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991.
P. M. L. A. van den Bemt A. C. G. Egberts A. W. Lenderink J. M. Verzijl K. A. Simons W. S. C. J. M. van der Pol H. G. M. Leufkens 《European journal of clinical pharmacology》1999,55(2):155-158
Objective: This study investigated the relative value of adverse drug events reported by doctors, nurses and patients.
Methods: The study was conducted on a total of four wards: the paediatric and internal medicine wards (including geriatric patients)
of two peripheral hospitals in the Netherlands. Adverse drug events were collected by spontaneous reporting (doctor and nurse
reports) and by daily ward visits, during which the patients were interviewed by a hospital pharmacist (patient reports).
Criteria for relative value of the reported adverse drug events were the number of potentially serious reactions, the number
of reactions not mentioned in the patient information leaflet and the number of reactions reported to new drugs (5 years or
less on the Dutch market). No formal causality assessment was applied.
Results: Over a period of 2 months in 1996 (Hospital I) and 2 months in 1997 (Hospital II) a total of 620 patients were included
in the study and adverse drug events were reported in 179 (29%) of these cases. Doctors reported a statistically significant
larger number of serious (26% of all doctor reports; odds ratio (OR) 3.2; confidence interval (CI) 1.2–8.7) and unknown (39%;
OR 2.5; CI 1.0–6.0) adverse drug events than patients themselves during the daily ward visit. Doctors also reported more serious
and unknown adverse drug events than nurses. Adverse reactions to new drugs were reported during the daily ward visit only
(8% of all daily ward visit reports).
Conclusion: This study reconfirms that doctors are the main source for reports of serious and unknown adverse drug events in hospitalized
patients. However, patients themselves seem to report more adverse reactions to new drugs (during the daily ward visit). By
focusing on patients using new drugs, the daily ward visit might become cost-effective. This needs to be explored in future
studies.
Received: 10 September 1998 / Accepted in revised form: 30 November 1998 相似文献
992.
Statins and peripheral neuropathy 总被引:3,自引:0,他引:3
Jeppesen U Gaist D Smith T Sindrup SH 《European journal of clinical pharmacology》1999,54(11):835-838
Within the past 3 years seven cases of reversible peripheral neuropathy apparently caused by statins have been reported.
Here we report seven additional cases associated with long-term statin therapy, in which other causes of neuropathy were thoroughly
excluded. The neuropathy was in all cases axonal and with affection of both thick and thin nerve fibers. The symptoms of neuropathy
persisted during an observation period lasting from 10 weeks to 1 year in four cases after statin treatment had been withdrawn.
We suggest that long-term statin treatment may be associated with chronic peripheral neuropathy.
Received: 6 July 1998 / Accepted in revised form: 1 October 1998 相似文献
993.
T. J. De Vries Anton N. M. Schoffelmeer R. Binnekade Louk J. M. J. Vanderschuren 《Psychopharmacology》1999,143(3):254-260
Rationale: The neurobiological mechanisms underlying the persistence of drug craving in detoxified addicts are still poorly understood.
Objective: The present study was designed to evaluate dopaminergic mechanisms in drug-seeking behaviour following long-term (>3 weeks)
extinction of IV drug self-administration in rats. Methods: To that end, we studied the effects of direct and indirect dopamine (DA) agonists on reinstatement of previously extinguished
responding for heroin (50 μg/kg per injection; 14–15 daily 3-h sessions) and cocaine (500 μg/kg per injection; 10–11 daily
2-h sessions). Results: In animals with a cocaine history, priming with cocaine, the selective DA reuptake inhibitor GBR-12909 and the DA D2 receptor agonist quinpirole resulted in robust and selective reinstatement of non-reinforced nose poking behaviour in the
previously drug-paired hole. In contrast, the D1 agonist SKF-82958 failed to reinstate responding and the non-selective DA agonist apomorphine even suppressed responding
in these animals. In heroin-trained rats, heroin and GBR-12909 strongly reinstated responding, whereas all direct DA agonists
were ineffective. Again, the two highest doses of apomorphine decreased responding in these animals. In a parallel study,
the ability of DA ligands to express behavioural sensitization in animals pretreated with amphetamine or morphine was evaluated.
