Model-Based Virtual PK/PD Exploration and Machine Learning Approach to Define PK Drivers in Early Drug Discovery.

While poor translatability of preclinical efficacy models can be responsible for clinical phase II failures, misdefinition of the optimal PK properties required to achieve therapeutic efficacy can also be a contributing factor. In the present work, the pharmacological dependency of PK end points in driving efficacy is demonstrated for six common pharmacological processes via model-based analysis. The analysis shows that the response is driven by multiple pharmacology-specific PK end points that change with how the response is defined. Moreover, the results demonstrate that the most important chemical structural features influencing response are specific to both target and downstream pharmacology, meaning the design and screening criteria must be defined uniquely for each target and corresponding pharmacology. The model-based virtual exploration of PK/PD relationships presented in this work offers one approach to identify target pharmacology-specific PK drivers and the associated potency-ADME space early in discovery to increase the probability of success and, ultimately, clinical attrition.

Detección y resolución de Problemas Relacionados con Medicamentos en un servicio de Atención Farmacéutica en Argentina / Detection and resolution of Drug Therapy Problems in a Pharmaceutical Care service in Argentina

Introducción: La Atención Farmacéutica consiste en un proceso asistencial sistemático para detec-tar, resolver y prevenir Problemas Relacionados con Medicamentos. El objetivo del presente trabajo es describir el número y perfil de problemas detecta-dos y resueltos en un conjunto de pacientes adul-tos atendidos en una Unidad de Optimización de la Farmacoterapia en Argentina, durante un segui-miento farmacoterapéutico promedio de un año.Método: Se realizó un estudio cuasi-experimental, abierto y prospectivo en 40 pacientes ambulatorios. Se registraron las características clínicas y medica-mentos, así como su adherencia o no al servicio. Se empleó la clasificación de Problemas Relacionados con Medicamentos de Minnesota, registrando su dimensión, categoría, causa, patología o condición clínica asociada, medicamento asociado, estado de riesgo, estado final y método de resolución.Resultados: Los grupos farmacoterapéuticos mayormente utilizados fueron beta-bloqueantes, estatinas, vitaminas y minerales, analgésicos, inhibidores de la bomba de protones y benzodiace-pinas. Los problemas de indicación, especialmente por necesidad de farmacoterapia adicional, prevale-cieron como los más frecuentes, incluyendo la falta de farmacoterapia preventiva con vacunas. Se lo-gró resolver el 73,6% de los problemas detectados, de los cuales el 60,3% se hizo a través de informes a los médicos tratantes. El resto se pudo abordar mediante la educación al paciente, especialmente los de adherencia.Conclusiones: La Atención Farmacéutica permitió una descripción sistemática del perfil de problemas farmacológicos detectados y resueltos en un con-junto de pacientes adultos mayores ambulatorios, principalmente de sexo femenino, en el contexto de una Unidad de Optimización de la Farmacoterapia montada en un hospital universitario de Argentina. (AU)

Introduction: Pharmaceutical Care is a systematic process to detect, solve, and prevent Drug Relat-ed Problems. The aim of this study is to describe the number and profile of problems detected and solved in a group of adult patients interviewed in a Pharmacotherapy Optimization Unit in Argentina, during an average pharmacotherapeutic follow-up of one year.Method: A quasi-experimental, open-label, pro-spective study was carried out in 40 outpatients. The Clinical characteristics and medications were revealed, as well as their adherence to the service. The Minnesota classification of Drug Therapy Problems was used, recording dimension, category, cause, associated clinical condition, associated medication, risk status, final status, and resolution method.Results: The most widely used pharmacotherapeu-tic groups were beta-blockers, statins, vitamins and minerals, analgesics, proton pump inhibitors, and benzodiazepines. Indication problems, especially due to the need for additional pharmacotherapy, prevailed as the most frequent, including the lack of preventive vaccines. It was possible to solve 73.6% of the detected problems, of which 60.3% was done through reports to the treating physicians. The rest could be addressed through patient education, especially those related to adherence.Conclusions: Pharmaceutical Care allowed a systematic pharmacotherapy work-up of Drug Related Problems detected and solved in a group of elderly outpatients, mainly female, in the context of a Pharmacotherapy Optimization Unit set up in a university hospital in Argentina. (AU)

