High mobility group box 1 (HMGB1), a nuclear protein, once released into the extracellular space under pathological conditions, plays a pronociceptive role in redox-dependent distinct active forms, all-thiol HMGB1 (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), that accelerate nociception through the receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4), respectively. Thrombomodulin (TM), an endothelial membrane protein, and soluble TM, known as TMα, promote thrombin-mediated activation of protein C and also sequester HMGB1, which might facilitate thrombin degradation of HMGB1. The present study aimed at clarifying the role of thrombin in TMα-induced suppression of peripheral HMGB1-dependent allodynia in mice. Thrombin-induced degradation of at-HMGB1 and ds-HMGB1 was accelerated by TMα in vitro. Intraplantar (i.pl.) injection of bovine thymus-derived HMGB1 in an unknown redox state, at-HMGB1, ds-HMGB1 or lipopolysaccharide (LPS), known to cause HMGB1 secretion, produced long-lasting mechanical allodynia in mice, as assessed by von Frey test. TMα, when preadministered i.pl., prevented the allodynia caused by bovine thymus-derived HMGB1, at-HMGB1, ds-HMGB1 or LPS, in a dose-dependent manner. The TMα-induced suppression of the allodynia following i.pl. at-HMGB1, ds-HMGB1 or LPS was abolished by systemic preadministration of argatroban, a thrombin-inhibiting agent, and accelerated by i.pl. co-administered thrombin. Our data clearly indicate that TMα is capable of promoting the thrombin-induced degradation of both at-HMGB1 and ds-HMGB1, and suppresses the allodynia caused by either HMGB1 in a thrombin-dependent manner. Considering the emerging role of HMGB1 in distinct pathological pain models, the present study suggests the therapeutic usefulness of TMα for treatment of intractable and/or persistent pain. 相似文献
This article gives an overview of a technique called optimal control, which is used to optimize real-world quantities represented by mathematical models. I include background information about the historical development of the technique and applications in a variety of fields. The main focus here is the application to diseases and therapies, particularly the optimization of combination therapies, and I highlight several such examples. I also describe the basic theory of optimal control, and illustrate each of the steps with an example that optimizes the doses in a combination regimen for leukemia. References are provided for more complex cases. The article is aimed at modelers working in drug development, who have not used optimal control previously. My goal is to make this technique more accessible in the biopharma community. 相似文献
The current study is an example of drug–disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology—ten Tusscher ventricular cardiomyocyte cell model—was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies. Simulated and observed mean QTc values with standard deviation (SD) for each reported study point were compared and differences were analyzed with Student’s t test (α?=?0.05). The simulated results reflected the QTc interval changes measured in patients, as well as their clinically observed interindividual variability. The QTc interval changes were highly correlated with the change in plasma potassium both in clinical studies and in the simulations (Pearson’s correlation coefficient?>?0.55). The results suggest that the modeling and simulation approach could provide valuable quantitative insight into the cardiological effect of the potassium and heart rate changes caused by electrophysiologically inactive, non-cardiological drugs. This allows to simulate and predict the joint effect of several risk factors for QT prolongation, e.g., drug-dependent QT prolongation due to the ion channels inhibition and the current patient physiological conditions. 相似文献
Thrombocytopenia is the second most common hematological disease during pregnancy and is mainly caused by gestational thrombocytopenia, immune thrombocytopenia, or preeclampsia/HELLP syndrome. This study aims to investigate the causes and pregnancy outcomes of thrombocytopenia in pregnancies with platelet counts below 50 × 109/L. We retrospectively analyzed the pregnancies diagnosed with severe thrombocytopenia at a tertiary care center in western China between January 2009 and December 2017. All enrolled pregnancies were divided into three groups according to the lowest platelet counts: group A (30–50 × 109/L), group B (10–30 × 109/L), and group C (< 10 × 109/L). Maternal and fetal outcomes were observed and compared among these three platelet levels. A total of 533 consecutive pregnancies were included. A relatively large proportion (37.3%, 199/533) of them showed a history of thrombocytopenia before pregnancy or during a previous pregnancy. Most of the women (70.2%, 374/533) received corticosteroids, intravenous immunoglobulin, or platelet transfusion treatments. The incidence of preterm birth < 37 weeks (26.3%, 15/57), cesarean section (93%, 53/57), and neonatal intensive care unit (NICU) admission (31.6%, 18/57) occurred significantly more often in group C than in groups A and B. Neonatal platelet counts were detected in 28.2% of the infants (155/549), and neonatal thrombocytopenia was found in 40.6% of the infants (63/155). Intracranial hemorrhage occurred in 0.9% of the neonates (5/549) throughout the study period, with neonatal nadir platelet counts between 20 × 109/L and 245 × 109/L. One perinatal death occurred in group C. Pregnancies with the lowest platelet counts below 10 × 109/L are more often complicated by preterm birth, cesarean section, and NICU admission compared with those lowest platelet counts 30–50 × 109/L and 10–30 × 109/L. Neonatal intracranial hemorrhage was uncommon in pregnancies with severe thrombocytopenia. Active management should be performed to avoid possible preterm birth and neonatal NICU admission in pregnancies with the lowest platelet counts below 10 × 109/L.
