Quantitative Structure–Activity Study on Human Pharmacokinetic Parameters of Benzodiazepines Using the Graph Theoretical Approach

The graph theoretical indices for a series of 13 benzodiazepines were calculated using a graph-path topological method. The total molecule, the ring fragments, and combinations of ring fragments were subjected to a quantitative structure–activity analysis using eight pharmacokinetic parameters. The metabolic clearance and the blood-to-plasma concentration ratios were most highly correlated with the graph theoretical indices, with R values of 0.975 and 0.938, respectively. These correlations were found when the diazepine + benzo fragment and phenyl fragment were used to calculate the graph-path indices. Terminal disposition half-life was correlated with the benzo + diazepine fragment, with R = 0.969. Truncating the graph-path codes by eliminating cycles in the total molecule markedly improved the correlation coefficients. When compared to the graph-path indices for the total molecule, the correlation coefficients for the terminal disposition half-life and metabolic clearance data rose from 0.721 to 0.935 and from 0.770 to 0.968, respectively, using the graph-path indices of the truncated molecule. Intrinsic clearance of unbound drug also was poorly correlated with the total molecule (r < 0.7) but rose significantly using the graph-path indices of the truncated moleucle (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively.)     

Benzodiazepine and Z-Drug Use and the Risk of Developing Dementia

BackgroundBenzodiazepines (BZDs) and Z-drugs (BZDRs) are among the most prescribed medications for anxiety and insomnia, especially among older adults. Our objective was to investigate the association between the use of BZDRs and the risk of dementia.MethodsA community-based retrospective cohort study was conducted based on the data available from 2002 to 2015 in Catalan Health Service. This cohort included all BZDR users (N = 83 138) and nonusers (N = 84 652) older than 45 years. A minimum 5-year lag window and an adjustment for psychiatric problems were applied for the data analysis.ResultsThe hazard ratio (HR) for the risk of incident dementia among BZDR users was 1.22 (95% CI = 1.15 to 1.31). This risk was not significant after adjusting the data confounding factors (HR = 1.01; 95% CI = 0.94 to 1.08). We observed a higher risk with short-to-intermediate half-life BZDs (HR = 1.11; 95% CI = 1.04 to 1.20) and Z-drugs (HR = 1.20; 95% CI = 1.07 to 1.33) than for intermediate-to-long half-life BZDs (HR = 1.01; 95% CI = 0.94 to 1.08). We demonstrated a higher risk of incident dementia (HR = 1.23; 95% CI = 1.07 to 1.41 and odds ratio = 1.38; 95% CI = 1.27 to 1.50, respectively) in patients who received 91 to 180 defined daily doses (DDDs) and >180 DDDs compared with patients who received <90 DDD. Regarding patient sex, the risk of dementia was higher in women than in men.ConclusionWe found that the incidence of dementia was not higher among all BZDR users. Short half-life BZDs and Z-drugs increased the risk of dementia at the highest doses, especially in female patients, showing a dose-response relationship.     

Pharmacophore, 3D‐QSAR,and Bayesian Model Analysis for Ligands Binding at the Benzodiazepine Site of GABAA Receptors: the Key Roles of Amino Group and Hydrophobic Sites

Ligands binding at the benzodiazepine site of GABA_A receptor play important pharmacological roles in clinical application. In this study, ligand‐based pharmacophore modeling, 3D‐QSAR analysis, and Bayesian model studies have been performed on a set of 84 diverse ligands binding at the benzodiazepine site. The results showed the best pharmacophore hypothesis AADHR.4, which included two hydrogen acceptors (A), one hydrogen donor (D), one hydrophobic group (H), and one aromatic ring (R). Atom‐based 3D‐QSAR model was built, and it showed good statistical significance (R² = 0.936) and excellent predictive ability (Q² = 0.821). Moreover, Bayesian model was developed and used to identify the key molecular features which are good or bad for the ligand binding activity. All the results from the pharmacophore, 3D‐QSAR, and Bayesian modeling studies revealed that a hydrogen‐bond donor (e.g., N‐H) and a hydrophobic group (e.g., Br) are critical structural features for the ligands binding at the benzodiazepine site.     

