Complement activation reaches maximum during equilibrium between antigen and antibody in an in vitro model for thrombolysis with streptokinase

Treatment with streptokinase (SK) of patients with acute myocardial infarction (AMI) is known to activate the complement system. In a previous investigation we found a great variation in the degree of complement activation taking place during infusion of SK in patients with AMI (range: 0-293% increase in pretreatment complement split product 3d (C3d) levels). In this in vitro study we added SK to serum with different concentrations of SK-antibodies (SK-Ab) and found that both the relative concentrations and the total concentrations of SK and Ab determined the degree of complement activation elicited by SK. This finding was in accordance with the Kendall-Heidelberger equation of antigen-antibody equivalence. Furthermore, we found parallel rises in C3d and C4d, indicating that complement was activated via the classical pathway. A condition for maximal complement activation is antigen-antibody equivalence.     

Comparative in vitro study of oesophageal adhesiveness of different commercial formulations containing alendronate

Cases of oesophageal irritation have been reported in patients ingesting alendronate with little liquid or reclining shortly after taking the medication. Pill-induced oesophagitis principally occurs because of adherence of ingested tablets to the epithelial surface. The objective of this in vitro study was to evaluate the oesophageal bioadhesive characteristics of alendronate generics marketed in Europe, the proprietary Fosamax^®, one negative and two positive polymer controls. A texture analyser was used for qualitative analysis and to determine the maximal detachment force and the adhesion work developed by each formulation on porcine oesophageal mucosa. Fosamax^® showed few or no bioadhesive characteristics, but the detachment of few tablets powder particles in some of the experiments does not preclude the potential risk of oesophageal lesions. The 10-mg generic Teva^® tablets had bioadhesive characteristics similar to a positive control. Other generic formulations (Alenat^®, Stada^®, Aliud^®, Ratiopharm^®) showed “cleavage” rupture, leaving a large piece of the tablet mass attached to the mucosa. The bioadhesive characteristics seem to be related to the inactive ingredients: the presence of adhesive polymers such as HPC or very active disintegration agents, such as sodium croscarmellose. The demonstrated differences in adhesiveness suggest that differences in oesophageal tolerance between Fosamax^® tablets and generics of sodium alendronate may exist.     

A randomized, double-blind, crossover comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced cutaneous responses in healthy adult volunteers

BACKGROUND: Cetirizine is a highly efficacious and long-acting second-generation H1-receptor antagonist for the treatment of allergic diseases, such as allergic rhinitis and chronic idiopathic urticaria, in adults and children. Pharmacologic studies have demonstrated that cetirizine, a racemate mixture composed of equal amounts of two enantiomers, does not undergo hepatic metabolism to any significant level. The enantiomers are excreted mainly unchanged, predominantly in the urine and to a lesser extent in the faeces. METHODS: The pharmacologic activity and potency of the two enantiomers of cetirizine in the management of allergic skin conditions were investigated by studying the effect of treatment with 5.0 mg cetirizine; 2.5 mg levocetirizine, the (R)-enantiomer; and 2.5 mg ucb 28557, the (S)-enantiomer, on histamine-induced wheal and flare response in 18 healthy volunteers. Each treatment was administered as a single oral dose in randomized, double-blind, and crossover manner, and the efficacy of treatment was assessed over a period of 32 h, as per cent inhibition of the histamine-induced wheal and flare areas before treatment. Blood and urine samples were collected in a time-dependent manner and analyzed for the total amounts of each study drug, to elucidate their pharmacokinetic profiles. RESULTS: Both cetirizine and levocetirizine caused a marked inhibition of histamine-induced wheal and flare, whereas ucb 28557 was inactive in this model. Inhibition of the wheal response observed for cetirizine and levocetirizine was apparent by 1 h after dosage and lasted for mean durations of 24.4 and 28.4 h, respectively. In addition, the response for cetirizine and levocetirizine became maximal by 6 h after treatment, rising to 79.5% and 83.8%. Similarly, cetirizine and levocetirizine also markedly inhibited the histamine-induced flare response. This effect was evident for both drugs by 1 h after dosage and lasted over a mean period of 28.4 and 26.0 h, respectively, for cetirizine and levocetirizine. The inhibitory effect of these compounds on histamine-induced flare response was also maximal by approximately 6 h after dosage, peaking at 88.5%) and 83.6%, respectively. Statistical evaluation showed that cetirizine and levocetirizine were equivalent for maximum inhibition of histamine-induced wheal and flare. However, levocetirizine was found to be superior to cetirizine when area under the curve was compared. In contrast, ucb 28557 was not found to inhibit histamine-induced wheal and flare responses at any time during the study period. Plasma concentrations of levocetirizine were found to be approximately double those of ucb 28557 at 4 and 8 h after dosing, and 50-60% of the drugs were excreted unchanged in urine over a period of 32 h. CONCLUSIONS: The finding that, in this model, levocetirizine 2.5 mg has comparable antihistaminic activity to cetirizine 5 mg, whereas its other enantiomer ucb 28557 has no pharmacodynamic effect, suggests that the antihistaminic properties of cetirizine observed in the management of allergic skin conditions are likely to be attributable to levocetirizine.     

