Utilizing a user-centered approach to develop and assess pharmacogenomic clinical decision support for thiopurine methyltransferase.

BMC Med Inform Decis Mak. 2019 Oct 17;19(1):194

Authors: Nguyen KA, Patel H, Haggstrom DA, Zillich AJ, Imperiale TF, Russ AL

Abstract
BACKGROUND: A pharmacogenomic clinical decision support tool (PGx-CDS) for thiopurine medications can help physicians incorporate pharmacogenomic results into prescribing decisions by providing up-to-date, real-time decision support. However, the PGx-CDS user interface may introduce errors and promote alert fatigue. The objective of this study was to develop and evaluate a prototype of a PGx-CDS user interface for thiopurine medications with user-centered design methods.
METHODS: This study had two phases: In phase I, we conducted qualitative interviews to assess providers' information needs. Interview transcripts were analyzed through a combination of inductive and deductive qualitative analysis to develop design requirements for a PGx-CDS user interface. Using these requirements, we developed a user interface prototype and evaluated its usability (phase II).
RESULTS: In total, 14 providers participated: 10 were interviewed in phase I, and seven providers completed usability testing in phase II (3 providers participated in both phases). Most (90%) participants were interested in PGx-CDS systems to help improve medication efficacy and patient safety. Interviews yielded 11 themes sorted into two main categories: 1) health care providers' views on PGx-CDS and 2) important design features for PGx-CDS. We organized these findings into guidance for PGx-CDS content and display. Usability testing of the PGx-CDS prototype showed high provider satisfaction.
CONCLUSION: This is one of the first studies to utilize a user-centered design approach to develop and assess a PGx-CDS interface prototype for Thiopurine Methyltransferase (TPMT). This study provides guidance for the development of a PGx-CDS, and particularly for biomarkers such as TPMT.

PMID: 31623616 [PubMed - in process]

Molecular Imaging of Opioid and Dopamine Systems: Insights Into the Pharmacogenetics of Opioid Use Disorders.

Front Psychiatry. 2019;10:626

Authors: Burns JA, Kroll DS, Feldman DE, Kure Liu C, Manza P, Wiers CE, Volkow ND, Wang GJ

Abstract
Opioid use in the United States has steadily risen since the 1990s, along with staggering increases in addiction and overdose fatalities. With this surge in prescription and illicit opioid abuse, it is paramount to understand the genetic risk factors and neuropsychological effects of opioid use disorder (OUD). Polymorphisms disrupting the opioid and dopamine systems have been associated with increased risk for developing substance use disorders. Molecular imaging studies have revealed how these polymorphisms impact the brain and contribute to cognitive and behavioral differences across individuals. Here, we review the current molecular imaging literature to assess how genetic variations in the opioid and dopamine systems affect function in the brain's reward, cognition, and stress pathways, potentially resulting in vulnerabilities to OUD. Continued research of the functional consequences of genetic variants and corresponding alterations in neural mechanisms will inform prevention and treatment of OUD.

PMID: 31620026 [PubMed]

The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity.

Pharmaceutics. 2019 Oct 15;11(10):

Authors: Simper GS, Gräser LS, Celik AA, Kuhn J, Kunze-Schumacher H, Hò GT, Blasczyk R, Pich A, Bade-Doeding C

Abstract
Drug hypersensitivity reactions that resemble acute immune reactions are linked to certain human leucocyte antigen (HLA) alleles. Severe and life-threatening Stevens Johnson Syndrome and Toxic Epidermal Necrolysis following treatment with the antiepileptic and psychotropic drug Carbamazepine are associated with HLA-B*15:02; whereas carriers of HLA-A*31:01 develop milder symptoms. It is not understood how these immunogenic differences emerge genotype-specific. For HLA-B*15:02 an altered peptide presentation has been described following exposure to the main metabolite of carbamazepine that is binding to certain amino acids in the F pocket of the HLA molecule. The difference in the molecular mechanism of these diseases has not been comprehensively analyzed, yet; and is addressed in this study. Soluble HLA-technology was utilized to examine peptide presentation of HLA-A*31:01 in presence and absence of carbamazepine and its main metabolite and to examine the mode of peptide loading. Proteome analysis of drug-treated and untreated cells was performed. Alterations in sA*31:01-presented peptides after treatment with carbamazepine revealed different half-life times of peptide-HLA- or peptide-drug-HLA complexes. Together with observed changes in the proteome elicited through carbamazepine or its metabolite these results illustrate the mechanistic differences in carbamazepine hypersensitivity for HLA-A*31:01 or B*15:02 patients and constitute the bridge between pharmacology and pharmacogenetics for personalized therapeutics.

