Role of Genetic Variations in the Hepatic Handling of Drugs.

Int J Mol Sci. 2020 Apr 20;21(8):

Authors: Marin JJG, Serrano MA, Monte MJ, Sanchez-Martin A, Temprano AG, Briz O, Romero MR

Abstract
The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.

PMID: 32326111 [PubMed - in process]

Ser100-Phosphorylated RORα Orchestrates CAR and HNF4α to Form Active Chromatin Complex in Response to Phenobarbital to Regulate Induction of CYP2B6.

Mol Pharmacol. 2020 03;97(3):191-201

Authors: Fashe M, Hashiguchi T, Negishi M, Sueyoshi T

Abstract
We have previously shown that the retinoid-related orphan receptor alpha (RORα) phosphorylation plays a pivotal role in sulfotransferase 1E1 gene regulation within mouse liver. Here, we found serine 100-phosphorylated RORα orchestrates constitutive androstane receptor (CAR) and hepatocyte nuclear factor 4 alpha (HNF4α) to induce CYP2B6 by phenobarbital (PB) in human primary hepatocytes (HPHs). RORα knockdown using small interfering RNAs suppressed CYP2B6 mRNAs in HPH, whereas transient expression of RORα in COS-1 cells activated CYP2B6 promoter activity in reporter assays. Through chromatin immunoprecipitation (IP) and gel shift assays, we found that RORα in the form of phosphorylated (p-) S100 directly bound to a newly identified RORα response element (RORα response element on CYP2B6 promoter, -660/-649) within the CYP2B6 promoter in untreated or treated HPH. In PB-treated HPH, p-Ser100 RORα was both enriched in the distal phenobarbital response element module (PBREM) and the proximal okadaic acid response element (OARE), a known HNF4α binding site. Chromatin conformation capture assay revealed direct contact between the PBREM and OARE only in PB-treated HPH. Moreover, CAR preferably interacted with phosphomimetically mutated RORα at Ser100 residue in co-IP assay. A gel shift assay with a radiolabeled OARE module and nuclear extracts prepared from PB-treated mouse liver confirmed that HNF4α formed a complex with Ser 100-phosphorylated RORα, as shown by supershifted complexes with anti-p-Ser100 RORα and anti-HNF4α antibodies. Altogether, the results established that p-Ser100 RORα bridging the PBREM and OARE orchestrates CAR and HNF4α to form active chromatin complex during PB-induced CYP2B6 expression in human primary hepatocytes. SIGNIFICANCE STATEMENT: CYP2B6 is a vital enzyme for the metabolic elimination of xenobiotics, and it is prone to induction by xenobiotics, including phenobarbital via constitutive androstane receptor (CAR) and hepatocyte nuclear factor 4 alpha (HNF4α). Here, we show that retinoid-related orphan receptor alpha (RORα), through phosphorylated S100 residue, orchestrated CAR-HNF4α interaction on the CYP2B6 promoter in human primary hepatocyte cultures. These results signify not only the role of RORα in the molecular process of CYP2B6 induction, but it also reveals the importance of conserved phosphorylation sites within the DNA-binding domain of the receptor.

PMID: 31924695 [PubMed - indexed for MEDLINE]

The role of phase I and II genetic polymorphisms, smoking, alcohol and cancer family history, in the risk of developing testicular cancer.

Pharmacogenet Genomics. 2019 09;29(7):159-166

Authors: Roco A, Lavanderos A, Cayún JP, Acevedo C, Celedón C, Rubilar JC, Sandoval C, Cerpa L, García-Martín E, Agúndez JA, Esguevillas G, Amo G, Canepa A, Cerda B, Peña K, Cáceres DD, Varela NM, Quiñones LA

