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The refined Developability Classification System (rDCS) provides a comprehensive animal-free approach for assessing biopharmaceutical risks associated with developing oral formulations. This work demonstrates practical application of a recently advanced rDCS framework guiding formulation design for six diverse active pharmaceutical ingredients (APIs) and compares rDCS classifications with those of the Biopharmaceutics Classification System (BCS). While the BCS assigns five of the APIs to class II/IV, indicating potentially unfavorable biopharmaceutical attributes, the rDCS provides a more nuanced risk assessment. Both BCS and rDCS assign acetaminophen to class I at therapeutic doses. Voriconazole and lemborexant (both BCS II) are classified in rDCS class I at therapeutic doses, indicating suitability for development as conventional oral formulations. Fedratinib is classified as BCS IV but the rDCS indicates a stratified risk (class I, IIa or IIb), depending on the relevance of supersaturation/precipitation in vivo. Voxelotor and istradefylline (both BCS II) belong to rDCS class IIb, requiring solubility enhancement to achieve adequate oral bioavailability. Comparing the rDCS analysis with literature on development and pharmacokinetics demonstrates that the rDCS reliably supports oral formulation design over a wide range of API characteristics, thus providing a strong foundation for guiding development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Supersaturation and precipitation within the gastrointestinal tract can influence oral absorption of active pharmaceutical ingredients (APIs). Supersaturation of weakly basic APIs upon transfer from the stomach into the small intestine may enhance their absorption, while salt forms of poorly soluble weak acids may generate supersaturated solutions in both stomach and intestine. Likewise, APIs with solubility-limited absorption may be developed as enabling formulations intended to produce supersaturated solutions of the API in the gut. Integrating the supersaturation/precipitation characteristics of the API into the biopharmaceutical risk classification enables comprehensive mapping of potential developability risks and guides formulation selection towards optimizing oral bioavailability (BA). The refined Developability Classification System (rDCS) provides an approach for this purpose. In this work, the rDCS strategy is revisited and a stratified approach integrating the in vitro supersaturation and precipitation behavior of APIs and their formulations is proposed., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The addition of antioxidants to pharmaceutical products is a potential approach to inhibit nitrosamine formation, particularly in solid oral dosage forms like tablets and capsules. The objective was to assess the effect of ten antioxidants on the permeability of four Biopharmaceutics Classification System (BCS) Class III drugs. Bi-directional drug permeability studies in the absence and presence of antioxidants were performed in vitro across MDCK-II monolayers. No antioxidant increased drug permeability, while the positive control sodium lauryl sulfate always increased drug permeability. Results support that any of the ten antioxidants, up to at least 10 mg, can be added to a solid oral dosage form without modulating passive drug intestinal permeability. Additional considerations are also discussed., Competing Interests: Declaration of Competing Interest There are no conflicts of interest for these authors to declare. The information in the paper reflects views from authors and should not be construed to represent FDA's views or policies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The process of drug discovery is widely known to be lengthy and resource-intensive. Artificial Intelligence approaches bring hope for accelerating the identification of molecules with the necessary properties for drug development. Drug-likeness assessment is crucial for the virtual screening of candidate drugs. However, traditional methods like Quantitative Estimation of Drug-likeness (QED) struggle to distinguish between drug and non-drug molecules accurately. Additionally, some deep learning-based binary classification models heavily rely on selecting training negative sets. To address these challenges, we introduce a novel unsupervised learning framework called DrugMetric, an innovative framework for quantitatively assessing drug-likeness based on the chemical space distance. DrugMetric blends the powerful learning ability of variational autoencoders with the discriminative ability of the Gaussian Mixture Model. This synergy enables DrugMetric to identify significant differences in drug-likeness across different datasets effectively. Moreover, DrugMetric incorporates principles of ensemble learning to enhance its predictive capabilities. Upon testing over a variety of tasks and datasets, DrugMetric consistently showcases superior scoring and classification performance. It excels in quantifying drug-likeness and accurately distinguishing candidate drugs from non-drugs, surpassing traditional methods including QED. This work highlights DrugMetric as a practical tool for drug-likeness scoring, facilitating the acceleration of virtual drug screening, and has potential applications in other biochemical fields., (© The Author(s) 2024. Published by Oxford University Press.)

Two highly simple, economical, accurate and sensitive spectrophotometric methods for determination of dopamine hydrochloride (DAH) in either pure form and pharmaceutical formulations are described. The first method is based on determination of (DAH) spectrophotometrically at maximum absorbance 280 nm (method A). The second one is based on reduction of alkaline KMnO 4 by (DAH) leading to the formation of green manganate species which are measured at 610 nm (method B). Under optimized conditions, the calibration graphs were linear in the range of 3.793 - 45.513, 0.190 - 4.362 μg.mL -1 of (DAH) for methods A and B respectively. The developed methods were successfully applied for the determination of dopamine hydrochloride in pharmaceutical samples., (Published by Elsevier B.V.)

New measures and research are needed to limit the ecological impact of pharmaceuticals.

The United States has a complex regulatory scheme for marketing drugs. Understanding drug regulatory status is a daunting task that requires integrating data from many sources from the United States Food and Drug Administration (FDA), US government publications, and other processes related to drug development. At NCATS, we created Inxight Drugs (https://drugs.ncats.io), a web resource that attempts to address this challenge in a systematic manner. NCATS Inxight Drugs incorporates and unifies a wealth of data, including those supplied by the FDA and from independent public sources. The database offers a substantial amount of manually curated literature data unavailable from other sources. Currently, the database contains 125 036 product ingredients, including 2566 US approved drugs, 6242 marketed drugs, and 9684 investigational drugs. All substances are rigorously defined according to the ISO 11238 standard to comply with existing regulatory standards for unique drug substance identification. A special emphasis was placed on capturing manually curated and referenced data on treatment modalities and semantic relationships between substances. A supplementary resource 'Novel FDA Drug Approvals' features regulatory details of newly approved FDA drugs. The database is regularly updated using NCATS Stitcher data integration tool that automates data aggregation and supports full data access through a RESTful API., (Published by Oxford University Press on behalf of Nucleic Acids Research 2021.)

