Field Of Clinical Pharmacology Research Articles

S20-03 Maternal-fetal physiologically-based (pharmaco)kinetic (PBK) modeling in the field of clinical pharmacology: insights and future directions

S20-03 Maternal-fetal physiologically-based (pharmaco)kinetic (PBK) modeling in the field of clinical pharmacology: insights and future directions

Визуализация графовой модели медицинских препаратов и их классов с учетом несовместимости

Currently, the world is actively undergoing digital transformation, which is associated with the introduction of digital technologies in various fields. Methods for predicting and combating various types of diseases are being developed more and more actively. A separate place in this issue is given to pharmacology and reducing the risks of poly-pharmacotherapy. Works in this area have become more and more active in the last three years, and relate primarily to the problems of experimental medicine - the search for new drugs or classification of patients by images. In this connection, the development of algorithms for processing big data in the field of clinical pharmacology, including regulatory documents, instructions for the use of drugs, reliable medical resources for machine learning and building a knowledge base focused on practical application in real medical practice, is becoming increasingly important. One of the considered approaches for solving the problems described above is the search for an effective vector representation of the found concepts (word embedding) to build models of recommendations for the practical use of drugs based on the diagnosis and models for identifying their compatibility. The article presents a software tool for visualizing a graph model of medicines and their classes, considering their incompatibility. The problem of incompatibility of medicines is being investigated. The considered database of medicines, obtained from various sources, and the advantages of its use are described. The article presents the results of the developed prototype of a software tool that allows you to visualize a complete graph of relationships between drugs, a graph of incompatible drugs for a selected drug, and a graph of compatibility of two drugs. Graph model visualization provides a visual representation of complex relationships and allows researchers and pharmacologists to better understand interactions between drugs. The software offer the necessary tools to make informed decisions when prescribing medications and improve safety when using medicines.

The potential and pitfalls of artificial intelligence in clinical pharmacology.

Artificial intelligence (AI) involves using data and algorithms to perform activities normally achieved through human intelligence. AI and its key component machine learning contextualize data and enhance decision making to transform how we operate, discover, and develop drugs. Transforming clinical pharmacology (CP) as AI-augmented CP (AI/CP) requires an ecosystem including digitized data collection, standardized processes, complementary technologies, and an ethical framework. This commentary aims to highlight the future perspectives of AI/CP in drug development.

Knowledge Mining of Interactions between Drugs from the Extensive Literature with a Novel Graph-Convolutional-Network-Based Method

Interactions between drugs can occur when two or more drugs are used for the same patient. This may result in changes in the drug’s pharmacological activity, some of which are beneficial and some of which are harmful. Thus, identifying possible drug–drug interactions (DDIs) has always been a crucial research topic in the field of clinical pharmacology. As clinical trials are time-consuming and expensive, current approaches for predicting DDIs are mainly based on knowledge mining from the literature using computational methods. However, since the literature contain a large amount of unrelated information, the task of identifying drug interactions with high confidence has become challenging. Thus, here, we present a novel graph-convolutional-network-based method called DDINN to detect potential DDIs. Combining cBiLSTM, graph convolutional networks and weight-rebalanced dependency matrix, DDINN is able to extract both contexture and syntactic information efficiently from the extensive biomedical literature. At last, we compare our DDINN with some other state-of-the-art models, and it is proved that our work is more effective. In addition, the ablation experiments demonstrate the advantages of DDINN’s optimization techniques as well.

Variable or variate? A conundrum in pharmacometrics exposure-response models.

Key elements of scientific writing-consistency and clarity-can be compromised in case of inaccurate use of methodological terms, especially in complex and multidisciplinary scientific fields. Such is the case in reports of pharmacometrics exposure-response analyses with the use of the terms univariate/multivariate and univariable/multivariable. This perspective outlines the issues in the use of these terms, clarifies their definitions, provides examples, and makes recommendations for authors, reviewers, and journals in the fields of clinical pharmacology and pharmacometrics.

