Search

The permeation of small molecules across biological membranes is a crucial process that lies at the heart of life. Permeation is involved not only in the maintenance of homeostasis at the cell level but also in the absorption and biodistribution of pharmacologically active substances throughout the human body. Membranes are formed by phospholipid bilayers that represent an energy barrier for permeating molecules. Crossing this energy barrier is assumed to be a singular event, and permeation has traditionally been described as a first-order kinetic process, proportional only to the concentration gradient of the permeating substance. For a given membrane composition, permeability was believed to be a unique property dependent only on the permeating molecule itself. We provide experimental evidence that this long-held view might not be entirely correct. Liposomes were used in copermeation experiments with a fluorescent probe, where simultaneous permeation of two substances occurred over a single phospholipid bilayer. Using an assay of six commonly prescribed drugs, we have found that the presence of a copermeant can either enhance or suppress the permeation rate of the probe molecule, often more than 2-fold in each direction. This can have significant consequences for the pharmacokinetics and bioavailability of commonly prescribed drugs when used in combination and provide new insight into so-far unexplained drug-drug interactions as well as changing the perspective on how new drug candidates are evaluated and tested.

Two-thirds of signaling substances, several sensory stimuli and over one-third of drugs act via receptors coupling to G proteins. Here, we present an online platform for G protein research with reference data and tools for analysis, visualization and design of scientific studies across disciplines and areas. This platform may help translate new pharmacological, structural and genomic data into insights on G protein signaling vital for human physiology and medicine. The G protein database is accessible at https://gproteindb.org., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Sulphonamides and their isosteres are classical inhibitors of the carbonic anhydrase (CAs, EC 4.2.1.1) metalloenzymes. The protozoan pathogen Trichomonas vaginalis encodes two such enzymes belonging to the β-class, TvaCA1 and TvaCA2. Here we report the first sulphonamide inhibition study of TvaCA1, with a series of simple aromatic/heterocyclic primary sulphonamides as well as with clinically approved/investigational drugs for a range of pathologies (diuretics, antiglaucoma, antiepileptic, antiobesity, and antitumor drugs). TvaCA1 was effectively inhibited by acetazolamide and ethoxzolamide, with K I s of 391 and 283 nM, respectively, whereas many other simple or clinically used sulphonamides were micromolar inhibitors or did not efficiently inhibit the enzyme. Finding more effective TvaCA1 inhibitors may constitute an innovative approach for fighting trichomoniasis, a sexually transmitted infection, caused by T. vaginalis .

CYP2C9 encodes a cytochrome P450 enzyme responsible for metabolizing up to 15% of small molecule drugs, and CYP2C9 variants can alter the safety and efficacy of these therapeutics. In particular, the anti-coagulant warfarin is prescribed to over 15 million people annually and polymorphisms in CYP2C9 can affect individual drug response and lead to an increased risk of hemorrhage. We developed click-seq, a pooled yeast-based activity assay, to test thousands of variants. Using click-seq, we measured the activity of 6,142 missense variants in yeast. We also measured the steady-state cellular abundance of 6,370 missense variants in a human cell line by using variant abundance by massively parallel sequencing (VAMP-seq). These data revealed that almost two-thirds of CYP2C9 variants showed decreased activity and that protein abundance accounted for half of the variation in CYP2C9 function. We also measured activity scores for 319 previously unannotated human variants, many of which may have clinical relevance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a significant threat to human health. Despite its similarity to related coronaviruses, there are currently no specific treatments for COVID-19 infection, and therefore there is an urgent need to develop therapies for this and future coronavirus outbreaks. Formation of the cap at the 5' end of viral RNA has been shown to help coronaviruses evade host defenses. Nonstructural protein 14 (nsp14) is responsible for N7-methylation of the cap guanosine in coronaviruses. This enzyme is highly conserved among coronaviruses and is a bifunctional protein with both N7-methyltransferase and 3'-5' exonuclease activities that distinguish nsp14 from its human equivalent. Mutational analysis of SARS-CoV nsp14 highlighted its role in viral replication and translation efficiency of the viral genome. In this paper, we describe the characterization and development of a high-throughput assay for nsp14 utilizing RapidFire technology. The assay has been used to screen a library of 1771 Food and Drug Administration (FDA)-approved drugs. From this, we have validated nitazoxanide as a selective inhibitor of the methyltransferase activity of nsp14. Although modestly active, this compound could serve as a starting point for further optimization.

Organoids allow the recapitulation of intestinal homeostasis and cancerogenesis in vitro; however, RNA sequencing (RNA-seq)-based methods for drug screens are missing. We develop targeted organoid sequencing (TORNADO-seq), a high-throughput, high-content drug discovery platform that uses targeted RNA-seq to monitor the expression of large gene signatures for the detailed evaluation of cellular phenotypes in organoids. TORNADO-seq is a fast, highly reproducible time- and cost-effective ($5 per sample) method that can probe cell mixtures and their differentiation state in the intestinal system. We apply this method to isolate drugs that enrich for differentiated cell phenotypes and show that these drugs are highly efficacious against cancer compared to wild-type organoids. Furthermore, TORNADO-seq facilitates in-depth insight into the mode of action of these drugs. Our technology can easily be adapted to many other systems and will allow for more systematic, large-scale, and quantitative approaches to study the biology of complex cellular systems., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective　Polypharmacy in elderly individuals may cause reduced flow of saliva and xerostomia. A dry mouth can lead to poor oral function; however, there are no reports on the relationship between polypharmacy and subjective or objective oral dysfunction. The purpose of this study was to clarify the relationship between the number of prescribed medications and subjective and objective oral dysfunction.Methods　The subjects of this study were 215 community-dwelling, elderly individuals, aged 75 years or older, who visited the dental clinic in the Chubu region for a dental health examination from January to February 2019. A medical interview was conducted to assess three items that were related to subjective oral function and record four measurements related to objective oral function. In addition, information was collected on the diseases being treated and prescribed medications. A subject with a decrease in any of the three subjective oral function categories was considered to have subjective oral dysfunction. Objective oral dysfunction was analyzed with respect to two types of oral dysfunction: a decrease in all four objective oral functions and a decrease in two or more of the four objective oral functions. Logistic regression analysis was performed to examine the relationship between subjective and objective oral dysfunction after adjustment for sex, age group, inveterate disease, and the number of prescribed medications.Results　Individuals who had eight or more prescribed medications had lower subjective oral function than those with seven or fewer medications (odds ratio, 95% confidence interval: 2.3, 1.0-5.1; P<0.05). Individuals with eight or more medications had lower scores in all four objective oral functions than those with seven or fewer medications (4.4 : 1.5-12.6, P<0.01). A decrease in two or more of the four objective oral functions was related to 10 or more prescribed medications (4.3 : 1.2-16.2, P<0.05).　In addition, taking eight or more prescribed medications was associated with a decrease in either subjective oral function or all four objective oral functions (8.1 : 2.1-30.8, P<0.01). A decrease in either subjective oral function or two or more objective oral functions was related to taking 10 or more prescribed medications (4.9 : 1.6-15.6, P<0.01).Conclusion　In conclusion, more than eight prescribed pharmaceutical medications in the elderly is associated with subjective or objective oral dysfunction.

