Effect of the mode of croscarmellose sodium incorporation on tablet dissolution and friability

A computer-optimized experimental design was used to study the effect of incorporating a "super disintegrant", croscarmellose sodium, intragranularly, extragranularly, or distributed equally between the two phases of a tablet in which a poorly soluble drug constituted at least 92.5% of the formulation. The results were analyzed by means of a general quadratic response surface model and suggest that tablets with the same total concentration of super disintegrant dissolve at a faster rate when the super disintegrant is included intragranularly. Tablet friability was not affected by the method of super disintegrant incorporation.     

Handling of contamination variability in exposure assessment: a case study with ochratoxin A.

The contamination of foods dedicated to human consumption varies over space and time. In exposure assessment, this is usually addressed through probabilistic modelling. The present work explores how the variability and uncertainty of exposures estimated at the population level are affected by: (a) the (non-)parametric nature of input contamination distributions; (b) the time-window used to sample contamination values within those distributions. Focusing on exposure of the French population to food mycotoxin ochratoxin A, we implement a range of second-order Monte-Carlo simulations that allow distinguishing variability of exposures from uncertainty of distributional parameters estimates. A simulation runs 10,000 iterations. Overall estimates of parameters are given by the median across iterations and 95%CI by 2.5th and 97.5th percentiles. Our results show that: (a) parametric (log-normal) input distributions may lead to over-estimation of variability and greater uncertainty as compared to non-parametric ones (P97.5 [95%CI] of 7.1 [6.6;7.7] for Parametric-Occasion, 4.6 [4.3;5.0] for Non-Parametric-Occasion), and that (b) the 'Occasion' time-window combines better estimate of variability and lower uncertainty when exposure modelling is applied to populations living in developed countries with complex agri-food systems (P97.5 [95%CI]: 7.3 [6.2;8.9] for Non-Parametric-Week, 4.6 [4.3;5.0] for Non-Parametric-Occasion). A deterministic approach is nevertheless preferred to probabilistic modelling every time input data quality is questionable.     

The influence of glucagon on sodium retention after fasting.

Two groups of five obese female subjects, having undergone a ten day therapeutic fast, were fed with either glucose 50 g/day or with L-alanine 50 g/day for three days. Plasma glucagon concentrations and urinary electrolyte excretion were compared in the two groups. Although 4.00pm plasma glucagon concentrations during refeeding were significantly greater in the alanine refeed group (P less than 0.05) the reduction in urinary sodium excretion in each of the two groups was identical. These observations do not support the hypothesis that glucose induced suppression of plasma glucagon concentrations is a mechanism whereby carbohydrate refeeding produces post-fast urinary sodium retention.     

A case of fatal intoxication with sodium azide

Summary A case of fatal intoxication with sodium azide is described. The poison was consumed in form of a soluble in water powder. The cause of decease was not explained by the section of the corpse nor by the supplementary microscopic examination. Chemical analysis demonstrated the presence of sodium azide in the stomach contend and small intestine.     

The influence of assay variability on pharmacokinetic parameter estimation

The impact of assay variability on pharmacokinetic modeling was investigated. Simulated replications (150) of three individuals resulted in 450 data sets. A one-compartment model with first-order absorption was simulated. Random assay errors of 10, 20, or 30% were introduced and the ratio of absorption rate (K _a )to elimination rate (K _e )constants was 2, 10, or 20. The analyst was blinded as to the rate constants chosen for the simulations. Parameter estimates from the sequential method (K _e )estimated with log-linear regression followed by estimation of K _a and nonlinear regression with various weighting schemes were compared. NONMEM was run on the 9 data sets as well. Assay error caused a sizable number of curves to have apparent multicompartmental distribution or complex absorption kinetic characteristics. Routinely tabulated parameters (maximum concentration, area under the curve, and, to a lesser extent, mean residence time) were consistently overestimated as assay error increased. When K _a /K _e =2,all methods except NONMEM underestimated K _e ,overestimated K _a ,and overestimated apparent volume of distribution. These significant biases increased with the magnitude of assay error. With improper weighting, nonlinear regression significantly overestimated K _e when K _a /K _e ,=20. In general, however, the sequential approach was most biased and least precise. Although no interindividual variability was included in the simulations, estimation error caused large standard deviations to be associated with derived parameters, which would be interpreted as interindividual error in a nonsimulation environment. NONMEM, however, acceptably estimated all parameters and variabilities. Routinely applied pharmacokinetic estimation methods do not consistently provide unbiased answers. In the specific case of extended-release drug formulations, there is clearly a possibility that certain estimation methods yield K _a and relative bioavailability estimates that would be imprecise and biased.     

