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Summary. The relationship of inhibitory quotient (IQ) with the virologic response to specific inhibitors of human hepatitis C virus (HCV) and the best method to correct for serum protein binding in calculating IQ have not been addressed. A common method is to determine a fold shift by comparing the EC 50 values determined in cell culture in the absence and presence of human serum (fold shift in EC 50 ), but this method has a number of disadvantages. In the present study, the fold shifts in drug concentrations between 100% human plasma (HP) and cell culture medium (CCM) were directly measured using a modified comparative equilibrium dialysis (CED) assay for three HCV protease inhibitors (PIs) and for a novel HCV inhibitor GS‐9132. The fold shift values in drug concentration between the HP and CCM (CED ratio) were ∼1 for SCH‐503034, VX‐950 and GS‐9132 and 13 for BILN‐2061. These values were ∼3–10‐fold lower than the fold shift values calculated from the EC 50 assay for all inhibitors except BILN‐2061. Using the CED values, a consistent pharmacokinetic and pharmacodynamic relationship was observed for the four HCV inhibitors analysed. Specifically, an approximate 1 log 10 reduction in HCV RNA was achieved with an IQ close to 1, while 2–3 and greater log 10 reductions in HCV RNA were achieved with IQ values of 3–5 and greater, respectively. Thus, use of CED to define IQ provides a predictive and quantitative approach for the assessment of the in vivo potency of HCV PIs and GS‐9132. This method provides a framework for the evaluation of other classes of drugs that are bound by serum proteins but require the presence of serum for in vitro evaluation.
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis due to the absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D inhibitor. Therapeutic factor D inhibition was designed to control intravascular hemolysis and prevent C3-mediated extravascular hemolysis. In this open-label, phase II, dose-finding trial, ten untreated PNH patients with hemolysis received danicopan monotherapy (100-200 mg thrice daily). Endpoints included changes in the concentrations of lactate dehydrogenase (LDH) at day 28 (primary endpoint), of LDH at day 84, and of hemoglobin. Safety, pharmacokinetics/ pharmacodynamics, and patient-reported outcomes were assessed. Ten patients reached the primary endpoint; two later discontinued treatment: one because of a serious adverse event (elevated aspartate aminotransferase/ alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. Intravascular hemolysis was inhibited, as demonstrated by a mean decrease of LDH (5.7 times upper limit of normal [ULN] at baseline vs. 1.8 times ULN at day 28 and 2.2 times ULN at day 84; both P<0.001). Mean baseline hemoglobin, 9.8 g/dL, increased by 1.1 (day 28) and 1.7 (day 84) g/dL (both P<0.005). No significant C3 fragment deposition occurred on glycosylphosphatidylinositol- deficient erythrocytes. Mean baseline Functional Assessment of Chronic Illness Therapy–Fatigue score, 34, increased by 9 (day 28) and 13 (day 84) points. The most common adverse events were headache and upper respiratory tract infection. These phase II, monotherapy data show that proximal inhibition with danicopan provides clinically meaningful inhibition of intravascular hemolysis and increases hemoglobin concentration in untreated PNH patients, without evidence of C3-mediated extravascular hemolysis. This trial was registered at www.clinicaltrials.gov (#NCT03053102).
This study aimed to investigate the potential effects of Gomisin B, a natural compound known for its inhibition of CYP3A4, on cognitive dysfunction in APP/PS1 transgenic mice with Alzheimer's disease (AD). Additionally, the study explored the combined effects of Gomisin B and Osthole (OST). The research involved male wild-type (WT) mice and 7-month-old APP/PS1 transgenic AD mice. The assessment of behavioral changes included the use of the open field test (OFT) and the Morris water maze (MWM). OST levels in brain tissue were quantified using LC-MS/MS, while levels of oxidative stress were measured through an assay kit. Neuronal apoptosis was studied using Nissl staining, RT-qPCR, and immunofluorescence. Amyloid plaque clearance was assessed using thioflavine-S (Th-S) staining, RT-qPCR, and ELISA. The results of the study revealed that Gomisin B led to a significant improvement in cognitive dysfunction in APP/PS1 mice. Moreover, the simultaneous administration of OST and Gomisin B demonstrated enhanced therapeutic effects. These effects were attributed to the inhibition of β-site APP-Cleaving Enzyme 1 (BACE1) and oxidative stress by Gomisin B, along with its anti-apoptotic properties. The combined use of OST and Gomisin B exhibited a synergistic impact, resulting in more pronounced anti-oxidant and anti-apoptotic effects. In summary, this study pioneers the exploration of Gomisin B's multifunctional anti-AD properties in APP/PS1 mice. The findings provide a solid groundwork for the development of anti-Alzheimer's drugs based on natural active ingredients.
The anti-coagulation protocol of patients with hemorrhage risk primary disease who need extracorporeal membrane oxygenation (ECMO) supported is controversial. This study evaluated the feasibility of a new anti-coagulation strategy, that is heparin-free after 3000 IU heparin loaded in veno-venous ECMO (VV ECMO) supported acute respiratory failure patients with hemorrhage risk.A retrospective study was performed in a series of hemorrhage risk patients supported with VV ECMO at the First Affiliated Hospital of Zhengzhou University, between June 2012 to Sept 2020. A total of 70 patients received a low heparin bolus of 3000 units for cannulation but without subsequent, ongoing heparin administration. Patients were divided into survival (n = 25) and non-survival group (n = 45). Data of coagulation, hemolysis and membrane lung function were calculated and analyzed. The complications of patients were recorded. Finally, the binary Logistic regression was conducted.The longest heparin-free time was 216 h, and the mean heparin-free time was 102 h. Compared with survivors, the non-survivors were showed higher baseline SOFA score and lower platelet counts in 0.5 h, 24 h, 48 h and 96 h after ECMO applied. However, there was no significant differences between survivors and non-survivors in ACT, APTT, INR, D-dimer, fibrinogen, LDH, blood flow rate, Δp and Ppost-MLO2 (all p < 0.05) of all different time point. Moreover, only the baseline SOFA score was significantly associated with mortality (p < 0.001, OR(95%CI): 2.754 (1.486-5.103)) while the baseline levels of ACT, APTT, INR, platelet, D-dimer, fibrinogen and LDH have no association with mortality. The percentage of thrombosis complications was 54.3% (38/70) including 3 oxygenator changed but there was no significant difference of complications in survival and non-survival groups (p > 0.05).The anticoagulation protocol that no heparin after a 3000 units heparin bolus in VV ECMO supported acute respiratory failure patients with hemorrhage risk is feasible.
The reaction of the human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein p7 (NCp7) with a variety of electrophilic agents was investigated by experimental measurements of Trp37 fluorescence decay and compared with theoretical measures of reactivity based on density-functional theory in the context of the hard and soft acids and bases principle. Statistically significant correlations were found between rates of reaction and the ability of these agents to function as soft electrophiles. Notably, the molecular property that correlated strongest was the ratio of electronegativity to hardness, chi2/eta, a quantity related to the capacity of an electrophile to promote a soft (covalent) reaction. Electronic and steric determinants of the reaction were also probed by Fukui function and frontier-orbital overlap analysis in combination with protein-ligand docking methods. This analysis identified selective ligand docking regions within the conserved zinc finger domains that promoted reaction. The Cys49 thiolate was found overall to be the NCp7 site most susceptible to electrophilic attack.
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