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.

The public Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is an innovative digital ecosystem that relates toxicological information for chemicals, genes, phenotypes, diseases, and exposures to advance understanding about human health. Literature-based, manually curated interactions are integrated to create a knowledgebase that harmonizes cross-species heterogeneous data for chemical exposures and their biological repercussions. In this biennial update, we report a 20% increase in CTD curated content and now provide 45 million toxicogenomic relationships for over 16 300 chemicals, 51 300 genes, 5500 phenotypes, 7200 diseases and 163 000 exposure events, from 600 comparative species. Furthermore, we increase the functionality of chemical-phenotype content with new data-tabs on CTD Disease pages (to help fill in knowledge gaps for environmental health) and new phenotype search parameters (for Batch Query and Venn analysis tools). As well, we introduce new CTD Anatomy pages that allow users to uniquely explore and analyze chemical-phenotype interactions from an anatomical perspective. Finally, we have enhanced CTD Chemical pages with new literature-based chemical synonyms (to improve querying) and added 1600 amino acid-based compounds (to increase chemical landscape). Together, these updates continue to augment CTD as a powerful resource for generating testable hypotheses about the etiologies and molecular mechanisms underlying environmentally influenced diseases., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

One of the most prominent topics in drug discovery is efficient exploration of the vast drug-like chemical space to find synthesizable and novel chemical structures with desired biological properties. To address this challenge, we created the DrugSpaceX (https://drugspacex.simm.ac.cn/) database based on expert-defined transformations of approved drug molecules. The current version of DrugSpaceX contains >100 million transformed chemical products for virtual screening, with outstanding characteristics in terms of structural novelty, diversity and large three-dimensional chemical space coverage. To illustrate its practical application in drug discovery, we used a case study of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, to show DrugSpaceX performing a quick search of initial hit compounds. Additionally, for ligand identification and optimization purposes, DrugSpaceX also provides several subsets for download, including a 10% diversity subset, an extended drug-like subset, a drug-like subset, a lead-like subset, and a fragment-like subset. In addition to chemical properties and transformation instructions, DrugSpaceX can locate the position of transformation, which will enable medicinal chemists to easily integrate strategy planning and protection design., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Peptide-drug conjugates are organic molecules composed of (i) a small drug molecule, (ii) a peptide and (iii) a linker. The drug molecule is mandatory for the biological action, however, its efficacy can be enhanced by targeted delivery, which often also reduces unwanted side effects. For site-specificity the peptide part is mainly responsible. The linker attaches chemically the drug to the peptide, but it could also be biodegradable which ensures controlled liberation of the small drug. Despite the importance of the field, there is no public comprehensive database on these species. Herein we describe ConjuPepBD, a freely available, fully annotated and manually curated database of peptide drug conjugates. ConjuPepDB contains basic information about the entries, e.g. CAS number. Furthermore, it also implies their biomedical application and the type of chemical conjugation employed. It covers more than 1600 conjugates from ∼230 publications. The web-interface is user-friendly, intuitive, and useable on several devices, e.g. phones, tablets, PCs. The webpage allows the user to search for content using numerous criteria, chemical structure and a help page is also provided. Besides giving quick insight for newcomers, ConjuPepDB is hoped to be also helpful for researchers from various related fields. The database is accessible at: https://conjupepdb.ttk.hu/., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that provides information on drug-gene interactions and druggable genes from publications, databases, and other web-based sources. Drug, gene, and interaction data are normalized and merged into conceptual groups. The information contained in this resource is available to users through a straightforward search interface, an application programming interface (API), and TSV data downloads. DGIdb 4.0 is the latest major version release of this database. A primary focus of this update was integration with crowdsourced efforts, leveraging the Drug Target Commons for community-contributed interaction data, Wikidata to facilitate term normalization, and export to NDEx for drug-gene interaction network representations. Seven new sources have been added since the last major version release, bringing the total number of sources included to 41. Of the previously aggregated sources, 15 have been updated. DGIdb 4.0 also includes improvements to the process of drug normalization and grouping of imported sources. Other notable updates include the introduction of a more sophisticated Query Score for interaction search results, an updated Interaction Score, the inclusion of interaction directionality, and several additional improvements to search features, data releases, licensing documentation and the application framework., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The US Food and Drug Administration (FDA) and the National Center for Advancing Translational Sciences (NCATS) have collaborated to publish rigorous scientific descriptions of substances relevant to regulated products. The FDA has adopted the global ISO 11238 data standard for the identification of substances in medicinal products and has populated a database to organize the agency's regulatory submissions and marketed products data. NCATS has worked with FDA to develop the Global Substance Registration System (GSRS) and produce a non-proprietary version of the database for public benefit. In 2019, more than half of all new drugs in clinical development were proteins, nucleic acid therapeutics, polymer products, structurally diverse natural products or cellular therapies. While multiple databases of small molecule chemical structures are available, this resource is unique in its application of regulatory standards for the identification of medicinal substances and its robust support for other substances in addition to small molecules. This public, manually curated dataset provides unique ingredient identifiers (UNIIs) and detailed descriptions for over 100 000 substances that are particularly relevant to medicine and translational research. The dataset can be accessed and queried at https://gsrs.ncats.nih.gov/app/substances., (Published by Oxford University Press on behalf of Nucleic Acids Research 2020.)