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here. Graphical Abstract., (© 2022. The Author(s).)

Pregnancy can significantly change the pharmacokinetics of drugs, including those renally secreted by organic anion transporters (OATs). Quantifying these changes in pregnant women is logistically and ethically challenging. Hence, predicting the in vivo plasma renal secretory clearance (CL sec ) and renal CL (CL renal ) of OAT drugs in pregnancy is important to design correct dosing regimens of OAT drugs. Here, we first quantified the fold-change in renal OAT activity in pregnant versus nonpregnant individual using available selective OAT probe drug CL renal data (training dataset; OAT1: tenofovir, OAT2: acyclovir, OAT3: oseltamivir carboxylate). The fold-change in OAT1 activity during the 2 nd and 3 rd trimester was 2.9 and 1.0 compared with nonpregnant individual, respectively. OAT2 activity increased 3.1-fold during the 3 rd trimester. OAT3 activity increased 2.2, 1.7 and 1.3-fold during the 1 st , 2 nd , and 3 rd trimester, respectively. Based on these data, we predicted the CL sec , CL renal and total clearance ((CL total ) of drugs in pregnancy, which are secreted by multiple OATs (verification dataset; amoxicillin, pravastatin, cefazolin and ketorolac, R -ketorolac, S -ketorolac). Then, the predicted clearances (CLs) were compared with the observed values. The predicted/observed CL sec , CL renal , and CL total of drugs in pregnancy of all verification drugs were within 0.80-1.25 fold except for CL sec of amoxicillin in the 3 rd trimester (0.76-fold) and cefazolin in the 2 nd trimester (1.27-fold). Overall, we successfully predicted the CL sec , CL renal , and CL total of drugs in pregnancy that are renally secreted by multiple OATs. This approach could be used in the future to adjust dosing regimens of renally secreted OAT drugs which are administered to pregnant women. SIGNIFICANCE STATEMENT: To the authors' knowledge, this is the first report to successfully predict renal secretory clearance and renal clearance of multiple OAT substrate drugs during pregnancy. The data presented here could be used in the future to adjust dosing regimens of renally secreted OAT drugs in pregnancy. In addition, the mechanistic approach used here could be extended to drugs transported by other renal transporters., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Pharmacogenomic studies allowed the reasons behind the different responses to treatments to be understood. Its clinical utility, in fact, is demonstrated by the reduction in adverse drug reaction incidence and the improvement of drug efficacy. Pharmacogenomics is an important tool that is able to improve the drug therapy of different disorders. In particular, this review will highlight the current pharmacogenomics knowledge about biologics and small-molecule treatments for psoriasis. To date, studies performed on genes involved in the metabolism of biological drugs (tumor necrosis factor inhibitors and cytokines inhibitors) and small molecules (apremilast, dimethyl fumarate, and tofacitinib) have provided conflicting results, and further investigations are necessary in order to establish a set of biomarkers to be introduced into clinical practice.

In 2020, the US Food and Drug Administration approved 53 novel drugs. Thirty-six of the 53 (68%) drugs were reviewed and approved through an expedited review pathway, and 31 of the 53 (58%) were approved for treatment of a rare disease. This review includes a summary of the novel drugs approved by the US Food and Drug Administration in 2020., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hematopoietic stem cells (HSCs) are a specialized subset of cells with self-renewal and multilineage differentiation potency, which are essential for their function in bone marrow or umbilical cord blood transplantation to treat blood disorders. Expanding the hematopoietic stem and progenitor cells (HSPCs) ex vivo is essential to understand the HSPCs-based therapies potency. Here, we established a screening system in zebrafish by adopting an FDA-approved drug library to identify candidates that could facilitate HSPC expansion. To date, we have screened 171 drugs of 7 categories, including antibacterial, antineoplastic, glucocorticoid, NSAIDS, vitamins, antidepressant, and antipsychotic drugs. We found 21 drugs that contributed to HSPCs expansion, 32 drugs' administration caused HSPCs diminishment and 118 drugs' treatment elicited no effect on HSPCs amplification. Among these drugs, we further investigated the vitamin drugs ergocalciferol and panthenol, taking advantage of their acceptability, limited side-effects, and easy delivery. These two drugs, in particular, efficiently expanded the HSPCs pool in a dose-dependent manner. Their application even mitigated the compromised hematopoiesis in an ikzf1 -/- mutant. Taken together, our study implied that the larval zebrafish is a suitable model for drug repurposing of effective molecules (especially those already approved for clinical use) that can facilitate HSPCs expansion.

The concept of going 'green' and 'cold' has led to utilizing renewable resources for the synthesis of microbial biosurfactants that are both patient and eco-friendly. In this review, we shed light on the potential and regulatory aspects of biosurfactants in pharmaceutical applications and how they can significantly contribute to novel concepts for the Coronavirus 2019 (COVID-19) vaccine and future treatment. We emphasize that more specific guidelines should be formulated to regulate the approval of biosurfactants for human use. It is also crucial to implement a risk-based approach from the early research and development (R&D) phase in addition to establishing more robust standardized techniques and assays to evaluate the characteristics of biosurfactants., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium-glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance.

Many pharmacologic agents were investigated for the effect to prevent delirium. We aimed to comprehensively compare the effect of the pharmacological interventions to prevent postoperative delirium. A Bayesian network meta-analysis of randomized trials was performed using random effects model. PubMed, the Cochrane Central Register of Controlled Trials, and Embase were searched on 20 January 2021. Randomized trials comparing the effect of a drug to prevent postoperative delirium with another drug or placebo in adult patients undergoing any kind of surgery were included. Primary outcome was the postoperative incidence of delirium. Eighty-six trials with 26,992 participants were included. Dexmedetomidine, haloperidol, and atypical antipsychotics significantly decreased the incidence of delirium than placebo [dexmedetomidine: odds ratio 0.51, 95% credible interval (CrI) 0.40-0.66, moderate quality of evidence (QOE); haloperidol: odds ratio 0.59, 95% CrI 0.37-0.95, moderate QOE; atypical antipsychotics: odds ratio 0.27, 95% CrI 0.14-0.51, moderate QOE]. Dexmedetomidine and atypical antipsychotics had the highest-ranking probabilities to be the best. However, significant heterogeneity regarding diagnostic time window as well as small study effects precludes firm conclusion.