Determinants of COVID-19 vaccine acceptance amongst doctors practising in Cross River State, Nigeria

Background: COVID-19 vaccine is one of the most effective public health intervention approaches for prevention of COVID-19. Despite its well-known efficacy and safety, significant proportion of frontline COVID-19 healthcare workers remain hesitant about accepting the vaccine for whatever reasons. This study aimed to determine acceptance rate and determinants of vaccine refusal among doctors in Cross River State, Nigeria. Methodology: This was a cross-sectional survey of doctors using structured online questionnaire administered via the WhatsApp platform of the medical doctors' association, in order to assess their rate of acceptance of COVID-19 vaccines, and reasons for vaccine refusal. The predictors of vaccine acceptance were analysed by univariate and multivariate logistic regression analyses. Results: Of the 443 medical doctors targeted on the WhatsApp platform, 164 responded to the questionnaire survey, giving a response rate of 37.0% (164/443). The mean age of the respondents is 38 ±6.28 years, 91 (55.5%) are 38 years old and above, 97 (59.1%) are males and 67 (40.9%) are females, giving a male-to-female ratio of 1.4:1. The greater proportion of the respondents are physicians (70/148, 47.3%) and about three-quarter of the participants (127/164, 77.4%) had received COVID-19 vaccine. The proportion of physicians who had received COVID-19 vaccine (57/70, 81.4%) was more than the proportion of general practitioners (31/42, 73.8%) and surgeons (24/35, 68.6%). Low perceived benefit of vaccination was the main reason given for COVID-19 vaccine refusal (45.9%, 17/37). No significant association was found between vaccine refusal and suspected predictors (p>0.05). Conclusion: Our study revealed high rate of COVID-19 vaccine acceptance among medical doctors especially among the physicians, with the surgeons showing lowest acceptance rate. A significant proportion would not take vaccine because they perceived it lacks much benefits. To raise vaccine acceptance among doctors, more efforts on vaccine literacy that would target doctors from all sub-specialties especially surgeons and incorporate vaccine benefits should be made.

A Review of the Potential Roles of Antioxidant and Anti-Inflammatory Pharmacological Approaches for the Management of Mild-to-Moderate Symptomatic COVID-19.

In the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has driven investigational studies and controlled clinical trials on antiviral treatments and vaccines that have undergone regulatory approval. Now that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants may become endemic over time, there remains a need to identify drugs that treat the symptoms of COVID-19 and prevent progression toward severe cases, hospitalization, and death. Understanding the molecular mechanisms of SARS-CoV-2 infection is extremely important for the development of effective therapies against COVID-19. This review outlines the key pathways involved in the host response to SARS-CoV-2 infection and discusses the potential role of antioxidant and anti-inflammatory pharmacological approaches for the management of early mild-to-moderate COVID-19, using the examples of combined indomethacin, low-dose aspirin, omeprazole, hesperidin, quercetin, and vitamin C. The pharmacological targets of these substances are described here for their possible synergism in counteracting SARS-CoV-2 replication and progression of the infection from the upper respiratory airways to the blood, avoiding vascular complications and cytokine and bradykinin storms.

Potential risk groups and psychological, psychosocial, and health behavioral predictors of pharmacological neuroenhancement among university students in Germany.

