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971.
Shuisheng Zhang Can Huang Zhengzheng Li Yongjie Yang Tingting Bao Haibo Chen 《Drug delivery》2017,24(1):1011-1017
CalliSpheres® Beads (CB) is the first drug-eluting bead (DEB) product in China. Our aim was to compare the effect on the pharmacokinetics of doxorubicin (DOX) and its local concentration between lipiodol emulsions and CB in the process of TACE in rabbit livers. Twenty-five rabbits were distributed into two groups; Group 1 received lipiodol emulsions with DOX, and Group 2 received CB loaded with DOX (CBDOX). DOX was measured in the peripheral blood at different times after treatment. Livers were sampled at 1 week and 1 month for Group 2 after embolization. DOX concentration and distribution were measured in the liver. The administration of DOX by TACE with CBDOX resulted in peripheral blood DOX concentrations of 39.85?±?13.86?ng/mL at 5?min, with a gradual decrease to 6.89?±?1.62?ng/mL at 24?h, after treatment. Plasma concentration of DOX after chemoembolization with lipiodol was 225.91?±?64.88?ng/mL at 5?min and decreased with time by 24?h to 5.06?±?0.48?ng/mL. In CBDOX group, the drug impregnated an area as far as 200?μm from the bead edge. The tissue concentration of doxorubicin (tissCDOX) ranged from 40.27?μg/mL to 245.70?μg/mL at 1 week and from 5.64?μg/mL to 28.09?μg/mL at 1 month. Plasma concentrations of DOX resulting from CBDOX embolization were significantly lower than that for cTACE. CB could deliver relatively high concentrations of DOX to an area as far as 200?μm from the bead edge for at least 1 month. 相似文献
972.
目的 制备泼尼松择时释放片,评价其体内外的释药.方法 采用水不溶性包衣材料,干法压制包衣制备泼尼松择时释放片,用HPLC法测定泼尼松体外释放度,LC-MS/MS测定Beagle犬随机交叉口服单剂量泼尼松择时释放片与泼尼松普通速释片后血浆中泼尼松的浓度,计算药动学参数.结果 所制泼尼松择时释放片的体外时滞时间为4~5h,时滞后药物可达到0.5h内释放大于85%的爆破型脉冲释药效果.受试制剂与参比制剂泼尼松在Beagle犬体内的AUC0-t分别为62.01±3.57、59.96 ±2.72 ng·mL-1 ·h;AUC0-∞分别为63.35±3.51、62.76±3.27ng·mL-1 ·h;t1/2分别为1.00±0.16、1.22±0.54 h;Tmax分别为4.67±0.26、0.97±0.30 h;Cmax分别为27.84±3.03、28.05±1.94 ng·mL-1;Tlag分别为3.83±0.26、0h.结论 犬体内外的结果均证明该制剂具有延迟释放特性,其设计方案可行. 相似文献
973.
Ideal drug delivery process would exhibits zero-order kinetics. However, in practical, most drug delivery process is first-order
kinetics. This study is aimed to mathematically model, analyze and determine the optimal polymer shape of the drug micro-carrier
that achieves a near zero-order release. We also extend study in deriving and optimizing theoretically the optimal distance
between the two optimal micro-carrier shapes. A mathematical model that derived from Carslaw and Jaeger equation of conduction
of heat is used to model the relationship between the geometry shape of the carrier and the drug concentration. An optimization
objective function is formulated from the mathematical model and MATLAB Optimization Toolbox is used to perform the numerical
analysis. The results suggest that reducing the k value (ratio of volume of the fluid to that of the sphere) gives a near zero-order kinetics drug delivery response for all
the microcarrier geometry shapes (with equivalent surface area/volume ratio to a sphere with radius R
s
) investigated. Our preliminary results showed that tetrahedron microcarrier exhibits the best response and the worst response
is for tablet (with R = R
s
/2). 相似文献
974.
R. Brigg Turner Fawzy Elbarbry Lisa Biondo 《Journal of chemotherapy (Florence, Italy)》2016,28(4):304-307
The optimal dosing of intravenous tobramycin for treatment of pulmonary exacerbations in paediatric cystic fibrosis (CF) patients has not been completely delineated. We performed a retrospective study evaluating the pharmacokinetics and pharmacodynamics of once daily dosing (ODD) of IV tobramycin compared to twice daily dosing (TDD). Fifty-nine and 44 patients were included in the ODD and TDD groups, respectively. Once daily dosing achieved higher Cmax as compared to TDD (29.5?±?11.0 vs 19.0?±?4.9, P?0.001), lower 24?hour AUC (92.8?±?28.7 vs 128.5?±?34.6, P?0.001), and greater time that drug concentration was below the minimum inhibitory concentration (MIC) (13.4?±?1.7 vs 3.9?±?3.1?hour, P?0.001). Twice daily dosing failed to achieve goal Cmax:MIC for MICs >1.0?mg/l. Twice daily dosing may be a viable alternative to ODD in treating organisms with MICs ≤?1.0?mg/l; however, with MICs >1.0?mg/l, ODD is likely necessary to achieve goal Cmax:MIC ratios. 相似文献
975.
