modelling. While similar sampling techniques are limited in clinical studies, PK–PD models can be used to optimize the design of experiments to improve estimation of the parameters of interest. Ultimately, we propose that fully developed mechanistic models can simulate and rationalize ACT or other treatment strategies in antimalarial chemotherapy. 相似文献
93.
Azrin N Abd Rahman Susan E Tett Halim A Abdul Gafor Brett C McWhinney Christine E Staatz 《British journal of clinical pharmacology》2015,80(5):1064-1075
Aims
The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.Methods
Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0), maximum concentration (Cmax) and area under the concentration–time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.Results
Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l–1 h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l–1, P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l–1 h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l–1 h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l–1 h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).Conclusions
This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis. 相似文献94.
目的了解神经外科术后患者静脉输注替考拉宁时脑脊液药物浓度,探讨神经外科手术破坏血脑屏障后是否可增加脑脊液药物浓度,以及药物持续泵入对脑脊液药物浓度的影响。方法选择神经外科术后留置术区/脑室引流管的患者,分为常规给药组(替考拉宁400 mg,30 min泵入,1次/12 h重复给药)和持续给药组(替考拉宁400 mg,30 min泵入,再以200 mg,1次/6 h持续泵入),于给药后相应时间点采集脑脊液标本检测替考拉宁浓度。结果常规给药组脑脊液替考拉宁浓度泵入后即刻浓度为(0.004±0.0123)mg/L,泵入后1 h达峰值(0.712±1.028)mg/L,后逐渐下降,泵入后12、18、24 h分别为(0.254±0.222)、(0.173±0.152)、(0.355±0.207)mg/L。持续给药组脑脊液替考拉宁泵入后即刻浓度为(0.017±0.020)mg/L,4 h后达峰值(0.587±0.255)mg/L,泵入后6、12、18、24 h分别为(0.429±0.416)、(0.325±0.254)、(0.476±0.686)、(0.318±0.464)mg/L,6 h后药物浓度相对稳定,介于(0.318±0.464)~(0.476±0.686)mg/L。常规给药组、持续给药组的AUC0—24 h分别为5.590 mg/L·h、9.082 mg/L·h。两组患者仅峰值附近区域替考拉宁浓度达到凝固酶阴性葡萄球菌(CNS)MIC50,但其浓度高于CNS MIC50的时间占整个给药时间的比例远小于50%;两组患者脑脊液替考拉宁浓度均未能达到金黄色葡萄球菌MIC50。结论持续输注替考拉宁后,患者脑脊液药物浓度较常规给药组有所增加,但仍未能达所要求的MIC;结合血药浓度的实验,血液浓度增高有利于脑脊液药物浓度增加,可考虑适当增加剂量以达到临床治疗目的。 相似文献
95.
Ola Brodin Staffan Eksborg Marita Wallenberg Charlotte Asker-Hagelberg Erik H. Larsen Dag Mohlkert Clara Lenneby-Helleday Hans Jacobsson Stig Linder Sougat Misra Mikael Bj?rnstedt 《Nutrients》2015,7(6):4978-4994
Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients’ refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m2, with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m2 under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy. 相似文献
96.
建立测定血浆和置换液中达托霉素的高通量UPLC-MS/MS方法,采用Kinetex C18色谱柱(50 mm×2.1 mm,1.7 μm),柱温45 ℃,流动相为含0.1%甲酸水溶液-乙腈,流速0.4 mL/min,电喷雾离子化正离子扫描模式下,达托霉素m/z 810.9→159.1;内标来曲唑m/z 286.2→217.2,分析时长2.5 min。达托霉素在血浆(1~200 μg/mL)和置换液(0.005~20 μg/mL)中均呈现良好的线性关系,日内及日间精密度、准确度、稳定性等均符合生物样品测定要求。静脉滴注6 mg/kg达托霉素在接受持续肾脏替代治疗(CRRT)治疗的感染性休克患者体内的cmax和AUC0-24明显低于健康受试者,下降比例分别为50%和60%,未达到预期的杀菌效果。这可能与感染性休克患者毛细血管通透性增加联合间隙水肿,从而使药物的分布容积增加有关,此外,肾脏替代治疗模式可体外滤过约16%的达托霉素,导致剂量不足和感染治疗不彻底。研究结果推荐在接受CRRT治疗的感染性休克患者中使用达托霉素应适当增加剂量,且须对该类患者进行达托霉素治疗药物浓度监测。 相似文献
97.