Inhibitors that form covalent bonds with their targets have traditionally been considered highly adventurous due to their potential off-target effects and toxicity concerns. However, with the clinical validation and approval of many covalent inhibitors during the past decade, design and discovery of novel covalent inhibitors have attracted increasing attention. A large amount of scattered experimental data for covalent inhibitors have been reported, but a resource by integrating the experimental information for covalent inhibitor discovery is still lacking. In this study, we presented Covalent Inhibitor Database (CovalentInDB), the largest online database that provides the structural information and experimental data for covalent inhibitors. CovalentInDB contains 4511 covalent inhibitors (including 68 approved drugs) with 57 different reactive warheads for 280 protein targets. The crystal structures of some of the proteins bound with a covalent inhibitor are provided to visualize the protein-ligand interactions around the binding site. Each covalent inhibitor is annotated with the structure, warhead, experimental bioactivity, physicochemical properties, etc. Moreover, CovalentInDB provides the covalent reaction mechanism and the corresponding experimental verification methods for each inhibitor towards its target. High-quality datasets are downloadable for users to evaluate and develop computational methods for covalent drug design. CovalentInDB is freely accessible at http://cadd.zju.edu.cn/cidb/., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Docking is in demand for the rational computer aided structure based drug design. A review of docking methods and programs is presented. Different types of docking programs are described. They include docking of non-covalent small ligands, protein-protein docking, supercomputer docking, quantum docking, the new generation of docking programs and the application of docking for covalent inhibitors discovery. Taking into account the threat of COVID-19, we present here a short review of docking applications to the discovery of inhibitors of SARS-CoV and SARS-CoV-2 target proteins, including our own result of the search for inhibitors of SARS-CoV-2 main protease using docking and quantum chemical post-processing. The conclusion is made that docking is extremely important in the fight against COVID-19 during the process of development of antivirus drugs having a direct action on SARS-CoV-2 target proteins., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: A multitude of different versions of the same medication with different inactive ingredients are currently available. It has not been quantified how this has evolved historically. Furthermore, it is unknown whether healthcare professionals consider the inactive ingredient portion when prescribing medications to patients., Methods: We used data mining to track the number of available formulations for the same medication over time and correlate the number of available versions in 2019 to the number of manufacturers, the years since first approval, and the number of prescriptions. A focused survey among healthcare professionals was conducted to query their consideration of the inactive ingredient portion of a medication when writing prescriptions., Results: The number of available versions of a single medication have dramatically increased in the last 40 years. The number of available, different versions of medications are largely determined by the number of manufacturers producing this medication. Healthcare providers commonly do not consider the inactive ingredient portion when prescribing a medication., Conclusions: A multitude of available versions of the same medications provides a potentially under-recognized opportunity to prescribe the most suitable formulation to a patient as a step towards personalized medicine and mitigate potential adverse events from inactive ingredients.

Compounding of medications, such as crushing tablets and dispersing the contents of capsules, is a common practice in pharmacies and hospitals worldwide and is often done to provide age-appropriate formulations for oral use in pediatric patients. In the present study, a retrospective, descriptive, questionnaire-based survey was conducted to clarify the current status of drug compounding for pediatric patients in Japan. An electronic questionnaire was distributed to 740 hospitals in Japan with pediatric beds, and 208 (28.1%) of these hospitals responded. The total instances of compounding numbered 14,864 (9.6% of the total pediatric oral prescriptions) and comprised 266 active pharmaceutical ingredients (APIs), one-third of which (98 APIs) were compounded even though flexible dosage forms were available. The three most frequently compounded drugs were dantrolene sodium capsules (1152 prescriptions), ramelteon tablets (726 prescriptions), and hydrocortisone tablets (652 prescriptions), all of which were prescribed and administered in powder form. Although compounding of medications frequently varied by the patients' age, steroids such as prednisolone, dexamethasone, and hydrocortisone were commonly compounded in all age groups. To ensure the quality and safety of these compounded medications, developing a standard protocol for compounding methods is urgently needed in Japan., 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 © 2020 Elsevier B.V. All rights reserved.)

There are many gaps in scientific knowledge about the clinical significance of pharmacokinetic natural product-drug interactions (NPDIs) in which the natural product (NP) is the precipitant and a conventional drug is the object. The National Center for Complimentary and Integrative Health created the Center of Excellence for NPDI Research (NaPDI Center) (www.napdi.org) to provide leadership and guidance on the study of pharmacokinetic NPDIs. A key contribution of the Center is the first user-friendly online repository that stores and links pharmacokinetic NPDI data across chemical characterization, metabolomics analyses, and pharmacokinetic in vitro and clinical experiments (repo.napdi.org). The design is expected to help researchers more easily arrive at a complete understanding of pharmacokinetic NPDI research on a particular NP. The repository will also facilitate multidisciplinary collaborations, as the repository links all of the experimental data for a given NP across the study types. The current work describes the design of the repository, standard operating procedures used to enter data, and pharmacokinetic NPDI data that have been entered to date. To illustrate the usefulness of the NaPDI Center repository, more details on two high-priority NPs, cannabis and kratom, are provided as case studies. SIGNIFICANCE STATEMENT: The data and knowledge resulting from natural product-drug interaction (NPDI) studies is distributed across a variety of information sources, rendering difficulties to find, access, and reuse. The Center of Excellence for NPDI Research addressed these difficulties by developing the first user-friendly online repository that stores data from in vitro and clinical pharmacokinetic NPDI experiments and links them with study data from chemical characterization and metabolomics analyses of natural products that are also stored in the repository., (Copyright © 2020 by The Author(s).)

SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or Food and Drug Administration-approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein., (© 2020 International Union of Biochemistry and Molecular Biology.)

Objective. To assess student pharmacists' ability to impact the administration of complex prescription regimens using the universal medication schedule in a standardized laboratory exercise. Methods. First and third professional year (P1 and P3) student pharmacists at three colleges of pharmacy completed a required activity to simplify and organize a complex medication regimen. Using a medication box, students planned how and when they would advise a patient to take seven fictitious medications over a 24-hour period. Picture documentation of each students' activity was used for data analysis. Descriptive statistics were used to compare P1 and P3 students' performance, and an independent t test was used to assess the frequency of daily dosing. A chi-square analysis was used to compare differences between P1 and P3 students, and analysis of variance was used to compare differences among individual institutions. Results. Of 842 students invited, 459 P1 and 372 P3 students (98.7%) consented to participate. Student pharmacists recommended 5.1 (SD=1.0; Range=3-11) dosing intervals per 24 hours, with 27% of students successfully reducing the regimen to four total intervals. The P3 students were more effective than the P1 students in planning the number of dosing intervals (4.9 vs 5.4 per 24 hours). Conclusion. Student pharmacists may become more effective at organizing complex medication regimens as they proceed through the pharmacy curriculum and gain experience. Student pharmacists can translate what they learned from this exercise to potentially improve patients' self-organized medication regimens., (© 2020 American Association of Colleges of Pharmacy.)

Accumulating evidence has shown that drug-target interactions (DTIs) play a crucial role in the process of genomic drug discovery. Although biological experimental technology has made great progress, the identification of DTIs is still very time-consuming and expensive nowadays. Hence it is urgent to develop in silico model as a supplement to the biological experiments to predict the potential DTIs. In this work, a new model is designed to predict DTIs by incorporating chemical sub-structures and protein evolutionary information. Specifically, we first use Position-Specific Scoring Matrix (PSSM) to convert the protein sequence into the numerical descriptor containing biological evolutionary information, then use Discrete Cosine Transform (DCT) algorithm to extract the hidden features and integrate them with the chemical sub-structures descriptor, and finally utilize Rotation Forest (RF) classifier to accurately predict whether there is interaction between the drug and the target protein. In the 5-fold cross-validation (CV) experiment, the average accuracy of the proposed model on the benchmark datasets of Enzymes, Ion Channels, GPCRs and Nuclear Receptors reached 0.9140, 0.8919, 0.8724 and 0.8111, respectively. In order to fully evaluate the performance of the proposed model, we compare it with different feature extraction model, classifier model, and other state-of-the-art models. Furthermore, we also implemented case studies. As a result, 8 of the top 10 drug-target pairs with the highest prediction score were confirmed by related databases. These excellent results indicate that the proposed model has outstanding ability in predicting DTIs and can provide reliable candidates for biological experiments.

