Ayurveda and in silico Approach: A Challenging Proficient Confluence for Better Development of Effective Traditional Medicine Spotlighting Network Pharmacology / 中国结合医学杂志

Coalescence of traditional medicine Ayurveda and in silico technology is a rigor for supplementary development of future-ready effective traditional medicine. Ayurveda is a popular traditional medicine in South Asia, emanating worldwide for the treatment of metabolic disorders and chronic illness. Techniques of in silico biology are not much explored for the investigation of a variety of bioactive phytochemicals of Ayurvedic herbs. Drug repurposing, reverse pharmacology, and polypharmacology in Ayurveda are areas in silico explorations that are needed to understand the rich repertoire of herbs, minerals, herbo-minerals, and assorted Ayurvedic formulations. This review emphasizes exploring the concept of Ayurveda with in silico approaches and the need for Ayurinformatics studies. It also provides an overview of in silico studies done on phytoconstituents of some important Ayurvedic plants, the utility of in silico studies in Ayurvedic phytoconstituents/formulations, limitations/challenges, and prospects of in silico studies in Ayurveda. This article discusses the convergence of in silico work, especially in the least explored field of Ayurveda. The focused coalesce of these two domains could present a predictive combinatorial platform to enhance translational research magnitude. In nutshell, it could provide new insight into an Ayurvedic drug discovery involving an in silico approach that could not only alleviate the process of traditional medicine research but also enhance its effectiveness in addressing health care.

Strategy and challenge of innovative drug research and development from clinically effective ingredients of traditional Chinese medicine / 中国中药杂志

Novel drug discovery from the active ingredients of traditional Chinese medicine is the most distinctive feature and advantageous field of China, which has provided an unprecedented opportunity. However, there are still problems such as unclear functional substance basis, action targets and mechanism, which greatly hinder the clinical transformation of active ingredients in traditional Chinese medicine. Based on the analysis of the current status and progress of innovative drug research and development in China, this paper aimed to explore the prospect and difficulties of the development of natural active ingredients from traditional Chinese medicine, and to explore the efficient discovery of trace active ingredients in traditional Chinese medicine, and obtain drug candidates with novel chemical structure, unique target/mechanism and independent intellectual property rights, in order to provide a new strategy and a new model for the development of natural medicine with Chinese characteristics.

Innovation in Pharmaceutical Assistance

Abstract Innovation is the driving force that is able to create and transform products, processes, and organization in the health system. Innovation in the field of pharmaceutical assistance covers a wide spectrum of aspects, from drug discovery to pharmaceutical care, contributing to the improvement in treatments through novel drugs or methods. This work will present the major characteristics of innovation with special emphasis on aspects pertaining to pharmaceutical assistance. The types and models of innovation, as well as the interaction between academia and industry, will be presented with examples of successful products and methods. In addition, the challenges and perspectives for innovation in pharmaceutical assistance will be discussed with a focus on drug discovery.

Otimização de novos candidatos a fármacos para leishmaniose visceral canina / Optimization of new drug candidates for canine visceral leishmaniasis

A leishmaniose visceral canina se trata de enfermidade infecciosa, zoonótica, de caráter insidioso e multissistêmica. Fatores como a ineficácia dos métodos de controle aplicados sobre os reservatórios caninos (incluindo eutanásia) e a toxicidade dos fármacos atualmente disponíveis para o tratamento humano, justificam urgência na busca de novos candidatos a fármacos. O presente estudo teve por objetivo avaliar o potencial anti-Leishmania de 25 compostos sintéticos derivados do gibilimbol. Destes, quatro apresentaram atividade em amastigotas sem citotoxicidade a células de mamíferos, com o CE50 em amastigotas variando entre 5,1 e 13,5 µM, e dois (LPM-21 e LPM-22) foram submetidos à predição drug-likeness in silico e ensaios de mecanismo de ação em promastigotas de Leishmania (L.) infantum. Ambos demonstraram alta absorção gastrointestinal, permeabilidade à barreira hematoencefálica, solubilidade moderada e alta (respectivamente), ausência de moléculas de interferência, e perfil drug-likeness favorável para futuros candidatos a fármacos. Nos ensaios de mecanismo de ação, LPM-21 induziu tardiamente a permeabilização plasmática parasitária (220 minutos), além de ter ocasionado a despolarização da membrana mitocondrial, redução nos níveis de ROS, alcalinização dos acidocalcissomos e importante elevação do Ca2+ intracelular, fatos que sugerem um mecanismo de ação tendo como principal alvo de atuação os acidocalcissomos, resultando no extravasamento do Ca2+ e subsequente despolarização da membrana mitocondrial. O composto LPM-22 não alterou a permeabilidade da membrana plasmática, não atuou sobre o potencial de membrana mitocondrial, induziu a acidificação dos acidocalcissomos, elevação do Ca2+ e redução nos níveis de ROS, podendo sugerir danos à membrana mitocondrial e consequente elevação deste íon. A espectrometria de massas por MALDI-TOF revelou aumento na intensidade dos picos em promastigotas incubadas com LPM-21 e LPM-22. Logo, este trabalho concretiza o potencial anti-Leishmania dos derivados sintéticos do gibilimbol, em especial os compostos LPM-21 e LPM-22, os colocando como futuros candidatos para estudos in vivo. (AU)