‘When creativity gets you fired—why professionals tasked with innovation employ subversion when facing competing institutional demands in hybrid organizations’

Abstract How can professionals tasked with innovation navigate institutional complexity in hybrid organizations without contesting the various institutionalized expectations about what constitutes appropriate and beneficial new ideas? This article investigates this question through an ethnographic study of pharmaceutical professionals tasked with research and development at an internationally operating life science company producing pharmaceutical innovations. There, pharmaceutical professionals must address and satisfy three institutional demands to project legitimacy of their new ideas: (1) scientific validity expected by leading members of their profession; (2) commercial value demanded by management; and (3) legal responsibility enforced by state agencies. Facing the challenge of creating legitimate novelty opposite these competing institutional demands, the pharmaceutical professionals initially design new ideas to primarily meet the jurisdictional control exerted by key opinion leaders in the field of clinical pharmacology. Yet, the resultant scientifically tailored designs regularly conflict with the institutional demands enforced by other powerful institutional referents within their organization. To resolve this issue, the professionals utilize a strategy of subversion to undermine the power and authority of these powerful referents by employing tactics of withdraw, manipulation, collusion, and ambushing. Based on these findings, the present study contributes to institutional theory and to literature on creativity and innovation management by theorizing subversive ingenuity as a distinct strategy professionals employ to navigate competing institutional demands during innovation processes in hybrid organizations.

A new curriculum to strengthen pharmacology and clinical pharmacology training in fundamental nursing education

Among medical care incidents in Japan, an increase in medicine-related errors by nurses have been reported. These errors may be caused by a lack of knowledge of clinical pharmacology and drug interactions. It is important for nurses to acquire risk-management skills based on clinical pharmacology. In order to improve fundamental knowledge in pharmacology and clinical pharmacology for nurses, various training programs exist. We reviewed a number of educational programs in medicine and report our results. Based on our results, it is necessary for medical education programs to include the following 5 essential elements: 1) An analysis of frequently-occurring medication errors in the field of clinical pharmacology, 2) drugs administer for patient characteristic and patient observation practices, 3) an emphasis on the interactions between drugs and food or other drugs, 4) assessment of patient symptoms, risk-management, and the efficacy of drugs, 5) the necessity of using the package inserts. In a new curriculum, it is necessary to have systematic, step by step training in pharmacology and clinical pharmacology. It is also necessary to develop these teaching methods in cooperation with specialists and experts in the field.

Обзор материалов экспертного совета «Дифференциальная диагностика диарейного синдрома в зависимости от его патогенеза в практике врача-педиатра, роль пробиотических лекарственных средств в его лечении»

On November 10, 2021, an online meeting of the expert council was held on the conference platform of the First Medical Channel. The subject was “Diarrhea differential diagnosis depending on its pathogenesis in pediatric practice, the role of probiotic medications in its treatment”. Leading Russian experts in the field of clinical pharmacology, gastroenterology, pediatrics, infectious diseases, and allergology-immunology took part in this meeting. As a result of the meeting, the main principles of diagnosis, treatment, and prevention of diarrhea in children were formulated, and an algorithm for using probiotics to treat diarrhea in children was developed. Conclusion. It is preferable to prescribe medicinal probiotics (with registration status) than a dietary supplement containing probiotic bacteria. Medicinal products containing a combination of strains of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12, vitamins B1 and B6, which are approved for use in pediatric practice, are recommended for administration in diarrhea and in suspected antibiotic-associated diarrhea in children, regardless of etiology and pathogenesis, both during the acute period and the next 4 weeks as well as during the entire recovery period (the period of repair and convalescence). Key words: antibiotics, children, diarrhea, treatment, prophylaxis, strain-specific probiotics, Lactobacillus rhamnosus GG, Bifidobacterium animalis subsp. lactis BB-12

OBITUARY FOR YURI N. CHERNOV 5 Nov 1937 – 1 Jan 2021

On January 1, 2021, Yuri N.Chernov, Doctor of Sciences (Mediсine), Professor, Honored Doctor of the Russian Federation, Academician of the International Human Academy in Aerospace Systems, Corresponding Member of the Russian Academy of Natural Sciences, passed away. Yuri N.Chernov was Honorary Doctor of the State Research and TestInstitute of Military Medicine ofRF Ministry of Defense,a specialist in the field of clinical pharmacology and aerospace radiobiology, Honorary Professor of Voronezh State Medical University n. a. N.N. Burdenko.

