Noncoding RNA Roles in Pharmacogenomic Responses to Aspirin: New Molecular Mechanisms for an Old Drug.

Aspirin, as one of the most frequently prescribed drugs, can have therapeutic effects on different conditions such as cardiovascular and metabolic disorders and malignancies. The effects of this common cardiovascular drug are exerted through different molecular and cellular pathways. Altered noncoding RNA (ncRNA) expression profiles during aspirin treatments indicate a close relationship between these regulatory molecules and aspirin effects through regulating gene expressions. A better understanding of the molecular networks contributing to aspirin efficacy would help optimize efficient therapies for this very popular drug. This review is aimed at discussing and highlighting the identified interactions between aspirin and ncRNAs and their targeting pathways and better understanding pharmacogenetic responses to aspirin.

Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events.

PURPOSE: As gut microbiota composition is an important determinant of response to immune checkpoint inhibitors (ICIs), we examined the effect of various co-medications known for their interaction with microbiota, when given at ICI initiation. PATIENTS AND METHODS: We identified patients with advanced cancer treated with ICI between May 2015 and September 2017 in our institution. Co-medications given within 1 month before or 1 month after the first administration of ICI were reviewed from medical records. Survival data were analysed with univariable Cox regression, and the combined effect of multiple factors was assessed with factor analysis of mixed data (FAMD). The impact of co-medications on immune-related adverse events (irAEs) occurrence was also assessed. RESULTS: A total of 635 patients were included. Psychotropic drugs (41%), proton pump inhibitors (PPIs; 38%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs; 32%), glucocorticoids (26%), antibiotics (24%), statins (21%) and morphine (20%) were the most prescribed co-medications. Baseline use of antibiotics, glucocorticoids >10 mg/day, PPIs, psychotropic drugs, morphine and insulin was associated with significantly shortened overall survival and decreased tumour response, whereas coadministration of statins, ACEs and/or ARBs, non-steroidal anti-inflammatory drugs, aspirin and oral antidiabetic drugs did not impact patient outcomes. Treatments that altered the response to ICI were also associated with a decreased incidence of irAEs. FAMD revealed the respective weight of each factor or co-medication on the oncological outcomes. CONCLUSION: Co-medications must be carefully assessed at the time of ICI initiation and clinicians aware of their possible deleterious effect, notably for PPIs, glucocorticoids, antibiotics and psychotropic drugs.

High-content, targeted RNA-seq screening in organoids for drug discovery in colorectal cancer.

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.

Machine learning identifies candidates for drug repurposing in Alzheimer's disease.

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.

Medication Use Quality and Safety in Older Adults: 2019 Update.

Improving the quality of medication use and medication safety are important priorities for prescribers who care for older adults. The objective of this article was to identify four exemplary articles with this focus in 2019. We selected high-quality studies that moved the field of research forward and were not merely replication studies. The chosen articles cover domains related to aspects of suboptimal prescribing and medication safety. The first study used a nationally representative sample of Medicare beneficiaries to examine the continuation of medications with limited benefit in patients admitted for cancer and non-cancer diagnoses in hospice (domain: potentially inappropriate medications). The second study, a retrospective cohort study of older adults in Ontario, Canada, assessed the association between prescribing oral anticoagulants in an emergency department relative to not prescribing anticoagulants in the emergency department and their persistence at 6 months (domain: underuse of medications). The third study, a cluster randomized trial in Quebec, Canada, evaluated the effect of conducting electronic medication reconciliation on several outcomes including adverse drug events and medication discrepancies (domain: medication safety). Lastly, the fourth study, a retrospective study using national inpatient and outpatient Veteran Health Administration combined with clinical and Medicare Claims data, examined the effects of intensification of antihypertensive medications on older adults' likelihood for hospital re-admission and other important clinical outcomes (domain: medication safety). Collectively, this review succinctly highlights pertinent topics related to promoting safe use of medications and promotes awareness of optimizing older adults' medication regimens.

Quantitative Automated Assays in Living Cells to Screen for Inhibitors of Hemichannel Function.