Canine visceral leishmaniasis is an infectious, zoonotic, insidious and multisystemic disease. Factors such as the ineffectiveness of the control methods applied to canine reservoirs (including euthanasia) and the toxicity of the drugs currently available for human treatment, brings the urgency in search for new drug candidates. The present study aimed to evaluate the anti-Leishmania potential of 25 synthetic compounds derived from gibilimbol, a phenolic isolate extracted from the leaves of Piper malacophyllum. Four compounds showed activity in amastigotes without cytotoxicity to mammalian cells, with EC50 in amastigotes ranging between 5.1 and 13.5 µM, and two (LPM-21 and LPM-22) were submitted to the in silico drug-likeness prediction, and mechanism of action assays in Leishmania (L.) infantum promastigotes. Both demonstrated high gastrointestinal absorption, permeability to the blood-brain barrier, moderate and high solubility (respectively), and favorable drug-likeness profile for future drug candidates, without revealing PAINS molecules. In the mechanism of action assays, LPM-21 induced parasitic plasmatic permeabilization only at later times (220 minutes), in addition to depolarization of the mitochondrial membrane, reduction in ROS levels, acidocalcisomes alkalinization and significant increase in intracellular Ca2+, suggesting a mechanism of action targetting acidocalcisomes, resulting in extravasation of Ca2+ and subsequent depolarization of the mitochondrial membrane. In contrast, LPM-22 did not alter the permeability of the plasma membrane and the mitochondrial membrane potential, resulting in acidification of acidocalcisomes, elevation of Ca2+ and reduction in ROS levels, which may suggest damage to the mitochondrial membrane and consequent calcium elevation. Mass spectrometry by MALDI-TOF revealed an increase in peak intensity in promastigotes incubated with LPM-21 and LPM-22. Finally, this work realizes the anti-Leishmania potential of synthetic gibilimbol derivatives, especially the compounds LPM-21 and LPM-22, placing them as future candidates for in vivo studies. (AU)

A novel cell tool for α2δ-1-NMDAR target-based analgesic drug discovery / 生物工程学报

The α2δ-1 protein coded by Cacna2d1 is dramatically up-regulated in dorsal root ganglion (DRG) neurons and spinal dorsal horn following sensory nerve injury in various animal models of neuropathic pain. Cacna2d1 overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity. The α2δ-1-NMDAR interaction promotes surface trafficking and synaptic targeting of NMDARs in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury, as well as in other pathological conditions such as in the paraventricular nucleus (PVN) with neurogenic hypertension and in the brain with ischemic stroke. The lentiviral transfection method was used to construct a human embryonic kidney HEK293T cell line that could stably express α2δ-1-NMDAR complex. A stably transfected cell line was observed by florescence microscope, and identified by RT-qPCR and Western blotting. The results showed that the HEK293T cell line was successfully transfected and the genes could be stably expressed. Subsequently, the transfected cell line was successfully developed into a target drug screening system using patch clamp techniques. It provides a promising cell model for further research on the interaction mechanism of α2δ-1-NMDAR complex and drug screening for chronic pain and related diseases with low side effects.

Desarrollo y validación de técnicas analíticas para la determinación de biomarcadores sanguíneos en ensayos preclínicos. ¿Por qué y para qué? / Development and validation of analytical techniques for the determination of blood biomarkers in preclinical trials. Why and what for?

