Unique Genotyping Protocol of CYP2D6 Allele Frequency Using Real Time Quantitative PCR from Japanese Healthy Women.

Biol Pharm Bull. 2020;43(5):904-907

Authors: Kisoi M, Imai M, Yamamura M, Sakaguchi Y, Murata S, Ichikawa A, Kinoshita K

Abstract
CYP2D6 is an important drug-metabolizing enzyme involved in the metabolism of 20-25% of commonly prescribed drugs. Genetic polymorphism of CYP has clinically significant modifications in patients' drug-metabolizing capacities. Since gene copy number variation (CNV) and single nucleotide polymorphism (SNP) frequently occur in the CYP2D6 gene, which the activity of CYP2D6 particularly depend on the genetic factors. This study aimed to investigate the frequencies of CYP2D6 genotypes in a Japanese female subject of 216 healthy volunteers. The volunteers were genotyped for CNV Exon 9 and four CYP2D6 genetic variants (*2, *5, *10, *14, *41) performed by TaqMan® genotyping assays. The CNV allele frequencies were 82.9% for two copies, 11.6% for one copy, 4.6% for three copies and 0.9% for zero copy, respectively. The frequencies of CYP2D6*1, *2, *5, *10, *14, and *41 were 38.7, 16.7, 6.3, 34.7, 0.2, and 1.2%, respectively. CYP2D6*5 and *14 were the major defective alleles. However, this genotyping is labor intensive, time consuming, and costly. We report an optimized novel protocol for the determination of CNV and SNP in CYP2D6 gene by real-time quantitative PCR. This can lower the cost and accurately determine CNV and SNP in the CYP2D6 gene with a higher output and enabling reliable estimates of disease prediction in large epidemiological samples.

PMID: 32378566 [PubMed - in process]

Use of pharmacogenomics in elderly patients treated for cardiovascular diseases.

Croat Med J. 2020 Apr 30;61(2):147-158

Authors: Božina N, Vrkić Kirhmajer M, Šimičević L, Ganoci L, Mirošević Skvrce N, Klarica Domjanović I, Merćep I

Abstract
Older people are increasingly susceptible to adverse drug reactions (ADRs) or therapeutic failure. This could be mediated by considerable polypharmacy, which increases the possibility of drug-drug and drug-gene interactions. Precision medicine, based on individual genetic variations, enables the screening of patients at risk for ADRs and the implementation of personalized treatment regimens. It combines genetic and genomic data with environmental and clinical factors in order to tailor prevention and disease-management strategies, including pharmacotherapy. The identification of genetic factors that influence drug absorption, distribution, metabolism, excretion, and action at the drug target level allows individualized therapy. Positive pharmacogenomic findings have been reported for the majority of cardiovascular drugs (CVD), suggesting that pre-emptive testing can improve efficacy and minimize the toxicity risk. Gene variants related to drug metabolism and transport variability or pharmacodynamics of major CVD have been translated into dosing recommendations. Pharmacogenetics consortia have issued guidelines for oral anticoagulants, antiplatelet agents, statins, and some beta-blockers. Since the majority of pharmacogenetics recommendations are based on the assessment of single drug-gene interactions, it is imperative to develop tools for the prediction of multiple drug-drug-gene interactions, which are common in the elderly with comorbidity. The availability of genomic testing has grown, but its clinical application is still insufficient.

PMID: 32378381 [PubMed - in process]

Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015.

Breast Cancer Res Treat. 2020 May 06;:

Authors: O'Donnell PH, Trubetskoy V, Nurhussein-Patterson A, Hall JP, Nath A, Huo D, Fleming GF, Ingle JN, Abramson VG, Morrow PK, Storniolo AM, Forero A, Van Poznak C, Liu MC, Chang JC, Merkel DE, Peppercorn JM, Rugo HS, Dees EC, Hahn OM, Hoffman PC, Rosner GL, Huang RS, Ratain MJ, Cox N, Olopade OI, Wolff AC, Dolan ME, Nanda R, Translational Breast Cancer Research Consortium (TBCRC)

Abstract
PURPOSE: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool.
METHODS: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint.
RESULTS: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 × 10-23), representing a previously unidentified mechanism for HFS.
CONCLUSIONS: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

PMID: 32378051 [PubMed - as supplied by publisher]

Pharmacogenomics: an Update for Child and Adolescent Psychiatry.

