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81.
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Al Safarjalani ON Zhou XJ Rais RH Shi J Schinazi RF Naguib FN El Kouni MH 《Cancer chemotherapy and pharmacology》2005,55(6):541-551
Purpose The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the pharmacokinetics and bioavailability of oral uridine. PTAU is a potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. PTAU is fully absorbed after oral administration with 100% oral bioavailability.Methods Uridine (330, 660 or 1320 mg/kg) and/or PTAU (30, 45, 60, 120, 240 or 480 mg/kg) were orally administered to mice. The plasma levels of uridine, its catabolite uracil, and PTAU were measured using HPLC, and pharmacokinetic analysis was performed.Results Oral PTAU up to 480 mg/kg per day is not toxic to mice. Oral PTAU at 30, 45, 60, 120 and 240 mg/kg has a prolonged plasma half-life of 2–3 h, and peak plasma PTAU concentrations (Cmax) of 41, 51, 74, 126 and 161 M with AUCs of 70, 99, 122, 173 and 225 mol h/l, respectively. Coadministration of uridine with PTAU did not have a significant effect on the pharmacokinetic parameters of plasma PTAU at any of the doses tested. Coadministration of PTAU (30, 45, 60 and 120 or 240 mg/kg) with uridine (330, 660 or 1320 mg/kg) elevated the concentration of plasma uridine over that following the same dose of uridine alone, a result of reduced metabolic clearance of uridine as evidenced by decreased plasma exposure (Cmax and AUC) to uracil. Plasma uridine was elevated with the increase of uridine dose at each PTAU dose tested and no plateau was reached. Coadministration of PTAU at 30, 45, 60, 120 and 240 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9-, 9.9-, 11.7- and 12.5-fold, respectively, and reduced the AUC of plasma uracil (1227.8 mol h/l) by 5.7-, 6.8-, 8.2-, 6.3-, and 6.9-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45, 60, 120 and 240 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.7-, 2.4-, 2.6-, 5.2- and 4.3- fold, and that of 660 mg/kg uridine by 2.3-, 2.7-, 3.3-, 4.6- and 6.7-fold, respectively.Conclusion The excellent pharmacokinetic properties of PTAU, and its extraordinary effectiveness in improving the oral bioavailability of uridine, could be useful to rescue or protect from host toxicities of 5-fluorouracil and various chemotherapeutic pyrimidine analogues used in the treatment of cancer and AIDS, as well as in the management of medical disorders that are remedied by the administration of uridine including CNS disorders (e.g. Huntingtons disease, bipolar disorder), liver diseases, diabetic neuropathy, cardiac damage, various autoimmune diseases, and transplant rejection. 相似文献
83.
Rais RH Al Safarjalani ON Yadav V Guarcello V Kirk M Chu CK Naguib FN el Kouni MH 《Biochemical pharmacology》2005,69(10):1409-1419
Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-substituted purine nucleosides act as subversive substrates of T. gondii, but not the human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Herein, we report the testing of newly synthesized 6-benzylthioinosine analogues with various substituents on the phenyl ring of their benzyl group as subversive substrates of T. gondii adenosine kinases. The binding affinity of these compounds to T. gondii adenosine kinase and their efficacy as antitoxoplasmic agents varied depending on the nature and position of the various substituents on the phenyl ring of their benzyl group. p-Cyano-6-benzylthioinosine and 2,4-dichloro-6-benzylthioinosine were the best ligands. In general, analogues with substitution at the para position of the phenyl ring were better ligands than those with the same substitutions at the meta or ortho position. The better binding of the para-substituted analogues is attributed to the combined effect of hydrophobic as well as van der Waals interactions. The 6-benzylthioinosine analogues were devoid of host-toxicity but all showed selective anti-toxoplasmic effect in cell culture and animal models. These results further confirm that toxoplasma adenosine kinase is an excellent target for chemotherapy and that 6-substituted purine nucleosides are potential selective antitoxoplasmic agents. 相似文献
84.