Tuberculosis is one of the deadliest infectious diseases existing in the world since ancient times and still possesses serious threat across the globe. Each year the number of cases increases due to high drug resistance shown by Mycobacterium tuberculosis (Mtb). Available antimycobacterial drugs have been classified as First line, Second line and Third line antibiotics depending on the time of their discoveries and their effectiveness in the treatment. These antibiotics have a broad range of targets ranging from cell wall to metabolic processes and their non-judicious and uncontrolled usage in the treatment for years has created a significant problem called multi-drug resistant (MDR) tuberculosis. In this review, we have summarized the mechanism of action of all the classified antibiotics currently in use along with the resistance mechanisms acquired by Mtb. We have focused on the new drug candidates/repurposed drugs, and drug in combinations, which are in clinical trials for either treating the MDR tuberculosis more effectively or involved in reducing the time required for the chemotherapy of drug sensitive TB. This information is not discussed very adequately on a single platform. Additionally, we have discussed the recent technologies that are being used to discover novel resistance mechanisms acquired by Mtb and for exploring novel drugs. The story of intrinsic resistance mechanisms and evolution in Mtb is far from complete. Therefore, we have also discussed intrinsic resistance mechanisms of Mtb and their evolution with time, emphasizing the hope for the development of novel antimycobacterial drugs for effective therapy of tuberculosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The utilization of approved medication is a requisite to combat certain diseases for health; however, the undesirable adverse effects (AEs) due to medication are generally unavoidable. Hypertension is one of such AEs resulting from approved medication in which blood pressure in the arteries gets elevated and is a risk factor for several diseases including heart and kidney failure. HTs are the approved drugs that can cause hypertension as an AE. Here, the goal of the study is to investigate the structural and functional diversities of HTs. In our quest to unravel the structural parameters of the HTs, a systematic analysis of the HTs having a different number and type of ring systems was conducted. The cellular component, molecular function and biological processes adopted by the gene products were analyzed. Moreover, our systematically done analysis suggests that all the target families are active in a common pathway, that is, nerve transmission. A comparison of the selected structural and functional aspect of HTs with anti-hypertensives suggests that HTs follow certain structural and functional features in spite of many possibilities. Our study provides a promising methodology that considers the influence of structural diversity of AE causing agents on a functional perspective for precursory clinical decision making. This could be extended to explore the structural and functional trends that are adopted by agents causing certain diseases or AEs.

The advent of computational methods for efficient prediction of the druglikeness of small molecules and their ever-burgeoning applications in the fields of medicinal chemistry and drug industries have been a profound scientific development, since only a few amounts of the small molecule libraries were identified as approvable drugs. In this study, a deep belief network was utilized to construct a druglikeness classification model. For this purpose, small molecules and approved drugs from the ZINC database were selected for the unsupervised pre-training step and supervised training step. Various binary fingerprints such as Macc 166 bit, PubChem 881 bit, and Morgan 2048 bit as data features were investigated. The report revealed that using an unsupervised pre-training phase can lead to a good performance model and generalizability capability. Accuracy, precision, and recall of the model for Macc features were 97%, 96%, and 99%, respectively. For more consideration about the generalizability of the model, the external data by expression and investigational drugs in drug banks as drug data and randomly selected data from the ZINC database as non-drug were created. The results confirmed the good performance and generalizability capability of the model. Also, the outcomes depicted that a large proportion of misclassified non-drug small molecules ascertain the bioavailability conditions and could be investigated as a drug in the future. Furthermore, our model attempted to tap potential opportunities as a drug filter in drug discovery.

Background: Multimorbidity is increasing among older adults, but the impact of these recent trends on the extent and complexity of polypharmacy and possible variation by sex remains unknown. We examined sex differences in multimorbidity, polypharmacy (5+ medications) and hyper-polypharmacy (10+ medications) in 2003 vs 2016, and the interactive associations between age, multimorbidity level, and time on polypharmacy measures., Methods and Findings: We employed a repeated cross-sectional study design with linked health administrative databases for all persons aged ≥66 years eligible for health insurance in Ontario, Canada at the two index dates. Descriptive analyses and multivariable logistic regression models were conducted; models included interaction terms between age, multimorbidity level, and time period to estimate polypharmacy and hyper-polypharmacy probabilities, risk differences and risk ratios for 2016 vs 2003. Multimorbidity, polypharmacy and hyper-polypharmacy increased significantly over the 13 years. At both index dates prevalence estimates for all three were higher in women, but a greater absolute increase in polypharmacy over time was observed in men (6.6% [from 55.7% to 62.3%] vs 0.9% [64.2%-65.1%] for women) though absolute increases in multimorbidity were similar for men and women (6.9% [72.5%-79.4%] vs 6.2% [75.9%-82.1%], respectively). Model findings showed that polypharmacy decreased over time among women aged < 90 years (especially for younger ages and those with fewer conditions), whereas it increased among men at all ages and multimorbidity levels (with larger absolute increases typically at older ages and among those with 4 or fewer conditions)., Conclusions: There are sex and age differences in the impact of increasing chronic disease burden on changes in measures of multiple medication use among older adults. Though the drivers and health consequences of these trends warrant further investigation, the findings support the heterogeneity and complexity in the evolving association between multimorbidity and polypharmacy measures in older populations., Competing Interests: The authors have declared that no competing interests exist.

