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1.
Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin 总被引:7,自引:0,他引:7
M Manning M Kruszynski K Bankowski A Olma B Lammek L L Cheng W A Klis J Seto J Haldar W H Sawyer 《Journal of medicinal chemistry》1989,32(2):382-391
We describe the synthesis and some pharmacological properties of 16 new in vivo antagonists of oxytocin. These are based on modifications of three peptides: A, B, and C. A is our previously reported potent and selective antagonist of the vasopressor (V1 receptor) responses to arginine-vasopressin (AVP)/weak oxytocin antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid), 2-O-methyltyrosine]arginine-vasopressin (d(CH2)5[Tyr(Me)2]AVP. B reported here, the Ile3 analogue of A, is d(CH2)5[Tyr(Me)2]AVT (5 below) and C is our previously reported potent nonselective oxytocin antagonist/AVP V1 antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O- methyltyrosine,8-ornithine]vasotocin (d(CH2)5[Tyr(Me)2]OVT). The following substitutions and deletions, alone or in combination, were employed in A, B, and C: 1-deaminopenicillamine (dP); D-Tyr(Alk)2 (where Alk = Me or Et), D-Phe2; Val4, Thr4; delta 3-Pro7; Lys8, Cit8; desGly9, desGly-NH2(9), Ala-NH2(9); Leu-NH2(9); Arg-NH2(9). The 16 new analogues are (1) d(CH2)5[D-Tyr(Me)2]AVP, (2) d(CH2)5[D-Tyr(Me)2, Val4,delta 3-Pro7]AVP, (3) d(CH2)5[D-Tyr-(Et)2, Val4,Lys8]VP, (4) d(CH2)5[D-Tyr(Et)2,Val4,Cit8]VP, (5) d(CH2)5[Tyr(Me)2]AVT, (6) d(CH2)5[Tyr(Me)2,Lys8]VT, (7) dP[Tyr(Me)2]AVT, (8) dP[Tyr(Me)2,Val4]AVT, (9) d(CH2)5[D-Tyr(Me)2, Val4]AVT, (10) d(CH2)5[D-Phe2,Val4]AVT, (11) d(CH2)5[Tyr(Me)2,Thr4]OVT, (12) d(CH2)5[Tyr(Me)2,Thr4,Ala-NH2(9)]OVT, (13) d(CH2)5[Tyr(Me)2,Thr4,Leu-NH2(9)]OVT, (14) d(CH2)5[Tyr(Me)2,Thr4,Arg-NH2(9)]OVT, (15) desGly-NH2(9),d(CH2)5[Tyr(Me)2,Thr4]OVT, (16) desGly9,d(CH2)5[Tyr(Me)2,Thr4]OVT. 1-4 are analogues of A, 5-10 are analogues of B, and 11-16 are analogues of C. Their protected precursors were synthesized either entirely by the solid-phase method or by a combination of solid-phase and solution methods (1 + 8 or 8 + 1 couplings). All analogues were tested in rats for agonistic and antagonistic activities in oxytocic (in vitro, without and with Mg2+, and in vivo) assays as well as by antidiuretic and vasopressor assays. All analogues exhibit potent oxytocic antagonism in vitro and in vivo. With an in vitro pA2 (in the absence of Mg2+) = 9.12 +/- 0.09, dP[Tyr(Me)2]AVT is (7) one of the most potent in vitro oxytocin antagonists reported to date. Fifteen of these analogues (all but 6) appear as potent or more potent in vivo oxytocin antagonists than C (pA2 = 7.37 +/- 0.17). Analogues 1-9 and 14 are potent AVP V1 antagonists. Their anti-V1 pA2 values range from 7.92 to 8.45. They are thus nonselective oxytocin antagonists.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
2.
Ratnesh Murugan Kristin VanderEnde Veena Dhawan Pradeep Haldar Sourabh Chatterjee Deepa Sharma Kevisetuo Anthony Dzeyie Subramanya Balakuntlam Pattabhiramaiah Sudhir Khanal Lucky Sangal Sunil Bahl Sukarma S.S. Tanwar Michelle Morales Ahmed M. Kassem 《MMWR. Morbidity and mortality weekly report》2022,71(50):1569
3.
