枸橼酸莫沙必利口腔崩解片的制备及评价

目的制备枸橼酸莫沙必利口腔崩解片并对其进行评价。方法在预实验的基础上选择处方中所用辅料,以口腔中崩解时间为考察指标,综合运用效应面图和等高线图对口腔崩解片处方进行优化,直接压片法压片,并对枸橼酸莫沙必利口腔崩解片溶出度进行了考察。结果枸橼酸莫沙必利口腔崩解片的最佳处方为枸橼酸莫沙必利5 mg、微晶纤维素76 mg、甘露醇97 mg、低取代羟丙基纤维素20 mg、橘子香精1 mg、硬脂酸富马酸钠1 mg。口腔中崩解时间为19.4 s,溶出度为99.7%。结论采用直接压片法制备枸橼酸莫沙必利口腔崩解片,崩解时间短、溶出速度快、口感好。     

A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Publication bias and related bias in meta-analysis is often examined by visually checking for asymmetry in funnel plots of treatment effect against its standard error. Formal statistical tests of funnel plot asymmetry have been proposed, but when applied to binary outcome data these can give false-positive rates that are higher than the nominal level in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). We develop a modified linear regression test for funnel plot asymmetry based on the efficient score and its variance, Fisher's information. The performance of this test is compared to the other proposed tests in simulation analyses based on the characteristics of published controlled trials. When there is little or no between-trial heterogeneity, this modified test has a false-positive rate close to the nominal level while maintaining similar power to the original linear regression test ('Egger' test). When the degree of between-trial heterogeneity is large, none of the tests that have been proposed has uniformly good properties.     

Compaction Properties of L-Lysine Salts

Purpose. To examine the effects of salt form, i.e., different anions with a common cation (L-lysinium), on compaction properties and to identify the factors that determine the tensile strength of tablets. Methods. L-Lysine salts with the following anions were compressed at various pressures: acetate, monochloride, dichloride, L-aspartate, L-glutamate (dihydrate), and L-lysine (zwitterionic monohydrate). The yield strength of each salt was evaluated from the out-of-die Heckel plot. Results. At low compaction pressures, the tensile strength of the compacts increases linearly with increasing compaction pressure. Simultaneously, the compact tensile strength decreases exponentially with increasing yield strength of the salt. However, at high compaction pressures, the compact tensile strength is determined by the interparticulate bonding strength and not by the yield strength. The compact tensile strength, extrapolated to zero porosity, increases linearly with increasing melting temperature of the salts. Conclusions. The counterion affects the tableting properties of L-lysine salts. The tensile strength is controlled by both the yield strength and the interparticulate interaction strength with the former predominant at low compaction pressures and the latter predominant at high compaction pressures. The melting temperature of each L-lysine salt is a good indicator of the tensile strength of its compacts at zero porosity.     

The diagnostic plot

Iron balance is regulated by the rate of erythropoiesis and the size of the iron stores. Anemia that accompanies infection, inflammation, and cancer (anemia of chronic disease) features normal or increased iron stores, although patients may have functional iron deficiency, namely, an imbalance between iron requirements of the erythroid marrow and the actual supply. The proportion of hypochromic red cells and the hemoglobin content of reticulocytes are direct indicators of functional iron deficiency. Biochemical markers, especially the soluble transferrin receptor/log ferritin ratio (ferritin index), are useful indicators of the iron supply to erythropoiesis. The relationship between functional iron deficiency (reticulocyte hemoglobin content) and iron supply to erythropoiesis (ferritin index) can be described in a diagnostic plot. In normoproliferative and hypoproliferative erythropoiesis, the plot allows the differentiation of classic iron deficiency from anemia of chronic disease and the combined state of functional iron deficiency with anemia of chronic disease. The therapeutic implications of the plot are to differentiate patients into those who should be administered iron supplements, epoetin, or a combination of epoetin and iron. In patients receiving epoetin therapy, the plot is an important tool for monitoring erythropoietic activity, functional iron deficiency, and adequate iron stores for new red cell production. Enhanced erythropoiesis is reflected quantitatively by the ferritin index vector. A transgression of the 1.5 (3.2) cut-off value for the ferritin index indicates that extra doses of iron need to be administered to increase the body's iron stores. A lack of increase or a reticulocyte hemoglobin content below 28 picograms indicates functional iron deficiency. The diagnostic plot is a model for differentiating iron-deficient states and predicting those patients who will respond to epoetin therapy.     