Aiming to develop and implement intervention strategies targeting pharmacological neuroenhancement (PN) among university students more specifically, we (1) assessed the prevalence of PN among German university students, (2) identified potential sociodemographic and study-related risk groups, and (3) investigated sociodemographic, psychological, study-related psychosocial, general psychosocial and health behavior related factors predicting the 12-month prevalence of PN. Therefore, a cross-sectional online survey was administered to students of the University of Mainz, Germany. A binary logistic regression with stepwise inclusion of the five variable groups was performed to predict PN. A total number of 4351 students out of 31,213 registered students (13.9%) participated in the survey, of which N = 3984 answered the question concerning PN. Of these, 10.4% had used one substance for PN at least once in the past 12 months. The regression analysis revealed 13 variables that were significantly related to the 12-month prevalence of PN. Specifically, the group of health behavior related variables showed the strongest relationship with PN. Therefore, an approach to the prevention of PN should be multifactorial so that it addresses social conditions, as well as education on substance use and healthy behaviors in terms of non-pharmacological strategies as alternatives of PN.

Psychosocially-Assisted Pharmacological Treatment of Opioid Dependent Adults: A Systematic Review

Background: Opioid dependence is a conundrum that significantly contributes to global mortality, crimes, and transmission of diseases such as hepatitis (B and C), human immunodeficiency virus and perhaps, coronavirus disease 2019 (COVID-19). There are contradictory findings on the efficacy of psychosocially-assisted pharmacological treatment of opioid dependence in adults. Objective: The overall objective of this research is to investigate if psychosocially-assisted pharmacological therapy has significantly better effect than pharmacological therapy with regards treatment outcomes of opioid dependent adults. Methods: All methods employed in this study are in conformity with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) framework for systematic review which involve identification, screening, eligibility and inclusion. This systematic review involved PubMed literature search on randomized controlled trials published between 1st January 2015 to 1st October 2021. Results: PubMed search yielded 5,216 articles which were screened using inclusion and exclusion criteria resulting in 19 articled being retained for data extraction. Of the 19 articles used in this study, 13 (68.4%) articles having a combined sample size of 1,928 (60.6%) showed that addition of psychosocial intervention to pharmacotherapy significantly improved abstinence from opioid abuse. Conclusion: The outcome of evaluation of the overall evidences presented in the 19 articles used in this study is that psychosocially-assisted pharmacological therapy is significantly better than pharmacological treatment with respect to enhancement of abstinence from opioid abuse among opioid-dependent adults. Additionally, this study has provided specific combinations of psychosocial and pharmacological treatment that can produce significant beneficial effect on opioid abstinence. The huge downturn in randomized controlled trials on treatment of opioid dependence among adults has been highlighted in this study.

Angiotensin II Type 2 Receptor: A Target for Protection Against Hypertension, Metabolic Dysfunction, and Organ Remodeling.

The renin-angiotensin system is of vital significance not only in the maintenance of blood pressure but also because of its role in the pathophysiology of different organ systems in the body. Of the 2 Ang II (angiotensin II) receptors, the AT1R (Ang II type 1 receptor) has been extensively studied for its role in mediating the classical functions of Ang II, including vasoconstriction, stimulation of renal tubular sodium reabsorption, hormonal secretion, cell proliferation, inflammation, and oxidative stress. The other receptor, AT2R (Ang II type 2 receptor), is abundantly expressed in both immune and nonimmune cells in fetal tissue. However, its expression is increased under pathological conditions in adult tissues. The role of AT2R in counteracting AT1R function has been discussed in the past 2 decades. However, with the discovery of the nonpeptide agonist C21, the significance of AT2R in various pathologies such as obesity, hypertension, and kidney diseases have been examined. This review focuses on the most recent findings on the beneficial effects of AT2R by summarizing both gene knockout studies as well as pharmacological studies, specifically highlighting its importance in blood pressure regulation, obesity/metabolism, organ protection, and relevance in the treatment of coronavirus disease 2019 (COVID-19).

A protocol for simultaneous in vivo juxtacellular electrophysiology and local pharmacological manipulation in mouse cortex.