Professor Mats Karlsson is the BCPT Nordic Prize winner in Basic & Clinical Pharmacology & Toxicology for 2019

Professor Mats Karlsson is a world-renowned scientist in the field of clinical pharmacology and pharmaco-metrics, and he has made extraordinary contributions with a strong commitment to develop the field. In the following, some of his contributions will be highlighted: Mats Karlsson was born in Sweden in 1959. He graduated as a pharmacist from Uppsala University and earned his PhD in pharmacokinetics in 1989 from Uppsala University with the thesis: “Novel methods for estimation of ligand binding kinetics and drug absorption”. Subsequently, he had several post-doc positions, the last of which took place at the University of California San Francisco from 1992 to 1994. This resulted in a long-lasting collaboration with professor S.L. Beal and professor L.B. Sheiner and in several key publications. In 1994, he started the Pharmacometrics Research Group (PMG) at Uppsala University, and he was appointed the first (worldwide) professorship in Pharmacometrics in 2001. The PMG has now grown to the largest academic research group in this area, globally comprising approximately 45 members (7 faculty, 2 system developers, 7 post-docs, >20 PhD students, visiting scientists and several part-time employees). By providing an impressively generous, open and dynamic atmosphere in this cross­disciplinary area, researchers with different backgrounds have been attracted both with respect to competence (pharmacy, medicine, engineering, statistics and computational sciences) as well as origin (past and present researchers represent >20 nations from all parts of the world). While developing his own research, he has allowed younger researchers to grow and become independent scientists in their own right, and so far, two of his PhD students have become full professors and two have become associate professors. Mats Karlsson has outstanding achievements in the education of pharmacometricians. He has enthusiastically supervised 27 students to PhD degree as main supervisor and 29 students as co-supervisor. In addition, he has mentored more than 40 post-docs. The students and post-docs are now in positions at academic institutions, the pharmaceutical industry, contract research organisations and at drug regulatory authorities worldwide. He has developed several courses for PhD students and professionals, including the popular courses on covariate model building and PKPD modelling in NONMEM. He has also established the annual Uppsala Pharmacometric Summer School (UPSS), a free two-week summer course attracting PhD students from around the world. Mats Karlsson has successfully kept a uniquely broad research profile in both development of methodology for analysis of clinical data using non-linear mixed-effects modelling and applied modelling in several therapeutic areas. He has published in more than 300 peer-reviewed research articles, has an h-index of 48 and the top three publications are cited more than 300 times. Methodology improvements include new methods for covariate model building in non-linear mixed-effects modelling, efficient clinical trial design and model diagnostics. The developed methodology is widely available via free and open-source software. He has developed several platform models, now commonly used in drug development of drugs in diabetes, oncology, TB and inflammatory disease (e.g. RA and MS). He has also developed approaches for analysis of categorical type data, enabling efficient analysis of adverse event records. Mats Karlsson is partner of several European research consortia (PreDiCT-TB, Orbito, IDEAL and U-PGx) and was the academic principle investigator of the European research consortium DDMoRe, within which modelling standards, a modelling environment and a library of drug/disease models for the pharmacometrics community were developed. He is also on several editorial boards of scientific journals including being the European Editor of Journal of Pharmacokinetics and Pharmacodynamics.

Applications of Raman Spectroscopy on Quality Control of Hospital Formulations

Hospital formulation has several advantages, including the flexibility of customization as per the disease state or the patients' precise requirements. However, compared with commercial formulations, hospital formulations are usually not under the same level of quality check. In the present study, we tested mixed powder formulations prepared in a hospital pharmacy using Raman spectroscopy to investigate the feasibility of applying Raman spectroscopy as a quality-control tool of hospital formulations. For this purpose, we first established a numerical evaluation method to determine the uniformity of a powder mixture using Raman chemical imaging data with atropine sulfate/lactose mixture samples and revealed that the mixing uniformity correlated to the experience level of the pharmacist. Next, we developed a content quantification method in a one-dose packaged powder formulation by measuring the Raman spectra from the outside of the package. Because this method allows for quantification of the components inside the package in a non-destructive and non-contact manner, it can be applied for content confirmation after one-dose packaging. Using this method, the content uniformity of the mixed powder formulation in the one-dose package was compared between the formulations prepared by the pharmacists and those prepared by a pharmacy robot. Our study indicates the possibility of applying Raman spectroscopy as a quality-control tool of hospital formulations. Studies on further applications of Raman spectroscopy in the field of clinical pharmacology are expected.