PMID: 31618895 [PubMed]

Pharmacogenetic determinants of kidney-associated urinary and serum abnormalities in antiretroviral-treated HIV-positive patients.

Pharmacogenomics J. 2019 Oct 16;:

Authors: Cusato J, Calcagno A, Marinaro L, Avataneo V, DʹAvolio A, Di Perri G, Bonora S

Abstract
Tenofovir disoproxyl fumarate (TDF) has been associated with renal tubular abnormalities, phosphaturia and proteinuria (retinol binding protein, RBP, loss): vitamin D (VD) and PTH affect these markers. Aim was to understand if some single nucleotide polymorphisms (SNPs) were predictors of renal abnormalities in an Italian cohort of HIV-affected patients. DNA was analyzed through real-time PCR, urinary RBP corrected by creatinine (uRBP/Cr). The majority of patients received TDF. Abnormal uRBP/Cr was more frequent in TDF recipients: eGFR <90 mL/min and TDF were predictors in the whole cohort, whereas eGFR <90 mL/min, TDF concentrations and CYP24A1-3999TT in TDF-treated patients. Phosphate levels were higher low VD level patients: age <50 years, CYP27B1 + 2838CC genotype and non-European ancestry were predictors. PTH levels were border-line higher in TDF patients: non-European ancestry, females, TDF, VD levels < 30 ng/mL and SLC28A2-124CT/TT and ABCC2-24CC were predictors. For the first time, SNPs were associated with PTH, phosphate, calcium and tubular dysfunction in HIV-infected patients.

PMID: 31619748 [PubMed - as supplied by publisher]

Muscarinic receptors promote pacemaker fate at the expense of secondary conduction system tissue in zebrafish.

JCI Insight. 2019 Oct 17;4(20):

Authors: Burczyk MS, Burkhalter MD, Tena TC, Grisanti LA, Kauk M, Matysik S, Donow C, Kustermann M, Rothe M, Cui Y, Raad F, Laue S, Moretti A, Zimmermann WH, Wess J, Kühl M, Hoffmann C, Tilley DG, Philipp M

Abstract
Deterioration or inborn malformations of the cardiac conduction system (CCS) interfere with proper impulse propagation in the heart and may lead to sudden cardiac death or heart failure. Patients afflicted with arrhythmia depend on antiarrhythmic medication or invasive therapy, such as pacemaker implantation. An ideal way to treat these patients would be CCS tissue restoration. This, however, requires precise knowledge regarding the molecular mechanisms underlying CCS development. Here, we aimed to identify regulators of CCS development. We performed a compound screen in zebrafish embryos and identified tolterodine, a muscarinic receptor antagonist, as a modifier of CCS development. Tolterodine provoked a lower heart rate, pericardiac edema, and arrhythmia. Blockade of muscarinic M3, but not M2, receptors induced transcriptional changes leading to amplification of sinoatrial cells and loss of atrioventricular identity. Transcriptome data from an engineered human heart muscle model provided additional evidence for the contribution of muscarinic M3 receptors during cardiac progenitor specification and differentiation. Taken together, we found that muscarinic M3 receptors control the CCS already before the heart becomes innervated. Our data indicate that muscarinic receptors maintain a delicate balance between the developing sinoatrial node and the atrioventricular canal, which is probably required to prevent the development of arrhythmia.

PMID: 31619590 [PubMed - in process]

Molecular pathway analysis associates alterations in obesity related genes and antipsychotic-induced weight gain.