The 2017 Guidance by U.S. Food and Drug Administration (FDA) has recommended the criteria to qualify for a Biopharmaceutical Classification System (BCS)-based biowaiver that includes high solubility of the drug across the physiological pH range as well as the formulation considerations, e.g., being qualitatively the same and quantitatively very similar to the reference product. These were ratified by the International Council for Harmonization (ICH) in 2018. The FDA has used the similar verbiage when referring to the BCS-based biowaiver option for BCS class III drugs (highly soluble but poorly permeable). However, establishing in vitro-in vivo correlations (IVIVC) using conventional mass balance deconvolution approaches, which assumes a single absorption compartment, is not likely for very rapidly dissolving dosage forms containing BCS III drugs. Unlike conventional mass balance deconvolution techniques, physiologically based pharmacokinetic models are able to disentangle different processes contributing to the input function, e.g., dissolution, gastrointestinal transit, and permeation and to establish IVIVC using variants of the compartmental absorption and transit model, supporting biowaiver for formulations containing BCS III drugs. However, there are knowledge gaps that need to be filled. This review provides a systematic assessment of the advancements in applications of physiologically based pharmacokinetic (PBPK) models for IVIVC and biowaiver for such cases with the aim of identifying the most important gaps and hurdles. It concludes by calling for research efforts on the impact of excipients on dissolution and permeation, alongside the development of PBPK modeling to link these in vitro characteristics to in vivo bioequivalence outcomes through simulations of virtual clinical studies., (© 2021 John Wiley & Sons Ltd.)

Automatically identifying chemical and drug names in scientific publications advances information access for this important class of entities in a variety of biomedical disciplines by enabling improved retrieval and linkage to related concepts. While current methods for tagging chemical entities were developed for the article title and abstract, their performance in the full article text is substantially lower. However, the full text frequently contains more detailed chemical information, such as the properties of chemical compounds, their biological effects and interactions with diseases, genes and other chemicals. We therefore present the NLM-Chem corpus, a full-text resource to support the development and evaluation of automated chemical entity taggers. The NLM-Chem corpus consists of 150 full-text articles, doubly annotated by ten expert NLM indexers, with ~5000 unique chemical name annotations, mapped to ~2000 MeSH identifiers. We also describe a substantially improved chemical entity tagger, with automated annotations for all of PubMed and PMC freely accessible through the PubTator web-based interface and API. The NLM-Chem corpus is freely available.

Proteolysis-targeting chimeras (PROTACs), which selectively degrade targeted proteins by the ubiquitin-proteasome system, have emerged as a novel therapeutic technology with potential advantages over traditional inhibition strategies. In the past few years, this technology has achieved substantial progress and two PROTACs have been advanced into phase I clinical trials. However, this technology is still maturing and the design of PROTACs remains a great challenge. In order to promote the rational design of PROTACs, we present PROTAC-DB, a web-based open-access database that integrates structural information and experimental data of PROTACs. Currently, PROTAC-DB consists of 1662 PROTACs, 202 warheads (small molecules that target the proteins of interest), 65 E3 ligands (small molecules capable of recruiting E3 ligases) and 806 linkers, as well as their chemical structures, biological activities, and physicochemical properties. Except the biological activities of warheads and E3 ligands, PROTAC-DB also provides the degradation capacities, binding affinities and cellular activities for PROTACs. PROTAC-DB can be queried with two general searching approaches: text-based (target name, compound name or ID) and structure-based. In addition, for the convenience of users, a filtering tool for the searching results based on the physicochemical properties of compounds is also offered. PROTAC-DB is freely accessible at http://cadd.zju.edu.cn/protacdb/., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Adrenergic β-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the β-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those β-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. β-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, β-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John's wort and Yohimbine. This article focuses on clinically relevant drug interactions of β-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with β-blockers to prevent possible adverse drug interactions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: The Center of Drug Evaluation and Research (CDER) in the food and drug administration (FDA) approves new drugs every year. This review discusses the novel drugs of the FDA in 2018, with emphasis on the breakthrough drugs, the milestones in the approved list, and drugs with the highest expected sales in 2024., Methods: The following scientific search engines were surveyed for the clinical trials of the drugs approved by the FDA in 2018: Pubmed, Springer link, ScienceDirect, Scopus, Wiley online library, Taylor and Francis, and Google Scholar. The total forecast sales were compared based on information from the Cortellis database, EvaluatePharma, and Nature Biobusiness Briefs., Results: The 2018 year was full of good news for the drug market in the USA, with 59 new drug approvals by the FDA, which is the highest number of approvals in the last twenty years. The oncology and the antimicrobial drugs represent almost 50% of the new list, which gives hope to cancer patients and subjects with infectious diseases. In the 2018 FDA list, a number of drugs are expected to exceed 1$ billion dollars of sales by 2024., Conclusion: The new drugs approved by the FDA in 2018 have been reviewed. This year showed the highest number of new drug approvals in the last two decades. Among the 59 drugs approved in 2018, 14 drugs are considered breakthroughs, which revive hope for many poorly managed diseases. The list also contains 19 drugs that are first in class and 43 that were given priority reviews., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The research and development (R&D) of new drugs indicates scientific progress and economic development. However, little is known regarding ongoing or recent clinical trials in China. We analyzed data from clinical trials published before December 31, 2019, and found that the annual registration numbers are increasing annually in the country. Based on clinical indications, most tested drugs target cancers, nervous system, infections, and the cardiovascular system. Furthermore, clinical trials are mostly concentrated in Beijing, Shanghai, and Jiangsu, and conducted by large pharmaceutical companies, with multiple trials for several generic drugs. Going forward, it will be necessary to promote R&D in China of clinically relevant innovative drugs, drug delivery systems, and novel traditional Chinese medicine (TCM) and biological products, as well as to have a balanced distribution of clinical trials to sustainably meet public health needs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A variety of marketed drugs belonging to various therapeutic classes are known to cause nephrotoxicity. Nephrotoxicity can manifest itself in several forms depending on the specific site involved as well as the underlying pathophysiological mechanisms. As they often coexist with other pathophysiological conditions, the steps that can be taken to treat them are often limited. Thus, drug-induced nephrotoxicity remains a major clinical challenge. Prior knowledge of risk factors associated with special patient populations and specific classes of drugs, combined with early diagnosis, therapeutic drug monitoring with dose adjustments, as well as timely prospective treatments are essential to prevent and manage them better. Most incident drug-induced renal toxicity is reversible only if diagnosed at an early stage and treated promptly. Hence, diagnosis at an early stage is the need of the hour to counter it. Significant recent advances in the identification of novel early biomarkers of nephrotoxicity are not beyond limitations. In such a scenario, mathematical modeling and simulation (M&S) approaches may help to better understand and predict toxicities in a clinical setting. This review summarizes pathophysiological mechanisms of drug-induced nephrotoxicity, classes of nephrotoxic drugs, management, prevention, and diagnosis in clinics. Finally, it also highlights some of the recent advancements in mathematical M&S approaches that could be used to better understand and predict drug-induced nephrotoxicity., (© 2020, The American College of Clinical Pharmacology.)