Antifungal therapy: drug-drug interactions at your fingertips.

The Information Age has revolutionized the ability of healthcare professionals (HCPs) to oversee a substantial body of clinically relevant information literally at one's fingertips. In the field of clinical pharmacology, this may be particularly useful for managing drug-drug interactions (DDIs). A thorough understanding of the underlying mechanisms of DDIs allows the HCP to predict such interactions and avoid those of greatest clinical significance. Specifically, successful treatment with antifungal agents is complicated by the high potential to interact with other concomitant medications. We describe here the development of a real-time knowledge base of DDIs with antifungal agents, providing expert recommendations to HCPs on how to handle DDIs with these drugs. This new resource will facilitate rapid identification, quantification and classification of these DDIs by clinicians with varying levels of experience and resources worldwide, ultimately improving patient safety and strengthening health systems.

Pharmacology Portal: An Open Database for Clinical Pharmacologic Laboratory Services

PurposeMore than 50 Norwegian public and private laboratories provide one or more analyses for therapeutic drug monitoring or testing for drugs of abuse. Practices differ among laboratories, and analytical repertoires can change rapidly as new substances become available for analysis. MethodsThe Pharmacology Portal was developed to provide an overview of these activities and to standardize the practices and terminology among laboratories. The Pharmacology Portal is a modern dynamic web database comprising all available analyses within therapeutic drug monitoring and testing for drugs of abuse in Norway. Content can be retrieved by using the search engine or by scrolling through substance lists. The core content is a substance registry updated by a national editorial board of experts within the field of clinical pharmacology. This ensures quality and consistency regarding substance terminologies and classification. FindingsAll laboratories publish their own repertoires in a user-friendly workflow, adding laboratory-specific details to the core information in the substance registry. The user management system ensures that laboratories are restricted from editing content in the database core or in repertoires within other laboratory subpages. The portal is for nonprofit use, and has been fully funded by the Norwegian Medical Association, the Norwegian Society of Clinical Pharmacology, and the 8 largest pharmacologic institutions in Norway. ImplicationsThe database server runs an open-source content management system that ensures flexibility with respect to further development projects, including the potential expansion of the Pharmacology Portal to other countries.

Exodus of clinical pharmacologists and pharmacometricians from academia--Who is to blame? A policy statement from the American College of Clinical Pharmacology.

Academic institutes are breeding grounds of innovation and the cradle of future clinical pharmacologists and pharmacometricians. However, there is a crisis looming over academic institutions; funding for research in clinical pharmacology is at an all-time low. This crisis of academic funding is no longer a well-kept secret. This crisis is at a national level and has far-reaching consequences. Federal funding for biomedical research in the United States doubled between 1998 and 2003 and fueled academic research nationally.This funding was considered key to maintaining the edge of the United States in the pharmaceutical and biotechnology industries. However, federal funding for biomedical research has been in decline since that time. Federal funding for biomedical research is estimated to be at least 25% less in inflationadjusted dollars than it was in 2003, whereas demand for research dollars has skyrocketed. The increased demand for research money in the face of dwindling federal support may be attributed to several factors. Universities were able to expand their facilities and hire more faculty during the years of surplus funding and now must maintain those facilities and retain key faculty in the face of ever-shrinking federal dollars. Adding to the problem, public universities face decreased funding at the state level, as state governments attempt to balance their budgets. Other sources of funding, such as the pharmaceutical industry, have also dried up, as the industry itself comes under pressure to control costs and faces close scrutiny of its funding of academic research. Finally, the rising cost of conducting biomedical research (both as actual costs and the ever-increasing regulatory burden to conduct those studies) contributes to the problem, as even phase 1 clinical studies may now cost upwards of $4 million. As dire as things are for the biomedical research community as a whole, the situation is even worse when it comes to attracting major federal funding for research in the field of clinical pharmacology and pharmacometrics. The key characteristic of being a universally applicable field of research has a considerable downside; clinical pharmacology is a field without the face of a disease that the public cares about. There is no 5K race for “getting the dose right,” in contrast to diseases like breast cancer, diabetes, and AIDS. The public in general does not know what clinical pharmacology is and does not understand its role in the development of new medicines for the diseases that affect loved ones in their families and communities. This is even reflected in federal funding, where the National Institutes of Health (NIH) has traditionally funded basic research while being slow in funding clinical pharmacology–based research. The funding crisis may affect what kind of research is performed in academic institutions, as “fundability” takes precedence over good science. More time is now spent by researchers worrying about how to bring in funds rather than generating truly innovative ideas. The time that used to be spent brainstorming on the whiteboard that fueled and inspired great innovations and mentored and shaped future leaders in the field of clinical pharmacology and pharmacometrics is now spent on decorating, refining, and rewriting research proposals to make them “fundable.” As academic researchers compete for the same small share of grant money, they are realizing that they often need to abandon ambitious innovative ideas for The Journal of Clinical Pharmacology 2015, 55(9) 955–956 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.542