Acta Neuropsychiatr. 2019 Oct 17;:1-21

Authors: Corfitsen HT, Krantz B, Larsen A, Drago A

Abstract
OBJECTIVE: Antipsychotics often induce excessive weight gain. We hypothesized that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain. This hypothesis was tested in a subset of the CATIE trial data-set.
METHODS: The CATIE trial compared effects and side effects of five different antipsychotics through an 18 month period. Based on the maximum weight gain recorded, excessive weight gain was defined as >7% weight-gain. Cytoscape and GeneMania were instrumental in composing a molecular pathway from eight selected genes linked to obesity. Genetic information on a total of 495.172 SNPs were available from 765 (556 males) individuals. Enrichment test was conducted through reactomePA and Bioconductor. A permutation test was performed, testing the generated pathway against 105 permutated pathways (p</=0.05). In addition a standard GWAS-analysis was performed.
RESULT: GWAS analysis did not detect significant differences related to excessive weight gain. The pathway generated contained 28 genes. A total of 2067 SNPs were significantly expressed (p<0.01) within this pathway when comparing excessive weight gainers to the rest of the sample. Affected genes included PPARG and PCSK1 not previously related to treatment-induced weight gain.
CONCLUSIONS: The molecular pathway composed from high-risk obesity genes, was shown to overlap with genetics of patients who gained > 7% weight gain during the CATIE trial. This suggests that genes related to obesity, composes a pathway of increased risk of excessive antipsychotic-induced weight gain. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.

PMID: 31619305 [PubMed - as supplied by publisher]

MicroRNAs as a Potential Quality Measurement Tool of Platelet Concentrate Stored in Blood Banks-A Review.

Cells. 2019 Oct 15;8(10):

Authors: Maués JHDS, Aquino Moreira-Nunes CF, Rodriguez Burbano RM

Abstract
BACKGROUND: Platelet concentrate (PC) is one of the main products used in a therapeutic transfusion. This blood component requires special storage at blood banks, however, even under good storage conditions, modifications or degradations may occur and are known as platelet storage lesions.
METHODS: This research was performed on scientific citation databases PubMed/Medline, ScienceDirect, and Web of Science, for publications containing platelet storage lesions. The results obtained mainly reveal the clinical applicability of miRNAs as biomarkers of storage injury and as useful tools for a problem affecting public and private health, the lack of PC bags in countries with few blood donors. The major studies listed in this review identified miRNAs associated with important platelet functions that are relevant in clinical practice as quality biomarkers of PC, such as miR-223, miR-126, miR-10a, miR-150, miR-16, miR-21, miR-326, miR-495, let-7b, let-7c, let-7e, miR-107, miR-10b, miR-145, miR-155, miR-17, miR-191, miR-197, miR-200b, miR-24, miR-331, miR-376. These miRNAs can be used in blood banks to identify platelet injury in PC bags.
CONCLUSION: The studies described in this review relate the functions of miRNAs with molecular mechanisms that result in functional platelet differences, such as apoptosis. Thus, miRNA profiles can be used to measure the quality of storage PC for more than 5 days, identify bags with platelet injury, and distinguish those with functional platelets.

PMID: 31618890 [PubMed - in process]

Response.

AANA J. 2018 06;86(3):30

Authors: Aroke E

PMID: 31612852 [PubMed - indexed for MEDLINE]

Design and rational for the precision medicine guided treatment for cancer pain pragmatic clinical trial.

Contemp Clin Trials. 2018 05;68:7-13

Authors: Mosley SA, Hicks JK, Portman DG, Donovan KA, Gopalan P, Schmit J, Starr J, Silver N, Gong Y, Langaee T, Clare-Salzler M, Starostik P, Chang YD, Rajasekhara S, Smith JE, Soares HP, George TJ, McLeod HL, Cavallari LH

Abstract
INTRODUCTION: Pain is one of the most burdensome symptoms associated with cancer and its treatment, and opioids are the cornerstone of pain management. Opioid therapy is empirically selected, and patients often require adjustments in therapy to effectively alleviate pain or ameliorate adverse drug effects that interfere with quality of life. There are data suggesting CYP2D6 genotype may contribute to inter-patient variability in response to opioids through its effects on opioid metabolism. Therefore, we aim to determine if CYP2D6 genotype-guided opioid prescribing results in greater reductions in pain and symptom severity and interference with daily living compared to a conventional prescribing approach in patients with cancer.
METHODS: Patients with solid tumors with metastasis and a self-reported pain score ≥ 4/10 are eligible for enrollment and randomized to a genotype-guided or conventional pain management strategy. For patients in the genotype-guided arm, CYP2D6 genotype information is integrated into opioid prescribing decisions. Patients are asked to complete questionnaires regarding their pain, symptoms, and quality of life at baseline and 2, 4, 6, and 8 weeks after enrollment. The primary endpoint is differential change in pain severity by treatment strategy (genotype-guided versus conventional pain management). Secondary endpoints include change in pain and symptom interference with daily living.
CONCLUSION: Pharmacogenetic-guided opioid selection for cancer pain management has potential clinical utility, but current evidence is limited to retrospective and observational studies. Precision Medicine Guided Treatment for Cancer Pain is a pragmatic clinical trial that seeks to determine the utility of CYP2D6 genotype-guided opioid prescribing in patients with cancer.