Interestingly, all agonists that reinstated responding in the present study caused expression of locomotor sensitization and
vice versa. Conclusions: The differences between direct and indirect agonists indicate a clear, but complex, involvement of DA in drug-seeking behaviour
long after detoxification. Moreover, the results show an important role of D2 receptor activation in the persistence of cocaine- but not heroin-seeking behaviour. Finally, the results from both studies
suggest a relationship between drug-induced reinstatement and drug hyperresponsiveness in long-term abstinent rats.
Received: 14 May 1998 / Final version: 1 December 1998 相似文献
994.
Rationale: Previous research using an amphetamine (AM)-haloperidol (HA) drug- drug discrimination task has shown that predominant responding
on the HA-appropriate lever occurs 24 h after a single or multiple administrations of 10 mg/kg AM. Conversely, rebound responding
on the AM-appropriate lever occurs following single or multiple administrations of 1 mg/kg HA. HA-appropriate responding was
also observed 24 h following a single injection of AM using a three-lever, AM-vehicle-HA discrimination task. However, a single
administration of HA did not produce robust rebound responding on the AM-appropriate lever. The present studies seek to clarify
the discrepancy between responding following HA in the two- and three-choice tasks. Objective: Experiment 1 examined the extent of rebound responding that could be achieved following ten daily administrations of either
10 mg/kg AM or 1 mg/kg HA. Experiment 2 explored potential differences between the two- and three-choice tasks in characterizing
the post-HA cue. Methods: Animals were trained to discriminate 0.35 mg/kg AM, vehicle, and 0.033 mg/kg HA. In experiment 1, animals received ten daily
injections of 10 mg/kg AM, vehicle, or 1 mg/kg HA, and were tested 24 h after the final injection, and again 8, 15, and 22
days post-treatment. In experiment 2, animals were retrained and then treated daily with either vehicle or 1.0 mg/kg HA for
10 days, and then tested 24 h after the final injection, and again 5 and 11 days post-treatment, with either all three levers
or with only the AM- and HA-appropriate levers available. Results: In experiment 1, multiple injections of AM produced robust HA lever responding, which is consistent with results from previous
studies that used the two-choice, AM-HA discrimination task. However, multiple injections of HA did not produce predominant
responding on the AM-appropriate lever. In experiment 2, animals treated with either vehicle or HA responded predominantly
on the vehicle-appropriate lever when tested with all three levers present. When tested with the vehicle lever removed, however,
animals treated with vehicle responded predominantly on the HA-appropriate lever, whereas those treated with HA responded
predominantly on the AM-appropriate lever. Conclusions: These results suggest that the two-choice and three-choice task used here differ in how the post-HA withdrawal cue is characterized.
This finding emphasizes the importance of knowing the relative locations of the agonist-, vehicle-, and antagonist-produced
cues on the interoceptive stimulus continuum established by discrimination training.
Received: 3 December 1997/Final version: 16 November 1998 相似文献
995.
Chantal Etievant Jean-Marc Barret Anna Kruczynski Dominique Perrin Bridget T. Hill 《Investigational new drugs》1999,16(1):3-17
Vinflunine (VFL) is a novel derivative of vinorelbine (NVB, Navelbine®), which has shown markedly superior antitumor activity to NVB, in various experimental animal models. To establish whether this new Vinca alkaloid participates in P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), VFL-resistant murine P388 cells (P388/VFL) were established in vivo and used in conjunction with the well established MDR P388/ADR subline, to define the in vivo resistance profile for VFL. P388/VFL cells proved cross-resistant to drugs implicated in MDR (other Vinca alkaloids, doxorubicin, etoposide), but not to campothecin or cisplatin and showed an increased expression of Pgp, without any detectable alterations in topoisomerase II or in glutathione metabolism. The P388/ADR cells proved cross-resistant to VFL both in vivo and in vitro, and this VFL resistance was efficiently modulated by verapamil in vitro. Cellular transport experiments with tritiated-VFL revealed differential uptake by P388 sensitive and P388/ADR resistant cells, comparable with data obtained using tritiated-NVB. In various in vitro models of human MDR tumor cells, whilst full sensitivity was retained in cells expressing alternative non-Pgp-mediated MDR mechanisms, cross resistance was identified in Pgp-overexpressing cells. Differences were, however, noted in terms of the drug resistance profiles relative to the other Vincas, with tumor cell lines proving generally least cross-resistant to VFL. Overall, these results suggest that VFL, like other Vinca alkaloids, participates in Pgp-mediated MDR, with tumor cells selected for resistance to VFL overexpressing Pgp, yet MDR tumor cell lines proved generally less cross resistant to VFL relative to the other Vinca alkaloids. 相似文献
996.