Saklani AP Shah P Naguib N Tanner N Mekhail P Masoud AG 《Journal of minimal access surgery》2011,7(3):195-199
We performed a laparoscopic ultra low anterior resection in two patients with low rectal cancers (3 cm from dentate line). A transanal division and continuous suture closure of anorectal junction was performed first followed by laparoscopic low anterior resection. A handsewn anastomosis between colonic pouch/transverse coloplasty and anal canal was facilitated by use of a transanal balloon port. 相似文献
85.
Mazen Naga Serag Esmat Mohamed Naguib Heba Sedrak 《Arab Journal Of Gastroenterology》2011,12(1):40-43
Background and study aimsGastric antral vascular ectasia (GAVE) is a distinct vascular abnormality, mainly involving the gastric antrum. It is a rare but well-known cause of occult gastrointestinal bleeding. Various endoscopic treatment modalities have been tried in this condition. The aim of the study is to show the long-term effect of argon plasma coagulation (APC) on GAVE.Patients and methodsTwenty-nine patients with endoscopically proved GAVE were enrolled in the study. Clinical assessment of GAVE patients, haemoglobin (Hb) level and transfused blood units were recorded after APC using 60–80-W power setting. A second session was done 1 month after the therapeutic procedure to ensure complete ablation of all lesions.ResultsThe documented Hb levels and number of blood units transfused 3 months after APC were recorded. At endoscopy, all patients had the classic type of GAVE. The mean Hb level increased from 7.5 ± 1.7 g dl?1 before APC to 10.2 ± 0.8 g dl?1 after APC (p value <0.001). The transfusion requirements significantly decreased to 0.2 ± 0.5 units/patient (p value <0.001).ConclusionEndoscopic APC is a safe, effective and inexpensive modality in treating GAVE and could be an alternative to the currently available endoscopic methods. 相似文献
86.
Nour-Eldin A. Nour-Eldin Nagy N. N. Naguib Martin Mack John E. Abskharon Thomas J. Vogl 《European radiology》2011,21(1):197-204
Purpose
To assess risk factors and the extent of pulmonary hemorrhage complicating radiofrequency ablation (RFA) of pulmonary neoplasms. 相似文献87.
88.
89.
NV Bogdanova NN Antonenkova YI Rogov JH Karstens P Hillemanns T Dörk 《Clinical genetics》2010,78(4):364-372
Bogdanova NV, Antonenkova NN, Rogov YI, Karstens JH, Hillemanns P, Dörk T. High frequency and allele‐specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Breast cancer and ovarian cancer are common malignancies in Belarus accounting for about 3500 and 800 new cases per year, respectively. For breast cancer, the rates and age of onset appear to vary significantly in regions differentially affected by the Chernobyl accident. We assessed the frequency and distribution of three BRCA1 founder mutations 5382insC, 4153delA and Cys61Gly in two hospital‐based series of 1945 unselected breast cancer patients and of 201 unselected ovarian cancer patients from Belarus as well as in 1019 healthy control females from the same population. Any of these mutations were identified in 4.4% of the breast cancer patients, 26.4% of the ovarian cancer patients and 0.5% of the controls. In the breast cancer patients, BRCA1 mutations were strongly associated with earlier age at diagnosis, with oestrogen receptor (ER) negative tumours and with a first‐degree family history of breast cancer, although only 35% of the identified BRCA1 mutation carriers had such a family history. There were no marked differences in the regional distribution of BRCA1 mutations, so that the significant differences in age at diagnosis and family history of breast cancer patients from areas afflicted by the Chernobyl accident could not be explained by BRCA1. We next observed a higher impact and a shifted mutational spectrum of BRCA1 in the series of Byelorussian ovarian cancer patients where the three founder mutations accounted for 26.4% (53/201). While the Cys61Gly mutation appeared underrepresented in ovarian cancer as compared with breast cancer cases from the same population (p = 0.01), the 4153delA mutation made a higher contribution to ovarian cancer than to breast cancer (p < 0.01). BRCA1 mutations were significantly enriched among ovarian cancer cases with a first‐degree family history of breast or ovarian cancer, whereas the median age at ovarian cancer diagnosis was not different between mutation carriers and non‐carriers. Taken together, these results identify three BRCA1 founder mutations as key components of inherited breast and ovarian cancer susceptibility in Belarus and might have implications for cancer prevention, treatment and genetic counselling in this population. 相似文献
90.