Background A frequent problem in ageing patients, and thus in nursing home residents, is dysphagia, affecting the ability to swallow solid dosage forms. A promising and personalized drug delivery system for this patient group is the orodispersible film. Orodispersible films could be prepared extemporaneously in a (hospital) pharmacy setting or in specialty compounding community pharmacies using the solvent casting method. Little has been done to systematically investigate which medications should be chosen for orodispersible film formulation development. Objective In this study, the medication use of nursing home residents was examined to identify medications that are suitable for orodispersible film formulation development. Setting Nursing homes of three Northern provinces of Netherlands. Method Medication intake data from 427 nursing home residents from nine nursing homes from the three northern provinces of the Netherlands were used to identify candidates for orodispersible film formulation development. A stepwise approach, with exclusion steps, was used. Selection criteria included systemic use with a maximum amount of 100 mg per dose unit, no commercially available suitable dosage forms for administration in dysphagia, indication for diseases associated with dysphagia. Furthermore, the characteristics of the active pharmaceutical ingredient needed for the orodispersible film formulation development, such as water solubility and taste, were reviewed. Main outcome measure Active pharmaceutical ingredients suitable for orodispersible film formulation development. Results The nursing home residents used three hundred forty one different medications. Of those, 34 active pharmaceutical ingredients from six therapeutic groups were considered as candidates for orodispersible film formulation development. Most of these active pharmaceutical ingredients have a bitter taste and poor water solubility, which is a challenge for orodispersible film production. Conclusions The most suitable active pharmaceutical ingredient candidates for manufacturing of orodispersible films for the ageing patient population may be the combination of levodopa and carbidopa used to treat the symptoms of Parkinson's disease, and baclofen used to treat spasticity.

For a ketogenic diet to be effective, strict control of carbohydrate intake is paramount. Factors such as medications may upset this delicate balance. The aim of this commentary is to provide physicians who are treating patients with a ketogenic diet, with a step-by-step guide. A list of unsuitable excipients was established. A flowchart with the title "Can this drug be prescribed to a patient following a ketogenic diet?" was then drafted. The first step is to determine the international nonproprietary name, dosage, form and composition. The amount of unsuitable excipients is calculated. Suitable alternatives may be discussed with the pharmacist. As a last resort, the ketogenic diet itself may need to be adapted. The answers provided are included in a database. Determining the amount of unsuitable excipients is a complex task requiring pharmaceutical expertise. Our flowchart can be used in order to provide a clear pathway for answering such questions.

Polysaccharide (PS) nanoparticles (NP) are fascinating materials that combine huge application potential with the unique beneficial features of natural biopolymers. Different types of PS-NP can be distinguished depending on the basic preparation principles (top-down vs bottom-up vs coating of nanomaterials) and the material from which they are obtained (native PS vs chemically modified PS derivatives vs nanocomposites). This review provides a comprehensive overview of an approach towards PS-NP that has gained rapidly increasing interest within the last decade; the nanoself-assembling of hydrophobic PS derivatives. This facile process is easy to perform and offers a broad structural diversity in terms of the PS backbone and the additional functionalities that can be introduced. Fundamental principles of different NP preparation techniques along with useful characterization methods are presented in this work. A comprehensive summary of PS-NP prepared by different techniques and with various PS backbones and types/amounts of hydrophobic substituents is given. The intention is to demonstrate how different parameters determine the size, size distribution, and zeta-potential of the particles. Moreover, application trends in biomedical areas are highlighted in which tailored functional PS-NP are evaluated and constantly developed further., (© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lack of a safe and convenient disposal method for expired and unused medications may lead to many problems such as accidental exposure, intentional misuse, and food and water contamination. Activated carbon can offer safe disposal of medications due to its highly porous structure, which exerts strong physical adsorption forces with chemicals. This study aimed to evaluate the efficiency of an activated carbon-based drug disposal system for deactivating three model sedative prescription medications. Deactivation was performed by mixing the medication, activated carbon, and tap water. Desorption was evaluated by exposing the deactivation system to wash-out solutions. Rapid, precise, accurate, and sensitive HPLC-UV method for each drug was successfully developed, validated and employed. Results of the 28-day deactivation study showed that on average, more than 94.00% of drugs were rapidly deactivated within 8 hours. All drugs reached more than 99.00% deactivation by the end of 28-day period. Desorption study demonstrated that all medications were retained by the system, with insignificant amount of drug (0.25%) leached into the washout solutions within 24 hours. In conclusion, activated carbon rapidly and successfully deactivated the medications tested, suggesting activated carbon-based drug disposal system provides a convenient, secure, and effective method for unused medication.

Background: Transporter-mediated drug-nutrient interactions have the potential to cause serious adverse events. However, unlike drug-drug interactions, these drug-nutrient interactions receive little attention during drug development. The clinical importance of drug-nutrient interactions was highlighted when a phase III clinical trial was terminated due to severe adverse events resulting from potent inhibition of thiamine transporter 2 (ThTR-2; SLC19A3)., Objective: In this study, we tested the hypothesis that therapeutic drugs inhibit the intestinal thiamine transporter ThTR-2, which may lead to thiamine deficiency., Methods: For this exploration, we took a multifaceted approach, starting with a high-throughput in vitro primary screen to identify inhibitors, building in silico models to characterize inhibitors, and leveraging real-world data from electronic health records to begin to understand the clinical relevance of these inhibitors., Results: Our high-throughput screen of 1360 compounds, including many clinically used drugs, identified 146 potential inhibitors at 200 μM. Inhibition kinetics were determined for 28 drugs with half-maximal inhibitory concentration (IC50) values ranging from 1.03 μM to >1 mM. Several oral drugs, including metformin, were predicted to have intestinal concentrations that may result in ThTR-2-mediated drug-nutrient interactions. Complementary analysis using electronic health records suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs found to significantly inhibit ThTR-2, particularly in vulnerable populations (e.g., individuals with alcoholism)., Conclusions: Our comprehensive analysis of prescription drugs suggests that several marketed drugs inhibit ThTR-2, which may contribute to thiamine deficiency, especially in at-risk populations., (Copyright © The Author(s) 2019.)

Background: Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved)., Objective: Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance., Methods: The University of Washington Drug Interaction Database (DIDB ® ) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends., Results: Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight > 1 kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP > 3) and a high total polar surface area (> 75 Å 2 ) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively., Conclusions: The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity.