中药材珍珠的X衍射Fourier谱研究 总被引:18,自引:1,他引:17
目的:珍珠为常用名贵中药,应用粉未X衍射Fourier谱分析,建立各类珍珠的X衍射特征标记峰,对其进行鉴定。方法:西方应用粉未X衍射方法对珍珠贝科海水(天然与人工养殖)、淡水珍珠、蚌科三角帆蚌壳、珍珠未与珍珠层粉等9个榈进行了X衍射Fourier谱分析计算。结果:海水珍珠、淡水珍珠、珍珠粉与珍珠层粉中的主要成分为珍珠文石型碳酸钙;但后二者中尚含有10%以下方解石型碳酸钙。同时,获得了有别于文石矿的 相似文献
997.
Marina Ripamonti Laura Capolongo Giulia Melegaro Carlo Gornati Alberto Bargiotti Michele Caruso Maria Grandi Antonino Suarato 《Investigational new drugs》1996,14(2):139-146
Summary The relationship between different chemical modifications on morpholinylanthracyclines and their ability to overcome multidrug resistance (MDR) has been evaluated testing all compounds in vitro on LoVo and LoVo/DX human colon adenocarcinoma cells and in vivo on disseminated P388 and P388/DX murine leukemias.Results obtained led us to the following conclusions: 1) the insertion of the morpholinyl or the methoxymorpholinyl group on position 3 of the sugar moiety confers the ability to overcome MDR in vitro and in vivo; conversely, 4 morpholinyl compounds are effective on MDR cells only in vitro and result inactive in vivo on DX-resistant leukemia; 2) all chemical modifications performed on 3 morpholinyl or methoxymorpholinyl derivatives, that is substitutions on the aglycone or on position 2 of the morpholino ring, do not interfere with the activity of the compounds: all derivatives present in fact the same efficacy on sensitive and resistant models.It is concluded that position 3 in the sugar moiety plays a crucial role in the ability of morpholinylanthracyclines to overcome MDR. 相似文献
998.
Purpose. Oral bioavailability for antisense oligonucleotides has recently been reported but the mechanistic details are not known. The proposed oral delivery of nucleic acids will, therefore, require an understanding of the membrane binding interactions, cell uptake and transport of oligonucleotides across the human gastro-intestinal epithelium. In this initial study, we report on the cell-surface interactions of oligonucleotides with human intestinal cells.
Methods. We have used the Caco-2 cell line as an in vitro model of the human intestinal epithelium to investigate the membrane binding interactions of 20-mer phosphodiester (PO) and phosphorothioate (PS) oligonucleotides.
Results. The cellular association of both an internally [3H]-labelled and a 5end [32P]-labelled PS oligonucleotide (3.0% at 0.4 µM extracellular concentration) was similar and was an order of magnitude greater than that of the 5end [32P]-labelled PO oligonucleotide (0.2%) after 15 minutes incubation in these intestinal cells. The cellular association of PS was highly saturable with association being reduced to 0.9% at 5 µM whereas that of PO was less susceptible to competition (0.2% at 5 µM, 0.1% at 200 µM). Differential temperature-dependence was demonstrated; PS interactions were temperature-independent whereas the cellular association of PO decreased by 75% from 37°C to 17°C. Cell association of oligonucleotides was length and pH-dependent. A decrease in pH from 7.2 to 5.0 resulted in a 2- to 3-fold increase in cell-association for both backbone types. This enhanced association was not due to changes in lipophilicity as the octanol:aqueous buffer distribution coefficients remained constant over this pH range. The ability of NaCl washes to remove surface-bound PS oligonucleotides in a concentration-dependent manner suggests their binding may involve ionic interactions at the cell surface. Cell-surface washing with the proteolytic enzyme, Pronase®, removed approximately 50% of the cell-associated oligonucleotide for both backbone types.