PMID: 29535047 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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pharmacogenomics

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

Targeting the Versatile Wnt/β-Catenin Pathway in Cancer Biology and Therapeutics: From Concept to Actionable Strategy.

OMICS. 2019 Oct 15;:

Authors: Dzobo K, Thomford NE, Senthebane DA

Abstract
This expert review offers a critical synthesis of the latest insights and approaches at targeting the Wnt/β-catenin pathway in various cancers such as colorectal cancer, melanoma, leukemia, and breast and lung cancers. Notably, from organogenesis to cancer, the Wnt/β-catenin signaling displays varied and highly versatile biological functions in animals, with virtually all tissues requiring the Wnt/β-catenin signaling in one way or the other. Aberrant expression of the members of the Wnt/β-catenin has been implicated in many pathological conditions, particularly in human cancers. Mutations in the Wnt/β-catenin pathway genes have been noted in diverse cancers. Biochemical and genetic data support the idea that inhibition of Wnt/β-catenin signaling is beneficial in cancer therapeutics. The interaction of this important pathway with other signaling systems is also noteworthy, but remains as an area for further research and discovery. In addition, formation of different complexes by components of the Wnt/β-catenin pathway and the precise roles of these complexes in the cytoplasmic milieu are yet to be fully elucidated. This article highlights the latest medical technologies in imaging, single-cell omics, use of artificial intelligence (e.g., machine learning techniques), genome sequencing, quantum computing, molecular docking, and computational softwares in modeling interactions between molecules and predicting protein-protein and compound-protein interactions pertinent to the biology and therapeutic value of the Wnt/β-catenin signaling pathway. We discuss these emerging technologies in relationship to what is currently needed to move from concept to actionable strategies in translating the Wnt/β-catenin laboratory discoveries to Wnt-targeted cancer therapies and diagnostics in the clinic.

PMID: 31613700 [PubMed - as supplied by publisher]

Analysis of galanin receptor GALR2 in multiple sclerosis.

Pharmacogenomics J. 2019 Oct 14;:

Authors: Encarnacion M, Bernales CQ, Traboulsee AL, Sadovnick AD, Vilariño-Güell C

PMID: 31611593 [PubMed - as supplied by publisher]

Folyl polyglutamate synthethase (FPGS) gene polymorphisms may influence methotrexate adverse events in South Indian Tamil Rheumatoid Arthritis patients.

Pharmacogenomics J. 2019 Oct 14;:

Authors: Muralidharan N, Sundaram R, Kodidela S, Chengappa KG, Mariaselvam CM, Misra DP, Negi VS

Abstract
The aim of the study was to look for the association of FPGS 2752 G > A (rs1544105), FPGS 1994 A > G (rs10106), and GGH 452 C > T (rs 11545078), GGH -401C > T (rs 3758149) gene polymorphisms with methotrexate (MTX) treatment response and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). Further the influence of these gene polymorphisms on MTX polyglutamate levels was analyzed. A total of 330 patients with RA were investigated. FPGS gene polymorphisms were analyzed by TaqMan 5'nuclease assay and GGH gene polymorphisms were analyzed by PCR-RFLP. Methotrexate polyglutamates (nmol/L of packed erythrocytes) were measured by liquid chromatography mass spectrometry (LCMS/MS) method. We found that the heterozygous genotype of FPGS rs1544105 [p = 0.02, OR 1.93, 95% CI (1.15-3.35)] and FPGS rs10106 AG genotype [p = 0.01, OR 2.11, 95% CI (1.20-3.71)] were associated with MTX adverse events. FPGS rs1544105 and GGH -401C > T SNPs influenced the polyglutamate levels. None of the investigated SNPs seems to be associated with MTX treatment outcome.