Resumen El descubrimiento de un nuevo principio activo farmacéutico implica estudios preclínicos, que tienen como objetivo demostrar que es eficaz y seguro para un posterior ensayo en seres humanos. Esto conduce a la necesidad de desarrollar tecnologías que aprovechen las nuevas herramientas analíticas disponi bles dentro de un contexto donde los resultados de las pruebas realizadas, estén plenamente documentados, bajo sistemas de buenas prácticas de laboratorio auditables. En esta revisión se actualizan y describen algunos de los ensayos realizados en la etapa preclínica del desarrollo de un nuevo fármaco y el estado actual de la tecnología analítica empleada para el dosaje de diferentes biomarcadores sanguíneos de interés. Se analizaron los biomarcadores más relevantes, las normativas de validación de las técnicas analíticas empleadas para su determinación y los problemas que se presentan al tratar de aplicarlas.

Abstract New drug discovery involves preclinical studies to demonstrate its effectivity and safety for further tests in humans. This leads to the need to develop technologies that take advantage of the new analytical tools available within a context where the results of the tests carried out are fully documented, under auditable systems of good laboratory practice. This review updates and describes some of the tests carried out in the preclinical stage of the development of a new drug and the current state of the analytical technology used to measure different blood biomarkers of interest. Biomarker parameters were analyzed at the physiological level, considering both the validation regulations of the analytical techniques used for their determination as the problems that arise when trying to apply them, since many of these biomarkers are endogenous compounds in the used matrices.

Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.

State-regulating medicine: an integration of traditional Chinese medicine and biomedicine / 中国中药杂志

Currently available drugs for complex diseases have such limitations as unsatisfactory efficacy, drug resistance, and toxic side effects. Complexity of biological systems is a determinant of drug efficacy. It is not an effective approach to find disturbance strategies for the complicated biological network for complex diseases based on the static topological structures, as biological systems undergo dynamic changes all the time. Supported by profound theoretical basis and rich clinical experience, traditional Chinese medicine(TCM) emphasizes systematic and dynamic treatment depending on changes. Guided by TCM theory in practical treatment, Chinese medicine dynamically and comprehensively regulates the overall state. Therefore, if the dynamic factors are taken into consideration in design, the resultant drugs will be more effective. This study proposes state-regulating(SR) medicine from the perspective of system dynamics, elaborating the concept in terms of the connotations and principle and verifying the feasibility of SR medicine design with the attractor method. Thus, SR medicine is a new concept for drug discovery and design from the aspect of system dynamics, which integrates the TCM focusing on holistic dynamic regulation with biomedicine that features local microscopic research such as molecular mechanisms. The attractor method is a feasible techinical way for SR medicine design.

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infection that may break the healthcare system of several countries. Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. Finally, we also discuss patent protection issues, cost effectiveness and scalability of synthetic routes for some of the most studied repurposing candidates since these are key aspects to meet global demand for COVID-19 treatment.

Targeting Cullin-RING E3 ligases for anti-cancer therapy: efforts on drug discovery / 浙江大学学报·医学版

Cullin-RING E3 ligases (CRLs) are the major components of ubiquitin-proteasome system, responsible for ubiquitylation and subsequent degradation of thousands of cellular proteins. CRLs play vital roles in the regulation of multiple cellular processes, including cell cycle, cell apoptosis, DNA replication, signalling transduction among the others, and are frequently dysregulated in many human cancers. The discovery of specific neddylation inhibitors, represented by MLN4924, has validated CRLs as promising targets for anti-cancer therapies with a growing market. Recent studies have focused on the discovery of the CRLs inhibitors by a variety of approaches, including high through-put screen, virtual screen or structure-based drug design. The field is, however, still facing the major challenging, since CRLs are a large multi-unit protein family without typical active pockets to facilitate the drug design, and enzymatic activity is mainly dependent on undruggable protein-protein interactions and dynamic conformation changes. Up to now, most reported CRLs inhibitors are aiming at targeting the F-box family proteins (e.g., SKP2, β-TrCP and FBXW7), the substrate recognition subunit of SCF E3 ligases. Other studies reported few small molecule inhibitors targeting the UBE2M-DCN1 interaction, which specifically inhibits CRL3/CRL1 by blocking the cullin neddylation. On the other hand, several CRL activators have been reported, such as plant auxin and immunomodulatory imide drugs, thalidomide. Finally, proteolysis-targeting chimeras (PROTACs) has emerged as a new technology in the field of drug discovery, specifically targeting the undruggable protein-protein interaction. The technique connects the small molecule that selectively binds to a target protein to a CRL E3 via a chemical linker to trigger the degradation of target protein. The PROTAC has become a hotspot in the field of E3-ligase-based anti-cancer drug discovery.