Curr Psychiatry Rep. 2020 May 06;22(5):26

Authors: Namerow LB, Walker SA, Loftus M, Bishop JR, Ruaño G, Malik S

Abstract
PURPOSE OF REVIEW: This paper aims to acquaint child and adolescent psychiatrists with the field of pharmacogenomics (PGX) and review the most up-to-date evidence-based practices to guide the application of this field in clinical care.
RECENT FINDINGS: Despite much research being done in this area, the field of PGX continues to yield controversial findings. In the adult world, studies have focused on the impact of combinatorial gene panels that guide medication selection by providing reports that estimate the impact of multiple pharmacodynamic and pharmacokinetic genes, but to date, these have not been directly examined in younger patient populations. Pharmacokinetic genes, CYP2D6 and CYP2C19, and hypersensitivity genes, HLA-A and HLA-B, have the strongest evidence base for application to pharmacotherapy in children. Although the field is evolving, and the evidence is mixed, there may be a role for PGX testing in children to help guide dosing and monitoring strategies. However, evidence-based medicine, rather than PGX testing, continues to play the lead role in guiding medication selection in pediatric psychopharmacology.

PMID: 32377970 [PubMed - in process]

Altered Expression of Three EGFR Posttranslational Regulators MDGI, MIG6, and EIG121 in Invasive Breast Carcinomas.

Anal Cell Pathol (Amst). 2020;2020:9268236

Authors: Meseure D, Drak Alsibai K, Vacher S, Hatem R, Nicolas A, Callens C, Lerebours F, Bieche I

Abstract
Epidermal growth factor receptor (EGFR) signalling is a highly regulated process with a tight balance between receptor activation and inactivation in invasive breast carcinomas (IBCs) particularly in triple-negative carcinomas (TNC). Clinical trials using anti-EGFR therapies are actually performed although no activating alterations (mutations, amplifications, or rearrangements) of EGFR have been clearly recognized in order to identify new targeted modalities for IBCs. We explored mammary-derived growth inhibitor (MDGI), estrogen-induced gene-121 (EIG121), and mitogen-induced gene-6 (MIG6), three posttranslational EGFR trafficking molecules implicated in EGFR spatiotemporal regulatory pathway. We quantified MDGI, EIG121, and MIG6 at mRNA levels by using real-time quantitative RT-PCR in a series of 440 IBCs and at protein levels by using immunohistochemistry in a series of 88 IBCs. Results obtained by RT-PCR showed that in IBCs, MDGI, MIG6, and EIG121 mRNA were mainly underexpressed (25.7%, 45.0%, and 16.1%, respectively) particularly in the TNC subtype for EIG121 (60.3%). We also observed mRNA overexpression of MDGI and EIG121, respectively, in 12.7% and 22.3% of IBCs. These altered mRNA expressions were confirmed at the protein level. Some links were found between expression patterns of these three genes and several classical pathological and clinical parameters. Only EIG121 was found to have a prognostic significance (p = 0.0038). Altered expression of these three major EGFR posttranslational negative regulators could create an aberrant EGFR-mediated oncogenic signalling pathway in IBCs. MDGI, MIG6, and EIG121 expression status also may be potential useful biomarkers (sensitivity or resistance) in targeted EGFR therapy.

PMID: 32377505 [PubMed - in process]

Obesity and STING1 genotype associate with 23-valent pneumococcal vaccination efficacy.

JCI Insight. 2020 May 07;5(9):

Authors: Sebastian M, Hsiao CJ, Futch HS, Eisinger RS, Dumeny L, Patel S, Gobena M, Katikaneni DS, Cohen J, Carpenter AM, Spiryda L, Heldermon CD, Jin L, Brantly ML

