Putting Out the Fire: The Relationship of Pharmacogenetics and Proton Pump Inhibitors for the Treatment of Gastroesophageal Reflux Disease.

Cureus. 2018 May 24;10(5):e2687

Authors: Zheng CL, Alzghari SK

Abstract
Proton pump inhibitors (PPIs) are a mainstay treatment for gastroesophageal reflux disease (GERD) and are mainly metabolized by CYP2C19 in the liver. However, several polymorphisms of CYP2C19 exist that affect the metabolism of PPIs. Due to the large variability of PPI pharmacokinetics among the polymorphisms, this has implications in the management of patients with refractory GERD who may be potentially undertreated. Herein, we discuss the role of CYP2C19 and its relation to PPI therapy, particularly in those with GERD.

PMID: 30050742 [PubMed]

Pharmacogenetics of anticancer drug sensitivity and toxicity in colorectal cancer.

Curr Pharm Des. 2018 Jul 27;:

Authors: Moradi-Marjaneh R, Khazaei M, Seifi S, Hassanian SM, Ferns GA, Avan A

Abstract
Inter-individual differences in drug response are an important cause of failure in anticancer treatment and adverse drug events in cancer patients. Gene polymorphisms related to these outcomes have been investigated in an effort to find new genetic biomarkers to predict toxicity and response to anticancer drugs. Evaluating the value single nucleotide polymorphisms (SNPs) in the genes involved in transportation, activation and metabolism of anticancer drugs provides a promising approach to select the appropriate therapeutic regimes with at least adverse reactions. This review summarizes the current knowledge about the relationship between of SNPs involved in the transportation, activation and metabolism of anticancer drugs and treatment outcomes in colorectal cancer (CRC) patients.

PMID: 30051785 [PubMed - as supplied by publisher]

Impact of incorporating ABCB1 and CYP4F2 polymorphisms in a pharmacogenetics-guided warfarin dosing algorithm for the Brazilian population.

Eur J Clin Pharmacol. 2018 Jul 26;:

Authors: Tavares LC, Duarte NE, Marcatto LR, Soares RAG, Krieger JE, Pereira AC, Santos PCJL

Abstract
PURPOSE: Interpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population.
METHODS: Two independent cohorts of patients treated with warfarin (n = 832 and n = 133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan® assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates.
RESULTS: The inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%).
CONCLUSION: Although our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated.

PMID: 30051215 [PubMed - as supplied by publisher]

The CYP1A2 -163C>A polymorphism does not alter the effects of caffeine on basketball performance.

PLoS One. 2018;13(4):e0195943

Authors: Puente C, Abián-Vicén J, Del Coso J, Lara B, Salinero JJ

Abstract
PURPOSE: The aim of this investigation was to analyze the influence of the genetic variations of the -163C>A polymorphism of the CYP1A2 gene on the ergogenic effects of caffeine in elite basketball players.
METHODS: Nineteen elite basketball players (10 men and 9 women) ingested 3 mg⋅kg-1 of caffeine or a placebo 60 min before performing 10 repetitions of the following series: the Abalakov jump test followed by the Change-of-Direction and Acceleration Test (CODAT). The players then competed in a 20-min simulated basketball game. Self-perceived performance and side effects were recorded by questionnaires after the trials. The effects of caffeine on basketball performance were established according to players' CYP1A2 genotype (rs762551): AA homozygotes (n = 10) and C-allele carriers (n = 9).
RESULTS: In the 10 repetitions, caffeine increased Abalakov jump height by a mean of 2.9±3.6% in AA homozygotes (p = 0.03) while this effect did not reach statistical significance for C-allele carriers (2.3 ± 6.8%; p = 0.33). Caffeine did not affect sprint time in the CODAT test in either genotype group but it increased the number of impacts performed during the simulated game in both AA homozygotes (4.1 ± 5.3%; p = 0.02) and C-allele carriers (3.3 ± 3.2%; p = 0.01). During the 24 h following the test, AA homozygotes tended to experience increased insomnia with caffeine while C-allele carriers did not present this effect. The remaining variables were unaffected by the genotype.
CONCLUSION: The CYP1A2 -163C>A polymorphism minimally altered the ergogenicity derived from the consumption of a moderate dose of caffeine in elite basketball players.

