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1.
Synthesis and structure-activity relationships of new 9-N-alkyl derivatives of 9(S)-erythromycylamine 总被引:4,自引:0,他引:4
H A Kirst J A Wind J P Leeds K E Willard M Debono R Bonjouklian J M Greene K A Sullivan J W Paschal J B Deeter 《Journal of medicinal chemistry》1990,33(11):3086-3094
A series of new 9-N-alkyl derivatives of 9(S)-erythromycylamine has been synthesized by reductive alkylation of erythromycylamine with aliphatic aldehydes and sodium cyanoborohydride. Alternative syntheses employing hydrogenation methods have also been developed. These new 9-N-alkyl derivatives possess excellent antimicrobial activity in vitro and in vivo, especially when administered orally to treat experimental infections in mice. From structure-activity studies, 9-N-(1-propyl)erythromycylamine (LY281389) was selected as the most efficacious derivative. These methods have also been extended to the synthesis of some 9-N,N-dialkyl derivatives of erythromycylamine. 相似文献
2.
M Debono K E Willard H A Kirst J A Wind G D Crouse E V Tao J T Vicenzi F T Counter J L Ott E E Ose 《The Journal of antibiotics》1989,42(8):1253-1267
A series of 20-deoxo-20-cyclic (alkylamino) derivatives of tylosin, desmycosin, macrocin and lactenocin was prepared by reductive amination of the C-20 aldehyde group. The majority of the compounds were prepared using metal hydrides (sodium cyanoborohydride or sodium borohydride) as the reducing agents and a suitable cyclic alkylamine. Subsequently, a more convenient procedure was developed using formic acid as a reducing agent. The C-20 amino derivatives prepared from desmycosin exhibited good in vitro antimicrobial activity against Pasteurella haemolytica and Pasteurella multocida (MIC range of 0.78 approximately 6.25 micrograms/ml) as well as Mycoplasma species (MIC range of 0.39 approximately 6.25 micrograms/ml). Several derivatives showed excellent oral efficacy against infections caused by P. multocida in chicks. One of these derivatives, 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin or EL-870) was selected for development as a therapeutic agent for pasteurellosis in calves and pigs. 相似文献
3.
Structure-activity studies of 20-deoxo-20-amino derivatives of tylosin-related macrolides 总被引:1,自引:0,他引:1
H A Kirst K E Willard M Debono J E Toth B A Truedell J P Leeds J L Ott A M Felty-Duckworth F T Counter E E Ose 《The Journal of antibiotics》1989,42(11):1673-1683
Reductive amination of the C-20 aldehyde group of tylosin and related macrolides yielded a large series of derivatives with potentially useful antibiotic properties. Evaluation of these new compounds was conducted on the basis of: 1) Broad antimicrobial spectrum in vitro, with particular emphasis on inhibition of Pasteurella multocida and Pasteurella haemolytica; 2) in vivo efficacy, especially when given orally, against P. multocida in experimental infections in chicks; and 3) bioavailability after oral administration to laboratory animals. The most useful activity was found within a series of derivatives produced by reductive amination of desmycosin with secondary amines. 相似文献
4.
Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian Collaborative Study Group for Ewing Sarcoma Family Tumors—EWING1 下载免费PDF全文
Algemir L. Brunetto Luis A. Castillo Antonio S. Petrilli Carla D. Macedo Erica Boldrini Cecilia Costa Maria T. Almeida Daniela Kirst Carlos Rodriguez‐Galindo Waldir V. Pereira Flora M. Watanabe Maria Pizza Eliana Benites Vera Morais Andra Gadelha Antnio Nakasato Ana L. Abujamra Lauro J. Gregianin 《Pediatric blood & cancer》2015,62(10):1747-1753
5.