关于混杂效应、交互效应的探讨

目的:探讨在实际处理数据时对混杂效应、交互效应的处理方法。方法:通过具体实例说明混杂效应、交互效应的概念及正确应用。结果:判断变量间是否存在交互效应,需要在模型中纳入变量间的乘积项并通过统计学检验来评价;判断某变量是否为混杂因素,需比较模型中没有纳入该变量时得到的粗估计值与该变量纳入模型时得到的校正估计值的差别是否具有实际意义的不同,而不是通过统计学检验来评价;结论:在对数据进行统计分析时,当某变量可能与其它变量存在交互作用,同时又考虑其可能为混杂因素时,应先考虑其是否存在可能的交互作用,因为研究因素的效应随其他变量的取值不同而变化,如交互作用无统计学意义,进一步评价其是否为混杂因素。     

Pain prevalence and severity before, during, and after root canal treatment: a systematic review

Introduction

Anticipation and experience of root canal associated pain is a major source of fear for patients and a very important concern of dentists. Pretreatment, treatment, and posttreatment pain is anticipated, experienced, remembered, and shared by patients. The purpose was to determine the influence of root canal treatment on pain prevalence and severity and estimate the prevalence and severity of pretreatment, treatment, and posttreatment pain in patients receiving root canal treatment.

Methods

Defined searching of MEDLINE, Embase, Cochrane, and PsycINFO databases identified 5,517 articles. Systematic review, including title scanning, abstract scanning, full-text review, and quality rating, provided 72 studies for meta-analysis. L’Abbe plots were used to evaluate the influence of root canal treatment on pain prevalence and severity. Pretreatment, treatment, and posttreatment pain prevalence and severity data were analyzed.

Results

L’Abbe plots revealed that pain prevalence and severity decreased substantially after treatment. Mean pretreatment, 24-hour posttreatment, and 1-week posttreatment pain prevalences with associated standard deviations were 81 (28%), 40 (24%), and 11 (14%), respectively. Pretreatment, 24-hour posttreatment, and 1-week posttreatment pain severities, on a 100-point scale, were 54 (24%), 24 (12%), and 5 (5%), respectively. Supplemental injections were frequently required (60 [24%]).

Conclusions

Pretreatment root canal-associated pain prevalence was high but dropped moderately within 1 day and substantially to minimal levels in 7 days. Pretreatment root canal-associated pain severity was moderate, dropped substantially within 1 day of treatment, and continued to drop to minimal levels in 7 days. Supplemental anesthesia was often required.     

The mass-action law based algorithm for cost-effective approach for cancer drug discovery and development

The mass-action law based system analysis via mathematical induction and deduction lead to the generalized theory and algorithm that allows computerized simulation of dose-effect dynamics with small size experiments using a small number of data points in vitro, in animals, and in humans. The median-effect equation of the mass-action law deduced from over 300 mechanism specific-equations has been shown to be the unified theory that serves as the common-link for complicated biomedical systems. After using the median-effect principle as the common denominator, its applications are mechanism-independent, drug unit-independent, and dynamic order-independent; and can be used generally for single drug analysis or for multiple drug combinations in constant-ratio or non-constant ratios. Since the "median" is the common link and universal reference point in biological systems, these general enabling lead to computerized quantitative bio-informatics for econo-green bio-research in broad disciplines. Specific applications of the theory, especially relevant to drug discovery, drug combination, and clinical trials, have been cited or illustrated in terms of algorithms, experimental design and computerized simulation for data analysis. Lessons learned from cancer research during the past fifty years provide a valuable opportunity to reflect, and to improve the conventional divergent approach and to introduce a new convergent avenue, based on the mass-action law principle, for the efficient cancer drug discovery and the low-cost drug development.     

