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61.
Neurotoxic effects of colchicine: Differential susceptibility of CNS neuronal populations 总被引:1,自引:0,他引:1
Colchicine injected into the dentate gyrus of the hippocampus in adult rats preferentially destroys dentate granule cells. In the present study, we examine the light- and electron-microscopic correlates of the degeneration and evaluate whether the selectivity is preserved across the range of doses between 0.18 and 25 μg. Colchicine in a similar dose range was also injected into the cerebellum, olfactory bulb, striatum and cerebral cortex to examine local and regional differences in susceptibility to colchicine.The morphological changes accompanying degeneration in the dentate gyrus include fragmentation of the granule cell layer, appearance of small dark staining bodies in the cell layer, massive microglial invasion and profound disruption of granule cell axons and dendrites. Electron-microscopic observations suggest that the small dark bodies are probably condensed nuclei. The preferential vulnerability of dentate granule cells following intrahippocampal injection was observed at all doses. At doses between 0.18 and 2.5 μg there was little evidence of damage to neurons other than dentate granule cells. At the highest dose tested (25 μg) some pyramidal cells of regio superior near the injection site were destroyed, while granule cell destruction extended several mm from the injection site. Injection of 0.5–25 μg into the cerebellum resulted in the destruction of both granule cells and Purkinje cells, while cells which appeared to be neurons in the molecular layer were less affected. Following injection of 0.5 μg into the olfactory bulb, granule cells were extensively destroyed and there appeared to be some loss of mitral cells and an overall shrinkage of the injected bulb. Neuronal destruction in the striatum was observed with colchicine injections ranging from 2.5 to 25 μg, but at a given dose, the destruction was less extensive than for any other region tested except cerebral cortex.A possible application of this method and the implications of these results for other investigators using colchicine in the brain are discussed. 相似文献
62.
X-linked juvenile retinoschisis (XLRS, OMIM: 312700) s an inherited X-linked recessive vitreoretinal dystrophy that is a leading cause of juvenile retinal degeneration, with a worldwide prevalence ranging from 1:5 000 to 1:25 000. Finland has the highest reported incidence. The condition is characterized by microcystic- like changes of the macular region of the retina and schisis, 相似文献
63.
《Pharmaceutical development and technology》2013,18(8):930-941
AbstractThe aim of this study was to compare the specific characteristics of the S-enantiomer and the racemate of amlodipine besylate (AB) in order to design a robust and stable formulation of the active S-enantiomer which will guarantee continuous performance of the unichiral version of amlodipine.Preformulation studies showed that the S-enantiomer and the racemate exhibit different crystal morphology, particle size distribution and higroscopicity. The S-enantiomer exhibited significantly lower melting temperature compared to the racemate which was in accordance with its higher water solubility and its increased intrinsic dissolution rate. The thermograms of S-amlodipine besylate indicated that dehydration and melting occur at almost the same time and the dehydration event overlaps with the melting peak. Forced degradation tests conducted on both substances showed high levels of degradation into amlodipine related substance D as well as other impurities.Tablets prepared with S-AB, simulating originator’s formulation, failed in stability tests due to drug incompatibility with calcium hydrogen phosphate. Therefore, a tablet formulation based on excipients which were confirmed compatible with S-AB was developed and optimized using full factorial design to obtain a dissolution profile comparative to the brand product. Stability studies conducted at 40?°C/75% relative humidity (RH) confirmed that appearance, drug content and drug release of the optimized tablet formulation remained within the recommended limits. 相似文献
64.
