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41.
Alexander Mülsch Markus Hecker Petr I. Mordvintcev Anatoly F. Vanin Rudi Busse 《Naunyn-Schmiedeberg's archives of pharmacology》1993,347(1):92-100
Summary The molecular mechanism(s) underlying the vasodilator activity of CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnonimine) and its metabolites 3-(cis-2,6-dimethylpiperidino)-sydnonimine (C87 3754) and N-(cis-2,6-dimethylpiperidino)-N-nitroso-2-aminoacetonitril (C873786) was investigated. These compounds were tested for their relaxant activity in isolated rabbit arterial segments, activation of purified soluble guanylyl cyclase and release of nitric oxide (NO) in vitro and in vivo. C873754 and C873786 inhibited the noradrenalin-induced contraction and increased the cyclic GMP content of endothelium-denuded rabbit aortic and femoral segments, whereas CAS 936 was without effect. Similarly, both metabolites, but not CAS 936, activated purified soluble guanylyl cyclase (EC50 about 30 M) and released NO in buffered aqueous solutions, as detected by electron spin resonance (esr) spectrometry. Both in vitro and in vivo an accumulation of NO was detected by esr spectrometry in vascular tissues exposed to the metabolites of CAS 936, whereas a significant release of NO from CAS 936 was only detected in the isolated rabbit liver, but not in vascular tissue. It is conceivable, therefore, that the metabolites of CAS 936 appearing in the systemic circulation after hepatic biotransformation induce vasodilatation by release of NO and activation of soluble guanylyl cyclase in vascular smooth muscle. Moreover, the activation of soluble guanylyl cyclase in vitro by the metabolites of CAS 936 was significantly enhanced by co-incubation with certain particulate fractions from bovine aortic endothelial and smooth muscle cells. Thus, an enzymic release of NO from these metabolites in addition to their spontaneous decomposition may play a significant role for their vasodilator activity in vivo.Correspondence to A. Mülsch at the above address 相似文献
42.
Summary Ca2+ influx into stimulated endothelial cells is attenuated by depolarization. We hypothesized that Ca2+ influx is driven by the membrane potential and may be enhanced by hyperpolarizing drugs like activators of K+ channels. Therefore we studied the effects of pinacidil, cromakalim, and cicletanine on membrane currents and on the intracellular free calcium concentration ([Ca2+]i) in cultured endothelial cells from porcine aorta. In patch-clamped cells, pinacidil (1 mol/l) and cromakalim (1 mol/l) elicited outward currents carried by K+ and significantly prolonged the Ca2+-dependent K+ currents induced by bradykinin and ATP. Peak currents in response to bradykinin were not affected. In cells loaded with the fluorescent Ca2+ indicator indo-1 and prestimulated with thimerosal, pinacidil (0.1–1 mol/l elicited long-lasting increases in [Ca2+)i from 100 ± 10 to 550 ± 110 nmol/l. These effects were completely abolished in a medium containing 90 mmol/l K+. Similar results were obtained with cromakalim. Likewise, in cells stimulated with bradykinin, pinacidil raised [Ca2+]i when applied during the decline of [Ca2+]i after the initial peak. Cicletanine elicited K+ currents in resting and attenuated K+ currents in bradykinin-stimulated cells. It elevated [Ca2+]i even in the absence of extracellular Ca2+ and in K+-rich medium. Hence, the effects of cicletanine cannot be explained by direct actions on K+ channels. However, our studies demonstrate that pinacidil and cromakalim elevate [Ca2+]i secondary to their activation of K+ channels by inducing hyperpolarization and augmenting the driving force for potential-dependent Ca2+ influx. In this way, the two drugs may promote Ca2+-dependent formation of endothelium-derived relaxing factor.
Send offprint requests to A. Lückhoff at the above address 相似文献
43.
Lukas Wettstein Patrick Immenschuh Tatjana Weil Carina Conzelmann Yasser Almeida-Hernández Markus Hoffmann Amy Kempf Inga Nehlmeier Rishikesh Lotke Moritz Petersen Steffen Stenger Frank Kirchhoff Daniel Sauter Stefan Pöhlmann Elsa Sanchez-Garcia Jan Münch 《Journal of medical virology》2023,95(1):e28124
Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored. 相似文献
44.