C. Raul Gonzalez-Esquer Bryan Ferlez Sarathi M. Weraduwage Henning Kirst Alexandra T. Lantz Aiko Turmo Thomas D. Sharkey Cheryl A. Kerfeld 《RSC advances》2021,11(48):29997
Terpene synthases are biotechnologically-relevant enzymes with a variety of applications. However, they are typically poor catalysts and have been difficult to engineer. Structurally, most terpene synthases share two conserved domains (α- and β-domains). Some also contain a third domain containing a second active site (γ-domain). Based on the three-domain architecture, we hypothesized that αβ terpene synthases could be engineered by insertion of a heterologous domain at the site of the γ-domain (an approach we term “Insertion-engineering terpene synthase”; Ie-TS). We demonstrate that by mimicking the domain architecture of αβγ terpene synthases, we can redesign isoprene synthase (ISPS), an αβ terpene synthase, while preserving enzymatic activity. Insertion of GFP or a SpyCatcher domain within ISPS introduced new functionality while maintaining or increasing catalytic turnover. This insertion-engineering approach establishes that the γ-domain position is accessible for incorporation of additional sequence features and enables the rational engineering of terpene synthases for biotechnology.“Insertion-engineering” approach allows for the modification of αβ terpene synthases. 相似文献
6.
Kirst HA Creemer LC Naylor SA Pugh PT Snyder DE Winkle JR Lowe LB Rothwell JT Sparks TC Worden TV 《Current topics in medicinal chemistry》2002,2(7):675-699
The spinosyns are a novel family of fermentation-derived natural products that exhibit potent insecticidal activities. Spinosad, a naturally-occurring mixture of spinosyn A and spinosyn D, has successfully established its utility for crop protective applications in the agrochemical field. Potential applications of this unique chemical family of macrolides also have been investigated in the field of animal health. Applications for the control of blowfly strike and lice on sheep have now been commercially developed and registered in Australia and potential applications for the control of ectoparasites on cattle are being studied. 相似文献
7.
Abdelghaffar H Kirst H Soukri A Babin-Chevaye C Labro MT 《Journal of chemotherapy (Florence, Italy)》2002,14(2):132-139
Macrolide antibiotics have recently triggered much interest owing to the immunomodulatory potential of some derivatives, particularly in the field of inflammatory diseases. Among the possible mechanisms underlying these anti-inflammatory effects, macrolide-induced inhibition of oxidant production by phagocytes has attracted much attention. We and others have previously reported that erythromycin A-derived macrolides impair the phagocyte oxidative burst, a property linked to the presence of L-cladinose. However, we have also demonstrated that other substituents can be involved in the modulation of phagocyte function. Here we have extended the analysis of structure-activity relationships by studying the effects of five 9-N-alkyl derivatives of erythromycylamine on oxidant production by human neutrophils in vitro. LY211397 (2-methoxyethyl derivative) neither altered cell viability nor superoxide anion production. LY281389 (n-propyl derivative) did not alter cell viability and was slightly more inhibitory than erythromycylamine for the production of superoxide anion; its IC50 (concentration that inhibits 50% of the neutrophil response) was about 18 and 24 microM (versus 72 and 74 pM for erythromycylamine) after 60 min of incubation following fMLP and PMA stimulation, respectively. LY80576 (N-phenyl-3-indolylmethyl derivative), LY281981 (3-phenyl-n-propyl derivative) and LY57843 (benzyl derivative) all displayed cellular toxicity at high pharmacological concentrations after 30 to 60 min of incubation. Interestingly, these latter three drugs exhibited a rapid (5 min incubation) and strong inhibitory effect on the neutrophil oxidative burst from either stimulus, with IC50 values of 3 to 10 pM. Further in-vitro and in-vivo investigations are required to analyze the anti-inflammatory potential of these three derivatives. 相似文献
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10.
Post LK Lima FG Xavier CB Demarco FF Gerhardt-Oliveira M 《Brazilian dental journal》2010,21(5):416-419
This in vitro study evaluated the effect of different apicoectomy angles, instruments used in root-end preparation, and dental materials used in retrofilling on apical sealing. Root ends were resected at 45 or 90 degrees in 80 single-rooted teeth. For each type of apicoectomy, root-end cavities were prepared with either a round carbide #2 bur or an S12/90D ultrasonic tip. The root-end cavities in each subgroup (apicoectomy + root-end preparation) were filled with silver amalgam without zinc (Am) or with gray mineral trioxide aggregate -Angelus (MTA), and the specimens were immediately immersed in 0.2% rhodamine B for 24 h. Sealing was evaluated based on the dyed cross-sectional dentin area. Data were analyzed statistically by the Kruskal-Wallis test at 5% significance level. No group showed complete sealing of root-end areas. The only significant factor affecting microleakage was dental material, with MTA exhibiting less leakage. 相似文献