Here, we describe a protocol to simultaneously record and label single cortical neurons in vivo under local application of a chemical such as a receptor agonist. This protocol provides a useful tool to investigate how the chemical of interest affects the processing of sensory information by cortical neurons. The juxtacellular labeling allows identification of the cell type and morphology of the recorded neurons. We draw examples to show pharmacological modulations in encoding of vibrotactile stimuli in the mouse primary somatosensory cortex. For complete details on the use and execution of this protocol, please refer to Kheradpezhouh et al. (2020).

Toward Greater Insights on Applications of Modeling and Simulation in Pregnancy.

Pregnant women are often excluded from routine clinical trials. Consequently, appropriate dosing regimens for majority of drugs are unknown in this population, which may lead to unexpected safety issue or insufficient efficacy in this un-studied population. Establishing evidence through the conduct of clinical studies in pregnancy is still a challenge. In recent decades, physiologically-based pharmacokinetic (PBPK) modeling has proven to be useful to support dose selection under various clinical scenarios, such as renal and/or liver impairment, drug-drug interactions, and extrapolation from adult to children. By integrating gestational-dependent physiological characteristics and drug-specific information, PBPK models can be used to predict PK during pregnancy. Population pharmacokinetic (PopPK) modeling approach also could complement pregnancy clinical studies by its ability to analyze sparse sampling data. In the past five years, PBPK and PopPK approaches for pregnancy have made significant progress. We reviewed recent progress, challenges and potential solutions for the application of PBPK, PopPK, and exposure-response analysis in clinical drug development for pregnancy.

Identification, collection, and reporting of harms among non-industry-sponsored randomized clinical trials of pharmacologic interventions in the critically ill population: a systematic review.

BACKGROUND: Prescribing pharmacologic therapies for critically ill patients requires a careful balancing of risks and benefits. Defining, monitoring, and reporting harms that occur in clinical trials conducted in critically ill populations, however, is challenging given that the natural history of most critical illnesses includes progressive multiple organ failure and death. In this study, we assessed harms reporting in clinical trials performed in critically ill populations. METHODS: Randomized, non-industry-sponsored, human clinical trials of pharmacologic interventions in adult critically ill populations published between 2015 and 2018 in high-impact journals were included in this systematic review. Harms data, adherence to Consolidated Standards of Reporting Trials (CONSORT) harms reporting guidelines, and restrictions on harms reporting were recorded. RESULTS: A total of 707 abstracts were screened with 40 trials ultimately being included in the analysis. Included trials represent 28,636 randomized patients with a median of 292 (IQR 100-546) patients per trial. The most common disease states were general critical care (33%) and sepsis (28%). Of 18 included CONSORT items, the median number met was 12 (IQR 9, 14). The most commonly missed items were adverse event (AE) severity grading definitions and AE attribution (relationship of AE to study drug), which were only reported in 35 and 38% of manuscripts, respectively. Half of the manuscripts (48%) provided definitions for recorded AEs. There were 5 studies investigating the effects of corticosteroids in sepsis, with the number of AEs reported per analyzed patient ranging from 0.01 to 1.89. AE definitions in studies of similar/equivalent interventions often varied substantially. Study protocols were available for 30/40 (75%) of studies, with 13 (43%) of those not providing any guidance regarding AE attribution. CONCLUSIONS: Randomized trials of pharmacologic interventions conducted in critically ill populations and published in high impact journals often fail to adequately describe AE definitions, severity, attribution, and collection procedures. Among trials of similar interventions in comparable populations, variation in AE collection and reporting procedures is substantial. These factors may limit a clinician's ability to accurately balance the potential benefits and harms of an intervention.

Relating individual differences in nicotine dependence severity to underpinning motivational and pharmacological processes among smokers from vulnerable populations.

