[Too early for pharmacogenetics in psychiatric practice].

Tijdschr Psychiatr. 2019;61(5):298-300

Authors: Vinkers CH

Abstract
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PMID: 31180566 [PubMed - in process]

Clinical Use of FSH in Male Infertility.

Front Endocrinol (Lausanne). 2019;10:322

Authors: Behre HM

Abstract
The established clinical indication for FSH use in male infertility is the treatment of patients with hypogonadotropic hypogonadism for stimulation of spermatogenesis that allows the induction of a clinical pregnancy in the female partner and finally the birth of a healthy child. Several clinical studies with urinary, purified, and recombinant FSH preparations in combination with hCG have demonstrated the high treatment efficacy regarding these clinical endpoints. Shortcomings of this hormone therapy are the long duration of treatment, sometimes longer than 2 years, and the inconvenience of injections every second or third day. However, improvements of therapy might be expected with new hormonal treatment options already available for infertility treatment in the female. FSH use for treatment of patients with normogonadotropic idiopathic infertility and oligozoospermia is still considered experimental in most countries. Recent meta-analyses have shown that FSH can significantly increase pregnancy rates in the female partners of these patients, but the effect-size is relatively low. Therefore, predictive factors for treatment success have to be identified, including FSH pharmacogenetics, to select the right normogonadotropic patients with idiopathic infertility for FSH therapy.

PMID: 31178827 [PubMed]

Colchicine Myopathy: A Case Series Including Muscle MRI and ABCB1 Polymorphism Data.

Front Neurol. 2019;10:553

Authors: Gupta M, Nikolic A, Ng D, Martens K, Ebadi H, Chhibber S, Pfeffer G

Abstract
Colchicine is a medication most commonly used in the treatment of gout and familial mediterannean fever. A rare complication of therapy is toxicity causing proximal myopathy and polyneuropathy. Colchicine myopathy has been associated with the coadministration of other medications with colchicine, such as statins or tacrolimus, and is more common in patients with renal impairment. Otherwise, it is unclear which patients are at greatest risk of developing this adverse drug reaction. ABCB1 is important to the metabolism of colchicine, so we speculated that it was possible that colchicine myopathy patients may have a particular genotype that is associated with this side effect. We describe two cases of colchicine myopathy which occurred with co-administration of rosuvastatin. From one case, we present the first published data on muscle MRI in this condition. We additionally present an analysis of four genetic polymorphisms in ABCB1 and transcript levels in muscle tissue, and demonstrate the descriptive finding of reduced ABCB1 transcript levels in the colchicine myopathy patients.

PMID: 31178824 [PubMed]

Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy.

Front Pharmacol. 2019;10:520

Authors: García-Menaya JM, Cordobés-Durán C, García-Martín E, Agúndez JAG

Abstract
Asthma is a frequent disease, mainly characterized by airway inflammation, in which drug therapy is crucial in its management. The potential of pharmacogenomics testing in asthma therapy has been, to date, little explored. In this review, we discuss pharmacogenetic factors affecting asthma treatment, both related to drugs used as controller medications for regular maintenance, such as inhaled corticosteroids, anti-leukotriene agents, long-acting beta-agonists, and the new biologic agents used to treat severe persistent asthma. In addition, we discuss current pharmacogenomics knowledge for rescue medications provided to all patients for as-needed relief, such as short-acting beta-agonists. Evidence for genetic variations as a factor related to drugs response has been provided for the following genes and groups of drugs: Inhaled corticosteroids: FCER2; anti-leukotriene agents: ABCC1, and LTC4S; beta-agonists: ADRB2. However, the following genes require further studies confirming or rejecting association with the response to asthma therapy: ADCY9, ALOX5, ARG1, ARG2, CRHR1, CRHR2, CYP3A4, CYP3A5, CYSLTR1, CYSLTR2, GLCCI1, IL4RA, LTA4H, ORMDL3, SLCO2B1, SPATS2L, STIP1, T, TBX21, THRA, THRB, and VEGFA. Although only a minority of these genes are, at present, listed as associated with drugs used in asthma therapy, in the Clinical Pharmacogenomics Implementation Consortium gene-drug pair list, this review reveals that sufficient evidence to start testing the potential of clinical pharmacogenomics in asthma therapy already exists. This evidence supports the inclusion in pilot pharmacogenetics tests of at least four genes. Hopefully these tests, if proven useful, will increase the efficiency and the safety of asthma therapy.