In vertebrates, intercellular communication is largely mediated by connexins (Cx), a family of structurally related transmembrane proteins that assemble to form hemichannels (HCs) at the plasma membrane. HCs are upregulated in different brain disorders and represent innovative therapeutic targets. Identifying modulators of Cx-based HCs is of great interest to better understand their function and define new treatments. In this study, we developed automated versions of two different cell-based assays to identify new pharmacological modulators of Cx43-HCs. As HCs remain mostly closed under physiological conditions in cell culture, depletion of extracellular Ca2+ was used to increase the probability of opening of HCs. The first assay follows the incorporation of a fluorescent dye, Yo-Pro, by real-time imaging, while the second is based on the quenching of a fluorescent protein, YFPQL, by iodide after iodide uptake. These assays were then used to screen a collection of 2242 approved drugs and compounds under development. This study led to the identification of 11 candidate hits blocking Cx43-HC, active in the two assays, with 5 drugs active on HC but not on gap junction (GJ) activities. To our knowledge, this is the first screening on HC activity and our results suggest the potential of a new use of already approved drugs in central nervous system disorders with HC impairments.

Inhibition of the ß-carbonic anhydrase from the protozoan pathogen Trichomonas vaginalis with sulphonamides.

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 ß-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 KIs 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.

Potential drug-drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments.

Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs are of a significant health concern. Illicit substances are taken by healthy individuals as well as by patients with medical conditions such as mental illnesses, acquired immunodeficiency syndrome, diabetes mellitus and cancer. Many individuals that use illicit substances simultaneously take clinical drugs meant for targeted treatment. This concomitant usage can lead to life-threatening pharmacokinetic interactions between illicit substances and clinical drugs. Optimal levels and activity of drug-metabolizing enzymes and drug-transporters are crucial for metabolism and disposition of illicit substances as well as clinical drugs. However, both illicit substances and clinical drugs can induce changes in the expression and/or activity of drug-metabolizing enzymes and drug-transporters. Consequently, with concomitant usage, illicit substances can adversely influence the therapeutic outcome of coadministered clinical drugs. Likewise, clinical drugs can adversely affect the response of coadministered illicit substances. While the interactions between illicit substances and clinical drugs pose a tremendous health and financial burden, they lack a similar level of attention as drug-drug, food-drug, supplement-drug, herb-drug, disease-drug, or other substance-drug interactions such as alcohol-drug and tobacco-drug interactions. This review highlights the clinical pharmacokinetic interactions between clinical drugs and commonly used illicit substances such as cannabis, cocaine and 3, 4-Methylenedioxymethamphetamine (MDMA). Rigorous efforts are warranted to further understand the underlying mechanisms responsible for these clinical pharmacokinetic interactions. It is also critical to extend the awareness of the life-threatening adverse interactions to both health care professionals and patients.

Use of Medicines by Infants with Microcephaly Caused by Congenital Zika Virus Infection and Implications to Oral Health

Abstract Objective: To analyze the use of continued-use medications by Brazilian children with microcephaly caused by Congenital Zika Virus Infection. Material and Methods: Cross-sectional study with 76 children of both genders. Information on age, use of continued-use medications, number and type of drugs used was collected. Data were analyzed using descriptive statistics. Results: Continued-use medications were used by 89.4% of the children, anticonvulsants / antiepileptics (88.1%), and those indicated for behavioral disorders (27.1%) were the most frequent. Sodium saccharin, sucrose, and sorbitol are the most common sugars in the composition of these drugs. Conclusion: The use of medicines is high, predominantly anticonvulsants and antiepileptics, which contain sugars in their composition. These drugs can lead to irreversible dental problems, such as tooth decay if proper oral hygiene is not present. Therefore, parents/guardians should be advised about adopting healthy oral hygiene habits after the administration of these drugs.

Rhinacanthin-C Mediated Herb-Drug Interactions with Drug Transporters and Phase I Drug-Metabolizing Enzymes.

