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11.
Chuu JJ Liu JM Tsou MH Huang CL Chen CP Wang HS Chen CT 《Journal of biomedical science》2007,14(2):233-244
Summary Cancer has been the leading cause of death in Taiwan over the past two decades and liver cancer is the leading cause of all
cancer deaths in Taiwan with a trend of increase in incidence. Therapeutic options and efficacy for liver cancer have been
limited and the 5-year survival rate is less than 7% in the Unite States. The study was conducted to establish a histoculture
system of human hepatocellular carcinomas (HCC) for biological and pharmacological studies and to determine the efficacy of
anticancer drugs with the established HCC histocultures. Patient HCC tissues freshly obtained after surgeries were prepared
and histocultured. The histocultured HCC were treated with doxorubicin and paclitaxel of various concentrations for 96-h.
Upon drug treatments, the activity of tumor cell proliferation and extent of cell death induction were measured and changes
of the α-fetoprotein levels in the culture medium were determined. We demonstrated that human HCC can be successfully cultured
in a 3-dimensional histoculture system and used for pharmacological studies. Doxorubicin and paclitaxel showed concentration-dependent
activities in anti-proliferation and cell death induction against the human HCC. Inhibitory effects of both drugs on α-fetoprotein
production of the cultured HCC were in agreement with their anti-proliferative effects. Exposure time-dependent antitumoral
effects of paclitaxel treatments at 3-, 24-, and 96-h against the histocultured HCC PLC/PRF/5 xenograft tumors were also observed.
In conclusion, we have demonstrated a histoculture system for patient HCC and it can be utilized in selection of active drugs
prior to treatments in patients and in evaluation of new agents against HCC, for which therapeutic agents are in desperate
needs worldwide. 相似文献
12.
Scheerens H Su Z Irving B Townsend MJ Zheng Y Stefanich E Chindalore V Bingham CO Davis JC 《Arthritis research & therapy》2011,13(5):R177
Introduction
The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA). 相似文献13.
14.
Mitsunori Kono Tsuneo Oda Michiko Tawada Takashi Imada Yoshihiro Banno Naohiro Taya Tetsuji Kawamoto Hidekazu Tokuhara Yoshihide Tomata Naoki Ishii Atsuko Ochida Yoshiyuki Fukase Tomoya Yukawa Shoji Fukumoto Hiroyuki Watanabe Keiko Uga Akira Shibata Hideyuki Nakagawa Satoshi Yamamoto 《Bioorganic & medicinal chemistry》2018,26(2):470-482
A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay. 相似文献
15.
The risk assessment process for non-carcinogens must incorporate all available scientific information, including toxicokinetic and toxicodynamic data. The framework for exposure limit setting proposed by Renwick and the International Programme on Chemical Safety (IPCS) subdivides traditional 10X uncertainty factors (UFs) into separate partial-log default values based on kinetic and dynamic considerations and allows for incorporation of compound-specific data when available. In this investigation, an extensive literature search was conducted on nine pharmaceuticals in order to incorporate information on kinetics and dynamics to allow extrapolation across species and among susceptible humans. The drugs are diazepam, oxazepam, midazolam, buspirone, fluoxetine, venlafaxine, amlodipine, felodipine, and nifedipine. The composite factors were calculated using the highest ratio or the average ratio for appropriate parameters and default subfactor. For the drugs examined, most of the subfactors for kinetics and dynamics were less than the proposed values by Renwick and IPCS, and the composite factors were far less than 100. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce uncertainties associated with interspecies differences and interindividual variability. 相似文献
16.
Ryan J. Hansen Michael J. Berna Andrea E. Sperry Thomas P. Beyer Victor J. Wroblewski Krista M. Schroeder 《MABS-AUSTIN》2017,9(2):285-296
A recent report described a novel mechanism of action for an anti-proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibody (LY3015014, or LY), wherein the antibody has improved potency and duration of action due to the PCSK9 epitope for LY binding. Unlike other antibodies, proteolysis of PCSK9 can occur when LY is bound to PCSK9. We hypothesized that this allowance of PCSK9 cleavage potentially improves LY efficiency through two pathways, namely lack of accumulation of intact PCSK9 and reduced clearance of LY. A quantitative modeling approach is necessary to further understand this novel mechanism of action. We developed a mechanism-based model to characterize the relationship between antibody pharmacokinetics, PCSK9 and LDL cholesterol levels in animals, and used the model to better understand the underlying drivers for the improved efficiency of LY. Simulations suggested that the allowance of cleavage of PCSK9 resulting in a lack of accumulation of intact PCSK9 is the major driver of the improved potency and durability of LY. The modeling reveals that this novel ‘proteolysis-permitting’ mechanism of LY is a means by which an efficient antibody can be developed with a total antibody dosing rate that is lower than the target production rate. We expect this engineering approach may be applicable to other targets and that the mathematical models presented herein will be useful in evaluating similar approaches. 相似文献
17.