PMID: 31178722 [PubMed]

ECCR1 and NFKB2 Polymorphisms as Potential Biomarkers of Non-small Cell Lung Cancer in a Polish Population.

Anticancer Res. 2019 Jun;39(6):3269-3272

Authors: Chaszczewska-Markowska M, Kosacka M, Chryplewicz A, Dyła T, Brzecka A, Bogunia-Kubik K

Abstract
BACKGROUND/AIM: Although genetic factors are presumed to account only for a part of the inter-individual variation in lung cancer susceptibility, the results are conflicting and there are no data available regarding the Polish population. We, therefore, performed a case-control study to investigate the association of seven selected single nucleotide polymorphisms (SNPs), in genes coding for excision repair cross-complimentary group 1 (ERCC1: rs11615, rs3212986, rs2298881), nuclear factor ĸB (NFKB2: rs7897947, rs12769316), bone morphogenetic protein 4 (BMP4: rs1957860), complement receptor 1 (CR1: rs7525160) and del/ins polymorphism in the family hypoxia inducible factor 2 gene (EGLN2: rs10680577), with non-small cell lung cancer (NSCLC) risk.
MATERIALS AND METHODS: Real-time PCR with melting curve analysis was used for genotyping of NSCLC patients and healthy individuals of Polish origin.
RESULTS: The ERCC1 rs11615 T allele and rs3212986 GG homozygosity were found to be associated with a higher risk of developing NSCLC. In addition, NFKB2 rs12769316 GG homozygosity was more frequently detected among male patients than controls, while no significant differences were found between the five polymorphisms.
CONCLUSION: ERCC1 polymorphisms may affect NSCLC risk in the Polish population, while the NFKB2 variant may be a possible marker of the disease in males.

PMID: 31177178 [PubMed - in process]

Multidrug resistance-associated protein 4 in pharmacology: Overview of its contribution to pharmacokinetics, pharmacodynamics and pharmacogenetics.

Life Sci. 2019 Jun 06;:

Authors: Berthier J, Arnion H, Saint-Marcoux F, Picard N

Abstract
MRP4 is an ABC membrane transporter involved in clinical outcomes as it is located in many tissues that manages the transport and the elimination of many drugs. This review explores the implication of MRP4 in clinical pharmacology and the importance of its genetic variability. Although there is no specific recommendation regarding the study of MRP4 in drug development, it should be considered when drugs are eliminated by the kidney or liver or when drug-drug interactions are expected.

PMID: 31176778 [PubMed - as supplied by publisher]

Severe Hepatotoxicity of Mithramycin Therapy Caused by Altering Expression of Hepatocellular Bile Transporters.

Mol Pharmacol. 2019 Jun 07;:

Authors: Sissung TM, Huang PA, Hauke RJ, McCrea EM, Peer CJ, Barbier RH, Strope JD, Ley AM, Zhang M, Hong JA, Venzon D, Jackson JP, Brouwer KR, Grohar P, Glod J, Widemann BC, Heller T, Schrump DS, Figg WD

Abstract
Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (MDR3) rs2302387 and ABCB11 (BSEP) rs4668115 reduce transporter expression (P<0.05) and were associated with mean ≥ Grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25mcg/kg, 6hr/infusion, qdx7, every 28 days; P<0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, NTCP, OST mean α/β) in several cell lines (Huh7, HepaRG, HepaRG BSEP (-/-)) and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P<0.0001), and mithramycin inhibited CDCA- and GW4046-induced FXR-GAL4 luciferase reporter activity (P<0.001). Mithramycin promoted GCDC-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P<0.01). Mithramycin is an FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a mechanism of hepatotoxicity in which an FXR inhibitor causes deregulation of bile homeostasis in liver, which is currently the rationale for a genotype-directed clinical trial using mithramycin (NCT01624090).