Abstract
BACKGROUNDObesity has been associated with attenuated vaccine responses and an increased risk of contracting pneumococcal pneumonia, but no study to our knowledge has assessed the impact of obesity and genetics on 23-valent pneumococcal vaccine (PPSV23) efficacy. We assessed the relationship of obesity (primary analysis) and stimulator of interferon genes (STING1) genotype (secondary analysis) on PPSV23 efficacy.METHODSNonobese (BMI 22-25 kg/m2) and obese participants (BMI ≥30 kg/m2) were given a single dose of PPSV23. Blood was drawn immediately prior to and 4-6 weeks after vaccination. Serum samples were used to assess PPSV23-specific antibodies. STING1 genotypes were identified using PCR on DNA extracted from peripheral blood samples.RESULTSForty-six participants were categorized as nonobese (n = 23; 56.5% women; mean BMI 23.3 kg/m2) or obese (n = 23; 65.2% women; mean BMI 36.3 kg/m2). Obese participants had an elevated fold change in vaccine-specific responses compared with nonobese participants (P < 0.0001). The WT STING1 group (R232/R232) had a significantly higher PPSV23 response than individuals with a single copy of HAQ-STING1 regardless of BMI (P = 0.0025). When WT was assessed alone, obese participants had a higher fold serotype-specific response compared with nonobese participants (P < 0.0001), but no difference was observed between obese and nonobese individuals with 1 HAQ allele (P = 0.693).CONCLUSIONSThese observations demonstrate a positive association between obesity and PPSV23 efficacy specifically in participants with the WT STING1 genotype.TRIAL REGISTRATIONClinicalTrials.gov NCT02471014.FUNDINGThis research was supported by the NIH and the University of Florida MD-PhD Training Program.

PMID: 32376795 [PubMed - in process]

[Artificial intelligence empowers laboratory medicine in Industry 4.0].

Nan Fang Yi Ke Da Xue Xue Bao. 2020 Feb 29;40(2):287-296

Authors: Zhou Q, Qi S, Xiao B, Li Q, Sun Z, Li L

Abstract
Since 2017, China, the United States, and the European Union have successively issued national-level artificial intelligence (AI) strategic development plans, and the human history is about to witness the 4th industrial revolution with the theme of "intelligence". In the field of medical testing, the explosive growth of AI theories and technologies also provide a new direction for the development of medical testing theory, methods and applications. We review the evolution of AI and the recent progress in three major elements of AI, namely algorithms, data and computing power, and elaborate on the combined innovation of "AI + testing" in light of the key application dimensions of medical testing. The major applications include specimen collection robots, sample dilution robots and sample transfer robots involved in the processing of test specimens; test item mining such as tumor markers and pharmacogenomics; cytomorphology, laboratory medicine data processing, auxiliary diagnostic models, and internet-based medical tests. With the advent of the era of Industry 4.0, AI technology will promote the development of medical testing from automation to a highly intelligent stage.

PMID: 32376538 [PubMed - in process]

The influence of genetic polymorphisms in drug metabolism enzymes and transporters on the pharmacokinetics of different fluvastatin formulations.

Asian J Pharm Sci. 2020 Mar;15(2):264-272

Authors: Xiang Q, Wu W, Zhao N, Li C, Xu J, Ma L, Zhang X, Xie Q, Zhang Z, Wang J, Xu W, Zhao X, Cui Y

Abstract
The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics. In addition, we compared the fluvastatin pharmacokinetics differences between extended-release (ER) 80 mg tablet and immediate-release (IR) 40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms. In this open-label, randomized, two-period, two-treatment, crossover study (n = 24), effects of ABCG2, SLCO1B1, ABCB1, CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed. The administration dosage for IR 40 mg and ER 80 mg were twice and once daily, respectively, for total 7 d. Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d. The lower exposure following ER was observed. For ER tablets, SLCO1B1 T521C genotype correlated with AUC0-24 of repeat doses (P = 0.010). SLCO1B1 T521C genotype had no statistically significant effect on AUC0-24 of IR capsule of fluvastatin after single or repeated doses. In vitro study demonstrated that when the concentration of fluvastatin was low (< 1 µmol/l), the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1 521TT (Km =0.18 µmol/l) was faster than that with SLCO1B1 521CC (Km =0.49 µmol/l), On the other hand, when concentration reached to higher level (> 1 µmol/l), transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1 521TT (Km  = 11.4 µmol/l) and with SLCO1B1 521TCC (Km =15.1 µmol/l) tend to be the same. It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations. We recommend that formulation should be incorporated into future pharmacogenomics studies.