概括性的法律语言及其翻译方法

概括性的法律语言是立法的客观需要,能够体现立法的预见性、扩大法律的适用范围、实现法律的自我保护。在翻译概括性的法律语言时,译文应该如实反映原文的概括性特征。     

Comparing sampling methods for pharmacokinetic studies using model averaged derived parameters

Pharmacokinetic studies aim to study how a compound is absorbed, distributed, metabolised, and excreted. The concentration of the compound in the blood or plasma is measured at different time points after administration and pharmacokinetic parameters such as the area under the curve (AUC) or maximum concentration (C_max) are derived from the resulting concentration time profile. In this paper, we want to compare different methods for collecting concentration measurements (traditional sampling versus microsampling) on the basis of these derived parameters. We adjust and evaluate an existing method for testing superiority of multiple derived parameters that accounts for model uncertainty. We subsequently extend the approach to allow testing for equivalence. We motivate the methods through an illustrative example and evaluate the performance using simulations. The extensions show promising results for application to the desired setting.     

Optimum design and sequential treatment allocation in an experiment in deep brain stimulation with sets of treatment combinations

In an experiment including patients who underwent surgery for deep brain stimulation electrode placement, each patient responds to a set of 9 treatment combinations. There are 16 such sets, and the design problem is to choose which sets should be administered and in what proportions. Extensions to the methods of nonsequential optimum experimental design lead to identification of an unequally weighted optimum design involving 4 sets of treatment combinations. In the actual experiment, patients arrive sequentially and present with sets of prognostic factors. The idea of loss due to Burman is extended and used to assess designs with varying randomization structures. It is found that a simple sequential design using only 2 sets of treatments has surprisingly good properties for trials with the proposed number of patients.     

Potential role of monkey inferior parietal neurons coding action semantic equivalences as precursors of parts of speech

Abstract

The anterior portion of the inferior parietal cortex possesses comprehensive representations of actions embedded in behavioural contexts. Mirror neurons, which respond to both self-executed and observed actions, exist in this brain region in addition to those originally found in the premotor cortex. We found that parietal mirror neurons responded differentially to identical actions embedded in different contexts. Another type of parietal mirror neuron represents an inverse and complementary property of responding equally to dissimilar actions made by itself and others for an identical purpose. Here, we propose a hypothesis that these sets of inferior parietal neurons constitute a neural basis for encoding the semantic equivalence of various actions across different agents and contexts. The neurons have mirror neuron properties, and they encoded generalization of agents, differentiation of outcomes, and categorization of actions that led to common functions. By integrating the activities of these mirror neurons with various codings, we further suggest that in the ancestral primates’ brains, these various representations of meaningful action led to the gradual establishment of equivalence relations among the different types of actions, by sharing common action semantics. Such differential codings of the components of actions might represent precursors to the parts of protolanguage, such as gestural communication, which are shared among various members of a society. Finally, we suggest that the inferior parietal cortex serves as an interface between this action semantics system and other higher semantic systems, through common structures of action representation that mimic language syntax.     

普通话快速噪声下言语测听材料的等价性评估

目的开发一套标准的普通话版快速噪声下言语测听材料,评估依据听力学要求和语言学特征选取的300个语句材料的等价性,并获得其在50%正确识别时所对应的信噪比(记为SNR-50)的正常值。方法首先将这些语句材料按照数字化录制原则录制为女声音频材料,背景噪声为4人同时谈话的言语噪声。言语声和噪声混合在一起。选取30例正常受试者,采用听说复述方式,分别在+6、+3、0、-3、-6 dB信噪比条件下测试。对测试所得结果使用SPSS17.0统计软件进行数据分析和强度-识别率函数曲线的拟合。结果 300个语句在噪声环境下测试结果分析显示,斜率和阈值不呈正态分布。剔除斜率过大(>0.72)的语句,及曲线拟合相关系数过小(r<0.7)的语句,精选出等价性较好的78句。后者呈正态分布。结论经过对300个语句的等价性评估,经过严格的筛选及精细调整,最终保留的78个语句在正常人中的等价性较好,下一步可进行这些语句复测信度的测试。