PMID: 29668752 [PubMed - indexed for MEDLINE]

Individualizing Treatment Approaches for Epileptic Patients with Glucose Transporter Type1 (GLUT-1) Deficiency.

Int J Mol Sci. 2018 Jan 05;19(1):

Authors: Daci A, Bozalija A, Jashari F, Krasniqi S

Abstract
Monogenic and polygenic mutations are important contributors in patients suffering from epilepsy, including metabolic epilepsies which are inborn errors of metabolism with a good respond to specific dietetic treatments. Heterozygous variation in solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) and mutations of the GLUT1/SLC2A2 gene results in the failure of glucose transport, which is related with a glucose type-1 transporter (GLUT1) deficiency syndrome (GLUT1DS). GLUT1 deficiency syndrome is a treatable disorder of glucose transport into the brain caused by a variety of mutations in the SLC2A1 gene which are the cause of different neurological disorders also with different types of epilepsy and related clinical phenotypes. Since patients continue to experience seizures due to a pharmacoresistance, an early clinical diagnosis associated with specific genetic testing in SLC2A1 pathogenic variants in clinical phenotypes could predict pure drug response and might improve safety and efficacy of treatment with the initiation of an alternative energy source including ketogenic or analog diets in such patients providing individualized strategy approaches.

PMID: 29303961 [PubMed - indexed for MEDLINE]

Characterization of the B-cell receptor repertoires in peanut allergic subjects undergoing oral immunotherapy.

J Hum Genet. 2018 Feb;63(2):239-248

Authors: Kiyotani K, Mai TH, Yamaguchi R, Yew PY, Kulis M, Orgel K, Imoto S, Miyano S, Burks AW, Nakamura Y

Abstract
B-cell receptors (BCRs) play a critical role in adaptive immunity as they generate highly diverse immunoglobulin repertoires to recognize a wide variety of antigens. To better understand immune responses, it is critically important to establish a quantitative and rapid method to analyze BCR repertoire comprehensively. Here, we developed "Bcrip", a novel approach to characterize BCR repertoire by sequencing millions of BCR cDNA using next-generation sequencer. Using this method and quantitative real-time PCR, we analyzed expression levels and repertoires of BCRs in a total of 17 peanut allergic subjects' peripheral blood samples before and after receiving oral immunotherapy (OIT) or placebo. By our methods, we successfully identified all of variable (V), joining (J), and constant (C) regions, in an average of 79.1% of total reads and 99.6% of these VJC-mapped reads contained the C region corresponding to the isotypes that we aimed to analyze. In the 17 peanut allergic subjects' peripheral blood samples, we observed an oligoclonal enrichment of certain immunoglobulin heavy chain alpha (IGHA) and IGH gamma (IGHG) clones (P = 0.034 and P = 0.027, respectively) in peanut allergic subjects after OIT. This newly developed BCR sequencing and analysis method can be applied to investigate B-cell repertoires in various research areas, including food allergies as well as autoimmune and infectious diseases.

PMID: 29192240 [PubMed - indexed for MEDLINE]

Application of Coiled Coil Peptides in Liposomal Anticancer Drug Delivery Using a Zebrafish Xenograft Model.

