Physiologically Based Pharmacokinetic Model To Predict Metoprolol Disposition in Healthy and Disease Populations.

The evolution in the development of drugs has increased the popularity of physiologically based pharmacokinetic (PBPK) models. This study seeks to assess the PK of metoprolol in populations with healthy, chronic kidney disease (CKD), and acute myocardial infarction (AMI) conditions by developing and evaluating PBPK models. An extensive literature review for identifying and selecting plasma concentration vs time profile data and other drug-related parameters was undergone for their integration into the PK-Sim program followed by the development of intravenous, oral, and diseased models. The developed PBPK model of metoprolol was then evaluated using the visual predictive checks, mean observed/predicted ratios (Robs/pre), and average fold error for all PK parameters, i.e., the area under the curve (AUC), maximal plasma concentration, and clearance. The model evaluation depicted that none of the PK parameters were out of the allowed range (2-fold error) in the case of the mean Robs/pre ratios. The model anticipations were executed to determine the influence of diseases on unbound and total AUC after the application of metoprolol in healthy, moderate, and severe CKD. The dosage reductions were also suggested based on differences in unbound and total AUC in different stages of CKD. The developed PBPK models have successfully elaborated the PK changes of metoprolol occurring in healthy individuals and those with renal and heart diseases (CKD & AMI), which may be fruitful for dose optimization among diseased patients.

What interventions should we implement in England's mental health services? The mental health implementation network (MHIN) mixed-methods approach to rapid prioritisation.

Introduction: Setting mental health priorities helps researchers, policy makers, and service funders improve mental health services. In the context of a national mental health implementation programme in England, this study aims to identify implementable evidence-based interventions in key priority areas to improve mental health service delivery. Methods: A mixed-methods research design was used for a three step prioritisation approach involving systematic scoping reviews (additional manuscript under development), expert consultations and data triangulation. Groups with diverse expertise, including experts by experience, worked together to improve decision-making quality by promoting more inclusive and comprehensive discussions. A multi-criteria decision analysis (MCDA) model was used to combine participants' varied opinions, data and judgments about the data's relevance to the issues at hand during a decision conferencing workshop where the priorities were finalised. Results: The study identified mental health interventions in three mental health priority areas: mental health inequalities, child and adolescent mental health, comorbidities with a focus on integration of mental and physical health services and mental health and substance misuse problems. Key interventions in all the priority areas are outlined. The programme is putting some of these evidence-based interventions into action nationwide in each of these three priority mental health priority areas. Conclusion: We report an inclusive attempt to ensure that the list of mental health service priorities agrees with perceived needs on the ground and focuses on evidence-based interventions. Other fields of healthcare may also benefit from this methodological approach if they need to make rapid health-prioritisation decisions.

Application of a physiologically based pharmacokinetic model in predicting captopril disposition in children with chronic kidney disease.

Over the last several decades, angiotensin-converting enzyme inhibitors (ACEIs) have been a staple in the treatment of hypertension and renovascular disorders in children. One of the ACEIs, captopril, is projected to have all the benefits of traditional vasodilators. However, conducting clinical trials for determining the pharmacokinetics (PK) of a drug is challenging, particularly in pediatrics. As a result, modeling and simulation methods have been developed to identify the safe and effective dosages of drugs. The physiologically based pharmacokinetic (PBPK) modeling is a well-established method that permits extrapolation from adult to juvenile populations. By using SIMCYP simulator, as a modeling platform, a previously developed PBPK drug-disease model of captopril was scaled to renally impaired pediatrics population for predicting captopril PK. The visual predictive checks, predicted/observed ratios (ratiopred/obs), and the average fold error of PK parameters were used for model evaluation. The model predictions were comparable with the reported PK data of captopril in mild and severe chronic kidney disease (CKD) patients, as the mean ratiopred/obs Cmax and AUC0-t were 1.44 (95% CI 1.07 - 1.80) and 1.26 (95% CI 0.93 - 1.59), respectively. The successfully developed captopril-CKD pediatric model can be used in suggesting drug dosing in children diagnosed with different stages of CKD.

Self-evaluation and depression in adolescents with a chronic illness: A systematic review.