Abstract
BACKGROUND: Testicular cancer (TCa) is a malignant tumor with highest incidence and mortality rates in Chile. The genes coding for cytochrome P450, glutathione-S-transferases (GSTs), and UDP glucuronyl transferases (UGT) participate in the biotransformation and detoxification of xenobiotics. Mutations in these genes have been associated with a high incidence of various types of cancer and an increased risk of presenting adverse reactions to drugs.
OBJECTIVE: The aim of this study was to relate the presence of genetic polymorphisms in cytochrome P450 1A1 (CYP1A1), CYP3A4, GSTM1, GSTP1, GSTT1, and UGT1A1 genes and nongenetic factors with the risk of developing TCa.
METHODS: A total of 276 volunteers from the Chilean general population and 251 Chilean TCa patients were recruited for the study. Genotypic analyses were performed using qPCR and PCR-RFLP.
RESULTS: Variant alleles found to increase the risk of developing TCa were CYP1A1*2C (rs1048943), GSTP1 (rs1695), and GSTT1null, especially when in conjunction with a cancer family history and/or a smoking habit. The results of the multivariate analysis showed that the presence of variant alleles of GSTP1 (rs1695) together with a smoking habit and a family history of cancer accounted for a 15.9% risk of developing TCa in the Chilean population. CYP1A1*2C, GSTM1null, GSTT1null, and GSTP1 (rs1695) are statistically related to the risk of appearance of TCa, alone or associated with nongenetic factors.
CONCLUSION: Therefore, phase I and II variant alleles might be useful in evaluating susceptibility to TCa in the studied population.

PMID: 31107374 [PubMed - indexed for MEDLINE]

Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors.

Eur J Med Chem. 2020 Apr 06;196:112291

Authors: Nepali K, Chang TY, Lai MJ, Hsu KC, Yen Y, Lin TE, Lee SB, Liou JP

Abstract
This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA-MB-468 (IC50 = 0.65 μM), and liver cancer cells HepG2 (IC50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents.

PMID: 32325365 [PubMed - as supplied by publisher]

Incidence of Adverse Drug Reactions in COVID-19 patients in China: an active monitoring study by Hospital Pharmacovigilance System.

Clin Pharmacol Ther. 2020 Apr 23;:

Authors: Sun J, Deng X, Chen X, Huang J, Huang S, Li Y, Feng J, Liu J, He G

Abstract
To evaluate the incidence, type and risk factors associated with adverse drug reactions (ADRs) among COVID-19 patients by Hospital Pharmacovigilance System (CHPS). A retrospective analysis was performed on 217 COVID-19 patients admitted to the First Hospital of Changsha in China, from January 17, 2020 to February 29, 2020. The active monitoring model in CHPS was used to detect ADR signals of hospital information system. The risk factors for the ADRs were classified using the WHO-UMC system. Univariate and multivariate logistic regression was carried out to analyze the risk factors of ADRs. Our results showed that the prevalence of ADRs was 37.8% in the patients, which was predominated by drug-induced gastrointestinal disorders and liver system disorders (23.0% vs. 13.8% ). The ADR could be explained by the use of lopinavir/ ritonavir and umifenovir by 63.8% and 18.1%, respectively. 96.8% of ADRs occurred within 14 days of hospitalization. Multivariable analysis showed that length of stay (OR: 2.02, [95% CI: 1.03-3.96], P=0.04), number of drugs used in hospital (OR: 3.17, [95%CI: 1.60-6.27], P=0.001) and underlying basic diseases (OR:2.07, [95%CI: 1.02-4.23], P = 0.04) were independent risk factor for ADRs in the patients. Together, the incidence of ADRs was significantly high during the treatment period. Moreover, the active monitoring of the CHPS system reflected ADRs during COVID-19 treatment in the real world, which provided reference for safe medication in clinic.

PMID: 32324898 [PubMed - as supplied by publisher]

Ketamine Treatment in Depression: A Systematic Review of Clinical Characteristics Predicting Symptom Improvement.

Curr Top Med Chem. 2020 Apr 22;:

Authors: Lowe DJE, Müller DJ, George TP

Abstract
Ketamine has been shown to be efficacious for the treatment of depression, specifically among individuals who do not responded to first-line treatments. There is still, however, a lack of clarity surrounding the clinical features and response periods across samples that respond to ketamine. This paper systematically reviews published randomized, controlled trials that investigate ketamine as an antidepressant intervention in both unipolar and bipolar depression to determine the specific clinical features of the samples across different efficacy periods. Moreover, similarities and differences in clinical characteristics associated with acute versus longer-term drug response are discussed. Similarities across all samples suggest that the population that responds to ketamine's antidepressant effect have experienced chronic, long-term depression, approaching ketamine treatment as a "last resort". Moreover, differences between these groups suggest future research to investigate the potential of stronger efficacy towards depression in the context of bipolar disorder compared to major depression, and in participants who undergo antidepressant washout before ketamine administration. From these findings, suggestions for the future direction of ketamine research for depression are formed.