PMID: 31611592 [PubMed - as supplied by publisher]

A GALNT14 rs9679162 genotype-guided therapeutic strategy for advanced hepatocellular carcinoma: systemic or hepatic arterial infusion chemotherapy.

Pharmacogenomics J. 2019 Oct 14;:

Authors: Lin CC, Hsu CW, Chen YC, Chang ML, Liang KH, Lai MW, Lin CL, Chien RN, Lin KH, Yeh CT

Abstract
Although targeted agents are recommended as the first-line treatments for advanced hepatocellular carcinoma (aHCC), systemic chemotherapy or hepatic arterial infusion chemotherapy (HAIC) are still being used in Asian countries. Beside economic considerations, it was found that targeted drugs could not significantly prolong overall survival in aHCC patients with distant metastasis. In addition, chemotherapy could achieve complete response in a small proportion of patients. Here, we aimed to investigate whether combination of three previously identified single nucleotide polymorphism (SNP) predictors (GALNT14-rs9679162, WWOX-rs13338697, and rs6025211) could guide our choice between systemic chemotherapy, HAIC, and targeted agents in aHCC patients. A cohort of 237 real-world aHCC patients (171 receiving systemic chemotherapy followed by various anticancer treatments including sorafenib; 66 receiving HAIC) were included for outcome analysis. By combining the three SNP markers with or without addition of two clinical criteria (tumor diameter <8 cm, neutrophils <80%), small groups of patients were found to harbor high complete response rates to systemic chemotherapy (35.3% if the 3-SNP signature alone matched; 60.0% if clinical criteria also matched). Subsequent sorafenib treatment for chemotherapy non-responders was associated with longer overall survival (P < 0.001). In HAIC-treated patients, GALNT14-rs9679162 genotype "GG" was associated with longer overall survival (P = 0.019, median survival > 10.5 months). In conclusion, pre-test for the 3-SNP signature in aHCC patients could identify potential systemic chemotherapy or HAIC responders. Chemotherapy non-responders still benefited from subsequent sorafenib treatment. Accordingly, we propose a roadmap for aHCC patients when chemotherapy or HAIC is to be used.

PMID: 31611591 [PubMed - as supplied by publisher]

Effect of ABCB1 genetic polymorphisms on the transport of rivaroxaban in HEK293 recombinant cell lines.

Sci Rep. 2018 Jul 12;8(1):10514

Authors: Sennesael AL, Panin N, Vancraeynest C, Pochet L, Spinewine A, Haufroid V, Elens L

Abstract
Direct oral anticoagulants (DOAC) are substrates for the ABCB1 transporter (also called P-glycoprotein), an active efflux pump. ABCB1 polymorphisms have been previously reported to influence the pharmacokinetics of several drugs such as immunosuppressants and tyrosine kinase inhibitors. Recently, in vivo studies have suggested that genetic variants might contribute to the inter-individual variability in DOAC plasma concentrations. Therefore, we evaluated the in vitro effect of the most common coding ABCB1 single nucleotide polymorphisms (SNP), 1236 C > T-2677G > T-3435C > T, and the coding ABCB1 1199 G > A SNP on the transport activity towards rivaroxaban. HEK293 cells were transfected to overexpress the ABCB1 wild-type (1236C-2677G-3435C, 1199 G) or variant proteins (1236C-2677G-3435T, 1236T-2677T-3435T or 1199 A). ABCB1 expression decreased the intracellular accumulation of rivaroxaban, when compared to control cells. This confirms the involvement of ABCB1 in the active transport of rivaroxaban. However, the ABCB1 1236 C > T-2677G > T-3435C > T and 1199 G > A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein. These results suggest that the ABCB1 coding SNPs investigated in the present study are unlikely to contribute to the inter-individual variability in rivaroxaban plasma concentrations.

PMID: 30002384 [PubMed - indexed for MEDLINE]

Genetic prediction profile for adalimumab response in Slovenian Crohn's disease patients.