Drug entry into the adult brain is controlled by efflux mechanisms situated in various brain barrier interfaces. The effectiveness of these protective mechanisms in the embryo, fetus and newborn brain is less clear. The longstanding belief that "the" blood-brain barrier is absent or immature in the fetus and newborn has led to many misleading statements with potential clinical implications. Here we review the properties of brain barrier mechanisms in the context of drug entry into the developing brain and discuss the limited number of studies published on the subject. We noticed that most of available literature suffers from some experimental limitations, notably that drug levels in fetal blood and cerebrospinal fluid have not been measured. This means that the relative contribution to the overall brain protection provided by individual barriers such as the placenta (which contains similar efflux mechanisms) and the brain barriers cannot be separately ascertained. Finally, we propose that systematic studies in appropriate animal models of drug entry into the brain at different stages of development would provide a rational basis for use of medications in pregnancy and in newborns, especially prematurely born, where protection usually provided by the placenta is no longer present., (© 2020 John Wiley & Sons, Ltd.)

Introduction: Most drugs used in therapy have low water-solubility, a factor that could reduce their dissolution rate and oral bioavailability, representing a challenge in pharmaceutical development. Nanonization of drugs is the reduction of particles to nanoscale, increasing the surface area and consequently the saturation solubility and dissolution rate and resulting in higher bioavailability., Areas Covered: This review provides an overview of the consequences of the poor water-solubility and the main strategies applied to increase the solubility of poorly water-soluble drugs. The relationship between the biopharmaceutical classification system and the solubilization process of the drug is also considered. Finally, it includes how drug nanoparticles and nanocarriers, especially lipid-based nanosystems, can overcome these challenges and which of these approaches are already available on the market., Expert Opinion: Due to the growing importance of nanomedicines, especially for applications in poorly water-soluble drugs, it is important to clearly establish the specifications and quality criteria for nanonized drugs to ensure the quality and safety of nanoparticles.

Very recent data from cohorts, such as that of the French Observatory of Multiple Sclerosis (OFSEP) and the MSBase cohort, are the subject of new statistical analyses using propensity scores that enable the matching of relapses frequency, EDSS, age, and sex ratio in patient populations for comparisons with each other, which reduces selection biases. The first data from these cohorts revealed a decline in transition to secondary progressive MS with the most effective disease-modifying drugs currently available, especially when these drugs were used early in the disease. However, these studies remain limited regarding the number of patients, the duration of follow-up, the use of imperfect methodologies, and the level of evidence remains low. The Gothenburg cohort in Sweden, which has been followed since the 1950s, found that 14% of benign non-progressive multiple sclerosis (MS) never evolved to secondary progression after more than 45 years of evolution. EDSS 7 was reached after 48 years of disease (median), and 50% evolved to secondary progressive MS after 15 years (consistent with data from the historic London, Ontario cohort). These data demonstrate that most people living with MS evolve without treatment to a significant long-term disability and that this evolution is closely linked to secondary progression (more than the relapse frequency). Benign forms appear as MS that never passes into secondary progressive MS. Recent data demonstrate that the delay until transition to secondary progression (more than 30 years in the MSBase cohort) and the delay in reaching EDSS 6 decreased since the introduction of disease-modifying drugs 20 years ago. However, randomized placebo-controlled trials do not last more than 2 or 3 years, and many biases may be involved in long-term follow-up studies: worsening patients who are lost to follow-up ("informative censoring" bias: only good responders to treatment remain primarily under the same long-term treatment and are followed); changes in the populations in the most recent studies with a lower rate of relapse and lower progression of disability at the beginning of the disease prior to initiating treatments; and environmental changes that remain largely misunderstood and may contribute to a natural evolution towards less severe disease., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

RR MS evolution has changed since the beginning of the availability of MS disease-modifying drugs (DMD). Before concluding a unique impact of the efficiency of DMD, careful analysis of long-term studies has to be conducted. Analysis of the literature points out a few bias in the long-term follow of MS patients under DMD: indication of DMD has changed since 20 years, diagnosis criteria are not the same (including the Will Rogers phenomen), and so far population are not homogeneous and comparable. Analysis criteria of the efficiency of the treatments are not the same, pending on the date of the publications. References concerning the long-term impact of DMD are in fact very limited. In addition, long-term efficiency of 2nd line treatments is not available. Another explanation of the change of MS evolution could be the lower evolutivity of MS patients since 2 decades. Analysis of placebo group in pivotal studies, argues to a decrease of the relapse annual rate and mean EDSS score in the more recent studies and recent MS diagnosed patients. To conclude, long-term evolution of MS patients is more favorable, influence of DMD is likely, but not unique., (Copyright © 2020. Published by Elsevier Masson SAS.)

