Synthesis of Benzimidazole-Based Analogs as Anti Alzheimer's Disease Compounds and Their Molecular Docking Studies.

Molecules. 2020 Oct 20;25(20):

Authors: Adalat B, Rahim F, Taha M, Alshamrani FJ, Anouar EH, Uddin N, Shah SAA, Ali Z, Zakaria ZA

Abstract
We synthesized 10 analogs of benzimidazole-based thiosemicarbazide 1 (a-j) and 13 benzimidazole-based Schiff bases 2 (a-m), and characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) inhibition activities. All the synthesized analogs showed varying degrees of acetylcholinesterase and butyrylcholinesterase inhibitory potentials in comparison to the standard drug (IC50 = 0.016 and 4.5 µM. Amongst these analogs 1 (a-j), compounds 1b, 1c, and 1g having IC50 values 1.30, 0.60, and 2.40 µM, respectively, showed good acetylcholinesterase inhibition when compared with the standard. These compounds also showed moderate butyrylcholinesterase inhibition having IC50 values of 2.40, 1.50, and 2.40 µM, respectively. The rest of the compounds of this series also showed moderate to weak inhibition. While amongst the second series of analogs 2 (a-m), compounds 2c, 2e, and 2h having IC50 values of 1.50, 0.60, and 0.90 µM, respectively, showed moderate acetylcholinesterase inhibition when compared to donepezil. Structure Aactivity Relation of both synthesized series has been carried out. The binding interactions between the synthesized analogs and the enzymes were identified through molecular docking simulations.

PMID: 33092223 [PubMed - in process]

The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology.

Int J Mol Sci. 2020 Jan 17;21(2):

Authors: Fatunde OA, Brown SA

Abstract
As many novel cancer therapies continue to emerge, the field of Cardio-Oncology (or onco-cardiology) has become crucial to prevent, monitor and treat cancer therapy-related cardiovascular toxicity. Furthermore, given the narrow therapeutic window of most cancer therapies, drug-drug interactions are prevalent in the cancer population. Consequently, there is an increased risk of affecting drug efficacy or predisposing individual patients to adverse side effects. Here we review the role of cytochrome P450 (CYP450) enzymes in the field of Cardio-Oncology. We highlight the importance of cardiac medications in preventive Cardio-Oncology for high-risk patients or in the management of cardiotoxicities during or following cancer treatment. Common interactions between Oncology and Cardiology drugs are catalogued, emphasizing the impact of differential metabolism of each substrate drug on unpredictable drug bioavailability and consequent inter-individual variability in treatment response or development of cardiovascular toxicity. This inter-individual variability in bioavailability and subsequent response can be further enhanced by genomic variants in CYP450, or by modifications of CYP450 gene, RNA or protein expression or function in various 'omics' related to precision medicine. Thus, we advocate for an individualized approach to each patient by a multidisciplinary team with clinical pharmacists evaluating a treatment plan tailored to a practice of precision Cardio-Oncology. This review may increase awareness of these key concepts in the rapidly evolving field of Cardio-Oncology.

PMID: 31963461 [PubMed - indexed for MEDLINE]

Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature.

Pharmacol Ther. 2020 Oct 19;:107710

Authors: Dello Russo C, Scott KA, Pirmohamed M

Abstract
Dimethyl fumarate (DMF) is a first line medication for multiple sclerosis. It has a favourable safety profile, however, there is concern regarding the occurrence of moderate-severe and sustained lymphopenia and the associated risk of progressive multifocal leukoencephalopathy. We carried out an extensive literature review to understand the molecular mechanisms underlying this adverse reaction. Dynamic changes in certain components of the immune system are likely to be important for the therapeutic effects of DMF, including depletion of memory T cells and decrease in activated T cells together with expansion of naïve T cells. Similar modifications were reported for the B cell components. CD8+ T cells are particularly susceptible to DMF-induced cell death, with marked reductions observed in lymphopenic subjects. The reasons underlying such increased sensitivity are not known, nor it is known how expansion of other lymphocyte subsets occurs. Understanding the molecular mechanisms underlying DMF action is challenging: in vivo DMF is rapidly metabolized to monomethyl fumarate (MMF), a less potent immunomodulator in vitro. Pharmacokinetics indicate that MMF is the main active species in vivo. However, the relative importance of DMF and MMF in toxicity remains unclear, with evidence presented in favour of either of the compounds as toxic species. Pharmacogenetic studies to identify genetic predictors of DMF-induced lymphopenia are limited, with inconclusive results. A role of the gut microbiome in the pharmacological effects of DMF is emerging. It is clear that further investigations are necessary to understand the mechanisms of DMF-induced lymphopenia and devise preventive strategies. Periodic monitoring of absolute lymphocyte counts, currently performed in clinical practise, allows for the early detection of lymphopenia as a risk-minimization strategy.