Conclusions. Binding to surface proteins seems a major pathway for binding and internalization for both oligonucleotide chemistries and appear consistent with receptor (binding protein)-mediated endocytosis. Whether this binding protein-mediated entry of oligonucleotides can result in efficient transepithelial transport, however, requires further study. 相似文献
999.
Lue?en Henrik. L. de Leeuw Bas. J. Langeme?er Mariska W. E. de Boer A. G. Verhoef J. Coos. Junginger Hans E. 《Pharmaceutical research》1996,13(11):1668-1672
Purpose. To evaluate the effect of the crosslinked poly(acrylate) carbomer 934P (C934P) and its freeze-dried neutralized sodium salt (FNaC934P) as well as chitosan hydrochloride on the intestinal absorption of the peptide drug buserelin.
Methods. Buserelin was applied intraduodenally in control buffer, 0.5% (w/v) C934P, 0.5% (w/v) FNaC934P, 1.5% (w/v) chitosan hydrochloride or FNaC934P/chitosan hydrochloride (1:1 (v/v)) mixture in rats.
Results. All polymer preparation showed a statistically significant improvement of buserelin absorption compared to the control solution. The absolute bioavailabilities for the different polymer preparations were: control, 0.1%; 0.5% FNaC934P, 0.6%; 0.5% C934P, 2.0%; chitosan hydrochloride, 5.1% and FNaC934P/chitosan hydrochloride (1:1 (v/v)) mixture, 1.0%. The higher bioavailability with chitosan hydrochloride compared to C934P and FNaC934P indicates that for buserelin the intestinal transmucosal transport enhancing effect of the polymer plays a more dominant role than the protection against proteases such as -chymotrypsin.
Conclusions. The mucoadhesive polymers carbomer 934P and chitosan hydrochloride are able to enhance the intestinal absorption of buserelin in vivo in rats, and may therefore be promising excipients in peroral delivery systems for peptide drugs. 相似文献
1000.
R. Lupu M. Cardillo C. Cho L. Harris M. Hijazi C. Perez K. Rosenberg D. Yang C. Tang 《Breast cancer research and treatment》1996,38(1):57-66
Summary TheerbB-2 receptor plays an important role in the prognosis of breast cancer and is expressed at high levels in nearly 30% of tumors in breast cancer patients. While evidence accumulates to support the relationship betweenerbB-2 overexpression and poor overall survival in human breast cancer, understanding of the biological consequence(s) oferbB-2 overexpression remains elusive. The discovery ofheregulin has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through theerbB-2/4 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance, and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in human breast cancer. Preliminary studiesin vitro have shown thatheregulin induces a biphasic growth effect on cells witherbB-2 overexpression. Interestingly, we observed that expression ofheregulin correlates with a more aggressive/invasive, vimentin-positive phenotype in breast cancer cells lines. Therefore, we have postulated thatheregulin is involved in breast cancer tumor progression. We have shown thatheregulin inducesin vitro chemoinvasion and chemotaxis of breast cancer cells as well as growth in an anchorage dependent and independent manner. Interestingly, aheregulin neutralizing antibody inhibits chemotaxis and results in cell growth inhibition and blockade of the invasive phenotype. Strikingly, genetically engineered cells which constitutively expressheregulin demonstrate critical phenotypic changes that are associated with a more aggressive phenotype. Specifically, these cells are no longer dependent on estrogen for growth and are resistant to tamoxifenin vitro andin vivo, and moreover these cells metastasize to lymph nodes in athymic nude mice. These tumors appear to have lostbcl-2 expression as compared with the control tumors. In addition, presumably by activation/regulation of topoisomerase II, theheregulin-transfected cells become exquisitely sensitive to doxorubicin and VP-16. Clearly, mechanistic aspects of theerbB-2/4 andheregulin interaction need to be understood from a therapeutic standpoint which could provide additional insights into synergistic treatments for certain patients, or improve treatment regimens for a large number of women. The study ofheregulin and its co-expression witherbB-2/4 receptor and the assessment of its involvement in the progression from the in situ stage of breast tumors to the invasive one will additionally increase the relevance ofheregulin as a prognostic/diagnostic factor. We believe that our studies provide new insights into breast cancer diagnosis, prognosis, and treatment.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb. 相似文献