During the 20 past years, the management of multiple sclerosis (MS) has largely changed especially concerning therapeutical approach. Before 1996, treatments were restricted to corticosteroids for relapses, several symptomatic treatments and unselective immunosuppressive drugs (azathioprine, cyclophosphamide, methotrexate) with a low evidence of any efficacy. In the present review, we analyze the principal real-life cohorts of MS during several periods (before therapeutical modern area, first-generation treatment area and most recent period). Despite many methodological problems, we observe globally a delay of around 3-5 years between untreated cohorts and first-generation treatments for going to EDSS 6 which is probably the most robust score. This delay is clearly increase to at least 15 years with the most recent cohort treated first and second-line treatments confirming that early and more intensive treatment are necessary to have a long-term efficacy on disability progression and especially on severe disability represent by EDSS 6. Larger cohorts with longer follow-up is necessary to confirm these tendencies and OFSEP observatory or MS base will probably provide us the possibility to conclude in a couple of years., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background. Reviewing drugs to determine coverage or reimbursement level is a complex process that involves significant time and expertise. Review boards gather evidence from the submission provided, input from clinicians and patients, and results of clinical and economic reviews. This information consists of assessments on multiple criteria that often conflict with one another. Multiple-criteria decision analysis (MCDA) includes methods to address complex decision making problems with conflicting objectives and criteria. We propose an MCDA approach that infers a utility model based on reviews of previously submitted drugs. Methods. We use a recent extension of the UTilitiés Additives DIScriminantes approach, UTADIS GMS . This disaggregation approach deconstructs a portfolio of elements such as a set of drugs that have been reviewed and for which a decision has been made. It derives global and marginal utility functions that are consistent with the preferences exhibited by the review boards in their recommendations. We apply the method to oncology drugs reviewed in Canada between 2011 and 2017. We also illustrate how to conduct scenario analyses and predict the coverage decisions for new drugs. Results. Applying the method yields a utility value for each submission along with a set of thresholds that partition the utility values based on the submission outcomes. Scenario analyses illustrate the predictive ability of the method. Conclusion. Preference disaggregation is an indirect way of eliciting an additive global utility value function. It requires less of a cognitive effort from the decision making bodies because it infers preferences from the data rather than relying on direct assessments of model parameters. We illustrate how it can be applied to validate existing decisions and to predict the recommendation of a new drug.

Aims: Drug-induced gynecomastia accounts for up to 25% of cases of gynecomastia. The objective of the present study was to provide a comprehensive overview of drug-induced gynecomastia on the basis of spontaneously reported adverse drug reactions (ADRs) in the French national pharmacovigilance database (FPVD)., Methods: We performed a case - noncase study of drug-induced gynecomastia. Cases corresponded to reports of gynecomastia recorded in the FPVD between 1 January 2008 and 31 December 2015. The noncases corresponded to all other spontaneously reported ADRs recorded in the FPVD during the same period. Data were expressed as the reporting odds ratio (ROR) and its 95% confidence interval., Results: Of the 255,354 ADRs recorded in the FPVD between 1 January 2008 and 31 December 2015, 327 (0.31%) of relevant cases of gynecomastia and 106,800 noncases were analyzed. The RORs were statistically significant for 54 active compounds mentioned 429 times in cases of gynecomastia. A single drug was involved in 59% of cases. The most frequently implicated drug classes were antiretrovirals (23.5%), diuretics (15.5%), proton pump inhibitors (11.9%), HMG-CoA reductase inhibitors (9.1%), neuroleptics and related drugs (6.5%), calcium channel blockers (6.3%), and 5-alpha reductase inhibitors (4%)., Conclusions: A comprehensive analysis of a national pharmacovigilance database highlighted the main drug classes suspected of inducing gynecomastia. A physiopathological mechanism (a hormone imbalance with elevated estrogen levels) is known or suspected for most of the drugs involved in gynecomastia. However, we noticed a lack of harmonization in the summary of product characteristics for original vs. generic medicines., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Alkyl moieties-open chain or cyclic, linear, or branched-are common in drug molecules. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some hydroxy metabolites, which are equiactive with their parent drugs, have been developed into ester prodrugs while carboxy metabolites, which are equiactive to their parent drugs, have been developed into drugs as per se. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. The review provides a basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules, and (ii) pharmacologic activity of the metabolites resulting from hydroxy and/or carboxy functionalization of alkyl moieties.

Objective: A current assessment of case reports of possible drug-induced pancreatitis is needed. We systematically reviewed the case report literature to identify drugs with potential associations with acute pancreatitis and the burden of evidence supporting these associations., Methods: A protocol was developed a priori (PROSPERO CRD42017060473). We searched MEDLINE, Embase, the Cochrane Library, and additional sources to identify cases of drug-induced pancreatitis that met accepted diagnostic criteria of acute pancreatitis. Cases caused by multiple drugs or combination therapy were excluded. Established systematic review methods were used for screening and data extraction. A classification system for associated drugs was developed a priori based upon the number of cases, re-challenge, exclusion of non-drug causes of acute pancreatitis, and consistency of latency., Results: Seven-hundred and thirteen cases of potential drug-induced pancreatitis were identified, implicating 213 unique drugs. The evidence base was poor: exclusion of non-drug causes of acute pancreatitis was incomplete or poorly reported in all cases, 47% had at least one underlying condition predisposing to acute pancreatitis, and causality assessment was not conducted in 81%. Forty-five drugs (21%) were classified as having the highest level of evidence regarding their association with acute pancreatitis; causality was deemed to be probable or definite for 19 of these drugs (42%). Fifty-seven drugs (27%) had the lowest level of evidence regarding an association with acute pancreatitis, being implicated in single case reports, without exclusion of other causes of acute pancreatitis., Discussion: Much of the case report evidence upon which drug-induced pancreatitis associations are based is tenuous. A greater emphasis on exclusion of all non-drug causes of acute pancreatitis and on quality reporting would improve the evidence base. It should be recognized that reviews of case reports, are valuable scoping tools but have limited strength to establish drug-induced pancreatitis associations., Registration: CRD42017060473., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: BH has previously received honoraria from Eversana (previously Cornerstone Research Group) for provision of methodologic advice related to the conduct of systematic reviews and meta-analysis. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have no conflicts of interest to disclose.