Rhinacanthin-C is a major active constituent in Rhinacanthus nasutus (L.) Kurz, a plant widely used in herbal remedies. Its potential for pharmacokinetic herb-drug interaction may exist with drug transporters and drug metabolizing enzymes. This study assessed the possibility for rhinacanthin-C-mediated drug interaction by determining its inhibitory effects against major human efflux and influx drug transporters as well as various human cytochrome P450(CYP) isoforms. Rhinacanthin-C demonstrated a moderate permeability through the Caco-2 monolayers [Papp (AP-to-BL) = 1.26 × 10-6 cm/s]. It significantly inhibited transport mediated by both P-glycoprotein (P-gp) (IC50 = 5.20 µM) and breast cancer resistance protein (BCRP) (IC50 = 0.83 µM) across Caco-2 and BCRP-overexpressing Madin-Darby canine kidney II cells (MDCKII) cells. This compound also strongly inhibited uptake mediated by organic anion-transporting polypeptide 1B1 (OATP1B1) (IC50 = 0.70 µM) and OATP1B3 (IC50 = 3.95 µM) in OATP1B-overexpressing HEK cells. In addition to its inhibitory effect on these drug transporters, rhinacanthin-C significantly inhibited multiple human CYP isoforms including CYP2C8 (IC50 = 4.56 µM), 2C9 (IC50 = 1.52 µM), 2C19 (IC50 = 28.40 µM), and 3A4/5 (IC50 = 53 µM for midazolam and IC50 = 81.20 µM for testosterone), but not CYP1A2, 2A6, 2B6, 2D6, and 2E1. These results strongly support a high propensity for rhinacanthin-C as a perpetrator of clinical herb-drug interaction via inhibiting various influx and efflux drug transporters (i.e., P-gp, BCRP, OATP1B1, and OATP1B3) and CYP isoforms (i.e., CYP2C8, CYP2C9, and CYP2C19). Thus, the potential for significant pharmacokinetic herb-drug interaction should be addressed when herbal products containing rhinacanthin-C are to be used in conjunction with other prescription drugs.

Use of phthalate-containing prescription drugs and the risk of gastric cancer: a Danish nationwide case-control study.

Background: Phthalates are used as excipients in some drug products, and up to a 50-fold increased urinary excretion of phthalate metabolites compared to non-users has been demonstrated in users of such products. In vitro studies have demonstrated that phthalates stimulate mechanisms involved in gastric cancer development. We therefore examined the association between cumulative phthalate exposure from drug products and the risk of gastric adenocarcinomas. Methods: Using the Danish Cancer Registry, we identified all patients with incident gastric adenocarcinoma from 2008 to 2015 (n = 1525). Cancer cases were matched to 10 controls. Linking information retrieved from nationwide Danish registries, we determined individual cumulative phthalate exposure to the ortho-phthalates diethyl phthalate (DEP), dibutyl phthalate (DBP) and enteric phthalate polymers from prescription drugs. The association between cumulative phthalate exposure and gastric adenocarcinoma was estimated using conditional logistic regression, adjusting for socioeconomical status and drugs or comorbidities known or suspected to modify the risk of gastric adenocarcinoma. Results: No association was seen for the risk of gastric adenocarcinomas among individuals with high cumulative exposure to ortho-phthalates (exceeding 500 mg) (ORadj 1.22, 95% CI: 0.84-1.77). Likewise, no associations were observed individually for DEP (ORadj 1.06 95% CI: 0.63-1.76) or DBP (ORadj 1.32 95% CI: 0.78-2.23). Cumulative exposure to enteric phthalate polymers exceeding 10,000 mg, did not reveal an association with gastric adenocarcinoma (ORadj 0.79, 95% CI: 0.54-1.16) and no association was seen for individual compounds. Additionally, no dose-response pattern was observed across exposure strata (p = .39, test for trend). Conclusion: We did not find an increased risk of gastric adenocarcinoma among Danish users of phthalate-containing drug products. Our study is limited by a low number of cases exposed to high cumulative doses of phthalates.

Quantitative Information on Oncology Prescription Drug Websites.