ACS Nano. 2016 08 23;10(8):7428-35

Authors: Yang J, Shimada Y, Olsthoorn RC, Snaar-Jagalska BE, Spaink HP, Kros A

Abstract
The complementary coiled coil forming peptides E4 [(EIAALEK)4] and K4 [(KIAALKE)4] are known to trigger liposomal membrane fusion when tethered to lipid vesicles in the form of lipopeptides. In this study, we examined whether these coiled coil forming peptides can be used for drug delivery applications. First, we prepared E4 peptide modified liposomes containing the far-red fluorescent dye TO-PRO-3 iodide (E4-Lipo-TP3) and confirmed that E4-liposomes could deliver TP3 into HeLa cells expressing K4 peptide on the membrane (HeLa-K) under cell culture conditions in a selective manner. Next, we prepared doxorubicin-containing E4-liposomes (E4-Lipo-DOX) and confirmed that E4-liposomes could also deliver DOX into HeLa-K cells. Moreover, E4-Lipo-DOX showed enhanced cytotoxicity toward HeLa-K cells compared to free doxorubicin. To prove the suitability of E4/K4 coiled coil formation for in vivo drug delivery, we injected E4-Lipo-TP3 or E4-Lipo-DOX into zebrafish xenografts of HeLa-K. As a result, E4-liposomes delivered TP3 to the implanted HeLa-K cells, and E4-Lipo-DOX could suppress cancer proliferation in the xenograft when compared to nontargeted conditions (i.e., zebrafish xenograft with free DOX injection). These data demonstrate that coiled coil formation enables drug selectivity and efficacy in vivo. It is envisaged that these findings are a step forward toward biorthogonal targeting systems as a tool for clinical drug delivery.

PMID: 27504667 [PubMed - indexed for MEDLINE]

Diagnostic accuracy of NUDT15 gene variants for thiopurine-induced leukopenia: a systematic review and meta-analysis.

Pharmacol Res. 2018 Jul 23;:

Authors: Cargnin S, Genazzani AA, Canonico PL, Terrazzino S

Abstract
We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review. Among these, 16 studies were available for the meta-analysis of rs116855232, 6 studies for rs186364861 and 5 studies for rs554405994 of NUDT15. A higher DOR was found for rs116855232 (8.44, 95% CI: 5.46-13.03), as compared to rs554405994 (4.336, 95% CI 2.924-6.429) or rs186364861 (2.742, 95% CI 1.453-5.175). Results of meta-regression analysis showed that incidence of leukopenia (relative DOR: 0.96; 95%CI: 0.93-1.00, p = 0.037) and leukopenia onset (late vs early leukopenia, relative DOR: 0.41, 95% CI 0.20-0.85, p = 0.0189) significantly influenced diagnostic accuracy of rs116855232. Subgroup analysis for rs186364861 and rs554405994 revealed a significant DOR for early-onset leukopenia (rs186364861: 4.04, 95% CI 1.78-9.20; rs554405994: 2.94, 95% CI 1.74-4.95), but not for late-onset leukopenia (rs186364861: 1.52, 95% CI 0.52-4.43; rs554405994: 2.02, 95% CI 0.93-4.40). The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. Nevertheless, prospective studies of genotype-guided dosing of thiopurines are warranted to prove clinical benefit and cost-effectiveness of pretreatment NUDT15 gene testing across different populations.

PMID: 30048756 [PubMed - as supplied by publisher]

Cardiopulmonary, biomarkers, and vascular responses to acute hypoxia following cardiac transplantation.

Clin Transplant. 2018 Jul 26;:e13352

Authors: Sanz-de la Garza M, Iannino N, Finnerty V, Mansour A, Blondeau L, Gayda M, Chaar D, Sirois MG, Racine N, de Denus S, Harel F, White M

