Performance of two supervised cluster analysis (SVCA) algorithms for extracting reference tissue curves was evaluated to improve quantification of dynamic (R)-[11C]PK11195 brain positron emission tomography (PET) studies. Reference tissues were extracted from images using both a manually defined cerebellum and SVCA algorithms based on either four (SVCA4) or six (SVCA6) kinetic classes. Data from controls, mild cognitive impairment patients, and patients with Alzheimer''s disease were analyzed using various kinetic models including plasma input, the simplified reference tissue model (RPM) and RPM with vascular correction (RPMVb). In all subject groups, SVCA-based reference tissue curves showed lower blood volume fractions (Vb) and volume of distributions than those based on cerebellum time-activity curve. Probably resulting from the presence of specific signal from the vessel walls that contains in normal condition a significant concentration of the 18 kDa translocation protein. Best contrast between subject groups was seen using SVCA4-based reference tissues as the result of a lower number of kinetic classes and the prior removal of extracerebral tissues. In addition, incorporation of Vb in RPM improved both parametric images and binding potential contrast between groups. Incorporation of Vb within RPM, together with SVCA4, appears to be the method of choice for analyzing cerebral (R)-[11C]PK11195 neurodegeneration studies. 相似文献
1. Aldehyde oxidase (AO enzymes)-mediated oxidation predominantly occurs at a carbon atom adjacent to the nitrogen on aromatic azaheterocycles. In the current report, we identified that AO enzymes oxidation took place at both the C-2 and C-4 positions of the methylquinoline moiety of Compound A based on data from mass spectrometric analysis, AO enzymes “litmus” test, and comparison with authentic standards.
2. To assess the potential for inadequate coverage for these two AO enzyme-mediated metabolites in nonclinical safety studies, given concerns due to differences in AO enzymes expression between preclinical species and humans, the human circulating levels of the two AO enzyme-mediated metabolites were predicted prospectively using in vitro and in vivo models. Both formation clearance and elimination clearance of the two metabolites were predicted based on in vitro to in vivo correlation and comparison with in vivo data from rats.
3. The result showed that the 4-OH metabolite of Compound A would account for less than 3% of the total drug-related exposure in human plasma, while the exposure to the 2-oxo metabolite would be relatively high (~70%).
4. The predicted human exposure levels for the two metabolites are in similar ranges as those observed in monkeys. These data taken together support the advancement to clinical development of Compound A. 相似文献
Clinical drug development remains a mostly empirical, costly enterprise, in which decision-making is often based on qualitative assessment of risk, without properly leveraging all the relevant data collected throughout the development programme. Model-based drug development (MBDD) has been proposed by regulatory agencies, academia and pharmaceutical companies as a paradigm to modernize drug research through the quantification of risk and combination of information from different sources across time. We present here a historical account of the use of MBDD in clinical drug development, the current challenges and further opportunities for its application in the pharmaceutical industry. 相似文献
The use of engineered phages offers a unique opportunity to improve on wild-type (WT) phages to generate ever more successful therapeutics to combat bacterial infections. Here, we discuss how phage engineering could be used to overcome some of the technical challenges of phage therapy, and suggest some areas in which more research will be crucial to the development of further novel phage therapeutics. 相似文献
To compare the stability of stable and unstable water-in-oil emulsions and the efficacy and safety of these emulsions in a single-center, prospective double-blind trial of transarterial chemoembolization for hepatocellular carcinoma (HCC).
Materials and Methods
A total of 812 patients with inoperable HCC were randomized (stable emulsion, n = 402; unstable emulsion, n = 410). The 2 emulsions were prepared by using the same protocol except that different solvents were used for chemotherapy agents, including epirubicin, lobaplatin, and mitomycin C. The solvent in the stable emulsion arm was contrast medium and distilled water, and the solvent in the unstable emulsion arm was distilled water. The primary endpoint was overall survival (OS), and secondary endpoints were time to progression (TTP), tumor response, adverse events (AEs), and plasma epirubicin concentrations.