Levofloxacin is a third-generation fluoroquinolone antimicrobials drug that inhibits bacterial DNA replication. Driven by huge profit, one kind of particular counterfeit, e.g., repackaged expired tablets, becomes very common especially in developing countries. The feasibility of identifying expired levofloxacin tablets by combining NIR spectroscopy with chemometrics was investigated. Five kinds of levofloxacin samples from different manufacturers were collected for experiment. Two types of expired mode were considered and a simple model-independent algorithm was used for feature selection. Principal component analysis (PCA) was used for exploratory analysis and simple discriminant analysis. Taking seventy samples as the target class, a final one-class model based on Data Driven Soft Independent Modeling by Class Analogy with abbreviation DD-SIMCA was constructed, which achieved 97% sensitivity and 100% specificity on the independent set composed of 34 unexpired and 128 expired tablets. These results confirm that the combination of NIR spectroscopy, feature selection and class-modeling is feasible for identifying the expired levofloxacin tablets. Such a method can be extended to the analysis of similar drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A common drug repositioning strategy is the re-application of an existing drug to address alternative targets. A crucial aspect to enable such repurposing is that the drug's binding site on the original target is similar to that on the alternative target. Based on the assumption that proteins with similar binding sites may bind to similar drugs, the 3D substructure similarity data can be used to identify similar sites in other proteins that are not known targets. The Drug ReposER (DRug REPOSitioning Exploration Resource) web server is designed to identify potential targets for drug repurposing based on sub-structural similarity to the binding interfaces of known drug binding sites. The application has pre-computed amino acid arrangements from protein structures in the Protein Data Bank that are similar to the 3D arrangements of known drug binding sites thus allowing users to explore them as alternative targets. Users can annotate new structures for sites that are similarly arranged to the residues found in known drug binding interfaces. The search results are presented as mappings of matched sidechain superpositions. The results of the searches can be visualized using an integrated NGL viewer. The Drug ReposER server has no access restrictions and is available at http://mfrlab.org/drugreposer/., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Alternative to the conventional search for single-target, single-compound treatments, combination therapies can open entirely new opportunities to fight antibiotic resistance. However, combinatorial complexity prohibits experimental testing of drug combinations on a large scale, and methods to rationally design combination therapies are lagging behind. Here, we developed a combined experimental-computational approach to predict drug-drug interactions using high-throughput metabolomics. The approach was tested on 1,279 pharmacologically diverse drugs applied to the gram-negative bacterium Escherichia coli. Combining our metabolic profiling of drug response with previously generated metabolic and chemogenomic profiles of 3,807 single-gene deletion strains revealed an unexpectedly large space of inhibited gene functions and enabled rational design of drug combinations. This approach is applicable to other therapeutic areas and can unveil unprecedented insights into drug tolerance, side effects, and repurposing. The compendium of drug-associated metabolome profiles is available at https://zampierigroup.shinyapps.io/EcoPrestMet, providing a valuable resource for the microbiological and pharmacological communities., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Ascertain the optimal interaction scoring criteria for the Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun drug repurposing to improve benchmarking performance, thereby enabling more accurate prediction of novel therapeutic drug-indication pairs., Results: We have investigated and enhanced the interaction scoring criteria in the bioinformatic docking protocol in the newest version of our platform (v1.5), with the best performing interaction scoring criterion yielding increased benchmarking accuracies from 11.7% in v1 to 12.8% in v1.5 at the top10 cutoff (the most stringent one) and correspondingly from 24.9 to 31.2% at the top100 cutoff.

Background: Prescription food for special medical purposes (FSMPs) and modified milk products (MMPs), available in pharmacies, are important for newborns and infants that are not breastfed. In the scientific literature there is a lack of comprehensive studies and corresponding safety assessment of the essential trace elements in these products., Objective: The aim of this article was determination of Cu, Mn and Zn levels in the most frequently available prescription FSMPs (n = 6) and MMPs (n = 6) available in Polish pharmacies., Methods: Flame absorption spectrometry (FAAS) following microwave induced digestion (concentrated nitric acid) was applied to determine the levels of the elements in the products., Results: Our studies are based on a triple approach (1) the "raw results" of Cu, Mn and Zn levels (products in powdered form), (2) single intake - the level of each essential trace element consumed in one portion, (3) the daily intake depending on age and weight including comparison with Adequate Intake established by European Food Safety Authority., Conclusion: The results show the occurrence of differences between the manufacturer's declared composition and the finished product for consumption. The prescription FSMPs in comparison to MMPs available in Polish pharmacies contain similar levels of Cu, Mn and Zn. Our results show additionally that all of the products do not represent a health hazard to the newborns and infants. This is a pioneer study in terms of the safety assessment, and quality of prescription FSMPs and MMPs available in Polish pharmacies from toxicological and nutritional point of view., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Objectives: Drugs used to treat gastrointestinal diseases (GI drugs) are widely used either as prescription or over-the-counter (OTC) medications and belong to both the 10 most prescribed and 10 most sold OTC medications worldwide. The objective of this review article is to discuss the most frequent interactions between GI and other drugs, including identification of the mechanisms behind these interactions, where possible., Key Findings: Current clinical practice shows that in many cases, these drugs are administered concomitantly with other drug products. Due to their metabolic properties and mechanisms of action, the drugs used to treat gastrointestinal diseases can change the pharmacokinetics of some coadministered drugs. In certain cases, these interactions can lead to failure of treatment or to the occurrence of serious adverse events. The mechanism of interaction depends highly on drug properties and differs among therapeutic categories. Understanding these interactions is essential to providing recommendations for optimal drug therapy., Summary: Interactions with GI drugs are numerous and can be highly significant clinically in some cases. While alterations in bioavailability due to changes in solubility, dissolution rate, GI transit and metabolic interactions can be (for the most part) easily identified, interactions that are mediated through other mechanisms, such as permeability or microbiota, are less well-understood. Future work should focus on characterising these aspects., (© 2018 Royal Pharmaceutical Society.)