Roongta Rashmi Mondal Sumantro Haldar Subhankar Kumar Mavidi Sunil Ghosh Alakendu 《Clinical rheumatology》2022,41(5):1591-1596
Clinical Rheumatology - We report the case of an 18-year-old male with Still’s disease for the last 3 years, in remission, who developed two flares of his disease after receiving two... 相似文献
4.
Parihar Rashmi Shukla Ruchi Baishya Bikash Kalita Jayantee Haldar Rudrashish Misra Usha Kant 《Metabolic brain disease》2022,37(3):773-785
Metabolic Brain Disease - We report the potential role of 1H Nuclear Magnetic Resonance (NMR) based metabolomics in tuberculous meningitis (TBM). We also correlate the significant metabolites with... 相似文献
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6.
J. V. Lloyd E. E. Nishizawa J. Haldar J. F. Mustard 《British journal of haematology》1972,23(5):571-585
Summary . Suspensions of washed platelets from rabbits were labelled in vitro with 32PO4, washed, and then stimulated with ADP. Thirty seconds after the addition of ADP or of a control solution, samples of the suspension were subjected to lipid extraction. The phospholipid classes were isolated by thin layer chromatography. The results of phosphate estimation on the isolated phospholipids were in agreement with the previously described amounts of diphosphatidylinositol (DPI) and triphosphatidylinositol (TPI) in human platelets. In both ADP-treated and control plateletes the label in phospholipid was mainly in phosphatidic acid (PA), phosphatidylinositol (MPI), DPI and TPI. Thirty seconds after the addition of ADP there was an increase in labelling of PA, DPI and TPI but the amounts of PA, DPI and TPI in platelets did not change. The results indicate that ADP probably induces an increase in turnover of the phosphate moieties of these phospholipids. The changes observed represent changes in the metabolism of the phospholipids of the platelet membrane which may be important in the mechanism of platelet aggregation. 相似文献
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9.
Melatonin prevents dexamethasone‐induced testicular oxidative stress and germ cell apoptosis in golden hamster,Mesocricetus auratus 下载免费PDF全文
This study investigated the protective effect of melatonin on dexamethasone (Dex), an extensively used anti‐inflammatory and immunosuppressive synthetic glucocorticoid, induced testicular oxidative stress and germ cell apoptosis in golden hamster. Hamsters were randomly divided into four groups (n = 7): group I – control; group II – melatonin treated (10 mg kg?1 day?1); group III – Dex treated (7 mg kg?1 day?1) and group IV – combination of Dex and melatonin. All the injections were administered intraperitoneally for seven consecutive days. The histopathological changes, specific biochemical markers, including antioxidative enzymes, plasma melatonin level and the markers for germ cell apoptosis were evaluated. Dex administration decreased antioxidant enzyme activities (SOD, CAT, GSH‐PX), plasma melatonin level and melatonin receptor (MT1) expression with a concomitant increase in lipid peroxidation (TBARS) and altered testicular histopathology which might culminate into increased germ cell apoptosis as evident from increased Bax/Bcl‐2 ratio and caspase‐3 expression. However, melatonin pre‐treatment enhanced enzyme activities for SOD, CAT, GSH‐PX with a simultaneous decrease in Bax/Bcl‐2 ratio and caspase‐3 expression. Our findings clearly suggest that melatonin improved defence against Dex‐induced testicular oxidative stress and prevented germ cell apoptosis, suggesting a novel combination therapeutic approach for management of male reproductive health. 相似文献
10.
Arunaloke Chakrabarti Prashant Sood Shivaprakash M. Rudramurthy Sharon Chen Harsimran Kaur Malini Capoor Deepinder Chhina Ratna Rao Vandana Kalwaje Eshwara Immaculata Xess Anupama J. Kindo P. Umabala Jayanthi Savio Atul Patel Ujjwayini Ray Sangeetha Mohan Ranganathan Iyer Jagdish Chander Anita Arora Raman Sardana Indranil Roy B. Appalaraju Ajanta Sharma Anjali Shetty Neelam Khanna Rungmei Marak Sanjay Biswas Shukla Das B. N. Harish Sangeeta Joshi Deepak Mendiratta 《Intensive care medicine》2015,41(2):285-295