Regression Analysis of Fold-Increase Endpoints Using a Distributional Approach for Paired Interval-Censored Antibody Data

ABSTRACT

Biopharmaceutical research often uses a binary “fold-increase” response variable defined by the ratio of a pair of interval-censored measurements taken at baseline and end-of-study. Conventional practice ignores the interval-censoring nature of the data. Moreover, conventional practice dictates that the possible choices for cut-off to define the response must follow a geometric sequence. A novel method based on the “distributional approach” was proposed for the analysis of such paired measurements in a randomized trial context. The degree of fold-increase above which a response is defined can be chosen according to scientific rationale instead of being limited to a geometric sequence. The risk ratio is then estimated for comparison between trial arms. We extend the method to allow for adjustment for baseline covariates in both randomized trial and cohort study settings. The treatment effect is obtained by integrating over the covariate distribution. In the presence of heterogeneity, estimators of the population treatment effect and the average treatment effect are proposed and their performances are evaluated by simulation studies. We apply this method to analyze antibody data measured by the hemagglutination inhibition assay in an influenza study. Supplementary materials for this article are available online.     

Binarisms,Regressive Outcomes and Biases in the Drug Policy Interventions: A Theoretical Approach

The golden age of drug policy was characterized by the informal regulation of drug use. Formalization of the control over regulation and its increasingly strict, aggressive character led to the emergence of a binary attitude. The main binarisms: pharmaceutical or drug; ban or tolerance; punishment or treatment; psychopathological or pathopsychological approach; subjective or objective knowledge; traditional or alternative. On the basis of Kuhn's paradigm theory, these binarisms can be integrated. Drug policy interventions based on the binary attitude have had regressive effects. Using the work of Sam Sieber, the author distinguishes eight regressive influences: functional imbalance, perverse diagnosis, ricochet, overload, goal displacement, exploitation, provocation, and classification, placation. The regressive influences have caused the escalation of “the drug problem,” which in turn has led to further regressive interventions. This vicious circle could be broken by eliminating the four biases—the paternalistic, elitist, rationalist, and activist biases—underlying the regressive interventions.     

GM(1,1)灰色模型在尘肺患病人数预测的应用与评价

目的 探讨验证灰色模型在尘肺患病人数预测的应用效果。方法 利用该煤矿1996～1986年尘肺患病人数进行建模，并建立了数学模型X(I)=583e^0.038(T-II)-452，作外推预测验证。结果 该灰色预测模型的拟合程度较高，取得了较好的效果。结论 灰色模型可应用于尘肺患病人数的预测。     

Systematic Approach for Screening of Prodrugs: Evaluation Using Oseltamivir Analogues as Models

Prodrug development is a common approach in drug development. In a recent study, we established a systematic strategy for selecting prodrugs with improved membrane permeability or solubility based on log D value, solubility in artificial intestinal fluids, membrane permeability, and metabolic instability. The purpose of this study was to evaluate the utility of this strategy using oseltamivir and 23 kinds of oseltamivir analogues having various types of side chain as well as their active metabolite, oseltamivir acid. Log D values of oseltamivir and analogues (2.0 to 4.9) were higher than that of oseltamivir acid (0.7), supporting the previous development of oseltamivir to improve permeability of oseltamivir acid. Solubilities of analogues in artificial intestinal fluids were over 80%, except the compound with the highest lipophilicity. Positive correlation was observed between membrane permeability and log D values of analogues. In metabolic profiles, species differences in the hydrolysis efficiency were observed depending on analogues. Using our strategy, it was demonstrated that oseltamivir and some analogues are appropriate prodrugs that could be advanced to in vivo pharmacokinetic studies, with selection of suitable animals. This study confirmed the utility of our strategy for narrowing down of candidate compounds to proceed into in vivo study.     

Mathematical Approach for the Assessment of Similarity Factor Using a New Scheme for Calculating Weight

The objective of the present work was to propose a method for calculating weight in the Moore and Flanner Equation. The percentage coefficient of variation in reference and test formulations at each time point was considered for calculating weight. The literature reported data are used to demonstrate applicability of the method. The advantages and applications of new approach are narrated. The results show a drop in the value of similarity factor as compared to the approach proposed in earlier work. The scientists who need high accuracy in calculation may use this approach.     