PMID: 33091427 [PubMed - as supplied by publisher]

Correlation of body weight and composition with hepatic activities of cytochrome P450 enzymes.

J Pharm Sci. 2020 Oct 19;:

Authors: Krogstad V, Peric A, Robertsen I, Kringen MK, Vistnes M, Hjelmesæth J, Sandbu R, Johnson LK, Angeles PC, Jansson-Löfmark R, Karlsson C, Andersson S, Åsberg A, Andersson TB, Christensen H

Abstract
Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m2 were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CLint,u) values for CYP3A correlated negatively with body weight (r=-0.43, p<0.01), waist circumference (r=-0.47, p<0.01), hip circumference (r=-0.51, p<0.01), fat percent (r=-0.41, p<0.05), fat mass (r=-0.48, p<0.01) and BMI (r=-0.46, p<0.01). Linear regression analysis showed that CLint,u values for CYP3A decreased with 5 % with each 10 % increase in body weight (r2=0.12, β=-0.558, p<0.05). There were no correlations between body weight measures and CLint,u values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.

PMID: 33091408 [PubMed - as supplied by publisher]

Longitudinal trajectory analysis of antipsychotic response in patients with schizophrenia: 6-week, randomised, open-label, multicentre clinical trial.

BJPsych Open. 2020 Oct 22;6(6):e126

Authors: Dai M, Wu Y, Tang Y, Yue W, Yan H, Zhang Y, Tan L, Deng W, Chen Q, Yang G, Lu T, Wang L, Yang F, Zhang F, Yang J, Li K, Lv L, Tan Q, Zhang H, Ma X, Li L, Wang C, Ma X, Zhang D, Yu H, Zhao L, Ren H, Wang Y, Hu X, Zhang G, Du X, Wang Q, Li T, Chinese Antipsychotics Pharmacogenomics Consortium

Abstract
BACKGROUND: Understanding the patterns of treatment response is critical for the treatment of patients with schizophrenia; one way to achieve this is through using a longitudinal dynamic process study design.
AIMS: This study aims to explore the response trajectory of antipsychotics and compare the treatment responses of seven different antipsychotics over 6 weeks in patients with schizoprenia (trial registration: Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934).
METHOD: Data were collected from a multicentre, randomised open-label clinical trial. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) at baseline and follow-up at weeks 2, 4 and 6. Trajectory groups were classified by the method of k-means cluster modelling for longitudinal data. Trajectory analyses were also employed for the seven antipsychotic groups.
RESULTS: The early treatment response trajectories were classified into a high-trajectory group of better responders and a low-trajectory group of worse responders. The results of trajectory analysis showed differences compared with the classification method characterised by a 50% reduction in PANSS scores at week 6. A total of 349 patients were inconsistently grouped by the two methods, with a significant difference in the composition ratio of treatment response groups using these two methods (χ2 = 43.37, P < 0.001). There was no differential contribution of high- and low trajectories to different drugs (χ2 = 12.52, P = 0.051); olanzapine and risperidone, which had a larger proportion in the >50% reduction at week 6, performed better than aripiprazole, quetiapine, ziprasidone and perphenazine.
CONCLUSIONS: The trajectory analysis of treatment response to schizophrenia revealed two distinct trajectories. Comparing the treatment responses to different antipsychotics through longitudinal analysis may offer a new perspective for evaluating antipsychotics.

PMID: 33090091 [PubMed - as supplied by publisher]

Pharmacogenomics Biomarker Discovery and Validation for Translation in Clinical Practice.

