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61.
目的:对乳腺癌组织中,核苷酸切除修复交叉互补基因1(Excision repair cross comp-lementing,ERCC1)、Ki67蛋白、增殖细胞核抗原(Proliferating cell nuclear antigen,PCNA)表达与蒽环类化疗药物敏感性的关系进行探讨。方法:通过免疫组化法对93例乳腺癌组织的ERCC1、Ki67和PCNA表达进行检测;观察患者化疗疗效,对ERCC1、Ki67和PCNA表达水平不同患者使用蒽环类药物化疗的效果差异进行比较。结果:ERCC1的阳性率为65.59%,Ki67的阳性率为69.89%,PCNA的阳性率为64.52%。ERCC1阳性组总有效率为50.82%,ERCC1阴性组总有效率为84.38%;Ki67阳性组中,Ki67表达强度为25%~50%患者有效率为73.68%(14/19),50%~75%患者有效率为85.71%(24/28),75%患者有效率为88.89%(16/18),Ki67阴性组总有效率为60.71%;PCNA阳性组中,PCNA表达强度为25%-50%患者有效率为52.94%(9/17),50%~75%患者有效率为62.07%(18/29),75%患者有效率为71.43%(10/14),PCNA阴性组总有效率为81.82%,以上差异均有统计学意义(P0.01,P0.05,P0.05)。结论:乳腺癌患者ERCC1、Ki67和PCNA的表达情况与蒽环类化疗药物的敏感性均有相关关系,而在临床上对多因子的联合检测将更有助于化疗药物的选择以及化疗方案的制定。 相似文献
62.
目的研究卡培他滨在蒽环和紫杉类化疗失败的晚期乳腺癌的疗效和安全性,及其与激素受体和Her2状态与疗效关系。方法 61例晚期乳腺癌病人接受卡培他滨治疗,直到出现肿瘤进展或不能耐受毒性,分析其疗效及毒副反应。结果 CR、PR、SD和PD分别是1.7%、29.5%、39.3%和29.5%;ORR31.2%,临床获益率70.5%;平均缓解持续时间7.3个月,TTP6.0个月。ORR、临床获益率与TTP不受激素受体、Her2状态影响。大部分治疗相关性毒副反应是轻中度,可耐受。结论卡培他滨可能成为难治性转移性乳腺癌的治疗首选药物。 相似文献
63.
Tomas Simunek Martin Sterba Olga Popelova Helena Kaiserova Anna Potacova Michaela Adamcova 《Hemoglobin》2013,37(1-2):207-215
The risk of cardiotoxicity is the main drawback of anthracycline antibiotics. However, these drugs remain among the most effective and frequently used anti cancer drugs. In this study we aimed to assess the cardioprotective effects of aroylhydrazone iron (FE) chelators: pyridoxal isonicotinoyl hydrazone (PIH) and its two analogs: salicyladehyde isonicotinoyl hydrazone (SIH) and pyridoxal o-chlorbenzoyl hydrazone (o-108). In rabbits, chronic treatment with daunorubicin (DAU) (3 mg/kg weekly for 10 weeks) induced mortality (33%) as well as left ventricular (LV) dysfunction. Co-administrations of PIH (25 mg/kg, i.p.), SIH hydrochloride [1 mg/kg, iv] as well as o-108 (10 mg/kg, i.p.), fully prevented premature deaths and most of the DAU-induced functional impairments were significantly suppressed. However, when 2- to 2.5-fold higher doses of the chelators were used, they led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality. 相似文献
64.