Terapia antibacteriana: origen y evolución en el tiempo / Antibacterial therapy: origin and evolution in the time

Desde siempre, el ser humano buscó una explicación a los fenómenos y una solución a sus males. El instinto fue quien primero guió al hombre para buscar remedios con los que aliviar sus males lamiendo o limpiando sus heridas. Mediante el método de "ensayo-error", el hombre prehistórico fue encontrando plantas y sustancias minerales que resultaban eficaces. En la Edad Media y el Mundo Moderno, la medicina Hippocrático-galénica tuvo, en relación a la terapéutica, a Dioscórides como el gran referente Con el decurso de los años, científicos como Pasteur, Koch, Cantani, Emmerich, Low, Tiberio, sentaron las bases para que más tarde otros como Freudenreich, Domagk, Fleming, Waksman, entre otros, descubrieran y perfeccionaran la amplia gama de antibióticos que hoy conocemos. A pesar de estos avances, en la actualidad se observan múltiples mecanismos de resistencia bacteriana que ponen en peligro la eficacia antibiótica (AU).

The human beings have always looked for an explanation to the phenomena and a solution to his misfortunes. Firstly the instinct was what guided the man to look for remedies to alleviate his ills licking or cleaning his wounds. By means of the "trial-error" method, the prehistoric man was finding plants and mineral substances that were effective. In the Middle Ages and the Modern World, the Hippocratic-galenic medicine took Dioscorides as the great referent in relation to therapeutic. As the years went by, scientist like Pasteur, Koch, Cantani, Emmerich, Low, Tiberio, set the bases for Freudenreich, Domagk, Fleming, Waksman among others to discover and improve the wide range antibiotics known today. In spite of these advances, multiple mechanisms of bacterial resistance putting in danger antibiotic effectiveness are observed today (AU).

The Role of medical doctor in the era of artificial intelligence

Recent advances in new technologies such as artificial intelligence, big data, and virtual reality have led to significant innovations in various industries. Artificial intelligence, particularly in applications using deep learning algorithms, has shown performance superior to that of humans in several contexts. Accordingly, many researchers and companies have tried to apply artificial intelligence to the healthcare system, with applications including image interpretation, voice recognition, clinical decision support, risk prediction, drug discovery, medical robotics, and workflow improvement. However, several important technical, ethical, and social barriers must be overcome, such as overfitting, lack of interpretability, privacy, security, and safety. Doctors should be prepared to play a key role in applying artificial intelligence through the full course of development, validation, clinical performance, and monitoring.

Guanabenz Acetate Induces Endoplasmic Reticulum Stress–Related Cell Death in Hepatocellular Carcinoma Cells

BACKGROUND: Development of chemotherapeutics for the treatment of advanced hepatocellular carcinoma (HCC) has been lagging. Screening of candidate therapeutic agents by using patient-derived preclinical models may facilitate drug discovery for HCC patients. METHODS: Four primary cultured HCC cells from surgically resected tumor tissues and six HCC cell lines were used for high-throughput screening of 252 drugs from the Prestwick Chemical Library. The efficacy and mechanisms of action of the candidate anti-cancer drug were analyzed via cell viability, cell cycle assays, and western blotting. RESULTS: Guanabenz acetate, which has been used as an antihypertensive drug, was screened as a candidate anti-cancer agent for HCC through a drug sensitivity assay by using the primary cultured HCC cells and HCC cell lines. Guanabenz acetate reduced HCC cell viability through apoptosis and autophagy. This occurred via inhibition of growth arrest and DNA damage-inducible protein 34, increased phosphorylation of eukaryotic initiation factor 2α, increased activating transcription factor 4, and cell cycle arrest. CONCLUSIONS: Guanabenz acetate induces endoplasmic reticulum stress–related cell death in HCC and may be repositioned as an anti-cancer therapeutic agent for HCC patients.