Breathing patterns during progressive incremental cycle and treadmill exercise are different

Perceived breathlessness at comparable minute ventilation (V_E) is higher with cycling than with running. Different use of the upper extremities and chest wall may influence the breathing pattern. It was hypothetized that the relationship between tidal volume (V_T) and V_E throughout progressive incremental exercise is different with the two modes of exercise. Twelve well trained subjects (seven men) 20–25 years had incremental maximal exercise tests on a treadmill and a cycle ergometer on different days in random order. Heart rate, respiratory gases, V_E and V_T were measured on a computerized exercise testing system, and data were averaged over 20 s periods. The V_E?V_T relationship was characterized by maximum V_T, V_T at a V_E of 30 l min^?1 (V_T30), the Hey plot and by a least squares quadratic regression model. The increase in V_T by V_E was steeper and V_T30 was higher with cycling compared to running. V_Tmax was not different, but was achieved at a lower V_E with cycling. Breathing strategies are different with running and cycling in young well trained subjects, and exercise mode must be accounted for in normative studies of breathing pattern.     

Predicting clinical physiology: A Markov chain model of heart rate recovery after spontaneous breathing trials in mechanically ventilated patients

Analysis of heart rate (HR) dynamics before, during, and after a physiologic stress has clinical importance. For example, the celerity of heart rate recovery (HRR) after a cardiac stress test (eg, treadmill exercise test) has been shown to be an independent predictor of all-cause mortality. Heart rate dynamics are modulated, in part, by the autonomic nervous system. These dynamics are commonly abstracted using metrics of heart rate variability (HRV), which are known to be sensitive to the influence of the autonomic nervous system on HR. The patient-specific modulators of HR should be reflected both in the response to stress as well as in the recovery from stress. We therefore hypothesized that the patient-specific HR response to stress could be used to predict the HRR after the stress.We devised a Markov chain model to predict the poststress HRR dynamics using the parameters (transition matrix) calculated from HR data during the stress. The model correctly predicts the exponential shape of poststress HRR. This model features a simple analytical relationship linking poststress HRR time constant (T_off) with a standard measure of HRV, namely the correlation coefficient of the Poincaré plot (first return map) of the HR recorded during the stress. A corresponding relationship exists between the time constant (T_on) of R-R interval decrease at the onset of stress and the correlation coefficient of the Poincaré plot of prestress R-R intervals. Consequently, the model can be used for the prediction of poststress HRR using the HRV measured during the stress. This direct relationship between the event-to-event microscopic fluctuations (HRV) during the stress and the macroscopic response (HRR) after the stress terminates can be interpreted as an instance of a fluctuation-dissipation relationship. We have thus applied the fluctuation-dissipation theorem to the analysis of heart rate dynamics.The approach is specific neither to cardiac physiology nor to transitions between mechanical and free ventilation as a specific stress. It may therefore have wider applicability to physiologic systems subject to modest stresses.     

A Review of: “ Handbook of Adaptive Designs in Pharmaceutical and Clinical Development,by A. Pong and S.-C. Chow (Eds.)”

In practice, there exist many disease processes with three ordinal disease classes; for example, in the detection of Alzheimer’s disease (AD) a patient can be classified as healthy (disease-free stage), mild cognitive impairment (early disease stage), or AD (full disease stage). The treatment interventions and effectiveness of such disease processes will depend on the disease stage. Therefore, it is important to develop diagnostic tests with the ability to discriminate between the three disease stages. Measuring the overall ability of diagnostic tests to discriminate between the three classes has been discussed extensively in the literature. However, there has been little proposed on how to select clinically meaningful thresholds for such diagnostic tests, except for a method based on the generalized Youden index by Nakas et al. (2010). In this article, we propose two new criteria for selecting diagnostic thresholds in the three-class setting. The numerical study demonstrated that the proposed methods may provide thresholds with less variability and more balance among the correct classification rates for the three stages. The proposed methods are applied to two real examples: the clinical diagnosis of AD from the Washington University Alzheimer’s Disease Research Center and the detection of liver cancer (LC) using protein segments.