OBJECTIVE: To conduct a systematic review to establish what is known about the relationship between depression and self-evaluation in adolescents with a chronic illness. METHODS: A systematic search was conducted using MEDLINE, EMBASE, PsycINFO, Web of Science, The Cochrane Library, and hand-searching. We sought to identify primary research that examined both the cross-sectional and longitudinal associations between depression and self-evaluation in adolescents with chronic illness. The search resulted in 8941 retrieved articles that were screened against an inclusion criteria. A total of 4 papers were included in the review. The MMAT used to assess study methodological quality. RESULTS: A narrative synthesis was conducted, and a summary figure was included. These 4 studies included 236 adolescents aged 9-18 years with depression and either Type 1 Diabetes (T1D), chronic pain, headaches, or Inflammatory Bowel Disease (IBD). The limited existing evidence indicated that that depression was associated with negative self-evaluation in adolescents in some but not all chronic illnesses investigated to date. We also found some evidence that psychological intervention can help to improve self-evaluation, specifically in adolescents with T1D. CONCLUSIONS: More robust studies of the association between self-evaluation and depression in adolescents with a chronic illness is needed, with attention to the nuances of differences between chronic illnesses. The existing evidence indicates that there may be a stronger association in some chronic illnesses. Pilot data suggest that specific psychological therapies may improve self-evaluation, although much more extensive evaluation is needed.

A review on the clinical pharmacokinetics of hydralazine.

INTRODUCTION: Hydralazine is a vasodilator used to treat hypertension, pre-eclampsia, and heart failure. The current article reviews the clinical pharmacokinetics (PK) of hydralazine, which can be useful for clinicians in optimizing its dose and dosing frequency to avoid adverse effects and unexpected interactions that could risk patients' lives. AREAS COVERED: This review has summarized the PK parameters for hydralazine after performing an extensive literature search. It includes 20 publications that were selected after applying eligibility criteria out of a pool of literature that was searched using Google Scholar, PubMed, Cochrane Central, and EBSCO databases. The included studies consisted of concentration vs. time profiles of hydralazine. If the PK data were not tabulated in the given study, the concentration vs. time profiles were scanned for the extraction of the PK data. The PK parameters were calculated by applying a non-compartmental analysis (NCA). EXPERT OPINION: The current review will aid clinicians in understanding hydralazine PK in different disease populations. This clinical PK data might also be helpful in the development of a pharmacokinetic model of hydralazine.

A Physiologically Based Pharmacokinetic Model for Predicting Diazepam Pharmacokinetics after Intravenous, Oral, Intranasal, and Rectal Applications.

Diazepam is one of the most prescribed anxiolytic and anticonvulsant that is administered through intravenous (IV), oral, intramuscular, intranasal, and rectal routes. To facilitate the clinical use of diazepam, there is a need to develop formulations that are convenient to administer in ambulatory settings. The present study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for diazepam that is capable of predicting its pharmacokinetics (PK) after IV, oral, intranasal, and rectal applications using a whole-body population-based PBPK simulator, Simcyp®. The model evaluation was carried out using visual predictive checks, observed/predicted ratios (Robs/pred), and the average fold error (AFE) of PK parameters. The Diazepam PBPK model successfully predicted diazepam PK in an adult population after doses were administered through IV, oral, intranasal, and rectal routes, as the Robs/pred of all PK parameters were within a two-fold error range. The developed model can be used for the development and optimization of novel diazepam dosage forms, and it can be extended to simulate drug response in situations where no clinical data are available (healthy and disease).

Development and evaluation of physiologically based pharmacokinetic drug-disease models for predicting captopril pharmacokinetics in chronic diseases.

The advancement in the processing speeds of computing machines has facilitated the development of complex physiologically based pharmacokinetic (PBPK) models. These PBPK models can incorporate disease-specific data and could be used to predict pharmacokinetics (PK) of administered drugs in different chronic conditions. The present study aimed to develop and evaluate PBPK drug-disease models for captopril after incorporating relevant pathophysiological changes occurring in adult chronic kidney disease (CKD) and chronic heart failure (CHF) populations. The population-based PBPK simulator Simcyp was used as a modeling and simulation platform. The visual predictive checks and mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters were used for model evaluation. The developed disease models were successful in predicting captopril PK in all three stages of CKD (mild, moderate, and severe) and CHF, as the observed and predicted PK profiles and the ratio(obs/pred) for the PK parameters were in close agreement. The developed captopril PBPK models can assist in tailoring captopril dosages in patients with different disease severity (CKD and CHF).

Effect of 4 weeks daily wild blueberry supplementation on symptoms of depression in adolescents.