PMID: 32373204 [PubMed]

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

Pharmacogenomics. 2020 May 06;:

Authors: Gagné V, St-Onge P, Beaulieu P, Laverdière C, Leclerc JM, Tran TH, Sallan SE, Neuberg D, Silverman LB, Sinnett D, Krajinovic M

Abstract
Aim: To evaluate the association between human leukocyte antigen (HLA) alleles and native Escherichia coli asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods: HLA-DQA1, HLA-DRB1 and HLA-DQB1 alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts. Results: Two alleles in linkage disequilibrium (HLA-DRB1*07:01 and DQA1*02:01) were associated with AH. Additional analyses, performed to distinguish between HLA-DRB1*07:01 haplotypes with and without DQB1*02:02 allele, showed that the association was dependent on the presence of DQB1*02:02. Conclusion: This study confirms the implication of HLA-DRB1*07:01, DQA1*02:01 and DQB1*02:02 alleles in developing AH in childhood ALL.

PMID: 32372697 [PubMed - as supplied by publisher]

Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment.

Pharmacogenomics. 2020 May 06;:

Authors: Pisanu C, Congiu D, Manchia M, Caria P, Cocco C, Dettori T, Frau DV, Manca E, Meloni A, Nieddu M, Noli B, Pinna F, Robledo R, Sogos V, Ferri GL, Carpiniello B, Vanni R, Bocchetta A, Severino G, Ardau R, Chillotti C, Zompo MD, Squassina A

Abstract
Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

PMID: 32372689 [PubMed - as supplied by publisher]

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PG-path: Modeling and personalizing pharmacogenomics-based pathways.

PLoS One. 2020;15(5):e0230950

Authors: Hong JY, Kim JH

Abstract
A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a pharmacogenomics-based pathway that standardizes and visualizes the components (nodes) and actions (edges) involved in pharmacokinetic and pharmacodynamic processes. It provides an intuitive understanding of the drug response in the human body. A pharmacokinetic pathway visualizes the absorption, distribution, metabolism, and excretion (ADME) at the systemic level, and a pharmacodynamic pathway shows the action of the drug in the target cell at the cellular-molecular level. The genes in the pathway are displayed in locations similar to those inside the body. PG-path allows personalized pathways to be created by annotating each gene with the overall impact degree of deleterious variants in the gene. These personalized pathways play a role in assisting tailored individual prescriptions by predicting changes in the drug concentration in the plasma. PG-path also supports counseling for personalized drug therapy by providing visualization and documentation.

PMID: 32365122 [PubMed - as supplied by publisher]

The role of NAT2 polymorphism and methylation in anti-tuberculosis drug-induced liver injury in Mongolian tuberculosis patients.

J Clin Pharm Ther. 2020 Jun;45(3):561-569

Authors: Zhang D, Hao J, Hou R, Yu Y, Hu B, Wei L

Abstract
WHAT IS KNOWN AND OBJECTIVE: Anti-tuberculosis drug-induced liver injury (ATLI) is one of the most significant adverse reactions for this line of therapy. N-acetyltransferase 2 (NAT2) is an important metabolic enzyme involved in drug metabolism and detoxification. Genetic polymorphism and DNA methylation have been proven to be key factors that affect the expression of NAT2. Therefore, the objective of the study was to investigate the relationship between NAT2 gene polymorphism and DNA methylation in the promoter region with ATLI risk in Mongolian tuberculosis patients.
METHODS: Our study is a case-control design. Chi-square test, Mann-Whitney U non-parametric test and Pearson test were all used to analyse existing relationships. The association between NAT2 gene acetylation phenotype and the total methylation of the NAT2 promoter region was analysed by means of binary logistic regression analysis. The general situation of the patients was evaluated by questionnaire, and the NAT2 genotyping of the three major polymorphism loci of gene coding was carried out by a gene sequencing technique. The methylation status of the NAT2 gene promoter region was detected by bisulphite sequencing and mass spectrometry.
RESULT AND DISCUSSION: Our study found that the detection rate of ATLI in Mongolian tuberculosis patients was 27.6%. There were no significant differences in demographic characteristics and living habits amongst the two groups, while significant differences were observed in the polymorphism of the NAT2 genes 481 (rs1799929) and 590 (rs1799930) and the acetylation phenotype. Moreover, the composition and distribution of the NAT2*4/4 and NAT2*4/5 genotypes were found in the two groups. The risk of ATLI in the slow acetylation type was 3.56 times higher than that of the fast acetylation type. Compared with the control group, the CpG5, CpG10, CpG11.12 and total methylation of the NAT2 promoter region in the ATLI group showed a hypermethylated pattern (P < .05). However, on performing binary logistic regression, neither the slow acetylation, intermediate acetylation nor rapid acetylation were found to be associated with ATLI (P > .05). It was found that the total methylation of NAT2 gene promoter region was an independent influencing factor of ATLI in Mongolian tuberculosis patients. With the increase of the total methylation level of NAT2 gene promoter region, the risk of ATLI increased gradually. (OR = 8.371, 95% CI: 2.391 ~ 29.315). CpG1, CpG4, CpG9, CpG10 and CpG11.12 were positively correlated with a total methylation level in the ATLI group.
WHAT IS NEW AND CONCLUSION: The detection rate of ATLI in Mongolian tuberculosis patients was 27.6%, and there were differences in the NAT2 genotypes and acetylated phenotypes. The slow acetylated type was the risk factor for ATLI. Methylation in the promoter region of the NAT2 gene has an effect on the risk of ATLI. After adjusting for the interference of three acetylation types, it was found that the total methylation of the promoter region of NAT2 gene in Mongolian tuberculosis patients is an independent influencing factor of ATLI. Furthermore, there is a moderate to high correlation between some sites and the overall level of methylation.