PMID: 32324515 [PubMed - as supplied by publisher]

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

JCI Insight. 2020 Apr 23;5(8):

Authors: Portelli MA, Dijk FN, Ketelaar ME, Shrine N, Hankinson J, Bhaker S, Grotenboer NS, Obeidat M, Henry AP, Billington CK, Shaw D, Johnson SR, Pogson ZE, Fogarty A, McKeever TM, Nickle DC, Bossé Y, van den Berge M, Faiz A, Brouwer S, Vonk JM, de Vos P, Brandsma CA, Vermeulen CJ, Singapuri A, Heaney LG, Mansur AH, Chaudhuri R, Thomson NC, Holloway JW, Lockett GA, Howarth PH, Niven R, Simpson A, Blakey JD, Tobin MD, Postma DS, Hall IP, Wain LV, Nawijn MC, Brightling CE, Koppelman GH, Sayers I

Abstract
The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

PMID: 32324168 [PubMed - as supplied by publisher]

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines.

Front Cell Infect Microbiol. 2020;10:139

Authors: Azad AK, Lloyd C, Sadee W, Schlesinger LS

Abstract
Universal approaches to the prevention and treatment of human diseases fail to take into account profound immune diversity resulting from genetic variations across populations. Personalized or precision medicine takes into account individual lifestyle, environment, and biology (genetics and immune status) and is being adopted in several disease intervention strategies such as cancer and heart disease. However, its application in infectious diseases, particularly global diseases such as tuberculosis (TB), is far more complex and in a state of infancy. Here, we discuss the impact of human genetic variations on immune responses and how they relate to failures seen in current TB diagnostic, therapy, and vaccine approaches across populations. We offer our perspective on the challenges and potential for more refined approaches going forward.

PMID: 32322562 [PubMed - in process]

Extensive In Silico Analysis of ATL1 Gene : Discovered Five Mutations That May Cause Hereditary Spastic Paraplegia Type 3A.

Scientifica (Cairo). 2020;2020:8329286

Authors: Mustafa MI, Murshed NS, Abdelmoneim AH, Abdelmageed MI, Elfadol NM, Makhawi AM

Abstract
Background: Hereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP which is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. SPG3A gene mutations and the phenotype-genotype correlations have not yet been recognized. The aim of this work was to categorize the most damaging SNPs in ATL1 gene and to predict their impact on the functional and structural levels by several computational analysis tools.
Methods: The raw data of ATL1 gene were retrieved from dbSNP database and then run into numerous computational analysis tools. Additionally; we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0 and MUPro, respectively, to investigate their effect on the structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids.
Results: Five nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, and rs1242753115).
Conclusions: In this study, the impact of nsSNPs in the ATL1 gene was investigated by various in silico tools that revealed five nsSNPs (V67F, T120I, R217Q, R495W, and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein and, therefore, can be used as genomic biomarkers specifically before 4 years of age; also, it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.

PMID: 32322428 [PubMed]

Genetic Editing and Pharmacogenetics in Current And Future Therapy Of Neurocognitive Disorders.

Curr Alzheimer Res. 2020 Apr 22;:

Authors: Prendecki M, Kowalska M, Toton E, Kozubski W

Abstract
Dementia is an important issue in western societies, and in the following years, this problem will also rise in the developing regions, such as Africa and Asia. The most common types of dementia in adults are Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and vascular dementia (VaD), of which, AD accounts for more than half of the cases. The most prominent symptom of AD is cognitive impairment, currently treated with four drugs: donepezil, rivastigmine, and galantamine, enhancing cholinergic transmission; as well as memantine, protecting neurons against glutamate excitotoxicity. Despite ongoing efforts, no new drugs in the treatment of AD have been registered for the last ten years, thus multiple studies have been conducted on genetic factors affecting the efficacy of antidementia pharmacotherapy. The researchers investigate the effects of variants in multiple genes, such as ABCB1, ACE, CHAT, CHRNA7, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP3A7, NR1I2, NR1I3, POR, PPAR, RXR, SLC22A1/2/5, SLC47A1, UGT1A6, UGT1A9 and UGT2B7, associated with numerous pathways: the development of pathological proteins, formation and metabolism of acetylcholine, transport, metabolism and excretion of antidementia drugs and transcription factors regulating the expression of genes responsible for metabolism and transport of drugs. The most promising results have been demonstrated for APOE E4, dementia risk variant, BCHE-K, reduced butyrylcholinesterase activity variant, and CYP2D6 UM, ultrarapid hepatic metabolism. Further studies investigate the possibilities of the development of emerging drugs or genetic editing by CRISPR/Cas9 for causative treatment. In conclusion, the pharmacogenetic studies on dementia diseases may improve the efficacy of pharmacotherapy in some patients with beneficial genetic variants, at the same time, identifying the carriers of unfavorable alleles, the potential group of novel approaches to the treatment and prevention of dementia.

PMID: 32321403 [PubMed - as supplied by publisher]

[Genetics of Posttraumatic Stress Disorder (PTSD)].

Psychother Psychosom Med Psychol. 2019 Jul;69(7):266-274

Authors: Weiss EM, Parson W, Niederstätter H, Marksteiner J, Lampe A

Abstract
Post-traumatic stress disorder (PTSD) is a mental disorder following a severe traumatic experience and is characterized by high rates of comorbidity with related psychiatric disorders. However, even for individuals experiencing the same trauma, there is considerable inter-individual variability in the risk of PTSD, and this is largely thought to be determined by biological processes, such as genetic predisposition and epigenetic mechanism. In this review we will summarize recent research on genetics of PTSD, primarily focusing on candidate gene-association studies, targeting on functional genetic variants in the monoaminergic system and the hypothalamic-pituitary-adrenal (HPA) axis. In addition, results from recent genome-wide association studies (GWAS) will be reported and we will highlight the interplay of genetic factors with environmental factors, based on evidence from gene-environment interaction analysis and studies on the epigenetic regulation of PTSD. Finally, we will provide a brief outlook towards the potential and perspectives of pharmaco-genetic studies.

PMID: 30025422 [PubMed - indexed for MEDLINE]

Different Plasmodium falciparum clearance times in two Malian villages following artesunate monotherapy.

Int J Infect Dis. 2020 Apr 19;:

Authors: Kone A, Sissoko S, Fofana B, Sangare CO, Dembele D, Haidara AS, Diallo N, Coulibaly A, Traore A, Toure S, Haidara K, Sanogo K, Sagara I, Beshir KB, Gil JP, Doumbo OK, Djimde AA

Abstract
BACKGROUND: Artemisinin resistance described as increased parasite clearance time (PCT) is rare in Africa. More sensitive methods such as qPCR might better characterize the clearance phenotype in sub-Saharan Africa.
METHODS: PCT is explored in Mali using light microscopy and qPCR after artesunate for uncomplicated malaria. In two villages, patients were followed for 28 days. Blood smears and spots were collected respectively for microscopy and qPCR. Parasitemia slope half-life was calculated after microscopy. Patient residual parasitemia were measured by qPCR.
RESULTS: Uncorrected adequate clinical and parasitological responses (ACPR) observed in Faladje and Bougoula-Hameau were 78% and 92%, respectively (p=0.01). This reached 100% for both after molecular correction. Proportions of 24H microscopy positive patients in Faladje and Bougoula-Hameau were 97.2% and 72%, respectively (p<0.0001). Slope half-life was 2.8h in Faladje vs 2h in Bougoula-Hameau (p<0.001) and Proportions of 72h patients with residual parasitemia were 68.5% and 40% in Faladje and Bougoula-Hameau, respectively (p=0.003). The mean residual parasitemia was 2.9 in Faladje vs. 0.008 in Bougoula-Hameau (p=0.002). Although artesunate is efficacious in Mali, the longer parasite clearance time with submicroscopic parasitemia observed may represent early signs of developing P. falciparum resistance to artemisinins.