《Pharmaceutical development and technology》2013,18(3):701-709
Pilocarpine is used topically in the treatment of glaucoma. Various studies were performed to improve the bioavailability and prolong the residence time of drugs in ocular drug delivery. Drug loaded polymeric and lipid nanoparticles offer several favourable biological properties, such as biodegradability, nontoxicity, biocompatibility and mucoadhesiveness. Therefore, preparing positively-charged pilocarpine HCl-loaded polymeric and lipid nanoparticles was the purpose of this study. Nanoparticles were prepared by quasi-emulsion solvent evaporation technique. The non-biodegradable positively-charged polymer Eudragit® RS 100 and semi-solid lipid excipient Gelucire® 44/14 were used as a vehicle, the cationic lipid octadecylamine was used as a cationic agent. The formulations were evaluated in terms of particle size, size distribution, zeta potential measurement, thermal behavior (Differential Scanning Calorimetry DSC), entrapment efficacy and pH. Characterizations of nanoparticles were analyzed during the storage period of 6 months for stability tests. Polymeric and lipid nanoparticles could be prepared successfully promising their use for ophthalmic delivery. 相似文献
65.
66.
Anna Maria Pugliese M Beatrice Passani Renato Corradetti 《British journal of pharmacology》1998,124(1):93-100
- The actions of N-(2-(-4(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635), a novel and selective 5-hydroxytryptamine1A (5-HT1A) antagonist, on excitatory postsynaptic potentials (e.p.s.ps) were investigated by use of intracellular recordings in pyramidal cells of the CA1 region of rat hippocampal slices.
- WAY 100635 (10 nM) did not affect any of the investigated parameters of cell excitability such as membrane potential, total input resistance (Rin), firing threshold, action potential amplitude, action potential frequency adaptation, and slow afterhyperpolarization (sAHP) which follows repetitive firing of action potentials. WAY 100635 did not have any effect on either the slope or the amplitude of e.p.s.ps evoked by stimulation of the CA1 stratum radiatum.
- Bath application of either 5-hydroxytryptamine (5-HT, 10–30 μM) or 5-carboxamidotryptamine (5-CT, 300 nM) hyperpolarized the membrane potential (ΔVm=−4.1±0.9 and −6.0±0.9 mV, respectively), and reduced Rin (−25±8% and −18±1%, respectively). 5-HT blocked the action potential frequency adaptation and significantly reduced the amplitude of the sAHP that follows repetitive firing of action potentials.
- 5-HT significantly decreased the amplitude of evoked e.p.s.ps (−14±6%). This effect was greater in the presence of the GABAA receptor antagonist bicuculline (10 μM, −45±12%) and was mimicked by 5-CT (−49±5%). Both AMPA and NMDA components of e.p.s.ps were significantly reduced in amplitude by 5–HT (−38±8%, n=6, and −29±12%, n=3, respectively; P<0.05).
- WAY 100635 fully antagonized the hyperpolarization, the reduction of Rin, and the decrease in amplitude of e.p.s.ps elicited by 5-HT, while it did not affect the action of 5-HT on the action potential frequency adaptation. In the presence of WAY 100635, 5-HT elicited a depolarization which was blocked by 10–30 μM RS 23597-190, a selective 5-HT4 receptor antagonist.
- Our data demonstrate that WAY 100635 is devoid of direct effects on CA1 pyramidal cell excitability and on evoked e.p.s.ps, while it fully antagonizes the effects of 5-HT on excitatory synaptic transmission and on hyperpolarization, without affecting the 5-HT4 receptor-mediated response. Since WAY 100635 selectively antagonizes 5-HT1A receptor-mediated actions of 5-HT, our data also demonstrate that the inhibitory action of 5-HT on excitatory synaptic transmission in CA1 is mediated by 5-HT1A receptors.
67.
Since 1999, many laboratories have confirmed that mutations in the MECP2 gene are the primary cause of Rett syndrome (RTT or RS) and identified mutations in 70 to 90% of the sporadically affected girls. Most of the screenings are PCR-based and restricted to the coding part of the gene and therefore prone to miss gross rearrangements. By Southern blot analysis we identified large deletions (>1 kb) in three female patients with classical, severe Rett syndrome. Further characterization by semi-quantitative PCR and amplification of junction fragments confirmed the presence of a 7.6-kb deletion in one patient and an 8.1-kb deletion in the other patient, both including exon 3 and the coding part of exon 4. The exact nature of the rearrangement in the third patient remained elusive. These results underline the importance of screening for major genomic rearrangements in Rett syndrome. Hum Mutat 22:116-120, 2003. 相似文献
68.