《Toxicology mechanisms and methods》2013,23(6):488-498
Context: Doxorubicin is widely used anti-neoplastic drug but has serious cardiotoxicity. Long-term cardioprotective effects of statin and carvedilol against delayed cardiotoxicity of doxorubicin was not well elucidated.Objective: To evaluate long-term cardioprotective effects of co-administered rosuvastatin and carvedilol against chronic doxorubicin-induced cardiomyopathy (DIC) in rats.Methods: Sixty-one rats were assigned to six groups: group I, control; group II, doxorubicin only (1.25 mg/kg, bi-daily, I.P.); group III, doxorubicin + rosuvastatin (2 mg/kg/day, P.O.); group IV, doxorubicin + rosuvastatin(10 mg/kg/day, P.O.); group V, doxorubicin + carvedilol (5 mg/kg/day, P.O.); group VI, doxorubicin + carvedilol (10 mg/kg/day, P.O.). Drugs were administered for 4 weeks (by week 4) and rats were observed without drugs for 4 weeks (by week 8).Results: After 4 weeks discontinuation of drugs (week 8), group III showed higher +dP/dt (p = 0.058), lower ?dP/dt (p = 0.009), lower left ventricular (LV) tissue malondialdehyde (MDA; p = 0.022), and less LV fibrosis (p = 0.011) than group II. Group IV showed similar results to group III. However, in group V and VI, carvedilol failed to reduce LV dysfunction, elevation of troponin or myocardial fibrosis, although group V showed lower LV tissue MDA (p = 0.004) than group II.Discussion and conclusions: Myocardial injury and LV systolic/diastolic dysfunction at week 8 was alleviated by co-administered rosuvastatin, but not by carvedilol. It is unclear whether the cardioprotective effect of rosuvastatin is attributed to a suppression of oxidative stress induced by doxorubicin, because carvedilol did not exhibit a cardioprotective effect despite its antioxidant effects. 相似文献
65.
David Montaigne Xavier Marechal Riadh Baccouch Sebastien Preau Philippe Marchetti Remi Neviere 《Toxicology and applied pharmacology》2010,244(3):300-307
The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts.Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 μM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dtmax of 105 ± 8 mN/s in control hearts vs. 49 ± 7 mN/s in doxorubicin-treated hearts; ?p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 ± 0.2 in control hearts vs. 2.2 ± 0.2 in doxorubicin-treated hearts; ?p < 0.05) and cytochrome c oxidase kinetic activity (24 ± 1 μM cytochrome c/min/mg in control hearts vs. 14 ± 3 μM cytochrome c/min/mg in doxorubicin-treated hearts; ?p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity. 相似文献
66.
This paper reviews an early clinical experience with anthracycline (epirubicin; Epi or doxorubicin; Dox) containing an N-(2-hydroyxypropyl)methacrylamide copolymer carrier targeted with autologous or commercial human immunoglobulin in six patients aged 28–55 suffering from therapy-resistant metastatic cancer. More than 100 biochemical, hematological and immunological parameters, including nine tumor markers, were tested in blood samples taken 24 h after the first and up to 10 months after the last application. The intravenous application proceeded without serious adverse or side effects and did not require hospitalization. Cardiotoxicity was not observed. Four of six monitored patients attained stabilization of disease (liver ultrasound scan and bone computer tomography) with a very good quality of life lasting from seven up to 18 months. Positive response to the treatment was, among others, evaluated as decreased CA 15-3 and CEA tumor markers. In three of five tested patients the serum level of C-reactive protein was temporarily increased 72 h after the treatment. A stable or elevated number of peripheral blood reticulocytes together with activation of natural killer (NK) cells and lymphokine-activated killer (LAK) cells supports the data previously obtained in experimental animals pointing to a dual role, i.e. the cytotoxic and immunomobilizing character of doxorubicin–HPMA conjugates. 相似文献
67.
Cristiana Sessa Massimo Zucchetti Michele Ghielmini Jean Bauer Maurizio D'Incalci Jolanda de Jong Huguette Naegele Simona Rossi Maria Adele Pacciarini Letizia Domenigoni Franco Cavalli 《Cancer chemotherapy and pharmacology》1999,44(5):403-410
Purpose: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations
of its non-cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity
after oral administration. Methods: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 μg/m2. Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2–8, was required beginning
with the dose of 118 μg/m2. The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic
effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment
at all dose levels, were also assessed. Results: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 μg/m2, with neutropenia grade 3–4 in two of three patients. Dose-dependent nausea and vomiting were dose-limiting and the MTD for
gastrointestinal toxicity was fixed at 820 μg/m2, with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU
152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main
pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest
doses. The hematotoxicity tests showed a <70% colony growth inhibition with no correlation between the growth inhibition effect
and the degree of myelotoxicity in the same patient. Plasma concentrations of PNU 152243 were 1000 times lower than the concentration
inhibiting the growth of 70% of colonies. No objective tumor responses were seen. Conclusions: Owing to the occurrence of severe and prolonged nausea and vomiting, the clinical development of oral PNU 152243 was discontinued.
The higher-than-expected neutropenia and its lack of relationship with plasma levels of PNU 152243 and its 13-dihydroderivative
PNU 155051 might be related to the formation of potent cytotoxic metabolites present in human plasma at undetectable concentrations
and with prolonged half-life, as suggested by hematotoxicity tests performed with plasma from patients in GM-CFC assays.
