Safety of aerosolized INS 365 in patients with mild to moderate cystic fibrosis: results of a phase I multi-center study

Cystic fibrosis (CF) is characterized by defective cystic fibrosis transmembrane regulator (CFTR) expression and function, associated with abnormal ion transport and mucociliary clearance, and clinical lung disease. Triphosphate nucleotides such as uridine-5'-triphosphate (UTP) and INS 365, may be useful for CF through actions, mediated via P2Y(2) extracellular receptors, on chloride and liquid secretion, and ciliary beat frequency. INS 365 may offer chemical stability advantages over UTP. In a randomized, double-blind, multicenter phase I study, we studied the safety and maximally tolerated dose of escalating, single doses of aerosolized INS 365, in adult and pediatric patients with mild to moderate CF lung disease (FEV(1) > or = 45% predicted). In four successive dose cohorts of adult patients (n = 12 per cohort, age > or = 18 years) and four successive pediatric dose cohorts (n = 12 per cohort, age 5-12 years), patients were randomized 3:1 active/placebo (0.9% saline) to evaluate doses of 20, 40, 80, and 100 mg INS 365 delivered by nebulizer (Pari Star ). Sputum was collected pre- and post-dosing to obtain preliminary results on clinical efficacy. After each dose cohort, a Data Safety Monitoring Committee (DSMC) reviewed the data. Forty-eight adult and 36 pediatric patients completed the protocol (up to 100 mg for adults, 80 mg for pediatric patients). The predominant adverse events were cough, wheezing, chest tightness, and a decrease in FEV(1) (occurring in 8/48 adults, and 5/36 pediatric patients), which occurred predominantly in the 80-mg and 100-mg dose cohorts. Though a few adult patients had a tendency to increase sputum production, there was little consistent effect noted on sputum production in this acute, single-dose study. The data suggest that aerosolized INS 365 is safe when delivered at single doses of up to 40 mg in adults and children with CF, but that higher doses are unlikely to be tolerated.     

不同角度载荷下股骨头骨小梁的生物力学特性

目的探讨不同角度载荷对股骨头骨小梁形态学与力学性能的影响,为研究股骨头坏死、塌陷的生物力学机制提供理论依据。方法利用12月龄羊股骨头和人尸体股骨头分别制作羊股骨头骨小梁试件94个和人股骨头骨小梁试件43个。按照受力方向与骨小梁主压力方向之间的不同夹角,将骨小梁以10°间隔分为内翻10°、0°和外翻10°、20°、30°共计5组,模拟股骨颈骨折内固定术后不同戈登(Garden)对线指数下的复位情况。通过分别对羊股骨头骨小梁进行micro-CT扫描、计算与压缩破坏试验以及对人尸体股骨头骨小梁进行循环压缩试验,分析不同受力方向下股骨头骨小梁的骨体积分数(BV/TV)、骨表面积/骨体积(BS/BV)、骨小梁平均厚度(Tb.Th)、骨小梁数量(Tb.N)、骨小梁间距(Tb.Sp)等形态学指标以及弹性模量、极限强度、屈服强度、初始弹性模量、循环次数等力学指标。结果加载方向与骨小梁的主压力方向之间夹角为0°时,BV/TV、Tb.Th以及弹性模量、极限强度、屈服强度、初始弹性模量、循环次数均为最大,而BS/BV与Tb.N为最小,并随着夹角增大前者呈递减而后者呈递增趋势。结论 12月龄羊股骨头骨小梁BV/TV与极限强度随受力方向与骨小梁主压力方向之间夹角变化的趋势与人股骨头骨小梁一致;加载方向与主压力骨小梁之间夹角增大时,股骨头骨小梁形态学与力学性能均下降;Garden指数偏离160°越大时,股骨头内骨小梁越易发生损伤。     

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide (CO) is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins, it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, NO and cGMP levels, as well as regulate MAPK signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca²⁺-sensitive K⁺ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca²⁺ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6     

Cyclic AMP: A potent inhibitor of DNA synthesis in cultured arterial endothelial and smooth muscle cells

Summary The effect of dibutyryl cyclic AMP on DNA synthesis was studied in cultured human umbilical endothelial cells and rat aortic smooth muscle cells. Dibutyryl cyclic AMP (2×10^-4mol/l) inhibited DNA synthesis in both arterial cell types when they were grown in medium supplemented with whole serum or with platelet poor serum, but had no effect in the absence of serum. An effect was seen one hour after the addition of the nucleotide, and the threshold concentration was between 2×10^-6 and 2×10^-5mol/l. These results may have relevance to the interaction of platelets and insulin with the arterial wall in the development of atherosclerosis in diabetes.     

The presence of cyclic AMP-stimulated protein kinase substrates and evidence for endogenoudogenous protein kinase activity in various Na+, K+-ATPase preparations from brain, heart and kidney.