PMID: 32320811 [PubMed - as supplied by publisher]

Clinically relevant CYP3A4 induction mechanisms and drug screening in 3D spheroid cultures of primary human hepatocytes.

Clin Pharmacol Ther. 2020 Apr 22;:

Authors: Hendriks DFG, Vorrink SU, Smutny T, Sim SC, Nordling Å, Ullah S, Kumondai M, Jones BC, Johansson I, Andersson TB, Lauschke VM, Ingelman-Sundberg M

Abstract
CYP3A4 induction is an important cause of drug-drug interactions, making early identification of drug candidates with CYP3A4 induction liability in drug development a prerequisite. Here, we present 3D spheroid cultures of primary human hepatocytes (PHH) as a novel CYP3A4 induction screening model. Screening of 25 drugs (12 known CYP3A4 inducers in vivo and 13 negative controls) at physiologically relevant concentrations revealed a 100% sensitivity and 100% specificity of the system. Three of the in vivo CYP3A4 inducers displayed much higher CYP3A4 induction capacity in 3D spheroid cultures as compared to in 2D monolayer cultures. Among those, we identified AZD1208, a PIM kinase inhibitor terminated in phase I of development due to unexpected CYP3A4 autoinduction, as a CYP3A4 inducer only active in 3D spheroids but not in 2D monolayer cultures. Gene knockdown experiments revealed that AZD1208 requires PXR to induce CYP3A4. Rifampicin requires solely PXR to induce CYP3A4 and CYP2B6, while phenobarbital-mediated induction of these CYPs did not show absolute dependency on either PXR or CAR suggesting its ability to switch nuclear receptor activation. Mechanistic studies into AZD1208 uncovered an involvement of the MAPK/ERK pathway in CYP3A4 induction that is sensitive to the culture format used, as revealed by its inhibition of ERK1/2 Tyr204 phosphorylation and sensitivity to EGF pressure. In line, we also identified lapatinib, a dual EGFR/HER2 inhibitor, as another CYP3A4 inducer only active in 3D spheroid culture. Our findings offer insights into the pathways involved in CYP3A4 induction and suggest PHH spheroids for preclinical CYP3A4 induction screening.

PMID: 32320483 [PubMed - as supplied by publisher]

Pharmacogenetic associations and evidence-based pharmacogenomics guidelines: supporting label and off-label use of drug-gene interaction data.

Pharmacogenomics. 2020 Apr 22;:

Authors: Kisor DF, Monte AA, Müller DJ

PMID: 32319356 [PubMed - as supplied by publisher]

Generating evidence for precision medicine: considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study.

Pharmacogenet Genomics. 2020 Apr 20;:

Authors: van der Wouden CH, Böhringer S, Cecchin E, Cheung KC, Dávila-Fajardo CL, Deneer VHM, Dolžan V, Ingelman-Sundberg M, Jönsson S, Karlsson MO, Kriek M, Mitropoulou C, Patrinos GP, Pirmohamed M, Rial-Sebbag E, Samwald M, Schwab M, Steinberger D, Stingl J, Sunder-Plassmann G, Toffoli G, Turner RM, van Rhenen MH, van Zwet E, Swen JJ, Guchelaar HJ, Ubiquitous Pharmacogenomics Consortium

Abstract
OBJECTIVES: Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design.
METHODS: An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses.
RESULTS: Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene-drug interaction in a gatekeeping analysis.
CONCLUSIONS: Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene-drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.

PMID: 32317559 [PubMed - as supplied by publisher]

Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers.

Int J Mol Sci. 2020 Apr 16;21(8):

Authors: Jessurun NT, Wijnen PA, Bast A, van Puijenbroek EP, Bekers O, Drent M

Abstract
Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.

PMID: 32316326 [PubMed - in process]

Circulating miR-146a and miR-134 in predicting drug-resistant epilepsy in patients with focal impaired awareness seizures.

