Simultaneous determination of selective serotonin reuptake inhibitors and their main metabolites in human breast milk by liquid chromatography-electrospray mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Apr 27;1057:101-109

Authors: Weisskopf E, Panchaud A, Nguyen KA, Grosjean D, Hascoët JM, Csajka C, Eap CB, Ansermot N, collaborators of the SSRI-Breast Milk study

Abstract
A bioanalytical method by high performance liquid chromatography coupled to electrospray mass spectrometry (HPLC-ESI-MS), adapted from a previously published method in plasma, was validated in breast milk for the simultaneous quantification of all antidepressants belonging to the class of selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their major metabolites (desmethylcitalopram and norfluoxetine). Milk samples (250μl) first underwent protein precipitation followed by solid-phase extraction on a reversed phase/cation exchange sorbent. Analytes were thereafter separated on a XBridge C18 column (2.1mm×100mm; 3.5μm) using a mobile phase composed of ammonium acetate buffer (pH 8.1; 50mM) and acetonitrile in gradient mode. Detection was performed by a single quadrupole mass spectrometer running in selected ion monitoring in positive ionization mode. Method validation covered a wide concentration range of 2-500ng/ml for citalopram, desmethylcitalopram and paroxetine, 5-500ng/ml for sertraline, and 2-1000ng/ml for fluoxetine, norfluoxetine and fluvoxamine. Validation performances such as trueness (90.3-111.6%), repeatability (0.8-9.3%) and intermediate precision (0.9-9.5%) were in agreement with criteria from international guidelines and matrix effects for the analyte/internal standard ratios ranged from 92% to 110% (relative standard deviation <15%). Accuracy profiles (total error of trueness and precision) were lying within the limits of ±30% accepted in bioanalysis. Finally, the method was successfully applied to patient samples collected in a clinical pharmacokinetic study of nursing mothers taking an antidepressant treatment.

PMID: 28511118 [PubMed - as supplied by publisher]

Risk factors of allopurinol-induced severe cutaneous adverse reactions in a Thai population.

Pharmacogenet Genomics. 2017 May 15;:

Authors: Saksit N, Tassaneeyakul W, Nakkam N, Konyoung P, Khunarkornsiri U, Chumworathayi P, Sukasem C, Suttisai S, Piriyachananusorn N, Tiwong P, Chaiyakunapruk N, Sawanyawisuth K, Rerkpattanapipat T, Tassaneeyakul W

Abstract
BACKGROUND: Allopurinol is one of the most common causes of severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). This study identified the risk factors associated with the development of allopurinol-induced SCARs in a Thai population.
PATIENTS AND METHODS: Eighty-six allopurinol-induced SCARs (i.e. 19 DRESS and 67 SJS/TEN) and 182 allopurinol-tolerant patients were enrolled in the study. The HLA-B*58:01 allele was determined. Clinical and medicinal data were collected.
RESULTS: Results from multivariate analysis showed that only the HLA-B*58:01 and female sex were identified as risk factors of allopurinol-induced SCARs in this Thai population. Patients who carried the HLA-B*58:01 allele were at a higher risk of allopurinol-induced DRESS [odds ratio (OR)=149.2, 95% confidence interval (CI)=24.0-∞, P<1.00×10]. Similar results were observed in allopurinol-induced SJS/TEN (OR=175.0, 95% CI=44.3-690.9, P=1.69×10). The risk of allopurinol-induced SCARs in women was higher than that in men (OR=4.6, 95% CI=1.4-15.6, P=1.44×10). The overall mortality rate of allopurinol-induced SCARs was 11.39% and a higher mortality rate was observed in elderly women.
CONCLUSION: Among the risk factors identified, the HLA-B*58:01 allele had the greatest impact on the development of both phenotypes of allopurinol-induced SCARs in this studied Thai population. In case HLA-B*58:01 genotyping cannot be accessed, close monitoring of allopurinol usage, especially in elderly women with impaired renal function, is necessary to reduce the mortality rate of these life-threatening SCARs.

PMID: 28509689 [PubMed - as supplied by publisher]

The Importance of Gene-Drug-Drug-Interactions in Pharmacogenomics Decision Support: An Analysis Based on Austrian Claims Data.

Stud Health Technol Inform. 2017;236:121-127

Authors: Blagec K, Kuch W, Samwald M

Abstract
While pharmacogenomic testing combined with clinical decision support has the potential to increase the safety and efficacy of medical treatments, the intake of multiple prescription drugs can - if not sufficiently addressed by decision support solutions - impair the effectiveness of such interventions by modulating the capacity of precisely those enzymes whose function pharmacogenomic tests try to predict. We quantified the potential extent of such drug-mediated mismatches between genotype-derived phenotypes and real phenotypes, commonly called "phenoconversion", by screening claims data from 1,587,829 Austrian health insurance holders of the years 2006 and 2007 for concomitant prescriptions of drugs that can be dosed based on pharmacogenomics, and drugs that modulate enzyme activity. In total, 232,398 such prescription overlaps were detected, of which more than half (54.6%) could be attributed to co-prescriptions of moderate or strong modulators. Our results indicate that prescription drug-mediated phenoconversion is not uncommon, and should therefore be adequately reflected in decision support solutions by integrating algorithms to detect potential gene-drug-drug interactions.

PMID: 28508787 [PubMed - in process]

Supporting Molecular Tumor Boards in Molecular-Guided Decision-Making - The Current Status of Five German University Hospitals.