Adolescence is an important period for cognitive maturation and emotional regulation, and this age group is particularly vulnerable to developing depression. Diets rich in fruits and vegetables have been associated with decreased risk of developing depressive disorders across the lifespan, maybe due to the high flavonoid content of these foods. Previously, we have shown increases in transient positive affect (PA) in both children and young adults 2 h after administration of a wild blueberry (WBB) intervention. Here, using a randomised double-blind, placebo-controlled trial, we investigated the effects of 4 weeks, daily WBB supplementation (containing about 253 mg anthocyanins) on transient and chronic mood in adolescents. Healthy 12-17-year old (n 64, thirty-five females) participants were randomly assigned to receive either a WBB or matched placebo supplementation. Depression and anxiety symptoms were assessed before and after the intervention period using the Mood and Feeling Questionnaire and Revised Child Anxiety and Depression Scale. Transient affect was assessed before, 2 weeks and at 4 weeks using PA and negative affect. Following the intervention period, there were significantly fewer self-reported depression symptoms in participants who were supplemented with WBB compared with placebo (P = 0·02, 95 % CI -6·71, -5·35). There was no between-group effect on anxiety symptoms or on transient affect. Further investigation is required to identify specific mechanisms that link flavonoids consumption and mood. If replicated, the observed effects of WBB supplementation may be a potential prevention strategy for adolescent depression and may have benefits for public mental health.

Development and Evaluation of Physiologically Based Pharmacokinetic Drug-Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations.

The physiologically based pharmacokinetic (PBPK) approach facilitates the construction of novel drug-disease models by allowing incorporation of relevant pathophysiological changes. The aim of the present work was to explore and identify the differences in rifampicin pharmacokinetics (PK) after the application of its single dose in healthy and diseased populations by using PBPK drug-disease models. The Simcyp® simulator was used as a platform for modeling and simulation. The model development process was initiated by predicting rifampicin PK in healthy population after intravenous (i.v) and oral administration. Subsequent to successful evaluation in healthy population, the pathophysiological changes in tuberculosis and cirrhosis population were incorporated into the developed model for predicting rifampicin PK in these populations. The model evaluation was performed by using visual predictive checks and the comparison of mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters. The predicted PK parameters in the healthy population were in adequate harmony with the reported clinical data. The incorporation of pathophysiological changes in albumin concentration in the tuberculosis population revealed improved prediction of clearance. The developed PBPK drug-disease models have efficiently described rifampicin PK in tuberculosis and cirrhosis populations after administering single drug dose, as the ratio(Obs/pred) for all the PK parameters were within a two-fold error range. The mechanistic nature of the developed PBPK models may facilitate their extension to other diseases and drugs.

Effects of Acute Blueberry Flavonoids on Mood in Children and Young Adults.

Epidemiological evidence suggests that consumption of flavonoids (usually via fruits and vegetables) is associated with decreased risk of developing depression. One plausible explanation for this association is the well-documented beneficial effects of flavonoids on executive function (EF). Impaired EF is linked to cognitive processes (e.g., rumination) that maintain depression and low mood; therefore, improved EF may reduce depressionogenic cognitive processes and improve mood. Study 1: 21 young adults (18-21 years old) consumed a flavonoid-rich blueberry drink and a matched placebo in a counterbalanced cross-over design. Study 2: 50 children (7-10 years old) were randomly assigned to a flavonoid-rich blueberry drink or a matched placebo. In both studies, participants and researchers were blind to the experimental condition, and mood was assessed using the Positive and Negative Affect Schedule before and 2 h after consumption of the drinks. In both studies, the blueberry intervention increased positive affect (significant drink by session interaction) but had no effect on negative affect. This observed effect of flavonoids on positive affect in two independent samples is of potential practical value in improving public health. If the effect of flavonoids on positive affect is replicated, further investigation will be needed to identify the mechanisms that link flavonoid interventions with improved positive mood.

Is there an association between diet and depression in children and adolescents? A systematic review.

This review critically evaluates previous studies investigating the association between dietary intake of children and young people and depression and related mental health problems. A systematic literature search was conducted using electronic databases such as PsycINFO, MEDLINE, PubMed and Cochrane. A total of twenty studies were identified that met inclusion criteria and were subsequently rated for quality. The studies used a range of methods to measure dietary intake and mental health. Important potential confounding variables (e.g. socio-economic status) were often not included or controlled. There were also inconsistencies in the use of key constructs, which made comparisons between studies difficult. Despite some contradictory results, overall there was support for an association between healthy dietary patterns or consumption of a high-quality diet and lower levels of depression or better mental health. Similarly, there was a relationship between unhealthy diet and consumption of low-quality diet and depression or poor mental health. However, where significant relationships were reported, effect sizes were small. Future research on the relationship between diet and mental health in young people should use more clearly defined constructs to define diet and include or control for important confounders.