The influence of assay variability on pharmacokinetic parameter estimation

The impact of assay variability on pharmacokinetic modeling was investigated. Simulated replications (150) of three "individuals" resulted in 450 data sets. A one-compartment model with first-order absorption was simulated. Random assay errors of 10, 20, or 30% were introduced and the ratio of absorption rate (Ka) to elimination rate (Ke) constants was 2, 10, or 20. The analyst was blinded as to the rate constants chosen for the simulations. Parameter estimates from the sequential method (Ke estimated with log-linear regression followed by estimation of Ka) and nonlinear regression with various weighting schemes were compared. NONMEM was run on the 9 data sets as well. Assay error caused a sizable number of curves to have apparent multicompartmental distribution or complex absorption kinetic characteristics. Routinely tabulated parameters (maximum concentration, area under the curve, and, to a lesser extent, mean residence time) were consistently overestimated as assay error increased. When Ka/Ke = 2, all methods except NONMEM underestimated Ke, overestimated Ka, and overestimated apparent volume of distribution. These significant biases increased with the magnitude of assay error. With improper weighting, nonlinear regression significantly overestimated Ke when Ka/Ke = 20. In general, however, the sequential approach was most biased and least precise. Although no interindividual variability was included in the simulations, estimation error caused large standard deviations to be associated with derived parameters, which would be interpreted as interindividual error in a nonsimulation environment. NONMEM, however, acceptably estimated all parameters and variabilities. Routinely applied pharmacokinetic estimation methods do not consistently provide unbiased answers. In the specific case of extended-release drug formulations, there is clearly a possibility that certain estimation methods yield Ka and relative bioavailability estimates that would be imprecise and biased.     

磷酸肌酸钠对缺血性心肌病心功能及心律变异性的影响研究

目的探讨磷酸肌酸钠对缺血性心肌病心功能及心律变异性的影响。方法选取2009年6月～2011年7月笔者所在医院收治的112例缺血性心肌病患者,随机分为对照组和治疗组,每组各56例,对照组采用常规治疗,治疗组在常规治疗的基础上给予磷酸肌酸钠治疗。检测治疗前后患者左室射血分数和心律变异性。用药治疗半个月,观察指标治疗前后的变化。结果治疗前对照组和治疗组各项指标间比较,差异无统计学差异(P>0.05),用药半个月后,两组各指标均较治疗前升高,但治疗组较治疗前改善更明显,差异有统计学意义(P<0.05)。结论磷酸肌酸钠对缺血性心肌病患者心功能及心律变异性有较好的改善作用,值得临床推广使用。     

A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets

The aim of this case study was to develop a drug‐specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus? software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration–time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate‐release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro–in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyright © 2012 John Wiley & Sons, Ltd.     

Performance comparison of a co-crystal of carbamazepine with marketed product.