重症急性胰腺炎的外科治疗和手术时机探讨

目的 探讨重症急性胰腺炎（SAP）的手术时机．以降低死亡率。方法 对1985年至2003年收冶的35例SAP进行回顾性分析，所有患者均在ICU行监护及支持治疗。结果 非手术治疗26例，治愈24例（92．3％），死亡2例、1例死于多系统器官功能衰竭（MSOF），1例死于急性肾功能衰竭（ARF）。手术治疗9例，治愈5例（55．6％），死亡4例．2例死于MSOF，2例死于ARF。结论 手术要根据患者的情况，主要是影像检查结果。对胆源性胰腺炎尽早手术治疗。     

Patients Stratification Strategies to Optimize the Effectiveness of Scavenging Biogenic Aldehydes: Towards a Neuroprotective Approach for Parkinson's Disease

Parkinson’s disease (PD) is a clinically heterogeneous disorder with a multi-factorial pathology. Various molecular mechanisms are involved in the pathogenesis of PD, converging to oxidative stress and proteinopathy. The accumulation of reactive aldehydes (i.e., the dopamine metabolite DOPAL, lipid-peroxidation products, and advanced glycation end-products) has been reported in PD patients’ brains. Aldehydes easily react with primary amines such as lysine residues, which are involved in several regulatory processes in cells. Therefore, aldehyde adducts lead to severe consequences, including neuronal proteostasis, mitochondrial dysfunction, and cell death. In this review, we analyzed the scavenging role of amines toward toxic aldehydes in the brain. Interestingly, small molecules like metformin, rasagiline, hydralazine are already clinically available and used in the therapy for PD and other diseases. Hence, we propose to reevaluate this class of drugs as a disease-modifiers for PD, and we suggest that improved analysis of their pharmacology and bioavailability in the brain, together with a more precise patients stratification, should be considered before planning future clinical trials.     

A Novel Experimental and Theoretical Method for Estimating Albumin-Mediated Hepatic Uptake Based on the Albumin Binding Fraction in Plasma and Human PK Prediction Using a Physiologically-Based Pharmacokinetic Approach

Recently, protein-facilitated uptake has been suggested to be an important factor in the precise prediction of the pharmacokinetic (PK) profiles of drugs. In our previous study, a physiologically-based pharmacokinetic (PBPK) approach considering the mechanism of albumin-mediated hepatic uptake was developed for predicting human PK profiles. It was assumed that drugs affected by albumin-mediated hepatic uptake would bind only to albumin, which means that there would be over-estimation of the contribution of protein-facilitated uptake for a drug that could bind to multiple proteins. In this study, we developed a method that can evaluate the albumin binding fraction in plasma considering the affinity for other proteins. Based on the albumin binding fraction, the contribution of albumin-mediated hepatic uptake was theoretically estimated, and then the human PK profiles were predicted by our proposed PBPK approach incorporating this mechanism. As a result, the predicted human PK profiles agreed well with the observed ones, and the absolute average fold error of PK parameters was almost within a 1.5-fold error on average. These findings show the importance of considering protein-facilitated uptake and also suggest that our proposed PBPK approach can be useful in scientific discussions with regulatory authorities.     

Identification of the Minimum Effective Dose for Normally Distributed Endpoints Using a Model Selection Approach

When identifying the minimum effective dose (MED) or the lowest observed adverse event level (LOAEL), researchers usually employ multiple comparison procedures (MCPs). The ones preferred are the Dunnett-type difference-to-placebo and ratio-to-control test. In this article, we will use a model selection criterion, namely the generalized order-restricted information criterion (GORIC). The GORIC can evaluate a set of hypotheses regarding the response means directly and simultaneously, where in this case in each hypothesis a different dose is hypothesized to be the MED or LOAEL. It takes different patterns of increasing response with increasing dose into account without pooling response means, whereas MCPs with order restrictions do. The GORIC chooses the best hypothesis of the set leading to the identification of the MED and, depending on the set, to a specific pattern of response means. We will show, by simulation, that the GORIC has advantages in identifying the MED or LOAEL, besides theoretical ones. Supplementary materials for this article are available online.     