Caizheng Li Jiayu Sun Yongping Qin Ying Wang Rujia Yu 《Journal of chemotherapy (Florence, Italy)》2016,28(3):172-179
The objective of the study was to use Monte Carlo simulation to determine the optimal treatment dosing regimen of the cefetamet sodium for injection by analysing the pharmacokinetics (PK) parameters in healthy Chinese volunteers, and antibacterial activity in vitro was also examined. A three-cross Latin square single-dose PK study was designed. Twelve healthy volunteers were randomized to receive 500, 1000, and 2000 mg of cefetamet sodium for IV infusion over 30 minutes in three periods sequentially; and the washout time in between periods was 3 days. The drug concentrations in plasma were analysed by high-performance liquid chromatography, and the PK parameters were calculated using DAS2.0 PK software. The peak concentrations (Cmax) at 0.5 hours were 37.78±7.29, 76.18±12.81, and 149.32±29.94 mg/l, the areas under concentration–time curve (AUC0–t) were 69.75±14.44, 139.06±22.62, and 278.54±53.12 mg h/l, and the elimination half-life (t1/2) were 1.69±0.19, 1.69±0.27, and 1.81±0.23 hours for 500, 1000, and 2000 mg of cefetamet sodium for injection, respectively. The disposition of cefetamet was appear to fit a two-compartment model with linear kinetics. Antibacterial activity in vitro showed that most Gram-negative bacteria, including non-extended-spectrum beta-lactamases (ESBL)-producing Enterobacter, Haemophilus influenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae, were sensitive to cefetamet. The result of Monte Carlo simulation showed that the probability of target attainment for bactericidal response (%fT>MIC≧50%) for susceptible bacteria was reached at all three dosing regimens of 500 mg, q6h, 1000 and 2000 mg, q8h and q6h. Considering the efficacy, safety, and pharmacoeconomy comprehensively, we recommended the dosing regimen of 500 mg, q6h for further clinical treatment based on the principle of minimum daily dosage. 相似文献
976.
AimDalotuzumab is a highly specific, humanised immunoglobulin G1 monoclonal antibody against insulin-like growth factor receptor 1. This multicenter phase 1 study (NCT01431547) explored the safety and pharmacokinetics of dalotuzumab monotherapy (part 1) and the combination of dalotuzumab with the mammalian target of rapamycin inhibitor ridaforolimus (part 2) in paediatric patients with advanced solid tumours.MethodsDalotuzumab was administered intravenously every 3 weeks starting at 900 mg/m2 and escalating to 1200 and 1500 mg/m2. Combination therapy included intravenous dalotuzumab at the defined single-agent recommended phase 2 dose (RP2D) and oral ridaforolimus 28 mg/m2 daily (days 1–5), repeated weekly. Pharmacokinetic studies were performed to evaluate the mean serum trough dalotuzumab concentration, which guided the RP2D.ResultsTwenty-four patients were enrolled (part 1, n = 20; part 2, n = 4). No dose-limiting toxicities were observed in patients receiving dalotuzumab alone. One patient experienced dose-limiting stomatitis in the combination arm. Pharmacokinetic data showed dose-dependent increases in exposure (area under the curve from zero to infinity [AUC0–∞]) (87,900, 164,000, and 186,000 h*mg/ml for the 900, 1200, and 1500 mg/m2 dose levels, respectively), maximum serum concentration (Cmax) (392, 643, and 870 mg/ml), and serum trough concentration (Ctrough) (67.1, 71.6, and 101 mg/ml). The mean half-life was 265, 394, and 310 h, respectively. Dalotuzumab pharmacokinetics were not affected by coadministration with ridaforolimus. One of six patients with Ewing sarcoma had confirmed partial response to dalotuzumab monotherapy at 900 mg/m2. Time to response was 41 d, and progression occurred at 126 d.ConclusionDalotuzumab was well tolerated in paediatric patients with advanced solid malignancies. The RP2D of dalotuzumab is 900 mg/m2 (ClinicalTrials.gov identifier: NCT01431547, Protocol PN062). 相似文献
977.