Our objective was to determine whether and how quantitative information about drug benefits and risks is presented to consumers and healthcare professionals on cancer-related prescription drug websites. We analyzed the content of 65 active cancer-related prescription drug websites. We assessed the inclusion and presentation of quantitative information for two audiences (consumers and healthcare professionals) and two types of information (drug benefits and risks). Websites were equally likely to present quantitative information for benefits (96.9 %) and risks (95.4 %). However, the amount of the information differed significantly: Both consumer-directed and healthcare-professional-directed webpages were more likely to have quantitative information for every benefit (consumer 38.5 %; healthcare professional 86.1 %) compared with every risk (consumer 3.1 %; healthcare professional 6.2 %). The numeric and graphic presentations also differed by audience and information type. Consumers have access to quantitative information about oncology drugs and, in particular, about the benefits of these drugs. Research has shown that using quantitative information to communicate treatment benefits and risks can increase patients' and physicians' understanding and can aid in treatment decision-making, although some numeric and graphic formats are more useful than others.

Medication Exposure in Highly Adherent Psychiatry Patients.

Medication exposure is dependent upon many factors, the single most important being if the patient took the prescribed medication as indicated. To assess medication exposure for psychotropic and other medication classes, we enrolled 115 highly adherent psychiatry patients prescribed five or more medications. In these patients, we measured 21 psychotropic and 38 nonpsychotropic medications comprising a 59 medication multiplex assay panel. Strict enrollment criteria and reconciliation of the electronic health record medication list prior to study initiation produced a patient cohort that was adherent with 91% of their prescribed medications as determined by comparing medications detected empirically in blood to the electronic health record medication list. In addition, 13% of detected medications were not in the electronic health record medication list. We found that only 53% of detected medications were within the literature-derived reference range with 41% below and 6% above the reference range specific to each medication. When psychotropic medications were analyzed near trough-level, only sertraline was found to be within the literature-derived reference range for all patients tested. Concentrations of the remaining medications indicated extensive exposure below the reference range. This is the first study to empirically and comprehensively assess medication exposure obtained in comorbid polypharmacy patients, minimizing the important behavioral factor of adherence in the study of medication exposure. These data indicate that low medication exposure is extensive and must be considered when therapeutic issues arise, including the lack of response to medication therapy.

Cardioprotective effects of total flavonoids from Jinhe Yangxin prescription by activating the PI3K/Akt signaling pathway in myocardial ischemia injury.

The purpose of the present study was to investigate the cardioprotective effects of total flavonoids of Jinhe yangxin prescription (JHTF) on myocardial ischemia (MI) injury rats induced by Isoproterenol (ISO) and explore the potential mechanisms underlying these effects. 128 male rats were randomized into 8 groups: Control, Model, Positive, JHTF-H (2.64 g/kg/d), JHTF-M (1.32 g/kg/day), JHTF-L (0.66 g/kg/d), LY + JHTF (JHTF-H plus LY294002, an inhibitor of PI3K/Akt) and LY groups. Electrocardiogram, histopathological examination and terminal deoxynucleotidyl transferase dUTP nickend labeling (TUNEL) assay were performed. Heart weight index, markers of cardiac marker enzymes [creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI)], oxidative stress [superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and nitric oxide (NO)] and inflammation [tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)] were also measured in each group. Proteins involved in PI3K/Akt pathway were detected by Western blot. JHTF decreased the ST elevation induced by MI, decreased serum levels of CK, CK-MB, cTnI, LDH, MDA, IL-6 and TNF-α, and increased serum SOD, GSH-Px and NO activities. Furthermore, JHTF inhibited myocardial apoptosis, which may be related to downregulated caspase-3 and Bax, upregulated Bcl-2, and increased the protein levels of phosphorylated Akt, GSK-3ß and endothelial nitric oxide synthase (eNOS). However, all the previously mentioned effects of JHTF were blocked when JHTF was coadministered with LY294002. In conclusion, these observations indicated that JHTF has cardioprotective effects against MI, and these effects seem to be related to the activation of PI3K/Akt signaling pathway in the myocardium.