目的:研究新型蒽环类衍生物HYY-014在大鼠体内的药代动力学和组织分布特征,为临床研究提供实验依据。方法大鼠单次尾静脉注射1.5 mg/kg的HYY-014后,采用LC-MS/MS法测定各时间点血浆和组织中HYY-014及其代谢物HYY-M3的浓度,药代动力学参数经DAS 3.0统计软件计算获得。结果采用统计矩方法处理药物浓度时间数据, HYY-014药代动力学参数 Cmax、T1/2、Vd、CL、AUC0-t、MRT0-t分别为(1628.6±618.6)μg/L、(24.4±3.6) h、(23.4±5.2) L/kg、(0.66±0.08) L/kg/h、(2219.5±276.9)μg/L ·h、(15.1±2.4) h;HYY-M3药代动力学参数Cmax、AUC0-t分别为(2.2±0.6)μg/L、(103.1±13.7)μg/L·h。静脉注射该药后,很快向机体的各组织广泛分布,且具有明显的靶向性,主要分布在脾、肾、肺、心脏、肝等组织,脑组织中浓度极低。结论静脉注射HYY-014组织分布广泛,具有明显的靶向性,肺、肝组织中的药物浓度均较高,不能通过血脑屏障。 相似文献
98.
目的 探讨益母草碱油包油微乳剂和益母草碱混悬剂在动物体内药物代谢动力学特征和组织靶向性。方法 采用高效液相色谱法测定小鼠血浆与组织中益母草碱浓度,计算药物代谢动力学参数。结果 与混悬剂比较,益母草碱微乳剂在体内平均滞留时间提高了7 h,其相对生物利用度为550.684%;益母草碱微乳剂AUC(0→∞)在小鼠各组织的分布整体提高到混悬组的3.626~26.265倍;益母草碱微乳剂在心、肺和脑组织的靶向指标分别为1.044、1.335和4.772。结论 益母草碱油包油微乳提高了生物利用度,对脑组织具有较好的趋向性分布。 相似文献
99.
100.
目的研究依托泊苷亚微乳在大鼠体内的药动学特征,并与依托泊苷注射剂比较。方法大鼠随机分为4组,每组6只,分别尾iv依托泊苷亚微乳2.5、5.0、10.0 mg/kg以及依托泊苷注射剂5 mg/kg,于给药后0.033、0.167、0.333、0.667、1、1.5、2、2.5、3、3.5、4、5、6 h取血。采用HPLC法测定大鼠全血中依托泊苷。结果大鼠iv依托泊苷亚微乳2.5、5、10 mg/kg后的药动学参数分别为t1/2:0.37、0.43、0.46 h;C0:4.72、8.7、15.5 mg/L;AUC0-t:1.57、2.84、6.21 mg·h/L。大鼠尾iv依托泊苷注射剂5 mg/L后的药动学参数分别为:t1/2为0.34 h,C0为7.53 mg/L,AUC0-t为2.63 mg·h/L。依托泊苷亚微乳给药剂量在2.5~10 mg时,t1/2无显著差异,C0、AUC0-t呈剂量相关性,符合线性药动学特点。与注射剂比较,依托泊苷亚微乳的t1/2延长,AUC增大。结论依托泊苷亚微乳的生物利用度有所提高,但半衰期仍然较短。 相似文献