Purpose: Some drug products contain phthalates as excipients, and in vitro studies have demonstrated that phthalates interfere with cellular mechanisms involved in colorectal cancer development. We therefore examined the association between cumulative phthalate exposure from drug products and risk of colorectal adenocarcinomas., Methods: We used the Danish Cancer Registry to identify all patients with incident colorectal adenocarcinoma from 2008 to 2015 (n = 25 814). Each cancer case was matched to ten population controls. Linking information from Danish registers, we quantified cumulative phthalate exposure to the ortho-phthalates diethyl phthalate (DEP) and dibutyl phthalate (DBP) as well as enteric phthalate polymers from orally administered drugs. The association between cumulative phthalate exposure and colorectal cancer was estimated using conditional logistic regression., Results: Cumulative exposure to ortho-phthalates exceeding 500 mg was associated with lower odds of colorectal cancer diagnosis (OR adj  = 0.89; 95% CI, 0.81-0.96). Similar associations were observed for all DEP exposure exceeding 500 mg. Subgroup analysis excluding NSAID users, demonstrated that ortho-phthalate exposure was positively associated with colorectal cancer (OR adj  = 1.26; 95% CI, 1.05-1.51)., Conclusion: We found an apparent overall protective effect of cumulative phthalate exposure from drug excipients for colorectal adenocarcinoma. Omitting NSAID users reversed the signal and suggested a slightly increased risk associated with high cumulative ortho-phthalate exposure., (© 2019 John Wiley & Sons, Ltd.)

There is currently a lack of risk assessments around Pb and Cd in prescription food for special medical purposes (FSMPs) and modified milk products available in from pharmacies in Poland. This article describes and evaluates a toxicological analysis of lead and cadmium in prescription FSMPs (n = 6) and modified milk products (n = 6) available in Polish pharmacies. The metals were determined using electrothermal atomisation atomic absorption spectrometry. To make the appropriate risk assessment, we considered (1) the levels of lead and cadmium in a powdered product, (2) the amount of the metals consumed in one portion (single exposure), (3) the daily dose depending on age (months) and body weight and (4) the weekly intake of Pb and Cd in samples in comparison to provisional tolerable weekly intake (PTWI). The results demonstrated that the samples analysed do not represent a health hazard to newborns and infants. This study is important because of the concerns around the complex risk assessment of prescription FSMP's and modified milk products available in Polish pharmacies related to lead and cadmium., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

In 2010, Congress created an abbreviated application pathway for biosimilars, versions of approved biologics made by different manufacturers. However, as of November 1, 2018, the US Food and Drug Administration (FDA) had approved only 13 biosimilars under this pathway, of which just 6 were available for patients to use. We review the history of US regulation of biologics and identify manufacturing, regulatory, and marketing issues that have limited biosimilar market entry and uptake, concluding with recommendations for reform., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Study Question: Does phthalate exposure from prescription drugs affect semen quality?, Summary Answer: Exposure to phthalate-containing drugs is associated with poor semen quality., What Is Known Already: Phthalates and their metabolites have been shown to disrupt the hormone signalling in animal studies. One study has shown associations between medicinal phthalate exposure and poor semen quality, suggesting similar effects in humans., Study Design, Size, Duration: We included 18 515 males with poor semen quality (cases) and 31 063 males with normal semen quality (controls) registered in the Danish IVF Registry from 2006 to 2016., Participants/materials, Setting, Methods: Exposure to phthalate-containing drugs was assessed from the Danish Register of Medicinal Product Statistics. Outcome measures were obtained at the first contact with the fertility clinic, and categorized according to the International Classification of Diseases (ICD-10). The association between current use of phthalate-containing medications <90 days prior to semen sampling and reduced semen quality was analysed using unconditional logistic regression, adjusting for potential confounders., Main Results and the Role of Chance: In total, 57 cases and 72 controls redeemed at least one prescription for a drug containing ortho-phthalates in the 90 days before their first semen sample, yielding an adjusted odds ratio (OR) of 1.30 (95% CI: 0.91-1.85) for poor semen quality when compared to males exposed to phthalate-free generic drugs. Similarly, 81 cases and 78 controls exposed to a drug containing polymers had increased odds of poor semen quality (OR = 1.71, 95% CI: 1.24-2.35). Current exposure to polymer containing products from alimentary tract and metabolism drugs was associated with the highest OR of 2.80 (95% CI: 1.63-4.84). Comparing males exposed to drugs containing ortho-phthalates or polymers with males unexposed to prescription drugs, we found adjusted ORs of 1.32 (95% CI: 0.93-1.87) and 1.73 (95% CI: 1.26-2.36), respectively. We saw no clear relationship between degree of exposure and odds of poor semen quality., Limitations, Reasons for Caution: The reliance on ICD-10 based register data restricted our ability to relate phthalate exposure to detailed semen parameters. Furthermore, due to imperfections in the registry, we could only include the first semen sample and could not follow semen quality over time., Wider Implications of the Findings: Our results support the likely negative effect of phthalate exposure from medicinal drugs on semen quality. As exposures from medicinal products are readily avoidable, our findings may be of relevance to regulatory authorities., Study Funding/competing Interest(s): This work was supported by Odense University Hospital, Denmark (Grant number A1003). None of the authors declare conflict of interest.

Antibodies against polyethylene glycol (PEG) can critically jeopardize the efficacy and safety of PEGylated therapeutics. For some PEG-drugs, a sizeable fraction of patients develop anti-PEG antibodies (APA), leading to reduced efficacy and potential adverse events. We surveyed physicians from several specialties to assess their awareness of APA. Overall, 83% of the physicians surveyed indicated that they have recently prescribed PEGylated drugs. Although 91% of respondents were aware of antidrug antibodies in general, only 22% were aware of APA responses. Further, there was limited awareness (35%) of PEG's inclusion in prescribed PEGylated therapeutics. These findings bring to light a need for improved awareness of APA, potentially via targeted education of physicians who prescribe specific PEGylated therapeutics that could induce or are otherwise affected by APA. Finally, it will be critical to quantitate the extent of knowledge transfer from the research community to clinicians, especially on topics of patient safety., (© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: In the past couple of years, the demand of galenic compounds has risen sharply. In order to plan the activity, our team designed and set up a database which stores all the necessary information related to drugs and ingredients. This allows our internal Galenic Laboratory to better manage the pharmaceutical prescriptions for the hospital and the outpatients, optimizing the use of raw materials., Methods: The application is based on the interconnection of prescription-related aspects (patients' and prescriber's details and prescription information). The prescription name is linked to the list of substances, which allows to monitor the stock levels. Inserting the daily dosage into the system, our personnel can calculate the monthly supply of the medicine. Each prescription contains specific warnings on printable labels. A printed sheet, inclusive of label and checks on the final preparation, is produced for each prescription., Results: After a testing phase, the application gradually replaced our traditional process of pharmaceutical activity management, allowing for a more accurate scheduling of the medicine requests. The worksheet and its specific label are automatically generated. Then a prediction scheme is generated for the ordinary programmable galenic activity., Conclusions: The project successfully achieved the following goals: 1) automate the information flow related to preparations; 2) improve the response time in terms of drug preparation and delivery; 3) minimize the number of emergencies.