Abstract
Previous studies have suggested good adaptation of cardiac transplant (CTx) recipients to exposure to a high altitude. No studies have investigated the cardiopulmonary and biomarker responses to acute hypoxic challenges following CTx. Thirty-six CTx recipients and seventeen age-matched healthy controls (HC) were recruited. Sixteen (16) patients (42%) had cardiac allograft vasculopathy (CAV). Cardiopulmonary responses to maximal and submaximal exercise at 21% O2 , 20-min hypoxia (11.5% O2 ), and following a 10-minute exposure to 11.5% O2 using 30% of peak power output were completed. Vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), suppression of tumorigenicity 2 (ST2) were measured at baseline and at peak stress. Endothelial peripheral function was assessed using near-infrared spectroscopy. Compared with HC, CTx presented a lesser O2 desaturation both at rest (-19.4±6.8 [CTx] versus -24.2±6.0% O2 [HC], P<0.05) and following exercise (-23.2 ±4.9 [CTx] versus -26.2±4.7% O2 [HC], P<0.05). CTx patients exhibited a significant decrease in peak oxygen uptake. IL-6 and VEGF levels were significantly higher in CTx recipients in basal conditions but did not change in response to acute stress. CTx patients exhibit a favorable ventilatory and overall response to hypoxic stress. These data provide further insights on the good adaptability of CTx to exposure to high altitude. This article is protected by copyright. All rights reserved.

PMID: 30047602 [PubMed - as supplied by publisher]

Teaching students in clinical programs about pharmacogenomics: do they understand drug-drug interactions?

Per Med. 2018 Jul 26;:

Authors: O'Brien TJ, Harralson AF

Abstract
Teaching the clinical implementation of pharmacogenomics to students in clinical programs first requires careful consideration of their aptitude in basic clinical pharmacologic concepts. Prior to developing training exercises on drug-gene interactions, educators must first assess student competency in identifying and managing drug-drug interactions given the similarities in identifying and managing these sources of medication error.

PMID: 30047305 [PubMed - as supplied by publisher]

Mouse Population-Based Approaches to Investigate Adverse Drug Reactions.

Drug Metab Dispos. 2018 Jul 25;:

Authors: Mosedale M

Abstract
Genetic variation is now recognized as a key factor in the toxicity of pharmaceutical agents. However, genetic diversity is not present in standard nonclinical toxicology models, and small clinical studies (Phase I/II) may not include enough subjects to identify toxicity liabilities associated with less common susceptibility factors. As a result, many drugs pass through preclinical and early clinical studies before safety concerns are realized. Furthermore, when adverse drug reactions are idiosyncratic in nature, suggesting a role for rare genetic variants in the toxicity susceptibility, even large clinical studies (Phase III) are often underpowered (due to low population frequency and/or small effect size of the risk factor) to identify associations that may be used for precision medicine risk mitigation strategies. Genetically diverse mouse populations can be used to help overcome the limitations of standard nonclinical and clinical studies and to model toxicity responses that require genetic susceptibility factors. Furthermore, mouse population-based approaches can be used to: 1) identify sensitive strains that can serve as a screening tool for next-in-class compounds, 2) identify genetic susceptibility factors that can be used for risk mitigation strategies, and 3) study mechanisms underlying drug toxicity . This review describes genetically diverse mouse populations and provides examples of their utility in investigating adverse drug response. It also explores recent efforts to adapt mouse population-based approaches to in vitro platforms thereby enabling the incorporation of genetic diversity and the identification of genetic risk factors and mechanisms associated with drug toxicity susceptibility at all stages of drug development.

PMID: 30045843 [PubMed - as supplied by publisher]

Physician-Reported Benefits and Barriers to Clinical Implementation of Genomic Medicine: A Multi-Site IGNITE-Network Survey.

J Pers Med. 2018 Jul 24;8(3):

Authors: Owusu Obeng A, Fei K, Levy KD, Elsey AR, Pollin TI, Ramirez AH, Weitzel KW, Horowitz CR