The carbamazepine: saccharin co-crystal (1) was studied in terms of a series of attributes, including suitability for multi-gram scale-up, propensity for crystal polymorphism, physical stability, in vitro dissolution and oral bioavailability, with the goal of comparing 1 with the marketed form of carbamazepine (Tegretol). Preparation of 1 was achieved on a 30g scale with a conventional cooling crystallization process from alcohol solution without seeding. The compound is not overtly polymorphic. This finding is in contrast to the form diversity of pure carbamazepine, which has four known polymorphs and a host of solvates, including a dihydrate, which is the stable form in the presence of water. Physical and chemical stability of the co-crystal is also shown to be quantitatively similar to the pure drug in the marketed product (Tegretol). Finally, comparison of oral bioavailability of 1 with Tegretol tablets in dogs shows the co-crystal to be a viable alternative to the anhydrous polymorph in formulated solid oral products. The balance of properties and performance of 1 as a model co-crystal is discussed.     

A non-fatal case of sodium toxicity

A non-fatal case of sodium toxicity in a six-year-old boy is presented. Hypernatremia is the clinical term for an excessive concentration of sodium relative to water in the body. The diagnosis of hypernatremia was made at serum sodium (Na(+)) concentrations exceeding 150 mEq/L, and few people have been reported to survive concentrations greater than 160 mEq/L. This case involves a six-year-old boy who was taken to the hospital following a seizure attack, and lab analyses revealed serum sodium (Na(+)) levels of 234 mEq/L and serum chloride (Cl(-)) levels of 205 mEq/L. Clinical tests ruled out diabetes insipidus, dehydration, renal pathology, and other primary causes of hypernatremia. The child's purported history of pica, and the lab results indicating corresponding increases in levels of serum sodium (Na(+)) and serum (Cl(-)), led to a diagnosis of acute sodium toxicity by ingestion of sodium chloride. A search of the boy's house led to the discovery of rock salt in the cabinet and a container of table salt. Extrapolating from the serum sodium (Na(+)) level, it was estimated that the child had ingested approximately four tablespoons of rock salt, leading to the acute toxicity. A literature search revealed that the serum sodium (Na(+)) concentration in the present report was the highest documented level of sodium in a living person.     

The influence of ipratropium bromide and sodium cromoglycate on benzalkonium chloride-induced bronchoconstriction in asthma.

1. Benzalkonium chloride, an antibacterial preservative that is added to nebuliser solutions, has been shown to cause bronchoconstriction when inhaled by asthmatic subjects. 2. To investigate the potential role of reflex and mast cell-dependent mechanisms in the pathogenesis of bronchoconstriction produced by benzalkonium chloride we examined the effects of ipratropium bromide and sodium cromoglycate on this response in both concentration-response and time-course studies in nine asthmatic subjects. 3. Pretreatment with inhaled ipratropium bromide (1 mg) and sodium cromoglycate (40 mg) displaced the benzalkonium chloride concentration-response curves to the right by a mean 2.2 fold and 3.1 fold respectively. 4. Ipratropium bromide and sodium cromoglycate markedly attenuated the airway response to benzalkonium chloride throughout the 45 min time course period, inhibiting the overall response by 56% and 78% respectively. 5. We conclude that benzalkonium chloride provokes bronchoconstriction in asthmatic subjects through a combination of mast cell activation and stimulation of peripheral and central neural pathways.     

A study of codispensing with sodium alendronate in Australia

AIM: To estimate the percentage of patients dispensed alendronate who were also dispensed another drug for treatment of an upper gastrointestinal disorder ('GI' drug). METHODS: The Australian Health Insurance Commission (HIC) Pharmaceutical Benefits Scheme (PBS) database was searched to identify a cohort of patients for whom alendronate or calcitriol had been dispensed and had also been dispensed a GI drug. RESULTS: The number of patients dispensed a GI drug were 6.7% for alendronate and 7.5% for calcitriol with H(2)-receptor antagonists accounting for the majority of usage. This difference of - 0.8% (95% confidence interval -1.6, 0.1) is not significant. CONCLUSION: There was no excess use of GI drugs in patients taking alendronate compared with those taking calcitriol and the Australian HIC PBS database is useful for identifying large numbers of patients who have been dispensed combinations of drugs.     