Drug induced liver injury (DILI) is one of the key safety concerns in drug development. To assess the likelihood of drug candidates with potential adverse reactions of liver, we propose a compound attributes-based approach to predicting hepatobiliary disorders that are routinely reported to US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Specifically, we developed a support vector machine (SVM) model with recursive feature extraction, based on physicochemical and structural properties of compounds as model input. Cross validation demonstrates that the predictive model has a robust performance with averaged 70% of both sensitivity and specificity over 500 trials. An independent validation was performed on public benchmark drugs and the results suggest potential utility of our model for identifying safety alerts. This in silico approach, upon further validation, would ultimately be implemented, together with other in vitro safety assays, for screening compounds early in drug development., Competing Interests: The authors declare the following competing interests: Amgen Inc. provided support in the form of salaries for authors LY, GH, HYD. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Potential risks associated with releases of human pharmaceuticals into the environment have become an increasingly important issue in environmental health. This concern has been driven by the widespread detection of pharmaceuticals in all aquatic compartments. Therefore, 22 pharmaceuticals, 6 metabolites and transformation products, belonging to 7 therapeutic groups, were selected to perform a review on their toxicity and environmental risk assessment (ERA) in different aquatic compartments, important issues to tackle the water framework directive (WFD). The toxicity data collected reported, with the exception of anxiolytics, at least one toxicity value for concentrations below 1 µg L -1 . The results obtained for the ERA revealed risk quotients (RQs) higher than 1 in all the aquatic bodies and for the three trophic levels, algae, invertebrates and fish, posing ecotoxicological pressure in all of these compartments. The therapeutic groups with higher RQs were hormones, antiepileptics, anti-inflammatories and antibiotics. Unsurprisingly, RQs values were highest in wastewaters, however, less contaminated water bodies such as groundwaters still presented maximum values up to 91,150 regarding 17α-ethinylestradiol in fish. Overall, these results present an important input for setting prioritizing measures and sustainable strategies, minimizing their impact in the aquatic environment.

Preterm birth occurs with 10% of deliveries and yet accounts for more than 85% of perinatal morbidity and mortality. Management of preterm labor prior to delivery includes a multipronged pharmacologic approach targeting utilization of reproductive hormones for continuation of pregnancy, advancement of fetal lung maturity, and the decrease of uterine contractility (tocolysis). This article will review and compare guidelines on pharmacologic management of preterm labor as recommended by the American College of Obstetricians and Gynecologists and the European Association of Perinatal Medicine. The classifications of drugs discussed include exogenous progesterone, corticosteroids, and tocolytics (β-adrenergic agonists, magnesium sulfate, calcium channel blockers, prostaglandin inhibitors, nitrates, and oxytocin receptor blockers). For each of these drug classes, the following information will be presented: mechanism of action, maternal/fetal side effects, and nursing implications.

Background: European data indicate that systemic sclerosis (SSc)-related death rates are increasing, thus raising concerns about SSc's optimal management. Herein, we describe current treatment modalities and drug survival in a real-life SSc cohort., Methods: Details on immunosuppressive/antiproliferative (methotrexate, mycophenolate, cyclophosphamide, azathioprine, rituximab, tocilizumab) and vasoactive agent [(endothelin receptor antagonists (ERAs), sildenafil, iloprost, and calcium channel blockers (CCB)] administration during the disease course (11.8 ± 8.4 years, mean + SD) of 497 consecutive patients examined between 2016 and 2018 were retrospectively recorded. Drug survival was assessed by Kaplan-Meier analysis., Results: Methotrexate was the most frequently administered immunosuppressive/antiproliferative agent (53% of patients), followed by cyclophosphamide (26%), mycophenolate (12%), and azathioprine (11%). Regarding vasoactive agents, CCB had been ever administered in 68%, ERAs in 38%, iloprost in 7%, and sildenafil in 7% of patients; 23% of patients with pulmonary fibrosis had never received immunosuppressive/antiproliferative agents, 33% of those with digital ulcers had never received ERAs, iloprost, or sildenafil, whereas 19% of all patients had never received either immunosuppressive/antiproliferative or other than CCB vasoactive agents. Survival rates of methotrexate, cyclophosphamide, and mycophenolate differed significantly, being 84/75%, 59/43%, and 74/63% at 12/24 months, respectively, with inefficacy being the most frequent discontinuation cause. Conversely, CCB, ERAs, and sildenafil had high and comparable retention rates of 97/91%, 88/86%, and 80/80%, respectively., Conclusions: Existing therapeutic limitations indicate that more evidence-based treatment is warranted for successful management of SSc. Vasculopathy seems to be managed more rigorously, but the low retention rates of immunosuppressive/antiproliferative drugs suggest that effective and targeted disease-modifying agents are warranted.

Importance: Prior lethality analyses of suicide means have historically treated drug poisoning other than alcohol poisoning as a lumped category. Assessing risk by drug class permits better assessment of prevention opportunities., Objective: To investigate the epidemiology of drug poisoning suicides., Design, Setting, and Participants: This cross-sectional study analyzed censuses of live emergency department and inpatient discharges for 11 US states from January 1, 2011, to December 31, 2012, as well as Healthcare Cost and Utilization Project national live discharge samples for January 1 to December 31, 2012, and January 1 to December 31, 2016, and corresponding Multiple Cause of Death census data. Censuses or national samples of all medically identified drug poisonings that were deliberately self-inflicted or of undetermined intent were identified using diagnosis and external cause codes. Data were analyzed from June 2019 to January 2020., Main Outcomes and Measures: Distribution of drug classes involved in suicidal overdoses. Logistic regressions on the state data were used to calculate the odds and relative risk (RR) of death for a suicide act that involved a drug class vs similar acts excluding that class., Results: Among 421 466 drug poisoning suicidal acts resulting in 21 594 deaths, 19.6% to 22.5% of the suicidal drug overdoses involved benzodiazepines, and 15.4% to 17.3% involved opioids (46.2% men, 53.8% women, and <0.01% missing; mean age, 36.4 years). Opioids were most commonly identified in fatal suicide poisonings (33.3%-47.8%). The greatest RR for poisoning suicide completion was opioids (5.20 times the mean for suicide acts that did not involve opioids; 95% CI, 4.86-5.57; sensitivity analysis range, 3.99-6.86), followed by barbiturates (RR, 4.29; 95% CI, 3.35-5.45), antidepressants (RR, 3.22; 95% CI, 2.95-3.52), antidiabetics (RR, 2.57; 95% CI, 1.94-3.41), and alcohol (conservatively, because 30% of death certifiers do not test for alcohol; RR, 2.04; 95% CI, 1.84-2.26). The updated toxin diagnosis coding in International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, used to code the 2016 data revealed that calcium channel blockers also had a high RR of 2.24 (95% CI, 1.89-2.61). Translated to attributable fractions, approximately 81% of suicides involving opioids would not have been fatal absent opioids. Similarly, 34% of alcohol-involved suicide deaths were alcohol attributable., Conclusions and Relevance: These findings suggest that preventing access to lethal means for patients at risk for suicide should extend to drugs with high case fatality rates. Blister packing and securely storing lethal drugs seems advisable.