Clin Transl Sci. 2020 Oct 22;:

Authors: Arbitrio M, Scionti F, Di Martino MT, Caracciolo D, Pensabene L, Tassone P, Tagliaferri P

Abstract
Interindividual variability in drug efficacy and toxicity is a major challenge in clinical practice. Variations in drug pharmacokinetics (PKs) and pharmacodynamics (PDs) can be, in part, explained by polymorphic variants in genes encoding drug metabolizing enzymes and transporters (absorption, distribution, metabolism, and excretion) or in genes encoding drug receptors. Pharmacogenomics (PGx) has allowed the identification of predictive biomarkers of drug PKs and PDs and the current knowledge of genome-disease and genome-drug interactions offers the opportunity to optimize tailored drug therapy. High-throughput PGx genotyping, from targeted to more comprehensive strategies, allows the identification of PK/PD genotypes to be developed as clinical predictive biomarkers. However, a biomarker needs a robust process of validation followed by clinical-grade assay development and must comply to stringent regulatory guidelines. We here discuss the methodological challenges and the emerging technological tools in PGx biomarker discovery and validation, at the crossroad among molecular genetics, bioinformatics, and clinical medicine.

PMID: 33089968 [PubMed - as supplied by publisher]

Association of FMO3 rs1736557 polymorphism with clopidogrel response in Chinese patients with coronary artery disease.

Eur J Clin Pharmacol. 2020 Oct 21;:

Authors: Zhu KX, Song PY, He-Li, Li MP, Du YX, Ma QL, Peng LM, Chen XP

Abstract
PURPOSE: Dual antiplatelet therapy with aspirin and clopidogrel is commonly used for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention to prevent stent thrombosis and ischemic events. However, some patients show high on-treatment platelet reactivity (HTPR) during clopidogrel therapy. Genetic factors such as loss-of-function variants of CYP2C19 are validated to increase the risk of HTPR. Flavin-containing monooxygenase 3 (FMO3) is reported to be associated with potency of platelet responsiveness and thrombosis. This study aimed to explore the association between FMO3 rs1736557 polymorphism and clopidogrel response.
METHODS: Five hundred twenty-two Chinese CAD patients treated with dual antiplatelet therapy were recruited from Xiangya Hospital. After oral administration of 300 mg loading dose (LD) clopidogrel for 12-24 h or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days, the platelet reaction index (PRI) was determined by vasodilator-stimulated phosphoprotein-phosphorylation assay. FMO3 rs1736557, CYP2C19*2, and CYP2C19*3 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
RESULTS: Mean PRI value was significantly higher in CYP2C19 poor metabolizers (PMs) and intermediate metabolizers (IMs) than the extensive metabolizers (EMs) (p < 0.001). In addition, FMO3 rs1736557 AA homozygotes showed significantly lower PRI as compared with carriers of the major rs1736557 G allele in the entire cohort and in the MD cohort (p = 0.011, p = 0.008, respectively). The risk of HTPR was decreased significantly in carriers of the rs1736557 A allele (AA vs GG: OR = 0.316, 95% CI: 0.137-0.726, p = 0.005; AA vs GA: OR = 0.249, 95% CI: 0.104-0.597, p = 0.001; AA vs GG+GA: OR = 0.294, 95% CI: 0.129-0.669, p = 0.002), and the association was observed mainly in patients carrying the CYP2C19 LOF allele and in those administered with MD.
CONCLUSION: The FMO3 rs1736557 AA genotype was related to an increased the antiplatelet potency of clopidogrel in Chinese CAD patients. Additional studies are required to verify this finding.

PMID: 33089397 [PubMed - as supplied by publisher]

DBCSMOTE: a clustering-based oversampling technique for data-imbalanced warfarin dose prediction.