Z Gastroenterol. 2019 Oct;57(10):1218-1225

Authors: Gorenjak M, Repnik K, Jezernik G, Jurgec S, Skok P, Potočnik U

Abstract
INTRODUCTION:  Response to anti-TNF therapy is crucial for life expectancy and life quality in patients with severe Crohn's disease. We investigated if a previously reported gene expression profile predictive for infliximab response could be also applied to adalimumab response in an independent cohort.
METHODS:  Forty-seven Slovene Crohn's disease patients indicated for adalimumab therapy were enrolled in the study. Inflamed and non-inflamed colon biopsy samples were obtained during routine colonoscopy prior to adalimumab treatment. Response to adalimumab was measured with IBDQ. Gene expression in inflamed and non-inflamed colon biopsy samples was measured with RT-qPCR. Genotypes were extracted from previously available genotype data. Statistical analysis was performed with SPSS software. The R package e1071 was used to train bootstrap aggregated support vector machines (SVM).
RESULTS:  SVM prediction model analysis was used to analyze pooled, non-inflamed, and inflamed colon tissue datasets using IBDQ response after 4, 12, 20 and 30 weeks of adalimumab treatment. The bagging approach was used in an endeavor to obtain 100 % accuracy using 10 × 100 or 100 × 100 iterations. Average adalimumab response prediction accuracy is 75.5 % for pooled samples, 90.5 % for inflamed samples, and 100 % for non-inflamed samples. Moreover, models trained on selected SNPs from analyzed genes had an average accuracy of 92.8 %, confirming the involvement of genetic regions mapping the reported genes. Finally, using combined gene expression and SNP data we observed 100 % adalimumab response prediction accuracy for pooled, inflamed, and non-inflamed datasets.
DISCUSSION:  Our study supports the reported genetic anti-TNF response profile and extends it for adalimumab prediction.

PMID: 31610585 [PubMed - in process]

Disease associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue specific activity of the cannabinoid-1 receptor gene promoter; implications for cannabinoid pharmacogenetics.

Hum Mutat. 2019 Oct 14;:

Authors: Hay EA, Cowie P, McEwan AR, Ross R, Pertwee RG, MacKenzie A

Abstract
Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response. Towards addressing the hypothesis that genetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we characterised the effects of disease associated allelic variation within a conserved regulatory sequence (ECR1) in CNR1 intron 2 that had previously been shown to modulate cannabinoid response, alcohol intake and anxiety-like behaviour. We used primary cell analysis of reporters carrying different allelic variants of the human ECR1 and found that human specific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in primary hippocampal cells than did the ancestral T-allele and demonstrated a differential response to CB1 agonism. We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity and evidence that the ancestral t-allele variant of ECR1 interacted with higher affinity with the insulator binding factor CTCF. The cell-specific approaches used in our study represent an important step in gaining a mechanistic understanding the roles of non-coding polymorphic variation in disease and in the increasingly important field of cannabinoid pharmacogenetics. This article is protected by copyright. All rights reserved.

PMID: 31608546 [PubMed - as supplied by publisher]

[Beta-blockers : myths and facts].

Rev Med Suisse. 2019 Sep 04;15(661):1566-1571

Authors: Gay Des Combes Gliven P, Girod G, Petignat PA, Gobin N

Abstract
Beta-blockers are very commonly drugs used in clinical practice, but whose mechanisms and clinical impacts are not always well understood, especially in certain specific clinical situations. This article proposes a review of some pharmacology notions over the different generations of β-blockers, as well as a review of indications and side effects in particular clinical situations, such as COPD, portal hypertension with esophageal varices and erectile dysfunction. Finally, an overview of response variability of these treatments is discussed from a genetic point of view.

PMID: 31496190 [PubMed - indexed for MEDLINE]

Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open-label clinical trial.

Br J Clin Pharmacol. 2018 09;84(9):1989-1999

Authors: Leroux S, Jacqz-Aigrain E, Elie V, Legrand F, Barin-Le Guellec C, Aurich B, Biran V, Dusang B, Goudjil S, Coopman S, Garcia Sanchez R, Zhao W, Manzoni P, FP7 TINN (Treat Infections in NeoNates) consortium

Abstract
AIMS: The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis.
METHODS: Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg-1 ; maintenance dose 12 mg kg-1 day-1 or 20 mg kg-1 day-1 , respectively, for infants <30 weeks or ≥30 weeks' corrected gestational age) or micafungin (loading dose 15 mg kg-1 day-1 ; maintenance dose 10 mg kg-1 day-1 ). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36 weeks' corrected gestational age or hospital discharge.
RESULTS: Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h-1 kg-1 ) and volume of distribution (l kg-1 ) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported.
CONCLUSION: Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.

PMID: 29744900 [PubMed - indexed for MEDLINE]