Establishing a clinical pharmacology fellowship program for physicians, pharmacists, and pharmacologists: a newly accredited interdisciplinary training program at the Ohio State University.

Studying the effect of drugs on humans, clinical pharmacologists play an essential role in many academic medical and research teams, within the pharmaceutical industry and as members of government regulatory entities. Clinical pharmacology fellowship training programs should be multidisciplinary and adaptable, and should combine didactics, applied learning, independent study, and one-on-one instruction. This article describes a recently developed 2 year clinical pharmacology fellowship program – one of only nine accredited by the American Board of Clinical Pharmacology – that is an integrative, multi faceted, adaptable method for training physicians, pharmacists, and scientists for leadership roles in the pharmaceutical industry, in academia, or with regulatory or accreditation agencies. The purpose of this article is to provide information for academic clinicians and researchers interested in designing a similar program, for professionals in the field of clinical pharmacology who are already affiliated with a fellowship program and may benefit from supplemental information, and for clinical researchers interested in clinical pharmacology who may not be aware that such training opportunities exist. This article provides the details of a recently accredited program, including design, implementation, accreditation, trainee success, and future directions.

Efforts and success world-wide in the field of clinical pharmacology

In this personal review I describe my early expectations and experiences when I first came to work with Prof. Folke Sjöqvist as a training fellow in the early 1970s. At that time Prof. Sjöqvist and his unit had already earned an international reputation, and in the following decades this success has been magnified many times. Although a description of the research performed by Prof. Sjöqvist during his long career is not the main objective of this article, it is clear that the research carried out in his unit has been instrumental in the development of his international reputation. Over an 18-year period from 1994 onwards, some 272 papers bearing the name of Folke Sjöqvist have been cited over 13,000 times, with an average of over 50 citations per paper. In terms of training clinical pharmacologists from around the world, at the last count 112 individuals from 37 different countries have received a substantial part of their training in his unit. As another measure of his world-wide success, 33 individuals from 18 different countries who received a substantial part of their training in his unit between 1968 and 1996 have gone on to become professors of clinical pharmacology. Prof. Sjöqvist has been requested to consult on various aspects of clinical pharmacology in 15 different countries, from Russia to Spain and from Egypt to Latvia. Here I describe the long-term involvement that Prof. Sjöqvist has had with IUPHAR (now the International Union of Basic and Clinical Pharmacology) and with institutions such as the World Health Organisation (WHO). In particular, I recount his role in the long-term saga involved in updating the original WHO manifesto on clinical pharmacology published in 1970 up to the eventual success of the new manifesto published by WHO in 2012. Finally, I briefly describe the international honours that have been bestowed on Prof. Sjöqvist, including various prizes, designated lectureships and honorary Doctorates (5). Taken together, these honours provide a magnificent measure of Prof. Sjöqvist's world wide-success-a success that has been emulated by very few clinical pharmacologists.