Lipopolysaccharide (LPS) endotoxin is an active component in the outer membrane of Gram-negative bacteria. LPS is usually used as an animal model of chronic inflammation such as sepsis. During inflammation, development of diarrhea, and changes in the plasma protein bindings, in the hepatic and/or intestinal microsomal cytochrome P450 (CYP) isozymes, and in the renal excretion of drugs have been reported. Thus, in rats pretreated with lipopolysaccharide endotoxin isolated from Escherichia Coli (ECLPS rats), the absorption, the distribution, the metabolism, and the excretion of drugs could be expected to alter. Interestingly, in ECLPS rats, the time-dependent effects on the hepatic CYP isozymes have been reported. Thus, in ECLPS rats, the pharmacokinetics of drugs which are mainly metabolized via hepatic CYP isozymes could be expected to be time-dependent. In this review, an attempt to explain changes in the pharmacokinetics of drugs reported in the literature was made in terms of hepatic CYP isozyme changes or urinary excretion changes in ECLPS rats. 相似文献
978.
Freise KJ Widness JA Schmidt RL Veng-Pedersen P 《Journal of pharmacokinetics and pharmacodynamics》2008,35(3):285-323
Many pharmacodynamic (PD) models of cellular response assume a single and time invariant lifespan of all cells, despite the existence of a true underlying distribution of cellular lifespans and known changes in the lifespan distributions with time. To account for these features of cellular populations, a time variant cellular lifespan distribution PD model was formulated and theoretical aspects of modeling cellular populations presented. The model extends prior work assuming time variant "point distributions" of cellular lifespans (Freise et al. J Pharmacokinet Pharmacodyn 34:519-547, 2007) and models assuming a time invariant lifespan distribution (Krzyzanski et al. J Pharmacokinet Pharmacodyn 33:125-166, 2006). The formulated time variant lifespan distribution model was fitted to endogenous plasma erythropoietin (EPO), reticulocyte, and red blood cell (RBC) concentrations in sheep phlebotomized on two occasions, 8 days apart. The time variant circulating reticulocyte lifespan was modeled as a truncated and scaled Weibull distribution, with the location parameter of the distribution non-parametrically represented by an end constrained quadratic spline function. The formulated time variant lifespan distribution model was compared to the identical time invariant distribution, time variant "point distribution", and time invariant "point distribution" cellular lifespan models. Parameters of the time variant lifespan distribution model were well estimated with low standard errors. The mean circulating reticulocyte lifespan was estimated at 0.304 days, which rapidly increased over 3-fold following the first phlebotomy to a maximum of 1.03 days (P = 0.009). On average, the percentage of erythrocytes being released as reticulocytes maximally increased an estimated two-fold following the phlebotomies. The primary features of immature RBC physiology were captured by the model and gave results consistent with other estimates in sheep and humans. The comparison of the four lifespan models gave similar parameter estimates of the stimulation function and fits to the RBC data. However, the time invariant models fit the reticulocyte data poorly, while the time variant "point distribution" cellular lifespan model gave physiologically unrealistic estimates of the changes in the circulating reticulocyte lifespan under stress erythropoiesis. Thus the underlying physiology must be considered when selecting the most appropriate cellular lifespan model and not just the goodness-of-fit criteria. The proposed PD model and the numerical implementation allows for a flexible framework to incorporate time variant lifespan distributions when modeling populations of cells whose production or stimulation depends on endogenous growth factors and/or exogenous drugs. 相似文献
979.
980.
Aim It has been reported that verapamil and atorvastatin are inhibitors of both P-glycoprotein (P-gp) and microsomal cytochrome
P450 (CYP) 3A4, and verapamil is a substrate of both P-gp and CYP3A4. Thus, it could be expected that atorvastatin would alter
the absorption and metabolism of verapamil.
Methods The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared after oral administration
of verapamil (60 mg) in the presence or absence of oral atorvastatin (40 mg) in 12 healthy volunteers.
Results Pharmacokinetics of verapamil were significantly altered by the coadministration of atorvastatin compared with those of without
atorvastatin. For example, the total area under the plasma-concentration time curve to the last measured time, 24 h, in plasma
(AUC0−24 h) of verapamil increased significantly by 42.8%. Thus, the relative bioavailability increased by the same magnitude with atorvastatin.
Although the AUC0−24 h of norverapamil was not significantly different between two groups of humans, the AUC0−24 h, norverapamil/ AUC0−24 h, verapamil ratio was significantly reduced (27.5% decrease) with atorvastatin.
Conclusion The above data suggest that atorvastatin could inhibit the absorption of verapamil via inhibition of P-gp and/or the metabolism
of verapamil by CYP3A4 in humans. 相似文献