BMC Med Genomics. 2020 Oct 22;13(Suppl 10):152

Authors: Tao Y, Zhang Y, Jiang B

Abstract
BACKGROUND: Vitamin K antagonist (warfarin) is the most classical and widely used oral anticoagulant with assuring anticoagulant effect, wide clinical indications and low price. Warfarin dosage requirements of different patients vary largely. For warfarin daily dosage prediction, the data imbalance in dataset leads to inaccurate prediction on the patients of rare genotype, who usually have large stable dosage requirement. To balance the dataset of patients treated with warfarin and improve the predictive accuracy, an appropriate partition of majority and minority groups, together with an oversampling method, is required.
METHOD: To solve the data-imbalance problem mentioned above, we developed a clustering-based oversampling technique denoted as DBCSMOTE, which combines density-based spatial clustering of application with noise (DBCSCAN) and synthetic minority oversampling technique (SMOTE). DBCSMOTE automatically finds the minority groups by acquiring the association between samples in terms of the clinical features/genotypes and the warfarin dosage, and creates an extended dataset by adding the new synthetic samples of majority and minority groups. Meanwhile, two ensemble models, boosted regression tree (BRT) and random forest (RF), which are built on the extended dataset generateed by DBCSMOTE, accomplish the task of warfarin daily dosage prediction.
RESULTS: DBCSMOTE and the comparison methods were tested on the datasets derived from our Hospital and International Warfarin Pharmacogenetics Consortium (IWPC). As the results, DBCSMOTE-BRT obtained the highest R-squared (R2) of 0.424 and the smallest mean squared error (mse) of 1.08. In terms of the percentage of patients whose predicted dose of warfarin is within 20% of the actual stable therapeutic dose (20%-p), DBCSMOTE-BRT can achieve the largest value of 47.8% among predictive models. The more important thing is that DBCSMOTE saved about 68% computational time to achieve the same or better performance than the Evolutionary SMOTE, which was the best oversampling method in warfarin dose prediction by far. Meanwhile, in warfarin dose prediction, it is discovered that DBCSMOTE is more effective in  integrating BRT than RF  for warfarin dose prediction.
CONCLUSION: Our finding is that the genotypes, CYP2C9 and VKORC1, no doubt contribute to the predictive accuracy. It was also discovered left atrium diameter, glutamic pyruvic transaminase and serum creatinine included in the model actually improved the predictive accuracy; When congestive heart failure, diabetes mellitus and valve replacement were absent in DBCSMOTE-BRT/RF, the predictive accuracy of DBCSMOTE-BRT/RF decreased. The oversampling ratio and number of minority clusters have a large impact on the effect of oversampling. According to our test, the predictive accuracy was high when the number of minority clusters was 6 ~ 8. The oversampling ratio for small minority clusters should be large (> 1.2) and for large minority clusters should be small (< 0.2). If the dataset becomes larger, the DBCSMOTE would be re-optimized and its BRT/RF model should be re-trained. DBCSMOTE-BRT/RF outperformed the current commonly-used tool called Warfarindosing. As compared to Evolutionary SMOTE-BRT and RF  models, DBCSMOTE-BRT and RF models take only a small computational time to achieve the same or higher performance in many cases. In terms of predictive accuracy, RF is not as good as BRT. However, RF still has a powerful ability in generating a highly accurate model as the dataset increases; the software "WarfarinSeer v2.0" is a test version, which packed DBCSMOTE-BRT/RF. It could be a convenient tool for clinical application in warfarin treatment.

PMID: 33087117 [PubMed - in process]

SREBP1 as a potential biomarker predicts levothyroxine efficacy of differentiated thyroid cancer.

Biomed Pharmacother. 2020 Mar;123:109791

Authors: Li C, Peng X, Lv J, Zou H, Liu J, Zhang K, Li Z

Abstract
BACKGROUND: SREBP1 is a well-known transcript factor regulating lipogenesis. It has been reported to play an important role in tumor progress in recent years. However, the roles of SREBP1 in differentiated thyroid cancer (DTC) are uncertain. Based on this, we aimed to investigate the expression of SREBP1 and the influence of SREBP1 on DTC patients.
METHODS: qRT-PCR and immunohistochemistry were used to detect the expression of SREBPs in DTC tissues and the adjacent normal tissues. The following methods, including the MTS, colony-forming assay, flow cytometry and Hoechst staining were used to detect the biological function of thyroid cancer cells based on SREBP1 interference or not.
RESULTS: the expression of SREBP1 was significantly different among DTCs, thyroid nodules and the adjacent normal tissues. Briefly, SREBP1 was upregulated follow with the malignancy, but there was no significant difference of SREBP2 between thyroid nodules and the adjacent normal tissues. Further, the ROC curve showed that SREBP1 has higher diagnostic value than SREBP2. SREBP1 expression was significantly related to the tumor size and lymph node metastasis in DTCs. In vitro, the proliferation of thyroid cancer cells was suppressed obviously after interfered with SREBP1, and the apoptotic cells was increased. Further, SREBP1 expression was also associated with the short-term efficacy of levothyroxine in DTC patients.
CONCLUSION: this is the first time to report that SREBP1 is an oncogene and a pro-proliferation factor in thyroid cancer, indicating that SREBP1 may serve as a potential biomarker and therapeutic target in thyroid cancer.

PMID: 31887541 [PubMed - indexed for MEDLINE]

Building a Pharmacogenomics Knowledge Model Toward Precision Medicine: Case Study in Melanoma.