Linda S. Richardson Robert B. Belshe William T. London D. Lewis Sly David A. Prevar Ena Camargo Robert M. Chanock 《Journal of medical virology》1978,3(2):91-100
Approximately 104 plaque-forming units (pfu) of five temperature-sensitive (ts) mutants of respiratory syncytial (RS) virus were administered intranasally to seronegative chimpanzees to evaluate their level of attenuation. When the ts-1 mutant was given to two chimpanzees, the pattern of viral growth and illness (rhinorrhea) was similar to that seen during wild-type RS virus infection. Two further defective subclones of ts-1, ts-1 NG-1 and ts-1 NG-16, appeared more attenuated than ts-1 with respect to severity of rhinorrhea. The ts-7 mutant infected the one animal tested; illness was similar to that induced by ts-1 or wild-type virus. 104 pfu of the ts-2 mutant failed to infect two chimpanzees; virus was not isolated, a serum antibody response was not detected, and unlike chimpanzees given the other ts mutants, these animals were not resistant to challenge with wild-type virus. A 40-fold larger inoculum of ts-2, 105, 6pfu, infected each of four chimpanzees, but the peak quantity of virus shed was approximately 500-fold lower than during wild-type virus infection. Significantly, the ts-2 infected chimpanzees did not become ill, but infection did stimulate the development of RS virus serum neutralizing antibodies. The one chimpanzee given 107, 6 pfu of the ts-2 mutant shed as much virus as the chimpanzees infected with wild-type virus; however, there were no signs of upper respiratory tract illness. Owl monkeys resembled chimpanzees in shedding s large amount of virus and developing rhinorrhea following administration of wild-type virus or the ts-1 mutant. Significantly, 105, 3 pfu of ts-2 infected only one of two owl monkeys tested, but a small quantity of virus (>10 pfu/ml) was shed. These observations suggested that the ts-2 mutant was the most attenuated vaccine cadidate strain tested, and that extent of infection with rs-2 appeared to be related to the quantity of virus administered. 相似文献
69.
Johanna M. Colijn Anneke I. den Hollander Ayse Demirkan Audrey Cougnard-Grégoire Timo Verzijden Eveline Kersten Magda A. Meester-Smoor Benedicte M.J. Merle Grigorios Papageorgiou Shahzad Ahmad Monique T. Mulder Miguel Angelo Costa Pascale Benlian Geir Bertelsen Alain M. Bron Birte Claes Catherine Creuzot-Garcher Maja Gran Erke Markus Zumbansen 《Ophthalmology》2019,126(3):393-406
70.
Delivery systems controlling drug release only in the colon holds great promises since they improve utilization of drug and decrease the dosing times comparison with conventional forms. The aim of the present study was to prepare polymeric microparticles on the basis of Ciprofloxacin via oral route for the treatment of inflammatory bowel disease. Ciprofloxacin was selected because of its extensive coverage for intestinal flora, relatively favorable side-effect profile and preliminary data suggesting its efficacy in the treatment of active Crohn's Disease. Microparticles were prepared using different acrylic compounds, namely Eudragit® RL (PO) and RS (PO) and a mixture of both. Spray-drying was used as a preparation method of Ciprofloxacin/Eudragit® microparticles using a Mini Spray Dryer B-290 (Büchi, Postfach, Switzerland). In vitro dissolution studies were performed to choose the best formulation and selected microparticles were characterized by size and morphology by environmental scanning electron microscopy. Yield and encapsulation efficiency were calculated and in vivo/ex vivo experiments were investigated both of which suggest that selected microparticles can be used for colon targeting of drugs increasing residence time of the drug in the affected area. 相似文献