G protein-coupled receptors are the most abundant mediators of both human signalling processes and therapeutic effects. Herein, we report GPCRome-wide homology models of unprecedented quality, and roughly 150 000 GPCR ligands with data on biological activities and commercial availability. Based on the strategy of 'Less model - more Xtal', each model exploits both a main template and alternative local templates. This achieved higher similarity to new structures than any of the existing resources, and refined crystal structures with missing or distorted regions. Models are provided for inactive, intermediate and active states-except for classes C and F that so far only have inactive templates. The ligand database has separate browsers for: (i) target selection by receptor, family or class, (ii) ligand filtering based on cross-experiment activities (min, max and mean) or chemical properties, (iii) ligand source data and (iv) commercial availability. SMILES structures and activity spreadsheets can be downloaded for further processing. Furthermore, three recent landmark publications on GPCR drugs, G protein selectivity and genetic variants have been accompanied with resources that now let readers view and analyse the findings themselves in GPCRdb. Altogether, this update will enable scientific investigation for the wider GPCR community. GPCRdb is available at http://www.gpcrdb.org., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: In 2014, the US Food and Drug Administration limited the production of prescription acetaminophen-opioid combination products to 325 mg per dose unit. The goal of this mandate was to decrease the likelihood of unintentional acetaminophen hepatotoxicity. This study was designed to determine if this federal regulation has succeeded in reducing unintentional acetaminophen-induced hepatotoxicity from opioid combination products., Methods: Using data from the National Poison Data System (NPDS), we analyzed all calls to US Poison Control Centers in the years 2013 and 2015 for acetaminophen-opioid combination product exposures. We then excluded cases that were classified as intentional and those aged 12 years and younger. We used a primary endpoint of N-acetylcysteine administration; secondary endpoints included evidence of hepatotoxicity as aspartate aminotransferase elevation, opioid antagonist administration and severity of overall medical outcome., Results: A total of 18,259 calls between the two yearlong periods met inclusion criteria. 5.16 and 5.01% of calls resulted in N-acetylcysteine administration in 2013 and 2015, respectively. 3.63 and 4.02% received naloxone in 2013 and 2015, respectively, and 0.9% in each year developed hepatotoxicity. Rates of N-acetylcysteine administration, naloxone administration, and hepatotoxicity did not differ significantly between 2013 and 2015. Severity of medical outcome was worse in 2015 as compared to 2013 with more cases being categorized as "major effect" and fewer cases being categorized as "no effect.", Conclusions: The Food and Drug Administration limitation on acetaminophen content per dose unit in opioid combination products did not reduce the occurrence of unintentional acetaminophen-induced hepatotoxicity or N-acetylcysteine administration as reported to NPDS.

Objective: The Food and Drug Administration approved the extended-release/long-acting (ER/LA) opioid analgesics risk evaluation and mitigation strategies (REMS) in July 2012 to educate healthcare providers and patients about safe and appropriate opioid analgesic use. The authors evaluated the impact of the REMS on ER/LA opioid analgesic utilization, overall and stratified by patient characteristics and prescriber type associated with greater expected need for analgesia., Design: Retrospective repeated cross-sectional study. QuintilesIMS's National Prescription Audit™ and LifeLink™ patient-level longitudinal prescription databases measured prescription volumes, projected to national estimates., Main Outcome Measures: Changes were assessed in ER/LA opioid analgesic prescriptions dispensed from the 2-year pre-REMS implementation (July 2010 to June 2012) to the 18-month post-REMS implementation (July 2013 to December 2014) periods (with 12-month transitional implementation period in between)., Results: Average quarterly ER/LA opioid prescription volume significantly decreased by 4.3 percent from Preimple-mentation to the Active Period (5.58 vs 5.34 million, p < 0.001). Differences in prescription volume change were observed between age, gender, and payer types. Prescription volume either significantly decreased or remained stable from Preimplementation to the Active Period among most provider specialties evaluated. The largest volume decreases were observed for dentists (-48.5 percent) and emergency medicine specialists (-25.5 percent) (both p < 0.001). The largest increases were observed for nurse practitioners (+33.7 percent) and physician assistants (+31.2 percent; both p < 0.001), whose overall prescribing of nonopioid medications also increased., Conclusions: A significant decrease in dispensed ER/LA opioid prescriptions was observed following REMS implementation compared to Preimplementation. The impact on volume varied by patient characteristics and prescriber specialty. The REMS program, in conjunction with other healthcare policies and initiatives, likely influenced these observations.

Objective: Misuse of codeine-containing medicines in combination with new psychoactive substances (NPS) is inadequately described. This study characterises codeine consumption amongst NPS users and non-NPS users to provide warning of health issues., Methods: Online survey conducted between July 2015 and March 2016., Results: Out of 340 respondents, residing in a country in Europe and using codeine recently, 63.8% were female. Mean age: 34.9 years (SD = 12.4). Substance use included NPS (18.5%) and illicit controlled drugs (55.9%). Factors relating to codeine use found to significantly predict NPS use were consuming codeine extracted from combination tablets (OR = 16.79, 95% CI [8.67, 32.51]), obtaining codeine from friends, family, and acquaintances (OR = 3.98, 95% CI [1.82, 8.7]), use of illicit controlled drugs (OR = 34.99, 95% CI [8.39, 145.94]) and use of codeine to experience euphoria (OR = 6.41, 95% CI [3.42, 12.04])., Conclusions: Amongst NPS users, codeine is less likely to be used daily but more likely to be used for recreational purposes. Smaller populations engaging in high-risk use exist who take multiple drugs in high doses. Combinations of misused codeine and NPS highlight the need for policy to respond to a more complex drug situation., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objectives: Hyperphosphatemia is associated with all-cause mortality in hemodialysis (HD) patients and is managed by restricting dietary phosphate. Many patients are unable to adhere to the recommended dietary phosphate limit. We sought to quantify the additional phosphate burden from prescription medication in a hemodialysis population., Design: Cross-sectional study., Subjects: Adult patients on hemodialysis at a single center., Setting: The Health Canada Drug Product Database was used to identify formulations of medications prescribed in an HD program that contain phosphate salts. The manufacturers of formulations containing a phosphate salt were contacted to request the phosphate content per tablet, and amounts were confirmed in select medications by the malachite green method., Main Outcome Measurements: Prescription bottles of 101 HD patients were evaluated. Reported phosphate contents were used to determine patients' daily phosphate load from prescribed medications., Results: A total 1,744 drug formulations of 124 different medications were reviewed. A total of 185 (11%) contained a phosphate salt. Central nervous system (CNS) and cardiovascular (CVS) medications accounted for 65% and 24% of phosphate-containing medications, respectively. Of HD patients, 30% were taking at least one medication that contained phosphate. The median phosphate burden from prescribed medications was 111 (67-168) mg per day., Conclusions: Knowledge about the phosphate content of commonly prescribed drugs within different classes should influence prescribing patterns. Particular consideration of which formulation of CVS and CNS drugs contain phosphate should be applied when prescribing. Phosphate-containing medications can meaningfully contribute to the daily phosphate load in HD patients; however, this burden will differ based on local dispensing patterns., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

