E5564, a synthetic lipid A analogue, is a selective, highly active antagonist of endotoxin-mediated activation of immune cells. Preclinical research has indicated that E5564 can block endotoxin-mediated induction of cytokines and endotoxin or Gram-negative bacterial-induced death in animal models. Recent phase I clinical trials have focused on the ability of E5564 to block responsiveness to endotoxin. This was done in two ways: in vivo challenge of human volunteers with 4 ng/kg endotoxin, and by use of an ex vivo assay which utilizes blood drawn from volunteers administered E5564 and challenged with endotoxin at concentrations that ranged from 50 pg/ml to 10 ng/ml. In vivo, > or = 100 microg of E5564 completely blocked signs, symptoms and cytokines induced by concomitantly-administered endotoxin. In contrast, subjects receiving a 50 microg dose of E5564 demonstrated a graded response; cytokines were inhibited > or = 95%, but many signs and symptoms of endotoxemia were still evident. E5564 demonstrated a long pharmacokinetic half-life (> 30 h); however, ex vivo analysis indicated that while single doses of 350 microg induced a nearly complete block of the effects of 1 ng/ml endotoxin immediately upon E5564 administration, antagonistic activity declined rapidly (t(1/2) < 1 h). Similar results were obtained in vivo using a delayed endotoxin challenge. These results have driven us to examine antagonistic activity of E5564 in vivo and ex vivo after administration by continuous infusion or twice-daily dosing. Results from these multiple-dose studies indicate that under these conditions of administration, plasma levels of E5564 can be predictive of long-term pharmacodynamic activity.
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http://dx.doi.org/10.1179/096805102125001127 | DOI Listing |
Rev Med Inst Mex Seguro Soc
May 2024
Instituto Mexicano del Seguro Social, Hospital General de Zona No. 3, Servicio de Anestesiología. San Juan del Río, Querétaro, México.
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Plast Reconstr Surg Glob Open
February 2024
From the AIC Kijabe Hospital, Kijabe, Kenya.
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View Article and Find Full Text PDFImmunobiology
May 2023
Department of Pharmacy, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China. Electronic address:
Type 2 T helper (Th2) cells-mediated immune response plays a pivotal role in the pathogenesis of cough variant asthma (CVA), and this study aims to determine the effect and mechanism of ethanol extract of Anacyclus pyrethrum root (EEAP) on regulating Th2 response in CVA. Peripheral blood mononuclear cells (PBMCs) collected from patients with CVA, and naive CD4T cells induced by Th2-polarizing medium were administrated with EEAP. Interestingly, through conducting flow cytometry and enzyme linked immunosorbent assay method, we found that EEAP significantly alleviated Th2 skewing and increased Th1 response in these two kinds of cells.
View Article and Find Full Text PDFBiomed Chromatogr
March 2023
Department of Resources and Identification of Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, P. R. China.
A quantitative analysis method and a chemical pattern recognition method were developed to evaluate raw Ligustri Lucidi Fructus (LLF) from different regions and different processed products. In this study, a comprehensive strategy using ultra-high-performance liquid chromatography-mass spectrometry quantitative analysis method was established for the simultaneous determination of 16 components in 47 batches of LLF covering 19 regions belonging to 8 provinces and 24 batches of different processed products (steamed LLF without auxiliary material, wine-steamed LLF, salt-steamed LLF, and vinegar-steamed LLF). The results of this study indicated that the proposed method was reliable and accurate for the rapid analysis proved by detection limit, quantification limit, precision, and accuracy.
View Article and Find Full Text PDFNihon Yakurigaku Zasshi
January 2022
Eisai Co., Ltd.
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