JMIR Med Inform. 2020 Oct 21;8(10):e20291

Authors: Kang H, Li J, Wu M, Shen L, Hou L

Abstract
BACKGROUND: Many drugs do not work the same way for everyone owing to distinctions in their genes. Pharmacogenomics (PGx) aims to understand how genetic variants influence drug efficacy and toxicity. It is often considered one of the most actionable areas of the personalized medicine paradigm. However, little prior work has included in-depth explorations and descriptions of drug usage, dosage adjustment, and so on.
OBJECTIVE: We present a pharmacogenomics knowledge model to discover the hidden relationships between PGx entities such as drugs, genes, and diseases, especially details in precise medication.
METHODS: PGx open data such as DrugBank and RxNorm were integrated in this study, as well as drug labels published by the US Food and Drug Administration. We annotated 190 drug labels manually for entities and relationships. Based on the annotation results, we trained 3 different natural language processing models to complete entity recognition. Finally, the pharmacogenomics knowledge model was described in detail.
RESULTS: In entity recognition tasks, the Bidirectional Encoder Representations from Transformers-conditional random field model achieved better performance with micro-F1 score of 85.12%. The pharmacogenomics knowledge model in our study included 5 semantic types: drug, gene, disease, precise medication (population, daily dose, dose form, frequency, etc), and adverse reaction. Meanwhile, 26 semantic relationships were defined in detail. Taking melanoma caused by a BRAF gene mutation into consideration, the pharmacogenomics knowledge model covered 7 related drugs and 4846 triples were established in this case. All the corpora, relationship definitions, and triples were made publically available.
CONCLUSIONS: We highlighted the pharmacogenomics knowledge model as a scalable framework for clinicians and clinical pharmacists to adjust drug dosage according to patient-specific genetic variation, and for pharmaceutical researchers to develop new drugs. In the future, a series of other antitumor drugs and automatic relation extractions will be taken into consideration to further enhance our framework with more PGx linked data.

PMID: 33084582 [PubMed]

Plasma miRNA profiles associated with stable warfarin dosage in Chinese patients.

PeerJ. 2020;8:e9995

Authors: Zhao L, Wang J, Shi S, Wu Y, Liu J, He S, Zou Y, Xie H, Ge S, Ye H

Abstract
Background: We used bioinformatic analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays to investigate the association between plasma microRNAs (miRNAs) and stable warfarin dosage in a Chinese Han population.
Methods: Bioinformatics analysis was used to screen out potential warfarin dose-associated miRNAs. Three plasma miRNAs were validated in 99 samples by RT-qPCR. Kruskal-Wallis test and multivariate logistic regression were used to compare differences in plasma miRNAs expression levels between three warfarin dosage groups.
Results: There were significant between-group differences among the three dose groups for hsa-miR-133b expression (p = 0.005), but we observed an "n-shaped" dose-dependent curve rather than a linear relationship. Expression levels of hsa-miR-24-3p (p = 0.475) and hsa-miR-1276 (p = 0.558) were not significantly different in the multivariate logistic regression.
Conclusion: miRNAs have received extensive attention as ideal biomarkers and possible therapeutic targets for various diseases. However, they are not yet widely used in precision medicine. Our results indicate that hsa-miR-133b may be a possible reference factor for the warfarin dosage algorithm. These findings emphasize the importance of a comprehensive evaluation of complex relationships in warfarin dose prediction models and provide new avenues for future pharmacogenomics studies.

PMID: 33083118 [PubMed]

The influence of genetic variability in IL1B and MIR146A on the risk of pleural plaques and malignant mesothelioma.