A high dietary intake of phosphorus is considered to be a significant health threat for hemodialysis (HD) patients. Prescription medications, which might be a major source of phosphorus, is largely unrecognized in Japan. However, the amount of phosphorus indicated on the package label, is not quantified. In this study, the phosphorus content of 22 of the most widely prescribed medications that are used in conjunction with HD therapy were examined and differences between branded and generic prescription medications were compared. All samples were selected from medications that are typically prescribed for HD patients. The samples were ground prior to analysis. Phosphorus was measured using the Wako L-Type Phosphate method. All instruments used in the study were calibrated according to the manufacturers' specifications. Amlodipine (15 mg/tablet) and paroxetine (30.0 mg/tablet) were found to contain higher contents of phosphorus than the medications tested. Differences in phosphorus content between branded and generic drugs was also determined. The phosphorus content of all generic paroxetine preparations was significantly lower than the values for identical branded medications. On the other hand, the phosphorus content of several generic amlodipine preparations were significantly different from those of similar, branded preparations. Specific information regarding the phosphorus content of prescribed medications used by HD patient needs to be made available to the dialysis community.

Objectives: The objective of this study was to determine if physicians would alter their prescribing preferences after sampling liquid formulations of medications for common pediatric diagnoses., Methods: This was a prospective interventional before/after study conducted at an academic medical center in the United States. The participants of interest included emergency, family medicine, and pediatric physicians. Participants initially completed a brief survey for their primary oral liquid medication of choice for the treatment of selected disease states. These included otitis media, sinusitis, cellulitis, asthma, colitis, and pneumonia. Participants were asked to choose one of the medication options for each disease and then were given all medications to sample for a taste test. The prescribing preference survey was then repeated. The primary outcome was change in prescribing. McNemar's test was used to evaluate change in proportion of medications chosen before and after taste testing., Results: There were 101 physicians who participated in the study. There were three conditions for which participants changed their prescribing preferences significantly. These were otitis media (change from amoxicillin to cefdinir, difference = 13.2%, 95% confidence interval [CI] = 5.5% to 21.0%), asthma exacerbation (change from dexamethasone or prednisone to prednisolone, 28%, 95% CI = 15.9% to 40.1%), and pneumonia (change from azithromycin to amoxicillin, 16.0%, 95% CI = 6.4% to 25.6%). There was no significant change with respect to the other scenarios., Conclusions: Physicians showed preferences for certain pediatric medications based on taste and showed significant changes in prescribing preferences for some common pediatric diagnoses after tasting different medications for these conditions., (© 2016 by the Society for Academic Emergency Medicine.)

There is great interest in drugs that are capable of modulating multiple aging pathways, thereby delaying the onset and progression of aging. Effective strategies for drug development include the repurposing of existing drugs already approved by the FDA for human therapy. FDA approved drugs have known mechanisms of action and have been thoroughly screened for safety. Although there has been extensive scientific activity in repurposing drugs for disease therapy, there has been little testing of these drugs for their effects on aging. The pool of FDA approved drugs therefore represents a large reservoir of drug candidates with substantial potential for anti-aging therapy. In this paper we employ FINDSITE comb , a powerful ligand homology modeling program, to identify binding partners for proteins produced by temperature sensing genes that have been implicated in aging. This list of drugs with potential to modulate aging rates was then tested experimentally for lifespan and healthspan extension using a small invertebrate model. Three protein targets of the rotifer Brachionus manjavacas corresponding to products of the transient receptor potential gene 7, ribosomal protein S6 polypeptide 2 gene, or forkhead box C gene, were screened against a compound library consisting of DrugBank drugs including 1347 FDA approved, non-nutraceutical molecules. Twenty nine drugs ranked in the top 1 % for binding to each target were subsequently included in our experimental analysis. Continuous exposure of rotifers to 1 µM naproxen significantly extended rotifer mean lifespan by 14 %. We used three endpoints to estimate rotifer health: swimming speed (mobility proxy), reproduction (overall vitality), and mitochondria activity (cellular senescence proxy). The natural decline in swimming speed with aging was more gradual when rotifers were exposed to three drugs, so that on day 6, mean swimming speed of females was 1.19 mm/s for naproxen (P = 0.038), 1.20 for fludarabine (P = 0.040), 1.35 for hydralazine (P = 0.038), as compared to 0.88 mm/s in the control. The average reproduction of control females in the second half of their reproductive lifespan was 1.08 per day. In contrast, females treated with 1 µM naproxen produced 1.4 offspring per day (P = 0.027) and females treated with 10 µM fludarabine or 1 µM hydralazine produced 1.72 (P = <0.001) and 1.66 (P = 0.001) offspring per day, respectively. Mitochondrial activity naturally declines with rotifer aging, but B. manjavacas treated with 1 µM hydralazine or 10 µM fludarabine retained 49 % (P = 0.038) and 89 % (P = 0.002) greater mitochondria activity, respectively, than untreated controls. Our results demonstrate that coupling computation to experimentation can quickly identify new drug candidates with anti-aging potential. Screening drugs for anti-aging effects using a rotifer bioassay is a powerful first step in identifying compounds worthy of follow-up in vertebrate models. Even if lifespan extension is not observed, certain drugs could improve healthspan, slowing age-dependent losses in mobility and vitality.

What Is Known and Objective: Physical bottle characteristics differ of brand name topical glaucoma medications and local generic equivalents. This study compares the bottle characteristics of international topical glaucoma brands versus local brands from the Kingdom of Saudi Arabia., Methods: Data were collected on bottle drum volume, drop volume, bottle squeezability, bottle tip diameter, labels and instructions, cap color coding, and clarity of the drug label. Density-based calculations of drops in bottle volume were assessed using an analytic balance. Bottle tip diameter was measured using 0.05 mm Vernier calipers. A Likert scale-based questionnaire was used to evaluate the subjective opinions of patients on bottle squeezability, clarity of usage and storage instructions, and the consistency of the cap color coding., Results: The volumes of international brands were statistically significantly higher than the local brands ( P < 0.001). A number of drops per bottle and tip diameter were comparable between the international local brands. Cap color coding was inconsistent for international and local brands. Patients were dissatisfied with the label font size. Patients reported that the international and local brands were similar in terms of the ease of opening the bottle, instilling a drop, and the clarity of the instructions; but the local brands were subjectively easier to squeeze than international brands., What Is New and Conclusions: This is the first study to compare bottle characteristics of local Saudi Arabia brands with international brands. The bottle characteristics and patient feedback were similar between the local and international topical glaucoma medications. However, there were differences between the local and international brands in drug volume, bottle squeezability. Hence, patient compliance and drop dosage may differ based on the origin of manufacture., Competing Interests: There are no conflicts of interest.