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71.
Prodrug research: futile or fertile? 总被引:5,自引:0,他引:5
Testa B 《Biochemical pharmacology》2004,68(11):2097-2106
The objective of this Commentary is to help clarify and illustrate what prodrugs are, what they are not, which benefits they can offer, and what their limits are. To this end, a number of criteria of classification and evaluation are presented. This is followed by a discussion of the pharmaceutical, pharmacokinetic and pharmacodynamic objectives of prodrug research. Recent examples (e.g. oseltamivir, bambuterol, capecitabine, clopidogrel and tirapazamine) are discussed in a biochemical perspective to illustrate these objectives and to demonstrate some of the therapeutic benefits afforded by successful prodrugs. Attention is also called to the fact that the in vitro and in vivo behavior of prodrug candidates may differ from that of the parent drug in ways that go beyond the original pharmaceutical, pharmacokinetic or pharmacodynamic objective being pursued. We conclude that prodrugs offer a viable strategy to disentangle pharmacodynamic and pharmacokinetic optimization. 相似文献
72.
73.
大孔树脂吸附解吸甘草多糖效果的研究 总被引:3,自引:0,他引:3
目的通过研究LSA-5B,D4020,D201等9种不同型号大孔树脂的吸附率及解吸率,确定分离纯化甘草多糖的树脂类型。方法以葡萄糖为标准品、利用紫外分光光度法,测定各树脂吸附及解吸前后的吸光度,并以甘草多糖的吸附量和解吸量为指标,对树脂进行筛选。结果在9种不同型号的大孔吸附树脂中,LSA-5B型大孔树脂的吸附和解吸性能均较好,对甘草多糖的动态吸附率为56%,动态解吸率为99%。结论在本实验条件下,LSA-5B型大孔树脂是一种较好的分离纯化甘草多糖的树脂材料。 相似文献
74.
Dietary resistant starch and chronic inflammatory bowel diseases 总被引:5,自引:0,他引:5
Jacobasch G Schmiedl D Kruschewski M Schmehl K 《International journal of colorectal disease》1999,14(4-5):201-211
These studies were performed to test the benefit of resistant starch on ulcerative colitis via prebiotic and butyrate effects.
Butyrate, propionate, and acetate are produced in the colon of mammals as a result of microbial fermentation of resistant
starch and other dietary fibers. Butyrate plays an important role in the colonic mucosal growth and epithelial proliferation.
A reduction in the colonic butyrate level induces chronic mucosal atrophy. Short-chain fatty acid enemas increase mucosal
generation, crypt length, and DNA content of the colonocytes. They also ameliorate symptoms of ulcerative colitis in human
patients and rats injected with trinitrobenzene sulfonic acid (TNBS). Butyrate, and also to a lesser degree propionate, are
substrates for the aerobic energy metabolism, and trophic factors of the colonocytes. Adverse butyrate effects occur in normal
and neoplastic colonic cells. In normal cells, butyrate induces proliferation at the crypt base, while inhibiting proliferation
at the crypt surface. In neoplastic cells, butyrate inhibits DNA synthesis and arrests cell growth in the G1 phase of the
cell cycle. The improvement of the TNBS-induced colonic inflammation occurred earlier in the resistant starch (RS)-fed rats
than in the RS-free group. This benefit coincided with activation of colonic epithelial cell proliferation and the subsequent
restoration of apoptosis. The noncollagenous basement membrane protein laminin was regenerated initially in the RS-fed group,
demonstrating what could be a considered lower damage to the intestinal barrier function. The calculation of intestinal short-chain
fatty acid absorption confirmed this conclusion. The uptake of short-chain fatty acids in the colon is strongly inhibited
in the RS-free group, but only slightly reduced in the animals fed with RS. Additionally, RS enhanced the growth of intestinal
bacteria assumed to promote health. Further studies involving patients suffering from ulcerative colitis are necessary to
determine the importance of RS in the therapy of a number of intestinal diseases and the maintenance of health.
Accepted: 11 August 1999 相似文献
75.
研究龙马酶(EC 3. 1. 1. 3)固定化载体、固定化条件和固定化酶的性质。方法:固定化采用吸附法。结果:固定化最适条件:酶液PH9.0,吸附时间1.5 h,酶浓度1.5 g/100 ml,在此条件下固定化酶活力53 u/g载体,活力回收率71%。固定化酶的最适作用温度和pH较游离酶高,范围较游离酶广,耐热性、酸碱稳定性比游离酶好。结论:固定化酶性能比游离酶得到提高。 相似文献
76.
Fattinger K Benowitz NL Jones RT Verotta D 《European journal of clinical pharmacology》2000,56(4):305-310
Objective: Several xenobiotics, including cocaine, are dosed by the nasal route for systemic effects. The aim of this study was to
estimate and compare cocaine input into the systemic circulation after oral and nasal dosing, and to determine the relevance
of local absorption through the nasal mucosa.
Methods: Cocaine was administered to healthy volunteers through the intravenous, oral, and nasal routes. Cocaine serum concentrations
were measured at frequent intervals. From these data, the gastrointestinal, nasal, and nasal mucosa input rate functions were
determined using nonparametric, subject-specific population deconvolution.
Results: After oral dosing, cocaine input into systemic circulation increased slowly and peaked around 45 min after ingestion. The
median systemic bioavailability after oral dosing was 33%. After nasal dosing, drug input was substantial even during the
first minute and showed two peaks at 10 min and 45 min after ingestion. Since the second peak after nasal dosing closely resembled
drug input after oral administration, we hypothesized that, after nasal administration, a part of the dose is swallowed and
thereafter absorbed gastrointestinally. The data from the sessions with nasal cocaine administration were reanalyzed assuming
the same shape for gastrointestinal drug input as after oral dosing. The fraction absorbed through the nasal mucosa was estimated
to be 19% (95% CI: 11–26%). The fraction absorbed through the nasal mucosa contributed 31% (95% CI: 23–37%) of total systemic
cocaine exposure.