We examined whether elucidating underpinning smoking motivation and related pharmacological processes enhances understanding of nicotine dependence among smokers from vulnerable populations. Data were obtained between Oct, 2016 and Sept, 2019 from 745 adult smokers with co-morbid psychiatric conditions or socioeconomic disadvantage at University of Vermont, Brown University, Johns Hopkins University. Smoking motivation was assessed using the Cigarette Purchase Task (CPT), a behavioral-economic task that models the relative reinforcing value of smoking under varying monetary constraint. Dependence severity was measured using the Heaviness of Smoking Index (HSI), Fagerström Test for Nicotine Dependence total scores (FTND), and FTND total scores minus items 1 and 4 (FTND2,3,5,6). We also assessed associations between dependence severity and smoking motivation with nicotine levels and metabolism rate. Principal Component Analysis was used to examine the latent structure of the conventional five CPT indices; bivariate and multivariable modeling was used to test associations. Factor analysis resulted in a two-factor solution, Amplitude (demand unconstrained by price) and Persistence (price sensitivity). CPT latent factors were associated with each dependence-severity measure (ps ≤ 0.0001), with associations stronger for Amplitude than Persistence across each, especially HSI which was exclusively associated with Amplitude. Amplitude and each dependence measure were associated with nicotine intake (ps ≤ 0.0002); Persistence was not (p = .19). Demand Amplitude more than Persistence appears key to understanding individual differences in dependence severity. Regarding potential application, the results suggest a need for interventions that more effectively target demand Amplitude to make greater headway in reducing smoking in vulnerable populations. Trial Registration:clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

Pharmacological Interactions in the Elderly.

Pharmacological therapy in the elderly is particularly complicated and challenging. Due to coexistence of three main predisposing factors (advanced age, multiple morbidity and polypharmacotherapy), this group of patients is prone to occurrence of drug interactions and adverse effects of incorrect drug combinations. Since many years patient safety during the treatment process has been one of key elements for proper functioning of healthcare systems around the world, thus different preventive measures have been undertaken in order to counteract factors adversely affecting the therapeutic effect. One of the avoidable medical errors is pharmacological interactions. According to estimates, one in six elderly patients may be at risk of a significant drug interaction. Hence the knowledge about mechanisms and causes of drug interactions in the elderly, as well as consequences of their occurrence are crucial for planning the process of pharmacotherapy. For the purpose of pharmacovigilance, a review of available methods and tools gives an insight into possible ways of preventing drug interactions. Additionally, recognizing the actual scale of this phenomenon in geriatric population around the world emphasizes the importance of a joint effort among medical community to improve quality of pharmacotherapy.

Pharmacological Treatment of Alzheimer's Disease: Insights from Drosophila melanogaster.

Aging is an ineluctable law of life. During the process of aging, the occurrence of neurodegenerative disorders is prevalent in the elderly population and the predominant type of dementia is Alzheimer's disease (AD). The clinical symptoms of AD include progressive memory loss and impairment of cognitive functions that interfere with daily life activities. The predominant neuropathological features in AD are extracellular ß-amyloid (Aß) plaque deposition and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Because of its complex pathobiology, some tangible treatment can only ameliorate the symptoms, but not prevent the disease altogether. Numerous drugs during pre-clinical or clinical studies have shown no positive effect on the disease outcome. Therefore, understanding the basic pathophysiological mechanism of AD is imperative for the rational design of drugs that can be used to prevent this disease. Drosophila melanogaster has emerged as a highly efficient model system to explore the pathogenesis and treatment of AD. In this review we have summarized recent advancements in the pharmacological research on AD using Drosophila as a model species, discussed feasible treatment strategies and provided further reference for the mechanistic study and treatment of age-related AD.

Pharmacokinetic studies in pregnancy.