PMID: 32364660 [PubMed - as supplied by publisher]

Annual changes in forced oscillation technique parameters correlate with FEV1 decline in patients with asthma, COPD, and asthma-COPD overlap.

Allergol Int. 2020 Apr 30;:

Authors: Tanaka Y, Hirai K, Nakayasu H, Tamura K, Masuda T, Takahashi S, Watanabe H, Kishimoto Y, Ohishi K, Saigusa M, Akamatsu T, Yamamoto A, Morita S, Asada K, Shirai T

PMID: 32362454 [PubMed - as supplied by publisher]

The near-infrared fluorescent dye IR-780 was coupled with cabazitaxel for castration-resistant prostate cancer imaging and therapy.

Invest New Drugs. 2020 May 02;:

Authors: Zheng Y, Hou G, Zhang G, Lan T, Yuan J, Zhang L, Yan F, Wang F, Meng P, Dun X, Li X, Chen G, Zhu Z, Wei D, He W, Yuan J

Abstract
A new drug, Caba-780, was synthesized by chemical coupling of the heptamethyl phthalocyanine near-infrared fluorescent (NIRF) dye IR-780 and the paclitaxel-based chemotherapeutic drug cabazitaxel. Then, the potential value of Caba-780 in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) was evaluated. The CRPC cell lines DU145 and PC-3, as well as the normal human prostate stromal cell line WPMY-1, were used to evaluate the uptake of Caba-780 and its antitumor effect in vitro. The distribution, antitumor effect, and safety of Caba-780 were also evaluated in tumor-bearing mouse xenograft models. Our results showed that Caba-780 was efficiently absorbed by DU145 and PC-3 cells and that the cytotoxicity of Caba-780 was significantly stronger than that of IR-780 and cabazitaxel. In addition, Caba-780 inhibited the migration and invasion of DU145 and PC-3 cells and promoted apoptosis by prolonging the G2 phase of the cell cycle. Further analysis indicated that Caba-780 could be used to effectively image tumor xenografts. At the same time, this drug inhibited the growth of tumors in vivo. Therefore, the new synthetic drug Caba-780 has potential applications in the diagnosis and treatment of CRPC.

PMID: 32361788 [PubMed - as supplied by publisher]

Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease.

J Antimicrob Chemother. 2020 May 03;:

Authors: Avataneo V, de Nicolò A, Cusato J, Antonucci M, Manca A, Palermiti A, Waitt C, Walimbwa S, Lamorde M, di Perri G, D'Avolio A

Abstract
BACKGROUND: Remdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2 h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24 h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification.
OBJECTIVES: The validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma.
METHODS: Remdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8 μm, 2.1 × 50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.
RESULTS: Analyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety.
CONCLUSIONS: This method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.

PMID: 32361744 [PubMed - as supplied by publisher]

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia.

Int J Mol Sci. 2020 Apr 26;21(9):

Authors: Cacabelos R

Abstract
Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6-10 drugs/day with the consequent risk for drug-drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

PMID: 32357528 [PubMed - as supplied by publisher]

Super High-Flux Hemodialysis Provides Comparable Effectiveness with High-Volume Post-dilution Online Hemodiafiltration in Removing Protein-bound and Middle-molecule Uremic Toxins: A Prospective Cross-over Randomized Controlled Trial.