PMID: 31175181 [PubMed - as supplied by publisher]

Structural bioinformatics analysis of variants on GPCR function.

Curr Opin Struct Biol. 2019 Jun 04;55:161-177

Authors: Syed Haneef SA, Ranganathan S

Abstract
G protein-coupled receptors (GPCRs) are key membrane-embedded receptor proteins, with critical roles in cellular signal transduction. In the era of precision medicine, understanding the role of natural variants on GPCR function is critical, especially from a pharmacogenomics viewpoint. Studies involved in mapping variants to GPCR structures are briefly reviewed here. The endocannabinoid system involving the central nervous system (CNS), the human cannabinoid receptor 1 (CB1), is an important drug target and its variability has implications for disease susceptibility and altered drug and pain response. We have carried out a computational study to map deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) to CB1. CB1 mutations were computationally evaluated from neutral to deleterious, and the top twelve deleterious mutations, with structural information, were found to be either close to the ligand binding region or the G-protein binding site. We have mapped these to the active and inactive CB1 X-ray crystallographic structures to correlate variants with available phenotypic information. We have also carried out molecular dynamics simulations to functionally characterize four selected mutants.

PMID: 31174013 [PubMed - as supplied by publisher]

Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids.

Drug Discov Today. 2019 Jun 04;:

Authors: Chen KG, Zhong P, Zheng W, Beekman JM

Abstract
Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.

PMID: 31173911 [PubMed - as supplied by publisher]

Investigation of bidirectional longitudinal associations between advanced epigenetic age and peripheral biomarkers of inflammation and metabolic syndrome.

Aging (Albany NY). 2019 Jun 07;:

Authors: Morrison FG, Logue MW, Guetta R, Maniates H, Stone A, Schichman SA, McGlinchey RE, Milberg WP, Miller MW, Wolf EJ

Abstract
Epigenetic age estimations based on DNA methylation (DNAm) can predict human chronological age with a high level of accuracy. These DNAm age algorithms can also be used to index advanced cellular age, when estimated DNAm age exceeds chronological age. Advanced DNAm age has been associated with several diseases and metabolic and inflammatory pathology, but the causal direction of this association is unclear. The goal of this study was to examine potential bidirectional associations between advanced epigenetic age and metabolic and inflammatory markers over time in a longitudinal cohort of 179 veterans with a high prevalence of posttraumatic stress disorder (PTSD) who were assessed over the course of two years. Analyses focused on two commonly investigated metrics of advanced DNAm age derived from the Horvath (developed across multiple tissue types) and Hannum (developed in whole blood) DNAm age algorithms. Results of cross-lagged panel models revealed that advanced Hannum DNAm age at Time 1 (T1) was associated with increased (i.e., accounting for T1 levels) metabolic syndrome (MetS) severity at Time 2 (T2; p = < 0.001). This association was specific to worsening lipid panels and indicators of abdominal obesity (p = 0.001). In contrast, no baseline measures of inflammation or metabolic pathology were associated with changes in advanced epigenetic age over time. No associations emerged between advanced Horvath DNAm age and any of the examined biological parameters. Results suggest that advanced epigenetic age, when measured using an algorithm developed in whole blood, may be a prognostic marker of pathological metabolic processes. This carries implications for understanding pathways linking advanced epigenetic age to morbidity and mortality.

PMID: 31173577 [PubMed - as supplied by publisher]

Three-Dimensional Spheroid Primary Human Hepatocytes in Monoculture and Coculture with Nonparenchymal Cells.