Phosphate is actively involved in many important biochemical pathways, such as energy and nucleic acid metabolism, cellular signaling, and bone formation. Hypophosphatemia, defined as serum phosphate levels below 2.5 mg/dL (0.81 mmol/L), is frequently observed in the course of treatment with commonly used drugs, such as diuretics, bisphosphonates, antibiotics, insulin, and antacids. Furthermore, this undesired effect may complicate the use of several novel medications, including teriparatide, denosumab, parenteral iron, and antiviral and antineoplastic agents. This review addresses drug-associated hypophosphatemia, focusing on underlying mechanisms and the most recent knowledge on this topic, in order to increase the insight of clinicians, with reference to early diagnosis and appropriate management.

Introduction: The fatal toxicity index (FTI) is a measure for assessing the relative risks of death due to the medicines prescribed in a population. This knowledge is useful for prescribers and informs medicine safety initiatives. This study aimed to calculate FTIs for the New Zealand population using three methodologies., Methods: New Zealand coronial data describing medicine-related deaths from 1 January 2008 to 31 December 2013 were retrospectively extracted from the National Coronial Information System. Three fatal toxicity indices were derived using the number of deaths attributed to each pharmaceutical as the numerator and the total defined daily doses, number of patients and number of prescriptions as denominators., Results: There were 703 medicine-related deaths, of which 627 were assessed as due to one primary contributor. Median decedent age was 48 years (interquartile range 37-58), and 319 (51%) were male. Deaths were intentional in 252 cases (40%), unintentional in 284 (45%) and unknown in 91 (15%). The majority of deaths (n = 486, 78%) occurred in the community. Opioids, antidepressants, antipsychotics and hypnotic-anxiolytics caused most fatalities. While the FTIs for individual medicines varied by denominator applied, methadone and clozapine fatalities were prominent in all three indices. The antidepressants clomipramine, dosulepin and doxepin consistently returned the highest FTIs in their group., Conclusion: New Zealand prescribers should be aware of the high relative risk of death associated with methadone and clozapine; that clomipramine, dosulepin and doxepin were identified as the most dangerous antidepressants; and that zopiclone carries a similar fatal risk to benzodiazepines. Varying results were found between the FTIs calculated, making comparisons, particularly between populations, difficult.

Retrometabolic drug design combines the structure-activity and structure-metabolism relationships, allowing the effective separation of drug action and side effects. This combination results in significant improvement of the therapeutic index. The main aim is not only to study the metabolism but to build into the drug molecule the desired metabolic route, in addition to the therapeutic activity. There are two basically different approaches to achieve this aim. Both use designed-in metabolism. The 1. chemical drug-targeting systems (CDS) and 2. soft drug, both control the drug targeting and action by strategically designed metabolism. In the case of the soft drugs, we want to rely on hydrolytic enzymes, avoiding the oxidative processes. In the present work, we focus on the clinical successes of the soft drugs designed in our laboratories. In order to show the difference, we briefly present a brain-targeted delivery system, where the originally inactive molecular construct undergoes sequential metabolism to allow specific concentration of the active drug in the brain. Among the soft drugs first we present the highly successful soft corticosteroids. Loteprednol etabonate has been used worldwide for over twenty years, and its use is constantly growing. In addition to the dramatically improved therapeutic index, the specific, serious ophthalmic side effects (elevation of intraocular pressure; glaucoma and cataract formation) were completely eliminated. Similarly designed second generation of soft corticosteroids are also presented, where the soft pharmacophore is structurally unexpected. The most recent soft drug design involves anticholinergics. Sofpironium bromide, a highly effective molecule but without the typical anticholinergic side effects, was first developed to treat hyperhidrosis, an unmet need. Phase III clinical studies were successfully completed and its marketing approval is pending. Since the soft drug design principles, methods and rules are general and specific in nature, a computerized expert system was also developed. Orv Hetil. 2020; 161(10): 363-373.

Extractables and leachables (E&L) are identified and quantified so that their impact on patient safety can be established and assessed. The uncertainty in the impact assessment is affected by the uncertainty in the substance's experimentally determined identity and concentration. Thus, these experimentally determined quantities must be reported not only in terms of their absolute result but also in terms of the uncertainty in the result, which is based on the amount and rigor of the information on which the result is based. In this way, the impact assessment can be tempered to account for the uncertainty in its input data. To facilitate the assignment and reporting of uncertainty, classification hierarchies are proposed and discussed for both identification and quantitation. Both hierarchies establish levels or degrees of identification and quantitation based on the uncertainty of the result and contain descriptions of the quality and quantity of information required to achieve a certain level within the hierarchy. The minimal levels that must be achieved to support impact assessment are also established., (© PDA, Inc. 2020.)

Given the liver's role in drug metabolism, it is uniquely sensitive to potential drug-induced liver injury (DILI) despite inherent protective mechanisms. In this article, we focus on the most common causes of DILI and their patterns of injury. Although not comprehensive, we attempt to cover several classes of commonly used drugs, and their associated patterns of injury and management., (Copyright © 2019 Elsevier Inc. All rights reserved.)