A case of nonfatal sodium fluoride ingestion

A nonfatal case of sodium fluoride ingestion is presented. The quantity of sodium fluoride ingested is unknown. Initial serum and urine samples were taken 24 h after ingestion and contained 3.4 and 21.3 mg/L fluoride, respectively. At that time the patient was essentially asymptomatic, but it is clear that he survived a plasma concentration greater than that usually considered lethal, 3 mg/L serum fluoride. The case illustrates the lack of correlation between plasma fluoride concentration and toxic effects and the importance of obtaining a history of fluoride ingestion.     

A case of fatal sodium azide ingestion

A fatal case of sodium azide poisoning in which exchange blood transfusions, charcoal hemoperfusion, hemodialysis and potent vasopressor agents failed to prevent the development of circulatory collapse associated with a wide complex cardiac rhythm is presented. The cellular toxin sodium azide resulted in the development of an altered mental status, profound metabolic acidosis, cardiac arrhythmia (atrial fibrillation and terminal wide complex arrhythmias), a relative decrease in cardiac output, hypotension and non-cardiogenic pulmonary edema. Further animal studies are needed to gain new approaches for the treatment of this rare cause of human poisoning.     

The influence of human variability upon food safety legislation

This paper considers the influence of human variations in the kinetics and dynamics of chemicals in food upon the formulation of food safety legislation. Legislation is designed to protect and benefit all and not solely specific groups or individuals within the population. A consideration of the adequacy of the safety factors used to calculate Acceptable Daily Intake (ADI) leads on to the discussion of those circumstances in which a part of the population may exceed the ADI for a particular chemical. The conclusion is that the ADI does take human variability into consideration and that current legislation is satisfactory and made more so through the surveillance of dietary additive and contaminant intakes in man.     

FDA对治疗性蛋白质产品与参照药可互换性研究的要求

美国食品药品管理局（FDA）于2019年5月发布了“供企业用证明与参照药可互换性考虑的问题的指导原则”（正式版本）。该指导原则介绍了FDA对治疗性蛋白质产品与参照药可互换性研究的原则要求和具体研究数据和信息的要求。而中国目前尚无类似指导原则。详细介绍该指导原则主要内容,期望对我国这方面的研究和监管能走在世界前列有所帮助。     

肝素钠精制工艺研究

目的：为改进肝素纳的精制工艺,运用离心技术和改进的丙酮脱水法,使肝素钠的回收率得到提高。方法：将肝素钠粗品制成10％左右的浓度,用盐酸调节pH,离心脱去大部分酸性蛋白,氧化后所得产物慢慢加入丙酮中脱水。精制后测定其回收率和效价并与传统方法进行对比。结果：回收率由传统工艺的（86.±0.9）％提高到（90.0±0.6）％,相关杂质的吸收度值下降;效价由传统工艺的（168.7±2.4）uspu·mg-1提高到（179.0±1.8）uspu·mg-1。与传统工艺比较,经t检验,回收率和效价P值均＜0.01。结论：这一方法确能提高肝素钠的质量。     

放松训练对职业紧张刑警心率变异性的影响

【摘要】目的 研究生物反馈放松训练对职业紧张刑警心率变异性（HRV）的影响。方法 使用职业健康量表（OSI-R）筛选我市中、高度紧张反应（即个人紧张反应分量表T分60以上）刑警538人,随机抽取52名为研究对象。运用心理素质训练评估系统分别于静息、应激、放松状态下测定其肌电水平（EMG）、心率（HR）、HRV时域指标（SDNN、 RMSSD、pNN50）和频域指标（VLF、LF、HF、TP、LF/HF）,并进行比较分析。结果 应激状态EMG（29.27±9.79）高于静息（14.13±8.00）及放松（10.02±6.74）状态（P < 0.05）,静息与放松状态差异无统计学差异（P > 0.05）;SDNN、RMSSD、VLF、 HF和TP均是应激状态最低,放松状态最高（P < 0.05）;LF、LF/HF均是应激状态最高,放松状态最低（P < 0.05）。结论 放松训练可以改善职业紧张刑警自主神经系统的功能活性状况。