Tissue Eng Part C Methods. 2018 09;24(9):534-545

Authors: Baze A, Parmentier C, Hendriks DFG, Hurrell T, Heyd B, Bachellier P, Schuster C, Ingelman-Sundberg M, Richert L

Abstract
Recent advances in the development of various culture platforms are promising for achieving more physiologically relevant in vitro hepatic models using primary human hepatocytes (PHHs). Previous studies have shown the value of PHHs three-dimensional (3D) spheroid models, cultured in low cell number (1330-2000 cells/3D spheroid), to study long-term liver function as well as pharmacological drug effects and toxicity. In this study, we report that only plateable PHHs aggregate and form compact 3D spheroids with a success rate of 79%, and 96% reproducibility. Out of 3D spheroid forming PHH lots, 65% were considered stable (<50% ATP decrease) over the subsequent 14 days of culture, with reproducibility of a given PHH lot being 82%. We also report successful coculturing of PHHs with human liver nonparenchymal cells (NPCs). Crude P1c-NPC fractions were obtained by low centrifugation of the PHH supernatant fraction followed by a few days of culture before harvesting and cryopreservation. At aggregation of PHHs/P1c-NPCs (2:1 ratio 3D spheroids), liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells were successfully integrated and remained present throughout the subsequent 14-day culture period as revealed by mRNA expression markers and immunostaining. Increased mRNA expression of albumin (ALB), apolipoprotein B (APOB), cytochrome P450 3A4 (CYP3A4), and increased albumin secretion compared to PHH 3D spheroid monocultures highlighted that in a 3D spheroid coculture, configuration with NPCs, PHH functionality is increased. We thus achieved the development of a more integrated coculture model system requiring low cell numbers, of particular interest due to the scarcity of human liver NPCs.

PMID: 30101670 [PubMed - indexed for MEDLINE]

CYP2C19 pharmacogenetics in patients undergoing coronary stent placement: Is it time to test everyone?

Catheter Cardiovasc Interv. 2019 Jun 01;93(7):1253-1254

Authors: Price DJ, Levy MS

Abstract
Although there are no current guidelines for when to test patients for CYP2C19 loss of function alleles, the current state of evidence suggests that testing high-risk patients should be considered. Based on this meta-analysis, there is no reduction in major adverse cardiovascular events (MACE) in patients that receive genotype-guided antiplatelet therapy, but there is a significant reduction in MACE when including only patients who present with acute coronary syndromes and a significant reduction in myocardial infarction. Genotype-guided therapy shows promise but requires further study to solidify this approach, and to determine which patients derive the most benefit.

PMID: 31172678 [PubMed - in process]

A comparative study of the depth, breadth, and perception of pharmacogenomics instruction in a subgroup of US pharmacy curricula.

Curr Pharm Teach Learn. 2019 May;11(5):476-484

Authors: Shatnawi A, Khanfar NM, Latif DA, Shear M

Abstract
INTRODUCTION: This study was designed to assess the depth, breadth, and perception of pharmacogenomics education in pharmacy curricula in the United States (US).
METHODS: A modified, online questionnaire from previous studies was sent to all accredited US schools and colleges of pharmacy. The survey covered three distinct areas related to the schools' educational environments, the depth and the extent of pharmacogenomics core competencies and topics taught, and the institutions' perceptions of the importance of pharmacogenomics in the curriculum and future plans for expanded pharmacogenomics education. Multiple approaches were used to increase the response rate, and results were analyzed using descriptive statistics.
RESULTS: Of the 133 eligible programs, 32 participated in the survey. Six invalid surveys were excluded from our study, resulting in a 19.6% response rate. Results revealed that all responding schools included pharmacogenomics in the curriculum. Interestingly, 76.9% of the respondents believed pharmacists do not have the appropriate knowledge of pharmacogenomics. However, only 30.7% indicated that their programs planned to expand pharmacogenomics in their curriculum.
CONCLUSIONS: The responding schools all included some pharmacogenomics in their curriculum. However, the depth and the extent of pharmacogenomics topics covered varied. Respondents perceived that pharmacists today do not possess the appropriate level of pharmacogenomics knowledge. Despite this, there is limited emphasis on expanding pharmacogenomics instruction in the responding schools' curriculums.