J. Engelstädter 《Journal of evolutionary biology》2014,27(5):840-853
Adaptive evolution often involves beneficial mutations at more than one locus. In this case, the trajectory and rate of adaptation is determined by the underlying fitness landscape, that is, the fitness values and mutational connectivity of all genotypes under consideration. Drug resistance, especially resistance to multiple drugs simultaneously, is also often conferred by mutations at several loci so that the concept of fitness landscapes becomes important. However, fitness landscapes underlying drug resistance are not static but dependent on drug concentrations, which means they are influenced by the pharmacodynamics of the drugs administered. Here, I present a mathematical framework for fitness landscapes of multidrug resistance based on Hill functions describing how drug concentrations affect fitness. I demonstrate that these ‘pharmacodynamic fitness landscapes’ are characterized by pervasive epistasis that arises through (i) fitness costs of resistance (even when these costs are additive), (ii) nonspecificity of resistance mutations to drugs, in particular cross‐resistance, and (iii) drug interactions (both synergistic and antagonistic). In the latter case, reciprocal drug suppression may even lead to reciprocal sign epistasis, so that the doubly resistant genotype occupies a local fitness peak that may be difficult to access by evolution. Simulations exploring the evolutionary dynamics on some pharmacodynamic fitness landscapes with both constant and changing drug concentrations confirm the crucial role of epistasis in determining the rate of multidrug resistance evolution. 相似文献
18.
Qiong Wu Yan Wang Xinyu Wang Ningxia Liang Jingjing Liu Donghui Pan Yuping Xu Lizhen Wang Junjie Yan Guangji Wang Liyan Miao Min Yang 《Journal of cellular and molecular medicine》2021,25(15):7451-7461
In recent years, chimeric antigen receptor T (CAR T)-cell therapy has shown great potential in treating haematologic disease, but no breakthrough has been achieved in solid tumours. In order to clarify the antitumour mechanism of CAR T cell in solid tumours, the pharmacokinetic (PK) and pharmacodynamic (PD) investigations of CD19 CAR T cell were performed in human leukaemic xenograft mouse models. For PK investigation, we radiolabelled CD19 CAR T cell with 89Zr and used PET imaging in the CD19-positive and the CD19-negative K562-luc animal models. For PD evaluation, optical imaging, tumour volume measurement and DNA copy-number detection were performed. Unfortunately, the qPCR results of the DNA copy number in the blood were below the detection limit. The tumour-specific uptake was higher in the CD19-positive model than in the CD19-negative model, and this was consistent with the PD results. The preliminary PK and PD studies of CD19 CAR T cell in solid tumours are instructive. Considering the less efficiency of CAR T-cell therapy of solid tumours with the limited number of CAR T cells entering the interior of solid tumours, this study is suggestive for the subsequent CAR T-cell design and evaluation of solid tumour therapy. 相似文献
19.
Bacterial growth environment strongly influences the efficacy of antibiotic treatment, with slow growth often being associated with decreased susceptibility. Yet in many cases, the connection between antibiotic susceptibility and pathogen physiology remains unclear. We show that for ribosome-targeting antibiotics acting on Escherichia coli, a complex interplay exists between physiology and antibiotic action; for some antibiotics within this class, faster growth indeed increases susceptibility, but for other antibiotics, the opposite is true. Remarkably, these observations can be explained by a simple mathematical model that combines drug transport and binding with physiological constraints. Our model reveals that growth-dependent susceptibility is controlled by a single parameter characterizing the ‘reversibility’ of ribosome-targeting antibiotic transport and binding. This parameter provides a spectrum classification of antibiotic growth-dependent efficacy that appears to correspond at its extremes to existing binary classification schemes. In these limits, the model predicts universal, parameter-free limiting forms for growth inhibition curves. The model also leads to non-trivial predictions for the drug susceptibility of a translation mutant strain of E. coli, which we verify experimentally. Drug action and bacterial metabolism are mechanistically complex; nevertheless, this study illustrates how coarse-grained models can be used to integrate pathogen physiology into drug design and treatment strategies. 相似文献
20.
The purpose of this research was to enhance the bioactivity of insulin by the pulmonary route using a combination of absorption
promoters. Aliquots (100 μL) containing 1.0 IU/kg to 7.0 IU/kg doses of porcine insulin solutions with different classes of
absorption promoters and combinations of these at 3 concentration levels were instilled intratracheally to the anesthetized
rats. Blood concentrations of glucose were measured at specific time points. Out of 3 concentration levels of each of the
absorption promoters used, the formulations having the leastconcentration with the maximum percentage of blood glucose reduction
were selected for combining absorption promoters, and their pharmacodynamic parameters related to insulin absorption were
determined. The pharmacodynamics of porcine insulin following subcutaneous administration of increasing doses were also determined.
The relative pulmonary bioactivity of insulin in phosphate buffer pH 7.4 and citrate buffer pH 3.5 was 11.36%±1.27% and 43.20%
±2.48%, respectively, compared to subcutaneous administration. Relative pulmonary bioactivity of 155.60%±5.19% was obtained
when oleic acid sodium salt, sodium tauroglycocholate, bestatin, and chymostatin were coadministered in citrate buffer pH
3.5 solution. However, only 61.91%±3.21, 67.09%±3.23%, 67.24%±2.11%, and 69.84%±3.02% were obtained, respectively, upon incorporation
of these absorption promoters individually. Absorption promoters in combination have significant potential for increasing
the pulmonary bioactivity of insulin. These studies support the argument that pulmonary administration of insulin is a viable
alternative to subcutaneous administration for diabetic patients. 相似文献