Radiol Oncol. 2020 Oct 21;54(4):429-436

Authors: Piber P, Vavpetic N, Goricar K, Dolzan V, Kovac V, Franko A

Abstract
Background Asbestos exposure is associated with the development of pleural plaques as well as malignant mesothelioma (MM). Asbestos fibres activate macrophages, leading to the release of inflammatory mediators including interleukin 1 beta (IL-1β). The expression of IL-1β may be influenced by genetic variability of IL1B gene or regulatory microRNAs (miRNAs). This study investigated the effect of polymorphisms in IL1B and MIR146A genes on the risk of developing pleural plaques and MM. Subjects and methods In total, 394 patients with pleural plaques, 277 patients with MM, and 175 healthy control subjects were genotyped for IL1B and MIR146A polymorphisms. Logistic regression was used in statistical analysis. Results We found no association between MIR146A and IL1B genotypes, and the risk of pleural plaques. MIR146A rs2910164 was significantly associated with a decreased risk of MM (OR = 0.31, 95% CI = 0.13-0.73, p = 0.008). Carriers of two polymorphic alleles had a lower risk of developing MM, even after adjustment for gender and age (OR = 0.34, 95% CI = 0.14-0.85, p = 0.020). Among patients with known asbestos exposure, carriers of at least one polymorphic IL1B rs1143623 allele also had a lower risk of MM in multivariable analysis (OR = 0.50, 95% CI = 0.28-0.92, p = 0.025). The interaction between IL1B rs1143623 and IL1B rs1071676 was significantly associated with an increased risk of MM (p = 0.050). Conclusions Our findings suggest that genetic variability of inflammatory mediator IL-1β could contribute to the risk of developing MM, but not pleural plaques.

PMID: 33085641 [PubMed - in process]

Projected utility of pharmacogenomic testing among individuals hospitalized with COVID-19: A retrospective multicenter study in the United States.

Clin Transl Sci. 2020 Oct 21;:

Authors: Stevenson JM, Alexander GC, Palamuttam N, Mehta HB

Abstract
Many academic institutions are collecting blood samples from patients seeking treatment for COVID-19 to build research biorepositories. It may be feasible to extract pharmacogenomic information from biorepositories for clinical use. We sought to characterize the potential value of multi-gene pharmacogenomic testing among individuals hospitalized with COVID-19 in the United States. We performed a cross-sectional analysis of electronic health records from consecutive individuals hospitalized with COVID-19 at a large, urban academic health system. We characterized medication orders, focusing on medications with actionable pharmacogenomic guidance related to 14 commonly-assayed genes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, DPYD, G6PD, HLA-A, HLA-B, IFNL3, NUDT15, SLCO1B1, TPMT, UGT1A1, VKORC1). A simulation analysis combined medication data with population phenotype frequencies to estimate how many treatment modifications would be enabled if multi-gene pharmacogenomic results were available. Sixty-four unique medications with pharmacogenomic guidance were ordered at least once in the cohort (n=1852, mean age 60.1 years). Nearly nine in ten individuals (89.7%) had at least one order for a medication with pharmacogenomic guidance and 427 patients (23.1%) had orders for 4 or more actionable medications. Using a simulation, we estimated that 17 treatment modifications per 100 patients would be enabled if pharmacogenomic results were available. The genes CYP2D6 and CYP2C19 were responsible for the majority of treatment modifications, and the medications most often affected were ondansetron, oxycodone, and clopidogrel. Pharmacogenomic results would be relevant for nearly all individuals hospitalized with COVID-19 and would provide the opportunity to improve clinical care.

PMID: 33085221 [PubMed - as supplied by publisher]

Nanodelivery of Resveratrol-Loaded PLGA Nanoparticles for Age-Related Macular Degeneration.

AAPS PharmSciTech. 2020 Oct 21;21(8):291

Authors: Bhatt P, Fnu G, Bhatia D, Shahid A, Sutariya V

Abstract
Age-related macular degeneration, precisely neovascular form, is the leading cause of vision loss and the key treatment includes intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents. A method to increase local concentration of drug at posterior segment of the eye and to reduce the frequency of intravitreal injections is an unmet need. Resveratrol, a naturally occurring antioxidant and anti-inflammatory polyphenol, was loaded in PLGA polymeric nanoparticles to study their sustained release property and effectiveness in reducing expression of VEGF protein in vitro. Nanoparticles were characterized using FTIR, DSC, size, encapsulation efficiency, TEM, and in vitro drug release studies. Using MTT assay, the cytotoxicity of formulation was evaluated on ARPE-19 cells. The cellular uptake and VEGF expression levels were also evaluated in in vitro settings. The optimized formulation had a particle size of 102.7 nm with - 47.30 mV of zeta potential. Entrapment efficiency was found to be 65.21%. The cell viability results suggested compatibility of developed formulation. Cellular uptake and VEGF expression levels for the formulated nanoparticles specified that the developed formulation showed potential cellular uptake and had displayed anti-angiogenic property by inhibiting VEGF expression in vitro. The results showed successful development of resveratrol-loaded nanoparticles which may be used for neovascular AMD treatment alone or in combination with anti-VEGF agents.