Abstract
Genetic medicine is one of the key components of personalized medicine, but adoption in clinical practice is still limited. To understand potential barriers and provider attitudes, we surveyed 285 physicians from five Implementing GeNomics In pracTicE (IGNITE) sites about their perceptions as to the clinical utility of genetic data as well as their preparedness to integrate it into practice. These responses were also analyzed in comparison to the type of study occurring at the physicians' institution (pharmacogenetics versus disease genetics). The majority believed that genetic testing is clinically useful; however, only a third believed that they had obtained adequate training to care for genetically "high-risk" patients. Physicians involved in pharmacogenetics initiatives were more favorable towards genetic testing applications; they found it to be clinically useful and felt more prepared and confident in their abilities to adopt it into their practice in comparison to those participating in disease genetics initiatives. These results suggest that investigators should explore which attributes of clinical pharmacogenetics (such as the use of simplified genetics-guided recommendations) can be implemented to improve attitudes and preparedness to implement disease genetics in care. Most physicians felt unprepared to use genetic information in their practice; accordingly, major steps should be taken to develop effective clinical tools and training strategies for physicians.

PMID: 30042363 [PubMed]

Premaxilla Stress Distribution and Bone Resorption Induced by Implant Overdenture and Conventional Denture.

J Prosthodont. 2018 Jul 25;:

Authors: Alsrouji MS, Ahmad R, Abdul Razak NH, Shuib S, Kuntjoro W, Baba NZ

Abstract
PURPOSE: To relate the principal stress, strain, and total deformation in the premaxilla region beneath a complete denture to the pattern of premaxilla bone resorption when opposed by a conventional complete denture (CD) or by a two-implant-retained overdenture (IOD) using finite element analysis (FEA).
MATERIALS AND METHODS: Three-dimensional solid models of the maxilla, mucosa, and denture of a selected edentulous patient were created using Mimics and CATIA software. The FEA model was created and duplicated in ANSYS 16.0 to perform two simulations for the IOD and the CD models. The values of maximum stress and strain and total deformation were obtained and compared to the outcomes of premaxilla resorption from a parallel clinical study.
RESULTS: The maximum principal stress in the premaxilla in the IOD model ranged from 0.019 to 0.336 MPa, while it ranged from 0.011 to 0.193 MPa in the CD model. The maximum principal strain in the IOD model was 1.75 times greater than that in the CD model. Total deformation was 1.8 times higher in the IOD model. Greater bone resorption was observed in regions of higher stress, which were on the occlusal and buccal sides of the premaxilla residual ridge.
CONCLUSION: Stress, strain, and total deformation values present in the premaxilla area beneath a CD were approximately two times greater in a comparison between an opposing mandibular two-IOD and an opposing mandibular CD. The results were consistent with a parallel clinical study in which the rate of premaxilla bone resorption was almost three times greater in the IOD group.

PMID: 30044033 [PubMed - as supplied by publisher]

Pharmacogenomic study on anti-VEGF medicine in treatment of macular Neovascular diseases: a study protocol for a prospective observational study.

BMC Ophthalmol. 2018 Jul 24;18(1):181

Authors: Jing J, Yinchen S, Xia C, Jing W, Chong C, Xun X, Hengye H, Kun L

Abstract
BACKGROUND: Macular neovascular diseases can cause severe vision loss. A newly approved anti-VEGF drug Conbercept has shown good efficacy and safety in rigorous random controlled trials (RCT), however, it cannot fully reflect the clinical application of Conbercept in real world clinical practice. Moreover, anti-VEGF drugs are expensive and often require multiple treatments, and some patients have poor or even no response to the drugs,this resulted enormous waste of medical resources. Therefore, how to find out those patients who have good response, and how to develop individualized therapeutic regimen in real world need to be urgently investigated in the aspect of pharmacogenomics and pharmacometabolomics.
METHODS: This study is a multicenter, prospective, observational study of Conbecept treating macular neovascular diseases in China. Patients suffered from age-related macular degeneration, polypoidal choroidal vasculopathy, and pathological myopia who already planned to receive Conbercept treatment will be recruited. We aimed to enroll more than 5000 patients from 43 ophthalmic centers in China. Patients' clinical data and blood samples will be collected during the one-year follow-up period. Finally, the safety and efficacy of Conbercept, and the potential predictors of patients' response to Conbercept will be investigated by pharmacogenomics and pharmacometabolomics analysis.
DISCUSSION: This study will provide important data of Conbercept in treating macular neovascular diseases in real world. Besides, finding the predictor of patients' response will help doctor make more precise individualized therapeutic regimens.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT03128463 . Registered on 9 March 2017.