Conclusions: Our data suggest that the main reason addicts prefer nasal to oral cocaine dosing is faster absorption, enhancing the subjective
effects rather than higher bioavailability.
Received: 28 December 1999 / Accepted in revised form: 23 March 2000 相似文献
77.
Zusammenfassung Ausgehend von der Ähnlichkeit der Transportsysteme für Aminosäuren in Niere und Darm wurde die Frage untersucht, ob bei Rachitis mit Hyperaminoacidurie auch der Aminosäurentransport im Dünndarm gestört ist. In umgestülpten Darmsäckchen wurde die Absorption von 14C-markierten Aminosäuren bei 2 Ferkeln mit erblicher Pseudomangelrachitis und 7 klinisch gesunden Tieren gemessen. Die Versuche ergaben, daß bei bestehender aktiver Rachitis mit Hyperaminoacidurie die intestinale Aminosäurenabsorption nicht beeinträchtigt ist. Die Absorption nahm dagegen mit dem Alter der Versuchstiere signifikant ab. Das isolierte Auftreten eines Transportschadens für Aminosäuren in der Niere läßt den Schluß zu, daß dieser Defekt nicht durch direkte Einwirkung hämatogener Faktoren (erhöhter PTH-Spiegel oder Mangel an Vitamin D-Metaboliten) auf die Transportsysteme hervorgerufen wird, sondern die Folge vorgeschalteter spezifischer Effekte auf die Tubulusepithelien darstellt.
Intestinal amino acid absorption in vitamin D dependent rickets
Since structure and specifity of amino acid transport systems are basically similar in kidney and intestines it was suspected that rickets associated with hyperaminoaciduria was linked with defective intestinal amino acid uptake. Therefore amino acid absorption from everted sacs of small intestines was studied in 2 piglets suffering from vitamin D dependent rickets, and 7 healthy piglets using 14C labelled amino acids. The experiments revealed an unaffected intestinal absorption in the rachitic animals, whereas the uptake decreased significantly with increasing age of the experimental animals. The results from these studies suggest that regulatory factors in the blood system, e. g. increased level of PTH or lack of specific vitamin D metabolites, do not directly affect amino acid transport systems in kidney and intestines. It is concluded that hyperaminoaciduria has to be mediated through specific and thus far unidentified effects at the tubular cell level.
Im Rahmen des Sonderforschungsbereichs 146 Versuchstierforschung finanziell gefördert. 相似文献
78.
Shibin Mathew David Tess Woodrow Burchett George Chang Nathaniel Woody Christopher Keefer Christine Orozco Jian Lin Samantha Jordan Shinji Yamazaki Rhys Jones Li Di 《Journal of pharmaceutical sciences》2021,110(4):1799-1823
Volume of distribution at steady state (Vss) is an important pharmacokinetic parameter of a drug candidate. In this study, Vss prediction accuracy was evaluated by using: (1) seven methods for rat with 56 compounds, (2) four methods for human with 1276 compounds, and (3) four in vivo methods and three Kp (partition coefficient) scalar methods from scaling of three preclinical species with 125 compounds. The results showed that the global QSAR models outperformed the PBPK methods. Tissue fraction unbound (fu,t) method with adipose and muscle also provided high Vss prediction accuracy. Overall, the high performing methods for human Vss prediction are the global QSAR models, Øie-Tozer and equivalency methods from scaling of preclinical species, as well as PBPK methods with Kp scalar from preclinical species. Certain input parameter ranges rendered PBPK models inaccurate due to mass balance issues. These were addressed using appropriate theoretical limit checks. Prediction accuracy of tissue Kp were also examined. The fu,t method predicted Kp values more accurately than the PBPK methods for adipose, heart and muscle. All the methods overpredicted brain Kp and underpredicted liver Kp due to transporter effects. Successful Vss prediction involves strategic integration of in silico, in vitro and in vivo approaches. 相似文献
79.
以水溶性α.β.γ.δ—四—(4—三甲铵苯基)卟啉[T-(4-TAP)P]作显色剂,测定了食品中的痕量铜。对实验条件及共存离子的干扰进行了探讨。在乙醇介质及强酸条件下测定时,其选择性及灵敏度均有显著提高。摩尔吸收系数为4.5×10~5 1mol~(-1).cm~(-1)最小检验量为:0.14ng/cm~2,回收率为96.2~106%,变异系数为:0.46~3.6%。操作简便,结果满意。 相似文献
80.
J. W. Wiechers 《Pharmacy World & Science》1989,11(6):185-198
There is currently a high level of interest in using the skin as a route for delivering drugs. The skin, however, provides an efficient barrier against percutaneous absorption of drugs. This barrier function can be ascribed to the macroscopical structure of the stratum corneum, which consists of alternating lipoidal and hydrophylic regions. For this reason, physico-chemical characteristics of the drug, such as partition coefficient and molecular weight, play an important role in determining the facility of percutaneous absorption. Another factor to consider in transdermal drug delivery, is the vehicle in which the drug is formulated as it acts on the release of drug from the formulation. Moreover, vehicles may also interact with human stratum corneum, thereby affecting its barrier function. Surfactants and penetration enhancers are well-known examples of the latter. Subsequently, dosing conditions, such as humidity, temperature and occlusion, also have their impact on the actual input (rate) of drug through human skin. Finally, all bits of information are combined to form a reasonably faithful picture of percutaneous absorption. 相似文献