PMID: 33085055 [PubMed - in process]

Structural and functional characterization of G protein-coupled receptors with deep mutational scanning.

Elife. 2020 Oct 21;9:

Authors: Jones EM, Lubock NB, Venkatakrishnan AJ, Wang J, Tseng AM, Paggi JM, Latorraca NR, Cancilla D, Satyadi M, Davis JE, Babu MM, Dror RO, Kosuri S

Abstract
In humans, the >800 G protein-coupled receptors (GPCRs) are responsible for transducing diverse chemical stimuli to alter cell state, and are the largest class of drug targets. Their myriad structural conformations and various modes of signaling make it challenging to understand their structure and function. Here we developed a platform to characterize large libraries of GPCR variants in human cell lines with a barcoded transcriptional reporter of G-protein signal transduction. We tested 7,800 of 7,828 possible single amino acid substitutions to the beta-2 adrenergic receptor (β2AR) at four concentrations of the agonist isoproterenol. We identified residues specifically important for β2AR signaling, mutations in the human population that are potentially loss of function, and residues that modulate basal activity. Using unsupervised learning, we resolve residues critical for signaling, including all major structural motifs and molecular interfaces. We also find a previously uncharacterized structural latch spanning the first two extracellular loops that is highly conserved across Class A GPCRs and is conformationally rigid in both the inactive and active states of the receptor. More broadly, by linking deep mutational scanning with engineered transcriptional reporters, we establish a generalizable method for exploring pharmacogenomics, structure and function across broad classes of drug receptors.

PMID: 33084570 [PubMed - as supplied by publisher]

Global distribution of CYP2C19 risk phenotypes affecting safety and effectiveness of medications.

Pharmacogenomics J. 2020 Oct 20;:

Authors: Biswas M

Abstract
Genetic variability of CYP2C19 may affect safety or efficacy of many clinically important medications as outlined in the clinical pharmacogenetics implementation consortium (CPIC) dosing guidelines. To determine the predictive prevalence of high-risk phenotypes due to CYP2C19 genetic variants collectively in the world population and to establish a correlation how the identified high-risk phenotypes may affect safety or effectiveness of drugs, this study was conducted. Frequency of CYP2C19*2, *3 and *17 alleles were obtained from 1000 Genomes project Phase III in line with Fort Lauderdale principles. Phenotypes were assigned using international standardized consensus terms based on the carrier of characteristics alleles. Association of predicted high-risk phenotypes with the safety or effectiveness of medications was gained from CPIC dosing guidelines. Ultrarapid and poor metabolizers were considered as being as high-risk phenotypes for at least ten clinically important medications. Meta-analysis of the prevalence of high-risk phenotypes showed that it was statistically significant (p<0.0001) in different ethnic groups with pooled prevalence of 27.4% (95% CI 18-37%). The present study suggests that African (37.2; 95% CI 34-41%) and European (35.4; 95% CI 31-40%) population are being at particularly higher risk of either sub therapeutic drug responses or toxicities due to combined effects of CYP2C19*2, *3 and *17 variants. Large scale clinical studies are warranted to assess clinical outcomes of these medications considering CYP2C19 pharmacogenomics effects.

PMID: 33082528 [PubMed - as supplied by publisher]

[Practical aspects of using donepezil in the treatment of dementia].

Zh Nevrol Psikhiatr Im S S Korsakova. 2020;120(9):137-143

Authors: Chebotareva AD, Levin OS

Abstract
Donepezil is the most commonly used drug of the group of cholinesterase inhibitors. It is recommended for tretament of Alzheimer's disease. Donepezil is also used to treat dementia in Lewy body disease, Parkinson's disease with dementia, and vascular dementia. In Russia, donepezil is not used as often, which is facilitated by the concern of doctors about the possibility of serious side-effects. Clinical studies demonstrate the safety and good tolerability of donepezil. Our study included 62 patients with dementia due to various neurodegenerative diseases (Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia). Thirty-seven patients (59.7%) started to receive donepezil. Side-effects, including bradycardia, hypertension, aggressive behavior, increased tremor, were observed in 7 patients (18.9%). There was no correlation between the development of side-effects and polymorphisms of the CYP2D6 and MDR1 genes.

PMID: 33081459 [PubMed - in process]

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/10/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

27 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/10/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

44 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/10/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.