Through the recent National Health Insurance Act (NHIA), the Philippines have committed themselves to introducing a social health insurance with universal coverage within 15 years. Germany was the first country to introduce a social health insurance system more than 100 years ago. Its system is based on the principles of corporatism, federalism and a mandate for equity. Based on a long-term German experience with equity, quality, cost and efficiency issues, the Philippines' NHIA is analysed concerning the entitlement to benefits and the benefit package, the organization of the health insurance programme, health insurance financing, and provider payment mechanisms. It is suggested that the Philippines could profit from including preventive and promotive services as well as pharmaceuticals in the benefits package. The organization of the health insurance system could be decentralized using the 13 regions as its principal units. To achieve financial equity between regions and health funds, a contribution compensation scheme is proposed. To prevent over-utilization in over-served areas and to promote utilization in under-served areas, a relative value scale for fee-for-service payments seem advisable. 相似文献
45.
The role of the common cold in asthma 总被引:1,自引:0,他引:1
Busse WW 《Journal of clinical pharmacology》1999,39(3):241-245
It has long been known that patients with viral respiratory infections develop temporary asthma-like symptoms or see a worsening of their existing asthmatic symptoms or develop full-blown asthma during the infection. It should not be surprising, in view of this observation, that these same viruses have been found to initiate the same inflammatory processes as seen and characterized in the asthmatic patient. This has clear implications for therapy of asthmatic patients. 相似文献
46.
The Medicinal Chemistry Section of IUPAC sent a questionnaire regarding academic training for medicinal chemists to major research pharmaceutical companies in various countries in July 1992 and again in July 1993. A total of 102 replies were received from 65 companies, mainly from Germany, Italy, Japan, the UK and the USA, and these have been analysed and the results are presented. Most companies (> 90%) indicated that they seek to hire organic chemists who may have received some additional education in medicinal chemistry, rather than hire specialists in medicinal chemistry. The subjects most often mentioned as being desirable for the additional education were biochemistry (or drug metabolism and pharmacokinetics), pharmacology and physiology, computer modelling and QSAR, and molecular biology. 相似文献
47.
H J Busse R Nilius 《Deutsche Zeitschrift für Verdauungs- und Stoffwechselkrankheiten》1983,43(6):241-245
A thickening of the stomach or intestinal wall as a result of neoplastic or inflammatory infiltrations can be principally recognized by sonography as a "Cocarde phenomen". The question of the accuracy of ultrasonic tomography in the recognition of infiltrative diseases of the gastrointestinal tract has been examined in a prospective study. 80 patients who were suspected of having such a disease were sonographed, using the real-time method. The diagnose were verified by an adequate comparative method, by surgery or autopsy. An infiltrative gastrointestinal disease was correctly diagnosed by sonography in 42 cases, including nine cases of gastric carcinoma and of 27 colon carcinoma. Two patients were suffering of Crohn's disease, and in the remaining four cases the final diagnoses were bulbitis, Ménétrier's disease, diverticulitis and penetrating ulcus ventriculi, respectively. In 27 cases an infiltrative gastro-intestinal disease was correctly exclused by sonography. Ultrasonic examination wrongly produced a negative diagnosis in five cases and a positive in six. Thus, the efficiency of the examination was 0,86, the sensitivity 0,89 and the specifity 0,82. Ultrasonic tomography should therefore be assigned a major place in gastrointestinal diagnostics, too. It could point the way in many cases. It is not possible, however, to exclude a disease by means of sonography. 相似文献
48.