PMID: 30041608 [PubMed - in process]

Human liver spheroids in chemically defined conditions for studies of gene-drug, drug-drug and disease-drug interactions.

Pharmacogenomics. 2018 Jul 25;:

Authors: Ingelman-Sundberg M, Lauschke VM

Abstract
Recent phenotypically and functionally relevant human hepatic in vitro systems combine the ability to preserve interindividual molecular differences between patients' livers in culture with the accessibility and high-throughput compatibility of in vitro assays. These features facilitate studies of specific genetic polymorphisms by using cells from donors with defined variants of interest or by selective gene knock-down experiments. Furthermore, these models constitute promising tools to evaluate drug-drug interactions as well as the effects of liver diseases on drug pharmacokinetics in co-cultures of hepatocytes and non-parenchymal cells. In the near future, we anticipate that these tools will be of high relevance for predicting the in vivo kinetics, toxicity and drug-drug interactions of drug candidates already during preclinical development.

PMID: 30041575 [PubMed - as supplied by publisher]

Genomic markers of resistance to targeted treatments in gastric cancer: potential new treatment strategies.

Pharmacogenomics. 2018 Jul 25;:

Authors: Raimondi A, Nichetti F, Peverelli G, Bartolomeo MD, Braud F, Pietrantonio F

Abstract
Gastric cancer is a highly heterogeneous disease, displaying a complex genomic landscape and an unfavorable outcome with standard therapies. Based on distinctive genomic alterations, novel targeted agents have been developed with the aim of personalizing treatments and improving patient outcome. However, a subgroup of patients is primarily treatment-resistant, and even in the initially sensitive population, secondary resistance emerges, thus limiting therapeutic benefit. In this review, we summarize the clinical data about standard targeted agents in gastric cancer, specifically anti-HER2 treatments and antivascular therapies. We also illustrate the available evidence regarding molecular mechanisms of resistance to these agents and we discuss potential strategies for new targeted treatments that could overcome such resistance.

PMID: 30041572 [PubMed - as supplied by publisher]

Serum folate concentrations, asthma, atopy, and asthma control in Peruvian children.

Respir Med. 2017 Dec;133:29-35

Authors: Nicholson A, Pollard SL, Lima JJ, Romero KM, Tarazona-Meza C, Malpartida-Guzmán G, Mougey E, Hansel NN, Checkley W, GASP Study Investigators

Abstract
BACKGROUND: The relationship between folate status and asthma-related outcomes has not been carefully examined in low- and middle-income countries where folate deficiency is common.
METHODS: Ancillary analysis of an unmatched case-control study in which we analyzed serum folate concentrations in 412 children with asthma and 342 controls living in peri-urban communities in Lima, Peru. We examined baseline associations between folate and asthma, atopy, total serum IgE, pulmonary function, and fractional exhaled nitric oxide. We then followed children with asthma longitudinally for 6-9 months and assessed associations between folate and odds of uncontrolled asthma (defined as Asthma Control Test score ≤ 19) and of ≥1 emergency visits during follow-up.
RESULTS: A 10 ng/mL decrease in serum folate was associated with 45% higher adjusted odds of asthma (OR = 1.45, 95% CI 1.05-2.02). The folate-asthma relationship differed by atopic status: a 10 ng/mL decrease in serum folate was associated with a 2.4-fold higher odds of asthma among children without atopy (2.38, 1.20-4.72) and 23% higher odds of asthma in children with atopy (1.23, 0.85-1.80). Among children with asthma, a 10 ng/mL decrease in serum folate was associated with 62% higher odds of uncontrolled asthma (1.62, 1.02-2.56) and 73% higher odds of ≥1 emergency visits during follow-up (1.73, 1.05-2.85).
CONCLUSIONS: Serum folate concentrations were inversely associated with asthma, but this effect was stronger in children without atopy. Among children with asthma, lower serum folate concentrations were associated with higher risk of uncontrolled asthma.