PMID: 31171249 [PubMed - in process]

Tumor suppressor gene glycine N-methyltransferase and its potential in liver disorders and hepatocellular carcinoma.

Toxicol Appl Pharmacol. 2019 Jun 03;:114607

Authors: Chen M, Yang MH, Chang MM, Tyan YC, Chen YA

Abstract
Glycine N-methyltransferase is a protein with many functions. In addition to catalyzing the production of sarcosine in the one carbon metabolism pathway, it plays a role in the detoxification of environmental carcinogens such as benzo[a]pyrene, aflatoxin B1, and aristocholic acid. There is also increasing evidence suggesting a role of GNMT deficiency in liver carcinogenesis. In this review, we discuss the role of GNMT in the detoxification of xenobiotics and the mechanism of GNMT suppression during liver tumorigenesis. The protective role of GNMT in the liver allows GNMT to not only serve as a marker of liver disease, but also potentially be applied in the treatment of liver disorders and hepatocellular carcinoma. We describe the potential use of GNMT in gene therapy and we introduce the development of a GNMT promoter reporter assay that can be used to screen medicinal drugs and herbal libraries for natural compounds with anti-cancer properties.

PMID: 31170416 [PubMed - as supplied by publisher]

Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic Stellate Cells and Liver Fibrogenesis in Mice.

Gastroenterology. 2019 Jun 03;:

Authors: Yan J, Tung HC, Li S, Niu Y, Garbacz WG, Lu P, Bi Y, Li Y, He J, Xu M, Ren S, Monga SP, Schwabe RF, Yang D, Xie W

Abstract
BACKGROUND & AIMS: The role of aryl hydrocarbon receptor (AHR) in liver fibrosis is controversial, because loss and gain of AHR activity each lead to liver fibrosis. The goal of this study is to investigate how the expression of AHR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice.
METHODS: We studied the effects of AHR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-seq analysis. C57BL/6J mice were given the AHR agonists TCDD or ITE, or carbon tetrachloride (CCl4), or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting.
RESULTS: AHR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AHR-knockout mice was accelerated, compared to HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor beta (TGFB)-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis following administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AHR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AHR prevents TGFB-induced fibrogenesis by disrupting the interaction of SMAD3 with beta-catenin, which prevents the expression of genes that mediate fibrogenesis.
CONCLUSIONS: In studies of human and mouse HSCs, we found that AHR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of non-toxic AHR agonists or strategies to activate AHR signaling in HSCs might be developed to prevent or treat liver fibrosis.

PMID: 31170413 [PubMed - as supplied by publisher]

Association of endothelin genetic variants and hospitalized infection complications in end-stage renal disease (ESRD) patients.

BMC Nephrol. 2019 Jun 05;20(1):203

Authors: Kao CC, Cheng SY, Wang YJ, Chien SC, Hsu YW, Wu MY, Lu HF, Nam S, Sun T, Wu MS, Chang WC

Abstract
BACKGROUND: Infection is the second most common cause of mortality for patients with end-stage renal disease (ESRD), accompanying with immune dysfunction. Endothelin (EDN) is known to be related to inflammation; however, it is unknown whether genetic variants of the EDN gene family are associated with increased risk of hospitalized infection events.
METHODS: Nineteen tagging single-nucleotide polymorphisms (tSNPs) of the EDN gene family were selected for genotyping a cohort of 190 ESRD patients. Patient demographics were recorded, the subtypes of infection events were identified, and association analysis between the EDN genetic variants and hospitalized infection events was performed.
RESULTS: In this study, 106 patients were hospitalized for infection events. The leading events were pneumonia, bacteremia, and cellulitis. The minor allele of rs260741, rs197173, and rs926632 SNPs of EDN3 were found to be associated with reduced risk of hospitalized bacteremia events.
CONCLUSIONS: The minor allele of rs260741, rs197173, and rs926632 in EDN3 were associated with reduced risk of hospitalized bacteremia events in ESRD patients.