Further Insights Into the Pharmacology of the Human Trace Amine‐Associated Receptors: Discovery of Novel Ligands for TAAR1 by a Virtual Screening Approach

Trace Amine‐Associated Receptor 1 (TAAR1) is a G protein‐coupled receptor that is expressed in brain and periphery and responds to a class of compounds called trace amines, such as β‐phenylethylamine ( β ‐PEA ), tyramine, tryptamine, octopamine. The receptor is known to have a very rich pharmacology and could be also activated by different classes of compounds, including dopaminergic, adrenergic and serotonergic ligands. It is expected that targeting hTAAR1 could provide a novel pharmacological approach for several human disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder, Parkinson's disease and metabolic diseases. Only recently, a small number of selective hTAAR1 agonists (among which RO5166017 and T ₁ AM ) and antagonist ( EPPTB ), have been reported in literature. With the aim to identify new molecular entities able to act as ligands for this target, we used an homology model for the hTAAR1 and performed a virtual screening procedure on an in‐house database of compounds. A number of interesting molecules were selected and by testing them in an in vitro assay we found several agonists and one antagonist, with activities in the low micromolar range. These compounds could represent the starting point for the development of more potent and selective TAAR1 ligands.     

A Behaviorally-Anchored Rating System to Monitor Treatment Integrity for Community Clinicians Using the Adolescent Community Reinforcement Approach

This study evaluated a process for training raters to reliably rate clinicians delivering the Adolescent Community Reinforcement Approach (A-CRA) in a national dissemination project. The unique A-CRA coding system uses specific behavioral anchors throughout its 73 procedure components. Five randomly selected raters each rated “passing” and “not passing” examples of the 19 A-CRA procedures. Ninety-four percent of the final intraclass correlation coefficients were at least “good” (≥.60) and 66.7% were “excellent” (≥.75), and 95% of the ratings exceeded the 60% or better agreement threshold between raters and the gold standard. Raters can be trained to provide reliable A-CRA feedback for large-scale dissemination projects.     

Science based guidance for the assessment of endocrine disrupting properties of chemicals

The European legislation on plant protection products (Regulation (EC) No. 1107/2009) and biocides (Directive 98/8/EC), as well as the regulation concerning chemicals (Regulation (EC) No. 1907/2006 ‘REACH’) only support the marketing and use of chemical products on the basis that they do not induce endocrine disruption in humans or non-target species. However, there is currently no agreed guidance on how to identify and evaluate endocrine activity and disruption. Consequently, an ECETOC task force was formed to provide scientific criteria that may be used within the context of these three legislative documents. Specific scientific criteria for the determination of endocrine disrupting properties that integrate information from both regulatory (eco)toxicity studies and mechanistic/screening studies are proposed. These criteria combine the nature of the adverse effects detected in studies which give concern for endocrine toxicity with an understanding of the mode of action of toxicity so that adverse effects can be explained scientifically. The criteria developed are presented in the form of flow charts for assessing relevant effects for both humans and wildlife species. In addition, since not all chemicals with endocrine disrupting properties are of equal hazard, assessment of potency is also proposed to discriminate chemicals of high concern from those of lower concern. The guidance presented in this paper includes refinements made to an initial proposal following discussion of the criteria at a workshop of invited regulatory, academic and industry scientists.     

Searching for the Fusarium spp. Which Are Responsible for Trichothecene Contamination in Oats Using Metataxonomy to Compare the Distribution of Toxigenic Species in Fields from Spain and the UK

The contamination of oats with Fusarium toxins poses a high risk for food safety. Among them, trichothecenes are the most frequently reported in European oats, especially in northern countries. The environmental conditions related to the climate change scenario might favour a distribution shift in Fusarium species and the presence of these toxins in Southern European countries. In this paper, we present an ambitious work to determine the species responsible for trichothecene contamination in Spanish oats and to compare the results in the United Kingdom (UK) using a metataxonomic approach applied to both oat grains and soil samples collected from both countries. Regarding T-2 and HT-2 toxin producers, F. langsethiae was detected in 38% and 25% of the oat samples from the UK and Spain, respectively, and to the best of our knowledge, this is the first report of the detection of this fungus in oats from Spain. The relevant type B trichothecene producer, F. poae, was the most frequently detected Fusarium species in oats from both origins. Other important trichothecene producers, such as the Fusarium tricinctum species complex or Fusarium cerealis, were also frequently detected in oat fields. Many Fusarium toxins, including T-2 and HT-2 toxins, deoxynivalenol, or nivalenol, were detected in oat samples. The results obtained in this work revealed a clear change in the distribution of trichothecene producers and the necessity to establish the potential of these species to colonize oats and their ability to produce mycotoxins.