Epilepsy Surgery in 2019: A Time to Change

Epilepsy has been known to humankind since antiquity. The surgical treatment of epilepsy began in the early days of neurosurgery and has developed greatly. Many surgical procedures have stood the test of time. However, clinicians treating epilepsy patients are now witnessing a huge tide of change. In 2017, the classification system for seizure and epilepsy types was revised nearly 36 years after the previous scheme was released. The actual difference between these systems may not be large, but there have been many conceptual changes, and clinicians must bid farewell to old terminology. Paradigms in drug discovery are changing, and novel antiseizure drugs have been introduced for clinical use. In particular, drugs that target genetic changes harbor greater therapeutic potential than previous screening-based compounds. The concept of focal epilepsy has been challenged, and now epilepsy is regarded as a network disorder. With this novel concept, stereotactic electroencephalography (SEEG) is becoming increasingly popular for the evaluation of dysfunctioning neuronal networks. Minimally invasive ablative therapies using SEEG electrodes and neuromodulatory therapies such as deep brain stimulation and vagus nerve stimulation are widely applied to remedy dysfunctional epilepsy networks. The use of responsive neurostimulation is currently off-label in children with intractable epilepsy.

New inhibitors targeting bacterial RNA polymerase / 浙江大学学报·医学版

Rifamycins, a group of bacterial RNA polymerase inhibitors, are the firstline antimicrobial drugs to treat tuberculosis. In light of the emergence of rifamycinresistant bacteria, development of new RNA polymerase inhibitors that kill rifamycinresistant bacteria with high bioavailability is urgent. Structural analysis of bacterial RNA polymerase in complex with inhibitors by crystallography and cryo-EM indicates that RNA polymerase inhibitors function through five distinct molecular mechanisms:inhibition of the extension of short RNA; competition with substrates; inhibition of the conformational change of the'bridge helix'; inhibition of clamp opening;inhibition of clamp closure. This article reviews the research progress of these five groups of RNA polymerase inhibitors to provide references for the modification of existing RNA polymerase inhibitors and the discovery of new RNA polymerase inhibitors.

Clinical and pharmacological application of multiscale multiphysics heart simulator, UT-Heart

A heart simulator, UT-Heart, is a finite element model of the human heart that can reproduce all the fundamental activities of the working heart, including propagation of excitation, contraction, and relaxation and generation of blood pressure and blood flow, based on the molecular aspects of the cardiac electrophysiology and excitation-contraction coupling. In this paper, we present a brief review of the practical use of UT-Heart. As an example, we focus on its application for predicting the effect of cardiac resynchronization therapy (CRT) and evaluating the proarrhythmic risk of drugs. Patient-specific, multiscale heart simulation successfully predicted the response to CRT by reproducing the complex pathophysiology of the heart. A proarrhythmic risk assessment system combining in vitro channel assays and in silico simulation of cardiac electrophysiology using UT-Heart successfully predicted druginduced arrhythmogenic risk. The assessment system was found to be reliable and efficient. We also developed a comprehensive hazard map on the various combinations of ion channel inhibitors. This in silico electrocardiogram database (now freely available at http://ut-heart.com/) can facilitate proarrhythmic risk assessment without the need to perform computationally expensive heart simulation. Based on these results, we conclude that the heart simulator, UT-Heart, could be a useful tool in clinical medicine and drug discovery.

Potency and plasma protein binding of drugs in vitro—a potentially misleading pair for predicting in vivo efficacious concentrations in humans

