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排序方式: 共有442条查询结果,搜索用时 15 毫秒
21.
Hilde M. Norum Annika E. Michelsen Tove Lekva Satish Arora Kari Otterdal Maria Belland Olsen Xiang Yi Kong Einar Gude Arne K. Andreassen Dag Solbu Kristjan Karason Gran Dellgren Lars Gullestad Pl Aukrust Thor Ueland 《American journal of transplantation》2019,19(4):1050-1060
Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta‐like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR‐based, calcineurin inhibitor‐free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers— SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962. 相似文献
22.
Van Damme-Lombaerts R Webb NA Hoyer PF Mahan J Lemire J Ettenger R McMahon L Cambon N Boger R Kovarik JM;Everolimus Study Group 《Pediatric transplantation》2002,6(2):147-152
Everolimus (Certican; RAD), a novel macrolide with potent immunosuppressive and anti-proliferative activities, prevents acute rejection in adult recipients of renal transplantation. This phase I trial conducted in stable pediatric renal transplant patients examined the single-dose pharmacokinetics, safety, and tolerability of everolimus in combination with cyclosporin A (CsA; Neoral) and corticosteroids, with or without azathioprine. Nineteen pediatric patients were enrolled and received a single 1.2 mg/m2 dose of everolimus. Everolimus was safe and well tolerated, with a low incidence of adverse events reported and none judged to be related to the study medication. Everolimus administration did not increase infection rates or produce clinically significant changes in vital signs or changes in electrocardiograms. Apparent clearance and volume of distribution of everolimus increased with age, weight, and body surface area in a generally linear manner across the pediatric demographic ranges. Compared with adults from a previous study, apparent clearance (L/h) and distribution volume (L) were lower in pediatric patients, whereas the elimination half-life was similar. Single-dose everolimus co-administration did not affect the steady-state pharmacokinetics of CsA. Based on this information, pediatric patients will need a dose scaled down for body size, but can probably maintain the same twice-daily dosing schedule used in adults. 相似文献
23.
Comparison Between an Automated and Manual Extraction for the Determination of Immunosuppressive Drugs Whole Blood Concentrations by Liquid Chromatography Tandem Mass Spectrometry
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24.
Heather Ross Peter Pflugfelder Haissam Haddad Marcelo Cantarovich Michael White rew Ignaszewski Jonathan Howlett Marc Vaillancourt Richard Dorent Jeffrey R. Burton for the CADENCE Study Group 《Transplant international》2010,23(1):31-37
Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48-week, multicenter, single-arm pilot study in heart transplant patients >12 months post-transplant, everolimus was started at 1.5 mg/day (subsequently adjusted to target C 0 5–10 ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C 0 and C 2 , respectively. Mean cGFR was 68.9 ± 14.5 ml/min at baseline and 61.6 ± 11.5 ml/min at week 48 ( P = 0.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease ≤25% of cGFR from baseline. Two patients experienced biopsy-proven acute rejection Grade 3A (5.6%). Between baseline and week 48, there were significant increases in total cholesterol, LDL-cholesterol and triglycerides, and small but significant elevations in liver enzymes. This 1-year pilot study suggests that CsA dose reduction of ca. 40% after initiation of everolimus was associated with a decrease in cGFR, however, based on the prespecified criteria stable renal function was attained. 相似文献
25.
26.
H. Tedesco-Silva M.I. Lorber C.E. Foster H.W. Sollinger R. Mendez D.B. Carvalho R. Shapiro P.R. Rajagopalan H. Mayer J. Slade B.D. Kahan for the FTYA clinical study group 《Clinical transplantation》2009,23(5):589-599
Abstract: This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2–12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4–8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF. 相似文献
27.