Received: 1 February 1999 / Accepted: 9 April 1999 相似文献
68.
C. G. Alexopoulos G. Rigatos A. P. Efremidis A. Papacharalambous A. Alexopoulos M. Vassilomanolakis E. Patila 《Cancer chemotherapy and pharmacology》1999,44(3):253-258
Purpose: The aim was to study the effectiveness of docetaxel (Taxotere) in patients with advanced breast cancer treated previously
with polychemotherapy. Patients and methods: Forty-nine patients received docetaxel (100 mg/m2; 1-h i.v. infusion) and corticosteroid premedication. Forty-one patients who had received previous anthracycline treatment
were divided into anthracycline-refractory and anthracycline-resistant (early and late) groups. Results: Of 45 evaluable patients, 66.7% had a partial response (PR) and 2.2% a complete response (CR), giving an overall response
rate (ORR) of 68.9%. The ORR in anthracycline-refractory patients was 60% versus 82.6% in anthracycline-resistant patients;
the difference was not significant. The ORR in early-resistance patients was 62.5% versus 93.4% in late-resistance patients
(0.05 < P < 0.1). The median response duration and overall survival was 8 months (range, 4–23+ months) and 11.5 months (range, 4–31+
months), respectively, in 39 patients treated previously for metastatic disease. For 295 courses, grade 3/4 neutropenia developed
in 28.6% of patients (12.5% of courses) and was febrile in 26.5% of patients (6.1% of courses), including one septic death.
Hypersensitivity reactions (HSR) developed in 16.3% of patients, and fluid retention developed in 34.7% of patients (11.9%
of courses). Conclusions: Docetaxel is an active second-line drug in advanced breast cancer. The time of relapse after cessation of anthracycline
treatment may be a significant prognostic factor.
Received: 4 November 1998 / Accepted: 5 February 1999 相似文献
69.
Kazuki Nagasawa Tomohiko Fumihara Noriaki Ohnishi Teruyoshi Yokoyama 《Cancer science》1999,90(7):781-787
Previously, we reported that pirarubicin (THP), an anthracycline, was transported, at least in part, via a nucleoside transport system in human leukemic HL60 cells, but not in mononuclear cells (MNCs). In this study, the contribution of the nucleoside transport system to the transport of other anthracyclines, doxorubicin (DOX), daunorubicin (DNR) and idarubicin (IDA), in HL60 cells and MNCs was investigated. The experiments were performed after both types of cells had been pretreated with a metabolic inhibitor, 2,4-dinitrophenol, to deplete cellular ATP. The DOX uptake by HL60 cells was partially inhibited by inhibitors of equilibrative nucleoside transporters. In HL60 cells, moreover, the uptake of DOX depended on an inwardly directed Na+ -gradient, and was inhibited by concentrative nucleoside transporters, but there was no change in the DNR or IDA uptake under any of these conditions. On the other hand, the uptake of the three drugs by MNCs was not affected by any inhibitors of the nucleoside transporters, and there was no dependence of the uptake on an Na+ -gradient. These results suggested that DOX, but not DNR or IDA, was partially transported in HL60 cells via the nucleoside transport system, whereas in MNCs the system did not contribute to the uptake of any of these three drugs. Thus, nucleoside transport systems contributing to the transport of anthracyclines may be different among different derivatives and cell types. 相似文献
70.
In vivo Efficacy and Tumor-selective Metabolism of Amrubicin to Its Active Metabolite 总被引:6,自引:4,他引:6
Toshihiro Noguchi Shinji Ichii Shinya Morisada Takashi Yamaoka Yoshikazu Yanagi 《Cancer science》1998,89(10):1055-1060
The tissue distribution of a novel antitumor anthracycline antibiotic, amrubicin, was studied using seven human tumor xenografts implanted into nude mice, in order to identify the principal factors determining its therapeutic efficacy. We found a good correlation between the level of the metabolite amrubicinol in the tumor and the in vivo efficacy. High metabolic activity of amrubicin to amrubicinol was detected in tumor tissue homogenates, especially in cell lines highly sensitive to amrubicin in vivo . In contrast to amrubicin, the administration of amrubicinol showed less tumor-selective toxicity in these human tumor xenograft models. These data indicate that the tumor-selective metabolism of amrubicin to amrubicinol resulted in a tumor-selective disposition of amrubicinol, leading to good efficacy in in vivo experimental therapeutic models. 相似文献