Characteristics and apprehensions of clinical pharmacologists in Swedish healthcare—a questionnaire study

To describe the discipline clinical pharmacology of today in the Swedish healthcare system from the performers' point of view. A questionnaire was administered in December 2012 to physicians working within the specialty clinical pharmacology in the Swedish healthcare system (7 sites; 1-26 physicians per site). The questionnaire included questions pertaining to the characteristics of the responder and statements to which the responder indicated his/her level of agreement using a score ranging from 1 (total disagreement) to 5 (total agreement). A total of 61 completed questionnaires were returned (response rate: 97 %; 55 % male; 74 % specialists and/or consultants). In the preceding month, 79 % of the responders had performed educational activities, 74 % had functioned as an "expert", and 75 % had performed research. The academic merits of the responders were high, with 72 % having at least a PhD degree and 23 % being professors. Among those performing research, the focus of 83 % was related to the field of clinical pharmacology, with the main sub-areas being pharmacoepidemiology (59 %) and/or pharmacogenetics (41 %). Regarding the apprehension questions, the responders strongly agreed that the specialty clinical pharmacology meets a need in the healthcare system (4.5 ± 0.7), that they wanted to continue to work within the specialty (4.5 ± 0.7), that their personal professional prospects were good (3.9 ± 1.0), and that they would recommend a colleague to specialize within the field (3.9 ± 1.1). The responders from the largest and first established site (Karolinska University Hospital) agreed with these points to a significantly greater extent than responders from other sites. The majority of the performers of clinical pharmacology in Swedish healthcare consider this specialty to be important to the medical community. By carrying out educational activities, providing expertise, and performing research, the performers seem to be content with their work and future prospects. Performers within the largest and oldest site in Sweden, generally held the most positive view of the specialty.

A review of drug isomerism and its significance

Isomerism finds its importance in the field of clinical pharmacology and pharmacotherapeutics, as isomers differ in their pharmacokinetic and pharmacodyanmic properties. Drug isomerism has opened a new era of drug development. Currently, knowledge of isomerism has helped us in introducing safer and more effective drug alternatives of the newer as well as existing drugs. Many existing drugs have gone chiral switch i.e., switching from racemic mixture to one of its isomers. Cetrizine to levocetrizine is one of such examples, where effective and safer drug has been made available. In this article, we have attempted to review the basic concepts of stereochemistry and chirality and their significance in pharmacotherapeutics. Various pharmacological aspects such as pharmacokinetic and pharmacodynamic variations resulting out of chirality has been discussed in detail in this article.

What is a biomarker? It’s time for a renewed definition

following definition of biomarker (or simply marker) might be provisionally used: “human or animal biological property whose in vitro measurement or identification is useful for the prevention, diagnosis, prognosis, treatment, and follow-up of human or animal diseases, and for their understanding”. As a final clarification, it should be kept in mind that in the field of clinical pharmacology (clinical trials) the concept of “biomarker” has a wider meaning than in clinical laboratory sciences: some biomarkers are in vitro measured or identified and others in vivo. In the field of clinical laboratory sciences, as reflected in the proposed definition, the concept of “biomarker” is always related to in vitro measurements or identifications.

Development and Validation of Extraction Method for the Determination of UC781 in Cervicovaginal Fluid

Liquid chromatography plays the important and critical role in the field of clinical pharmacology of evaluating drugs in biological matrices. Studying antiretroviral drugs in the female genital tract has important implications for using drugs as a vaginal microbicide for prevention of HIV-1 sexual transmission. Accurate measurement of drug levels is extremely important in optimizing drug concentration in gel formulation. Extracting drugs from small volumes of viscous, proteinaceous substances like cervicovaginal fluid (CVF) is a practically challenging process. The proposed method was designed to introduce procedure for sample collection and drug extraction procedure for CVF matrix before the chromatographic separation. Based on this extraction method, we validated a reverse phase high performance liquid chromatography with electrospray ionization mass spectrometry assay in order to quantify UC781 in female genital tract compartment. The LC-MS method was validated based on a novel extraction technique which proved to be efficient in reducing analyte degradation with an average extraction efficiency of 72%. This method is accurate, demonstrating an average accuracy over three QC (n = 30) concentrations ranging from 99.9% to 106.1%. Average precision within-day and between-day ranged from 3.1% to 10.2% and 5.1% to 6.4%, respectively. We demonstrated that the analyte was able to maintain its stability under various conditions using this extraction method. The sample preparation, extraction, and the powerful liquid chromatography and mass spectrometry can readily be applied for accurate quantification of similar drugs in CVF.