Summary The effects of angiotensin-converting enzyme (ACE) inhibitors on intracellular calcium concentration ([Ca2+]i) were examined under resting conditions and after stimulation with bradykinin in cultured human umbilical vein endothelial cells. The ACE inhibitors ramiprilat and enalaprilat (0.3 M) enhanced the increase in [Ca2+]i elicited by bradykinin (3 nM) and also caused an increase in resting [Ca2+]i when given alone. This increase in resting [Ca2+]i was long-lasting and accompanied by an increased formation of nitric oxide, as assessed by a NG-nitro-l-arginine-sensitive cyclic GMP accumulation in the cells. Both increases in resting [Ca2+]i and nitric oxide production by ACE inhibitors were inhibited by preincubation of the cells with the B2-receptor antagonist Hoe 140. These data indicate that ACE inhibitors are able to unmask a release of bradykinin from cultured human endothelial cells. This endothelium-derived bradykinin can exert an autocrine function by stimulating endothelial B2-receptors with a subsequent increase in [Ca2+]i and nitric oxide formation.
Send offprint requests to R. Busse at the above address 相似文献
49.
T L Busse M L Khristova V I Simonov A A Kushch V M Stakhanova I G Kharitonenkov 《Voprosy virusologii》1991,36(5):361-364
A competitive time-resolved fluoroimmunoassay (TR-FIA) system for the detection of antibodies to protein p24 of HIV was developed on the basis of monoclonal antibodies. The advantages of this test system over analogous enzyme immunoassay system and commercial test system "Antigen" (USSR) were demonstrated. The newly developed test system of TR-FIA was used for examination of sera from HIV-infected persons. 相似文献
50.
Paul M. Busse M.D. Ph.D. Blake Cady M.D. Albert Bothe Jr. M.D. Roger Jenkins M.D. William V. McDermott M.D. Glenn Steele Jr. M.D. Ph.D. Michael D. Stone M.D. 《World journal of surgery》1991,15(3):352-356
The recognition of a high incidence of local failure following surgical management of adenocarcinoma of the gallbladder has led to the use of adjuvant radiation therapy. In order to deliver higher doses to the gallbladder bed, intraoperative radiation therapy (IORT) has been used both with and without external beam radiation.The experience to date is reviewed. Ten patients have been treated, all of whom had either gross residual or unresected disease. The median survival for the group was approximately 1 year. There were no long-term survivors. The IORT did not contribute to the overall morbidity.Because of the limited number of patients and the advanced nature of the disease, the role of IORT in the management of gallbladder carcinoma has yet to be determined. The utility of this modality will most likely reside in the treatment of minimal residual disease at the time of cholecystectomy rather than in the palliative treatment of unresectable tumors.
Resumen El reconocimiento de la elevada tasa de falla local en el tratamiento del adenocarcinoma de la vesícula biliar, ha motivado el uso de radioterapia adyuvante. Con el objeto de administrar altas dosis de irradiación al lecho de la vesícula billiar, se ha utilizado la radioterapia intraoperatoria (RTIO) con y sin irradiación externa.Se revisa la experiencia hasta la fecha. Diez pacientes han sido tratados, todos con enfermedad macroscópica residual o no resecable. La sobrevida media para el grupo fue de aproximadamente un año; no hay sobrevivientes a largo plazo. La RTIO no contribuyó a la morbilidad global.Debido al limitado número de pacientes y a lo avanzado de la enfermedad, el rol de la RTIO está aun por determinar. La utilidad de esta modalidad muy posiblemente habrá de residir en el tratamiento de enfermedad residual miima en el momento de la colecistectomiá, más qu en el tratamiento paliativo de tumores no resecables.
Résumé Reconnaître la fréquence importante des échecs locaux à la suite du traitement chirurgical de l'adénocarcinome de la vésicule a amené à ajouter la radiothérapie. Pour pouvoir donner des doses plus importantes au lit de la vésicule, l'irradiation peropératoire (IP) a été administrée à la fois avec et sans irradiation externe. L'expérience à ce jour a été passée en revue. Dix patients ont été traités qui avaient soit une grosse tumeur résiduelle soit un cancer non réséqué. La survie moyenne du groupe était d'un an à peu près. Il n'y a eu aucun survivant à long terme. L'IP n'a rien changé à la mortalité globale. Compte tenu du nombre limité des patients et de la nature avancée de la maladie, le rôle de l'IP dans le traitement du cancer de la vésicule reste à déterminer. La valeur de l'IP sera probablement de traiter la petite tumeur résiduelle au moment de la cholécystectomie plutôt que les tumeurs non résécables.相似文献