Results
In vitro, stable emulsions did not occur until 1 day, and unstable emulsions, with a lower peak plasma concentration (P = .001) in vivo, exhibited rapid separation of the oil and aqueous phases after 10 minutes. Median OS times in the stable and unstable emulsion arms were 17.7 and 19.2 months, respectively (P = .81). No differences were found in TTP, tumor response, and AEs except for myelosuppression (anemia, 3.5% vs 7.6%; thrombocytopenia, 11.5% vs 17.7%), which was significantly more severe and frequent in the unstable emulsion arm (P = .013).
Conclusions
Chemoembolization is equally effective with the use of stable and unstable emulsions, but the use of a stable emulsion has the advantage of less myelosuppression and a favorable pharmacokinetic profile. 相似文献
To systematically review mechanism of action, pharmacokinetics (PKs), efficacy, and safety of ethiodized oil–based locoregional therapy (LRT) for liver cancer in preclinical models.
Materials and Methods
A MEDLINE search was performed from 1988 to 2016. Search terms included hepatocellular carcinoma (HCC), HCC, liver-cell carcinoma, liver, hepatic, hepatocarcinoma, transarterial or chemoembolization, TACE, animal, Lipiodol, Ethiodol, iodized oil, and/or poppy-seed oil. Inclusion criteria were: publication in a peer-reviewed journal, an accepted animal model, and PK/safety/efficacy data reported. Exclusion criteria were: inadequate PK, safety, or efficacy data; anticancer drug name/dose not available; and article not in English. Outcomes included intratumoral anticancer drug uptake, PKs, tolerance, tumor response, and survival.
Results
Of 102 identified articles, 49 (49%) met the inclusion criteria. Seventeen, 35, and 2 articles used rat, rabbit, and pig models. Mechanism of action was investigated in 11 articles. Eleven articles reported drug uptake, PK, and tolerance data, showing 0.5%–9.5% of injected chemotherapy dose in tumor. Tumor-to-liver drug distribution ratios were 2–157. Toxicology data across 6 articles showed transient liver laboratory level elevations 1 day after LRT. There was no noteworthy liver or extrahepatic histologic damage. Nine articles reported tumor response, with 0%–30% viable tumor and –10% to –38% tumor growth at 7 days after LRT. Two articles reported survival, showing significantly longer survival after LRT vs untreated controls (56/60 d vs 33/28 d). Several articles described ethiodized oil mixed with radiopharmaceutical (n = 7), antiangiogenic (n = 6), gene (n = 6), nanoembolic (n = 5), immune (n = 2), or other novel (n = 1) agents.
Conclusions
Animal studies show preferential tumor uptake of anticancer agent, good hepatic/systemic tolerance, high tumor response, and enhanced survival after ethiodized oil–based LRT. 相似文献
Glycogen content, glucose consumption and the production of metabolic end products by Calicophoron ijimai were determined under aerobic and anaerobic conditions. The major end products of fermentation were identified as lactic, acetic, propionic, isobutyric and α-methylbutyric acids, propionic acid predominating. The activities and properties of some of the enzymes of carbohydrate metabolism were determined. The worms showed high phosphoenolpyruvate carboxykinase, malate dehydrogenase and malate dehydrogenase (decarboxylating) but relatively low pyruvate kinase and very low lactate dehydrogenase activities. The pH optima, coenzyme, cofactor and ionic requirements of the enzymes were similar to those of other helminths. Malate dehydrogenase had an 8-fold greater affinity for oxaloacetate than malate, and was about 14 times more active for oxaloacetate reduction than malate oxidation. Phosphoenolpyruvate carboxykinase was 2.4 times more active and had a 2-fold greater affinity for phosphoenolpyruvate and dinucleotide than pyruvate kinase. The low activities of lactate dehydrogenase and pyruvate kinase but high activities of malate dehydrogenase and phosphoenolpyruvate carboxykinase suggest that anaerobic carbohydrate catabolism follows the fumarate reductase pathway. 相似文献