The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood. The dose-response relationship is affected by pharmacokinetics, or what the body does to a drug, and pharmacodynamics, or what a drug does to the body. Insights into the potential effects of the changes of pregnancy on one aspect of the dose-response relationship of a drug can be obtained by studying the pharmacokinetics of the drug in the various stages of pregnancy and the postpartum period. There are several available approaches to studying pharmacokinetic changes in pregnancy. Single trough screening studies can provide qualitative estimates of elimination clearance, which with the dosing rate determines the steady-state drug concentration, throughout pregnancy and into the postpartum period. Population pharmacokinetic studies such as two stage pharmacokinetic studies and studies using a nonlinear mixed effects pharmacokinetic modeling approach can characterize pharmacokinetic changes more rigorously.

Novel Pharmacological Targets for Combat PTSD-Metabolism, Inflammation, The Gut Microbiome, and Mitochondrial Dysfunction.

INTRODUCTION: Current pharmacological treatments of post-traumatic stress disorder (PTSD) have limited efficacy. Although the diagnosis is based on psychopathological criteria, it is frequently accompanied by somatic comorbidities and perhaps "accelerated biological aging," suggesting widespread physical concomitants. Such physiological comorbidities may affect core PTSD symptoms but are rarely the focus of therapeutic trials. METHODS: To elucidate the potential involvement of metabolism, inflammation, and mitochondrial function in PTSD, we integrate findings and mechanistic models from the DOD-sponsored "Systems Biology of PTSD Study" with previous data on these topics. RESULTS: Data implicate inter-linked dysregulations in metabolism, inflammation, mitochondrial function, and perhaps the gut microbiome in PTSD. Several inadequately tested targets of pharmacological intervention are proposed, including insulin sensitizers, lipid regulators, anti-inflammatories, and mitochondrial biogenesis modulators. CONCLUSIONS: Systemic pathologies that are intricately involved in brain functioning and behavior may not only contribute to somatic comorbidities in PTSD, but may represent novel targets for treating core psychiatric symptoms.

Fine Tuning of Intracellular Ca2+ Content by Pharmacological Agents - A Strategy to Prevent Synapse Loss in Alzheimer Disease Hippocampal Neurons.

Alzheimer disease is the dominant form of elderly dementia. Today all clinical trials that target ß-amyloid have failed to indicate that ß-amyloid may not be a causative agent in AD pathogenesis. Thus there is a need to search for alternative ways to treat AD patients. Neuronal store-operated calcium entry is a fine-tuning mechanism that regulates intracellular Ca2+ content. Recent evidence suggests that store-operated calcium channels may be targeted with pharmacological agents in order to prevent synapse loss, recover long-term potentiation and change behavior. Current mini-review discusses basic chemical structures that modulate intracellular calcium dysbalance via targeting store-operated calcium channels and their applicability as anti-AD pharmacological agents.

The Kinetic Component in Drug Discovery: Using the Most Basic Pharmacological Concepts to Advance in Selecting Drugs to Combat CNS Diseases.

To reach the central nervous system (CNS), drugs must cross the brain-blood barrier and have appropriate pharmacokinetic/dynamic properties. However, in early drug discovery steps, the selection of lead compounds, for example, those targeting G-protein-coupled receptors (GPCRs), is made according to i) affinity, which is calculated in in vitro equilibrium conditions, and ii) potency, a signal transduction-related parameter, usually quantified at a fixed time-point in a heterologous expression system. This paper argues that kinetics must be considered in the early steps of lead compound selection. While affinity calculation requires the establishment of a ligand-receptor equilibrium, the signal transduction starts as soon as the receptor senses the agonist. Taking cAMP production as an example, the in vitro-measured cytoplasmic levels of this cyclic nucleotide do not depend on equilibrium dissociation constant, KD. Signaling occurs far from the equilibrium and correlates more with the binding rate (kon) than with KD. Furthermore, residence time, a parameter to consider in lead optimization, may significantly vary from in vitro to in vivo conditions. The results are discussed from the perspective of dopaminergic neurotransmission and dopaminereceptor- based drug discovery.

Mitochondrial pharmacology: featured mechanisms and approaches for therapy translation.

LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.