Matteo Maurina MD Mauro Chiarito MD Pier Pasquale Leone MD Luca Testa MD PhD Matteo Montorfano MD Bernhard Reimers MD Giovanni Esposito MD PhD Francesco Monti MD Maurizio Ferrario MD Azeem Latib MD Antonio Colombo MD 《Catheterization and cardiovascular interventions》2023,102(6):1020-1033
Background
Diabetic patients are at higher risk of recurrent adverse events following percutaneous coronary intervention (PCI) than the nondiabetics. Despite the introduction of new generation drug-eluting stents, their efficacy in the diabetics is still limited.Aims
To evaluate the efficacy of the Abluminus DES+ biodegradable polymer sirolimus-eluting stent in reducing neointimal hyperplasia in diabetic patients, compared to a durable polymer everolimus-eluting stent (DP-EES).Methods
A total of 131 patients with diabetes and coronary artery disease were enrolled in six Italian centers and randomized in a 2:1 fashion to PCI with Abluminus DES+ or DP-EES: 85 were assigned to Abluminus DES+ and 46 to DP-EES. The primary endpoint was optimal coherence tomography (OCT)-derived neointimal volume at 9–12 months. Secondary endpoints included OCT-derived neointimal area, neointimal volume obstruction and adverse clinical events.Results
The primary endpoint, neointimal volume, did not differ between Abluminus DES+ and DP-EES (29.11 ± 18.90 mm3 vs. 25.48 ± 17.04 mm3, p = 0.40) at 9–12-month follow-up. This finding remained consistent after weighing for the sum of stents lengths (1.14 ± 0.68 mm3 vs. 0.99 ± 0.74 mm3 for Abluminus DES+ and DP-EES, respectively, p = 0.38). Similarly, other OCT-derived and clinical secondary endpoints did not significantly differ between the two groups. Rate of target lesion failure was high in both groups (21.2% for Abluminus DES+ and 19.6% for DP-EES).Conclusions
This preliminary study failed to demonstrate the superiority of the Abluminus DES+ over the DP-EES in diabetic patients in terms of neointimal proliferation. 相似文献28.
Dailly E Deslandes G Hourmant M Petit T Renaud C Treilhaud M Jolliet P 《Journal of clinical laboratory analysis》2008,22(4):282-285
Various methods [fluorescent polarization immunoassay (FPIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay] are used for therapeutic drug monitoring of everolimus. The aim of this study is to compare these assays in renal and heart transplantation. The correlation between results was investigated by linear regression in 44 patients (24 heart recipients and 20 renal recipients--137 samples). The comparison between assays was performed by a paired t-test. A highly significant correlation was found between FPIA and LC-MS/MS in heart and renal recipients [FPIA=0.851 x LC-MS/MS+1.773r(2)=0.8738 (P<0.001)]. Paired t-tests did not show a significant difference between everolimus whole blood concentrations in the populations of heart and renal recipients or heart recipients or renal recipients. FPIA and LC-MS/MS assays gave consistent overall results although some significant differences were observed in some samples between these methods indicating that FPIA assay has limitations that deserve further investigations. 相似文献
29.
Laplanche R Meno-Tetang GM Kawai R 《Journal of pharmacokinetics and pharmacodynamics》2007,34(3):373-400
Everolimus is a novel macrolide immunosuppressant developed for the prophylaxis of allogeneic renal or cardiac transplant
rejection. Treatments with immunosuppressants are often associated with organ toxicity that is linked to high organ exposure.
Therefore, gaining insight into the pharmacokinetics of everolimus in various organs is highly desirable especially those
organs of therapeutic interest or those that pose safety concerns. The aim of this work was to characterize the disposition
kinetics of everolimus in rats by physiologically based pharmacokinetic (PBPK) modeling.
Blood and tissue samples were collected from male Wistar rats over 24 hr following intravenous (iv) bolus and iv infusion
of 1 mg/kg and 10 mg/kg/2 hr of everolimus. Further blood samples were collected between 1 and 170 hr from a third group of
rats, which received iv infusion of 1 mg/kg/2 hr of everolimus. Drug concentrations in blood and tissues were determined by
a liquid chromatography reverse dilution method. Distribution of everolimus between blood fractions was determined in vitro
at 37°C.
The results of the study demonstrated that everolimus exhibited moderate non-linear binding to red blood cells. Also, the
tissue-to-blood concentration ratio decreased in all tissues as blood concentration increased. A PBPK model involving non-linear
tissue binding was able to successfully describe the observed data in blood and all the organs investigated. The highest binding
potential was observed in thymus, lungs, and spleen with the greatest tissue affinity observed in thymus, skin, and muscle
as compared to other tissues. Everolimus exhibited a high clearance rate that was limited to the hepatic blood flow (47.2 ml/min/kg).
The PBPK model was also able to predict the venous blood concentration reasonably well following oral administration. The
oral bioavailability value, as estimated with the PBPK, was 12% and was similar to the value obtained by non-compartmental
analysis.
In conclusion, A PBPK model has been developed that successfully predicts the time course of everolimus in blood and a variety
of organs. This model takes into account the non- linear binding of everolimus to red blood cells and tissues. This model
may be used to predict everolimus concentration–time course in organs from other species including humans. 相似文献
30.
Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer 总被引:4,自引:0,他引:4
Milton DT Riely GJ Azzoli CG Gomez JE Heelan RT Kris MG Krug LM Pao W Pizzo B Rizvi NA Miller VA 《Cancer》2007,110(3):599-605
BACKGROUND: Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC). METHODS: Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily. RESULTS: Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t(max), C(max), and AUC(0-8h) of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients. CONCLUSIONS: For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way. 相似文献