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RISS 인기검색어
- 검색키워드
- 저자 : Landersdorfer, Cornelia B. (검색결과 3 건)
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Bulitta, Jü,rgen B.,Ly, Neang S.,Landersdorfer, Cornelia B.,Wanigaratne, Nicholin A.,Velkov, Tony,Yadav, Rajbharan,Oliver, Antonio,Martin, Lisandra,Shin, Beom Soo,Forrest, Alan,Tsuji, Brian T. American Society for Microbiology 2015 Antimicrobial Agents and Chemotherapy Vol.59 No.4
<P>Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-negative bacteria remains poorly characterized. Here, we developed a novel quantitative model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three <I>Pseudomonas aeruginosa</I> strains. At low-intermediate tobramycin concentrations (<4 mg/liter), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concentrations (≥8 mg/liter). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 10<SUP>8.9</SUP> CFU/ml inoculum than that at the lower inocula. At 1 to 4 mg/liter tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quantitative model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens.</P>
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Shin, Beom Soo,Yoo, Sun Dong,Kim, Tae Hwan,Bulitta, Jurgen B.,Landersdorfer, Cornelia B.,Shin, Jeong Cheol,Choi, Jin Ho,Weon, Kwon-Yeon,Joo, Sang Hoon,Shin, Soyoung American Society for Pharmacology and Experimental 2014 Drug metabolism and disposition: the biological fa Vol.42 No.6
<P>Apicidin, a potential oral chemotherapeutic agent, possesses potent anti-histone-deacetylase activity. After oral administration, the total bioavailability of apicidin is known to be low (14.2%–19.3%). In the present study, we evaluated the factors contributing to the low bioavailability of apicidin by means of quantitative determination of absorption fraction and first-pass metabolism after oral administration. Apicidin was given to rats by five different routes: into the femoral vein, duodenum, superior mesenteric artery, portal vein, and carotid artery. Especially, the fraction absorbed (<I>F</I><SUB>X</SUB>) and the fraction that is not metabolized in the gut wall (<I>F</I><SUB>G</SUB>) were separated by injection of apicidin via superior mesenteric artery, which enables bypassing the permeability barrier. The <I>F</I><SUB>X</SUB> was 45.9% ± 9.7%, the <I>F</I><SUB>G</SUB> was 70.9% ± 8.1% and the hepatic bioavailability (<I>F</I><SUB>H</SUB>) was 70.6% ± 12.3%, while the pulmonary first-pass metabolism was minimal (<I>F</I><SUB>L</SUB> = 102.8% ± 7.4%), indicating that intestinal absorption was the rate-determining step for oral absorption of apicidin. The low <I>F</I><SUB>X</SUB> was further examined in terms of passive diffusion and transporter-mediated efflux by in vitro immobilized artificial membrane (IAM) chromatographic assay and in situ single-pass perfusion method, respectively. Although the passive diffusion potential of apicidin was high (98.01%) by the IAM assay, the in situ permeability was significantly enhanced by the presence of the P-glycoprotein (P-gp) inhibitor elacrider. These data suggest that the low bioavailability of apicidin was mainly attributed to the P-gp efflux consistent with the limited <I>F</I><SUB>X</SUB> measured in vivo experiment.</P>
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Bulitta, Jü,rgen B.,Paik, Soo Heui,Chi, Yong Ha,Kim, Tae Hwan,Shin, Soyoung,Landersdorfer, Cornelia B.,Jiao, Yuanyuan,Yadav, Rajbharan,Shin, Beom Soo Elsevier 2017 European journal of pharmaceutical sciences Vol.107 No.-
<P><B>Abstract</B></P> <P>Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-course of the antihypertensive activity of fimasartan <I>via</I> a new population pharmacokinetic/pharmacodynamic model and to define its optimal dose range. We simultaneously modelled all fimasartan plasma concentrations and 24-h ambulatory blood pressure monitoring (ABPM) data from 39 patients with essential hypertension and 56 healthy volunteers. Patients received placebo, 20, 60, or 180mg fimasartan every 24h for 28days and healthy volunteers received placebo or 20 to 480mg as a single oral dose or as seven doses every 24h. External validation was performed using data on 560 patients from four phase II or III studies. One turnover model each was used to describe diastolic and systolic blood pressure. The input rates into these compartments followed a circadian rhythm and were inhibited by fimasartan. The average predicted (observed) diastolic blood pressure over 24-h in patients decreased by 10.1±7.5 (12.6±9.2; mean±SD)mmHg for 20mg, 14.2±7.0 (15.1±9.3) mmHg for 60mg, and 15.9±6.8 (11.5±9.9)mmHg for 180mg daily relative to placebo. The model explained the saturation of antihypertensive activity by counter-regulation at high fimasartan concentrations. Drug effect was maximal at approximately 23ng/mL fimasartan for diastolic and 12ng/mL for systolic blood pressure. The proposed mechanism-based population model characterized the circadian rhythm of ABPM data and the antihypertensive effect of fimasartan. After internal and external model validation, 30 to 60mg oral fimasartan given once daily was predicted as optimal dose range.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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