PMID: 31167651 [PubMed - in process]

Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines.

Front Pharmacol. 2019;10:542

Authors: Dawood M, Ooko E, Efferth T

Abstract
Parthenolide (PT) is a sesquiterpene lactone isolated from Tanacetum parthenium. In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53+/+) colon carcinoma cells and their parental HCT116 knockout p53 (p53-/-) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activated EGFR cDNA (U87.MGΔEGFR) exhibited slight sensitivity toward PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive toward PT than sensitive MDA-MB-231-pcDNA cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) in MDA-MB-231-BCRP cell line is reported in this study for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines toward PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, PT exerted profound cytotoxic activity against various cancer cell lines mainly against BCRP-overexpressing tumor cells, suggesting PT as novel candidate for cancer treatment.

PMID: 31164821 [PubMed]

Differential lung tissue gene expression in males and females: implications for the susceptibility to develop COPD.

Eur Respir J. 2019 Jun 04;:

Authors: van den Berge M, Brandsma CA, Faiz A, de Vries M, Rathnayake SNH, Paré PD, Sin DD, Bossé Y, Laviolette M, Nickle DC, Hao K, Obeidat M, Dragani TA, Colombo F, Timens W, Postma DS

PMID: 31164434 [PubMed - as supplied by publisher]

Pharmacogenomics: A Practical Primer for Senior Care Pharmacists.

Sr Care Pharm. 2019 Jun 01;34(6):363-369

Authors: Hilden MP, Bright DR, Kisor DF, Christensen H

Abstract
Pharmacogenomics (PGx), the study of how an individual's genetic makeup affects his or her response to drugs, is a fast-growing field that gives health care providers a valuable tool to help safely and effectively manage medication. However, few providers have experience in applying the results of PGx tests to their practices, and this can lead to disregarding the data or unnecessarily modifying medication regimens. Pharmacists are uniquely positioned to become wellversed in the interpretation of PGx data, critically evaluating the "green-yellow-red" result categories that seemingly signal "go, caution, stop" regarding the use of a particular medication. Pharmacists also can evaluate genotype and phenotype information, commonly included in PGx laboratory reports, to optimize therapy. Using a case-based approach, this primer is intended to provide consultant pharmacists with practical direction to aid in PGx interpretation that will provide contextappropriate recommendations that contributes to positive patient outcomes.

PMID: 31164183 [PubMed - in process]

Pharmacogenetics of alcohol use disorder treatments: an update.

Expert Opin Drug Metab Toxicol. 2019 Jun 04;:

Authors: Hartwell EE, Kranzler HR

Abstract
INTRODUCTION: Alcohol use disorder (AUD) is a highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated disorder. The low rate of utilization of pharmacological treatments with demonstrated efficacy is particularly noteworthy. This is due, in part, to the modest efficacy of the medications approved to treat the disorder. One approach to increasing the utility and safety of these medications is to use precision medicine, which seeks to identify patients for whom specific medications are likely to have the most robust therapeutic effects and the fewest adverse effects. Areas Covered: Here we review the current literature on the pharmacogenetics of AUD treatment. We cover both laboratory studies and clinical trials that have provided valuable insights into the mechanisms and value of precision-based care for AUD. We discuss studies of genetic moderators for personalizing pharmacotherapy with medications approved by regulatory agencies in the United States and Europe and those that are used off-label to treat AUD. Expert Opinion: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, precision medicine is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications in development for this goal to be achieved. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data could provide important opportunities to develop this area of research.

PMID: 31162983 [PubMed - as supplied by publisher]