Epilepsia. 2020 Apr 21;:

Authors: Leontariti M, Avgeris M, Katsarou MS, Drakoulis N, Siatouni A, Verentzioti A, Alexoudi A, Fytraki A, Patrikelis P, Vassilacopoulou D, Gatzonis S, Sideris DC

Abstract
OBJECTIVE: Epilepsy is one of the most prevalent neurologic disorders, causing serious psychological problems and reducing quality of life. Although 20 different antiepileptic drugs (AEDs) have been approved by the US Food and Drug Administration (FDA), 30% of patients have drug-resistant epilepsy (DRE). Considering the role of miR-146a and miR-134 in neuroinflammation and dendritic functionality, respectively, the aim of this study was the clinical evaluation of circulating miR-146a and miR-134 as novel noninvasive molecular markers for the prognosis of refractory epilepsy.
METHODS: The study included 162 patients with focal impaired awareness seizures. Total RNA was extracted from serum samples spiked with synthetic cel-miR-39-3p for normalization purposes. First-strand complementary DNA (cDNA) synthesis was performed using microRNA-specific stem-loop primers, and hsa-miR-134/146a levels were quantified by quantitative polymerase chain reaction (qPCR). DRE was used as clinical end point event. Internal validation was performed by bootstrap analysis, and decision curve analysis was used to evaluate the clinical benefit on disease prognosis.
RESULTS: The circulating levels of both miR-134 and miR-146a were elevated in patients with drug-resistant seizures. The receiver-operating characteristic (ROC) curve and logistic regression analysis demonstrated that patients with increased circulating miR-134/146a levels are at significantly higher risk for developing DRE, independently of temporal lobe sclerosis, epilepsy duration, familial history, age at first seizure, age, body mass index (BMI), smoking behavior, and gender. Finally, decision curve analysis highlighted that the evaluation of circulating miR-134/146a led to superior clinical benefit for DRE prognosis and patients' risk stratification.
SIGNIFICANCE: Elevated serum miR-134/146a levels are associated with a higher risk for AED-resistant epilepsy and could constitute novel noninvasive molecular markers to improve disease early prognosis and support precision medicine.

PMID: 32314378 [PubMed - as supplied by publisher]

Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice.

J Clin Invest. 2019 04 15;129(5):2133-2144

Authors: Cohen TS, Takahashi V, Bonnell J, Tovchigrechko A, Chaerkady R, Yu W, Jones-Nelson O, Lee Y, Raja R, Hess S, Stover CK, Worthington JJ, Travis MA, Sellman BR

Abstract
Diabetic individuals are at considerable risk for invasive infection by Staphylococcus aureus, however, the mechanisms underlying this enhanced susceptibility to infection are unclear. We observed increased mortality following i.v. S. aureus infection in diabetic mice compared with nondiabetic controls, correlating with increased numbers of low-density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDNs have been implicated in the inflammatory pathology of diseases such as lupus, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the diabetic host and mechanisms that promote increased NET production by LDNs. LDN development is dependent on TGF-β, which we found to be more activated in the diabetic host. Neutralization of TGF-β, or the TGF-β-activating integrin αvβ8, reduced LDN numbers and improved survival during S. aureus infection. Targeting S. aureus directly with MEDI4893*, an α toxin-neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival. A comparison of gene and protein expression in high-density neutrophils and LDNs identified increased GPCRs and elevated phosphatase and tensin homolog (PTEN) in the LDN subset. Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival.

PMID: 30985291 [PubMed - indexed for MEDLINE]

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Pharmacologic treatment of transplant recipients infected with SARS-CoV-2: considerations regarding therapeutic drug monitoring and drug-drug interactions.

Ther Drug Monit. 2020 Apr 15;:

Authors: Elens L, Langman LJ, Hesselink DA, Bergan S, Moes DJAR, Molinaro M, Venkataramanan R, Lemaitre F

Abstract
BACKGROUND: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-corona virus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs. It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals.
METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of immunosuppressive drugs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature.
RESULTS: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining immunosuppressive drug concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight.
CONCLUSIONS: With the present manuscript, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with immunosuppressive drugs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.

PMID: 32304488 [PubMed - as supplied by publisher]