Protein kinase catalyzed the phosphorylation of membrane preparations possessing Na⁺, K⁺-ATPase activity from beef brain, beef heart and dog kidney. Cyclic AMP (10^?6m) stimulated phosphorylation from 1.9 to 2.8-fold for nearly all preparations in the presence of exogenous protein kinase. Cyclic AMP in the absence of exogenous protein kinase stimulated phosphorylation in all preparations examined except highly purified dog outer medulla kidney Na⁺, K⁺-ATPase, suggesting the presence of endogenous protein kinase activity in the former preparations, but a removal of protein kinase after purification of Na⁺, K⁺-ATPase. Cyclic AMP stimulated the phosphorylation of histone in the presence of the beef brain Na⁺, K⁺-ATPase-containing membrane fragments, further substantiating the presence of endogenous protein kinase activity in this preparation. The phosphorylated products were hydroxylamine-insensitive. Phosphorylation of glycerol-precipitated membrane preparations exhibiting various specific Na⁺, K⁺-ATPase activities including zero, in heat-denatured preparations, suggested that the level of phosphorylation is not influenced by Na⁺, K⁺-ATPase activity. SDS-polyacrylamide gel electrophoresis of a phosphorylated, highly purified dog outer medulla kidney Na⁺, K⁺-ATPase preparation suggested that cyclic AMP stimulated phosphorylation of the larger of the two Na⁺, K⁺-ATPase peptide components.     

脾虚证胃粘膜形态DNA cAMP微量元素改变的临床与实验研究

目的研究脾虚证实质、脾虚证与胃癌发生的关系。方法采用 IBAS2000型图象分析系统、501B 型扫描电镜附有9100/60型能量色散 X 分析仪,以及组织化学与放射免疫方法,检测脾虚证患者胃粘膜超微结构、肠化生亚型、DNA、cAMP、微量元素及其氧化物。结果脾虚色滞证患者中胃癌发生率、不完全性结肠型肠化生发生率和"背景病变"发生率均显著高于脾气虚证患者;胃粘膜 cAMP、Zn、Cu、ZnO 和 Cuo 含量,随着肠化生完全性至不完全性、小肠型至结肠型的顺序递减;而 DNA 含量则随以上顺序递增,P<0.05～0.001。胃粘膜不完全性结肠型肠化生组织内 DNA、cAMP、Zn、Cu、ZnO 和 CuO 含量则与胃癌组织同元显著性差异。结论脾虚气滞证胃病有癌变倾向;不完全性结肠型肠化生与胃癌的发生有密切关系。@何雪芬$目的!研究脾虚证实质、脾虚证与胃癌发生的关系。方法采用 IBAS2000型图象分析系统、501B 型扫描电镜附有9100/60型能量色散 X 分析仪,以及组织化学与放射免疫方法,检测脾虚证患者胃粘膜超微结构、肠化生亚型、DNA、cAMP、微量元素及其氧化物。结果脾虚色滞证患者中胃癌发生率、不完全性结肠型肠化生发生率和"背景病变"发生率均显著高于脾气虚证患者;胃粘膜 cAMP、Zn、Cu、ZnO 和 Cuo 含量,随着肠化生完全性至不完全性、小肠型至结肠型的顺序递减;而 DNA 含量则随以上顺序递增,P<0.05～0.001。胃粘膜不完全性结肠型肠化生组织内 DNA、cAMP、Zn、Cu、ZnO 和 CuO 含量则与胃癌组织同元显著性差异。结论脾虚气滞证胃病有癌变倾向;不完全性结肠型肠化生与胃癌的发生有密切关系。@尹玉芬$目的!研究脾虚证实质、脾虚证与胃癌发生的关系。方法采用 IBAS2000型图象分析系统、501B 型扫描电镜附有9100/60型能量色散 X 分析仪,以及组织化学与放射免疫方法,检测脾虚证患者胃粘膜超微结构、肠化生亚型、DNA、cAMP、微量元素及其氧化物。结果脾虚色滞证患者中胃癌发生率、不完全性结肠型肠化生发生率和"背景病变"发生率均显著高于脾气虚证患者;胃粘膜 cAMP、Zn、Cu、ZnO 和 Cuo 含量,随着肠化生完全性至不完全性、小肠型至结肠型的顺序递减;而 DNA 含量则随以上顺序递增,P<0.05～0.001。胃粘膜不完全性结肠型肠化生组织内 DNA、cAMP、Zn、Cu、ZnO 和 CuO 含量则与胃癌组织同元显著性差异。结论脾虚气滞证胃病有癌变倾向;不完全性结肠型肠化生与胃癌的发生有密切关系。     

Thiocarbohydrazide-crosslinked chitosan as a bioinspired corrosion inhibitor for protection of stainless steel in 3.5% NaCl

A facile single-step synthesis was performed to cross-link chitosan with thiocarbohydrazide to yield thiocarbohydrazide-chitosan (TC-Cht) which was for the first time evaluated as an inhibitor for corrosion of stainless steel in 3.5% NaCl solution. A comprehensive electrochemical analysis employing electrochemical impedance spectroscopy (EIS), potentiodynamic polarization (PDP), and cyclic voltammetry (CV) was undertaken and showed that the TC-Cht acts by adsorption on the steel surface and exhibits mixed type behavior with predominantly cathodic nature. The adsorption of TC-Cht molecules on the surface of stainless steel followed the Langmuir isotherm. The TC-Cht showed a high inhibition efficiency of >94% at 500 mg L^?1 concentration. Surface investigation using SEM and EDX supported the inhibitor adsorption on the steel surface.