PMID: 29173446 [PubMed - indexed for MEDLINE]

Cost Effectiveness of Genotype-Guided Warfarin Dosing in Patients with Mechanical Heart Valve Replacement Under the Fee-for-Service System.

Appl Health Econ Health Policy. 2017 Oct;15(5):657-667

Authors: Kim DJ, Kim HS, Oh M, Kim EY, Shin JG

Abstract
BACKGROUND: Although studies assessing the cost effectiveness of genotype-guided warfarin dosing for the management of atrial fibrillation, deep vein thrombosis, and pulmonary embolism have been reported, no publications have addressed genotype-guided warfarin therapy in mechanical heart valve replacement (MHVR) patients or genotype-guided warfarin therapy under the fee-for-service (FFS) insurance system.
OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of genotype-guided warfarin dosing in patients with MHVR under the FFS system from the Korea healthcare sector perspective.
METHODS: A decision-analytic Markov model was developed to evaluate the cost effectiveness of genotype-guided warfarin dosing compared with standard dosing. Estimates of clinical adverse event rates and health state utilities were derived from the published literature. The outcome measure was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed to explore the range of plausible results.
RESULTS: In a base-case analysis, genotype-guided warfarin dosing was associated with marginally higher QALYs than standard warfarin dosing (6.088 vs. 6.083, respectively), at a slightly higher cost (US$6.8) (year 2016 values). The ICER was US$1356.2 per QALY gained. In probabilistic sensitivity analysis, there was an 82.7% probability that genotype-guided dosing was dominant compared with standard dosing, and a 99.8% probability that it was cost effective at a willingness-to-pay threshold of US$50,000 per QALY gained.
CONCLUSION: Compared with only standard warfarin therapy, genotype-guided warfarin dosing was cost effective in MHVR patients under the FFS insurance system.

PMID: 28247199 [PubMed - indexed for MEDLINE]

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Does the 5-HT1A rs6295 polymorphism influence the safety and efficacy of citalopram therapy in the oldest old?

Ther Adv Drug Saf. 2018 Jul;9(7):355-366

Authors: Scutt G, Overall A, Scott R, Patel B, Hachoumi L, Yeoman M, Wright J

Abstract
Major depressive disorder (MDD) in older people is a relatively common, yet hard to treat problem. In this study, we aimed to establish if a single nucleotide polymorphism in the 5-HT1A receptor gene (rs6295) determines antidepressant response in patients aged > 80 years (the oldest old) with MDD. Nineteen patients aged at least 80 years with a new diagnosis of MDD were monitored for response to citalopram 20 mg daily over 4 weeks and genotyped for the rs6295 allele. Both a frequentist and Bayesian analysis was performed on the data. Bayesian analysis answered the clinically relevant question: 'What is the probability that an older patient would enter remission after commencing selective serotonin reuptake inhibitor (SSRI) treatment, conditional on their rs6295 genotype?' Individuals with a CC (cytosine-cytosine) genotype showed a significant improvement in their Geriatric Depression Score (p = 0.020) and cognition (p = 0.035) compared with other genotypes. From a Bayesian perspective, we updated reports of antidepressant efficacy in older people with our data and calculated that the 4-week relative risk of entering remission, given a CC genotype, is 1.9 [95% highest-density interval (HDI) 0.7-3.5], compared with 0.52 (95% HDI 0.1-1.0) for the CG (cytosine-guanine) genotype. The sample size of n = 19 is too small to draw any firm conclusions, however, the data suggest a trend indicative of a relationship between the rs6295 genotype and response to citalopram in older patients, which requires further investigation.

PMID: 30034777 [PubMed]