Ther Apher Dial. 2020 May 01;:

Authors: Thammathiwat T, Tiranathanagul K, Limjariyakul M, Chariyavilaskul P, Takkavatakarn K, Susantitaphong P, Meesangnin S, Wittayalertpanya S, Praditpornsilpa K, Eiam-Ong S

Abstract
Although high-volume post-dilution online hemodiafiltration (ol-HDF) is superior to high-flux hemodialysis (HD) in removing all kinds of uremic toxins and improving survival, this treatment is not available in most HD centers. The present study was conducted to compare the effectiveness in removals of protein-bound (indoxyl sulfate, IS), middle-molecule [beta-2 microglobulin (B2M) and alpha-1 microglobulin (A1MG)], and small-molecule uremic toxins between super high-flux HD (SHF-HD), HD with a novel SHF dialyzer and high-volume post-dilution ol-HDF in a non-inferiority fashion. Fifteen prevalent HD patients were randomly allocated into 2 sequences of 12-week treatment periods of SHF-HD treatment and later high-volume post-dilution ol-HDF period or vice versa. Each treatment period was divided by a wash out phase of 4-week high-flux HD. Twelve of fifteen patients could complete the study. When compared with high-volume post-dilution ol-HDF (convective volume of 24.4 ± 3.52 L), SHF-HD provided comparable RR values of IS, B2M, and A1MG with mean difference of 5.87 (95% CI,-1.63,13.37), 1.98 (95% CI,-0.21,4.18), and 22.96 (95%CI,-1.91,47.83), respectively. The spKt/Vurea was not different. The pre-dialysis levels of all uremic toxins at baseline and after 12-week treatment did not differ between both groups. Although albumin loss in dialysate in SHF-HD was greater than high-volume post-dilution ol-HDF, the serum albumin levels after 12-week SHF-HD treatment were significantly higher than baseline. In conclusion, SHF-HD provides non-inferior effectiveness to high-volume post-dilution ol-HDF in removing various uremic toxins with significantly increased serum albumin levels despite higher albumin loss. SHF-HD might be an effectively alternative treatment when high-volume post-dilution ol-HDF is not available.

PMID: 32356365 [PubMed - as supplied by publisher]

Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients.

J Hum Genet. 2020 May 01;:

Authors: Cha PC, Satake W, Ando-Kanagawa Y, Yamamoto K, Murata M, Toda T

Abstract
Long-term treatment of Parkinson's disease (PD) by levodopa leads to motor complication "wearing-off". Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose "off" time decreased ≥1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and "off" time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced "off" time (PAdjusted = 4.85 × 10-9). Carriers of responsive genotype showed >7-fold decrease in mean "off" time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 × 10-7). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing "off" time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of "wearing-off" in PD by genotype-guided zonisamide treatment.

PMID: 32355309 [PubMed - as supplied by publisher]

Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression.

Haematologica. 2020 Apr 30;:

Authors: Solimando AG, Da Vià MC, Leone P, Borrelli P, Croci GA, Tabares P, Brandl A, Di Lernia G, Bianchi FP, Tafuri S, Steinbrunn T, Balduini A, Melaccio A, De Summa S, Argentiero A, Rauert-Wunderlich H, Frassanito MA, Ditonno P, Henke E, Klapper W, Ria R, Terragna C, Rasche L, Rosenwald A, Kortüm KM, Cavo M, Ribatti D, Racanelli V, Einsele H, Vacca A, Beilhack A

Abstract
Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Elevated membrane expression of JAM-A on MMECs predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MMECs increased angiogenesis whereas its inhibition impaired angiogenesis and MM growth in 2D and 3D in vitro cell culture and chorioallantoic membrane-assays. To corroborate these findings, we treated MM bearing mice with JAM-A blocking mAb and demonstrated impaired MM progression corresponding to decreased MM-related vascularity. These findings support JAM-A as an important mediator of MM progression through facilitating MM-associated angiogenesis. Collectively, elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for patient survival in both NDMM and RRMM. Blocking JAM-A restricts angiogenesis in vitro, in embrio and in vivo and represents a suitable druggable molecule to halt neoangiogenesis and MM progression.

PMID: 32354870 [PubMed - as supplied by publisher]