In drug discovery or preclinical stages of development, potency parameters such as IC₅₀, K(i), or K(d) in vitro have been routinely used to predict the parameters of efficacious exposure (AUC, C(min), etc.) in humans. However, to our knowledge, the fundamental assumption that the potency in vitro is correlated with the efficacious concentration in vivo in humans has not been investigated extensively. Thus, the present review examined this assumption by comparing a wide range of published pharmacokinetic (PK) and potency data. If the drug potency in vitro and its in vivo effectiveness in humans are well correlated, the steady-state average unbound concentrations in humans [C(u_ss.avg) = f(u)·F·Dose/(CL·τ) = f(u)·AUCss/τ] after treatment with approved dosage regimens should be higher than, or at least comparable to, the potency parameters assessed in vitro. We reviewed the ratios of C(u_ss.avg)/potency in vitro for a total of 54 drug entities (13 major therapeutic classes) using the dosage, PK, and in vitro potency reported in the published literature. For 54 drugs, the C(u_ss.avg)/in vitro potency ratios were < 1 for 38 (69%) and < 0.1 for 22 (34%) drugs. When the ratios were plotted against f(u) (unbound fraction), “ratio < 1” was predominant for drugs with high protein binding (90% of drugs with f(u) ≤ 5%; i.e., 28 of 31 drugs). Thus, predicting the in vivo efficacious unbound concentrations in humans using only in vitro potency data and f(u) should be avoided, especially for molecules with high protein binding.

Molecular descriptors for drugs: A discriminant analysis

Background@#The biological activity of a compound is assumed to be encoded in its chemical composition and geometric structure, from which physico-chemical, electrotopological, and graph theory-derived properties can be determined.@*Objective@#This study aimed to identify the molecular descriptors derived from Dragon® 6 software that can discriminate compounds as drug or nondrug@*Methodology@#Over 4000 molecular properties were obtained for approximately 2000 known drugs and 2000 nondrugs on which Linear Discriminant Analysis was performed. @*Results@#Compounds can be discriminated between drug and nondrug with 81% accuracy using only two molecular descriptors, the information index HVcpx and the topological index MDDD. @*Conclusion@#A “Rule of Three” (HVcpx ≤ 3 and MDDD ≥ 30) seems to confer druglikeness in compounds. This rule can be used as additional filter in high throughput screening of compounds in any drug discovery research.

A review of three years' experience of the first pharmacometrics company in Korea

As the pharmaceutical industry in Korea is reaching the golden era of drug discovery due to increased investments in research and development and government funds, the need for a more efficient tool for the quantitative analysis has emerged. Therefore, the demand for pharmacometrics (PMx) consultancy services increased. Higher quality service suitable for regulatory submission and out-licensing deals were desired. In this analysis, we compiled and summarized 3 years of experiences of Q-fitter, the first PMx consultancy service company providing PMx analysis to the pharmaceutical industry in Korea. The projects were organized by companies, company types, indications, therapeutic areas, drug development stages, purposes, and scope of services. Within each category, we subcategorized the sections and assessed proportions and a year-over-year trend. As a result, we observed an increase in the number of projects in an average of ~170% per year, with the most frequent types of companies collaborated being the domestic pharmaceutical companies. Among the projects, ~72% involved modeling and simulation using population pharmacokinetic (PK) models, and the other included non-compartmental analysis (NCA), drug-drug interaction (DDI) prediction, and interpretation of the modeling results. The most sought-after purpose in PMx analysis was first-in-human (FIH) dose prediction followed by PK analysis, next clinical trial prediction, and scenario-based simulation. Oncology has been the top therapeutic area of interest every year consisting of ~38% of total projects, followed by Neurology (~13%). From this review, we were able to characterize the PMx service needs and spot the trend of current PMx practices in Korea.

Epilepsy Surgery in 2019: A Time to Change

Epilepsy has been known to humankind since antiquity. The surgical treatment of epilepsy began in the early days of neurosurgery and has developed greatly. Many surgical procedures have stood the test of time. However, clinicians treating epilepsy patients are now witnessing a huge tide of change. In 2017, the classification system for seizure and epilepsy types was revised nearly 36 years after the previous scheme was released. The actual difference between these systems may not be large, but there have been many conceptual changes, and clinicians must bid farewell to old terminology. Paradigms in drug discovery are changing, and novel antiseizure drugs have been introduced for clinical use. In particular, drugs that target genetic changes harbor greater therapeutic potential than previous screening-based compounds. The concept of focal epilepsy has been challenged, and now epilepsy is regarded as a network disorder. With this novel concept, stereotactic electroencephalography (SEEG) is becoming increasingly popular for the evaluation of dysfunctioning neuronal networks. Minimally invasive ablative therapies using SEEG electrodes and neuromodulatory therapies such as deep brain stimulation and vagus nerve stimulation are widely applied to remedy dysfunctional epilepsy networks. The use of responsive neurostimulation is currently off-label in children with intractable epilepsy.