Stud Health Technol Inform. 2017;236:48-54

Authors: Hinderer M, Boerries M, Haller F, Wagner S, Sollfrank S, Acker T, Prokosch HU, Christoph J

Abstract
BACKGROUND: German university hospitals have started to establish molecular tumor boards in order to enable physicians to make molecular-guided decisions.
OBJECTIVE: Our aim was to describe the organizational structure and procedures which are currently supporting the molecular tumor boards of five German university hospitals.
METHODS: We conducted semi-structured interviews with experts of five university hospitals between December 2016 and February 2017.
RESULTS: We observed heterogeneity in both the organization of genetic testing and the management of the molecular tumor boards among the five hospitals. They used free-text documents in most of their support procedures rather than machine-readable documents.
CONCLUSION: There are three potentialities to support the process from genetic testing to reporting within the molecular tumor boards: (i) standardized pipeline to integrate automated variant calling and annotation; (ii) tools supporting the experts in creating their reports and presentations and (iii) implementing pharmacogenomic CDSS into clinical routine.

PMID: 28508778 [PubMed - in process]

Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism Impacts on Migraine Susceptibility: A Meta-analysis of Case-Control Studies.

Front Neurol. 2017;8:159

Authors: Terrazzino S, Cargnin S, Viana M, Sances G, Tassorelli C

Abstract
Inconclusive results have been reported in studies investigating the association between the brain-derived neurotrophic factor (BDNF) rs6265 polymorphism and migraine. In the present study, we conducted a systematic review and meta-analysis on the published data in order to quantitatively estimate the relationship between rs6265 and migraine susceptibility. A comprehensive search was performed through PubMed, Web of Knowledge, and Cochrane databases up to October 2016. The pooled odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated to estimate the strength of the association with rs6265 under an additive, dominant, or recessive model of inheritance. A total of five studies including 1,442 cases and 1,880 controls were identified for the meta-analysis. The pooled data showed an increased risk of migraine for the allelic (OR: 1.17, 95% CI: 1.03-1.34, p = 0.014) or the dominant model of rs6265 (OR: 1.22, 95% CI: 1.05-1.41, p = 0.011). Statistical significance of rs6265 was lost when one single study was excluded from the analysis (dominant OR: 1.17, 95% CI: 1.00-1.38, p = 0.054; allelic OR: 1.14, 95% CI: 0.99-1.31, p = 0.067), suggesting lack of robustness of pooled estimates. When stratified by migraine type, a similar trend of association was detected with both MA and MO, but a statistically significant association of rs6265 was reached only with the MA subtype in the dominant model (OR: 1.22, 95% CI: 1.00-1.47, p = 0.047). The present meta-analysis supports that BDNF rs6265 may act as a genetic susceptibility factor for migraine. Nevertheless, large-scale studies are required to confirm our findings and to assess potential modifiers of the relationship between rs6265 and migraine.

PMID: 28507530 [PubMed - in process]

Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: influence on treatment response.

Pharmgenomics Pers Med. 2017;10:143-156

Authors: Abaji R, Krajinovic M

Abstract
The thiopurine S-methyltransferase (TPMT) gene encodes for the TPMT enzyme that plays a crucial role in the metabolism of thiopurine drugs. Genetic polymorphisms in this gene can affect the activity of the TPMT enzyme and have been correlated with variability in response to treatment with thiopurines. Advances in the pharmacogenetics of TPMT allowed the development of dosing recommendations and treatment strategies to optimize and individualize prescribing thiopurine in an attempt to enhance treatment efficacy while minimizing toxicity. The influence of genetic polymorphisms in the TPMT gene on clinical outcome has been well-documented and replicated in many studies. In this review, we provide an overview of the evolution, results, conclusions and recommendations of selected studies that investigated the influence of TPMT pharmacogenetics on thiopurine treatment in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders. We focus mainly on prospective studies that explored the impact of individualized TPMT-based dosing of thiopurines on clinical response. Together, these studies demonstrate the importance of preemptive TPMT genetic screening and subsequent dose adjustment in mitigating the toxicity associated with thiopurine treatment while maintaining treatment efficacy and favorable long-term outcomes. In addition, we briefly address the cost-effectiveness of this pharmacogenetics approach and its impact on clinical practice as well as the importance of recent breakthrough advances in sequencing and genotyping techniques in refining the TPMT genetic screening process.

PMID: 28507448 [PubMed - in process]

Non-maturational covariates for dynamic systems pharmacology models in neonates, infants, and children: Filling the gaps beyond developmental pharmacology.

Eur J Pharm Sci. 2017 May 12;:

Authors: Allegaert K, Simons SHP, Tibboel D, Krekels E, Knibbe C, van den Anker J

Abstract
Pharmacokinetics and -dynamics show important changes throughout childhood. Studies on the different maturational processes that influence developmental pharmacology have been used to create population PK/PD models that can yield individualized pediatric drug dosages. These models were subsequently translated to semi-physiologically or physiology-based PK (PBPK) models that support predictions in pediatric patient cohorts and other special populations. Although these translational efforts are crucial, these models should be further improved towards individual patient predictions by including knowledge on non-maturational covariates. These efforts are needed to ultimately get to systems pharmacology models for children. These models take developmental changes relating to the pediatric dynamical system into account but also other aspects that may be of importance such as abnormal body composition, pharmacogenetics, critical illness and inflammatory status.

PMID: 28506866 [PubMed - as supplied by publisher]

Antibiotics-induced gut microbiota dysbiosis promotes tumor initiation via affecting APC-Th1 development in mice.

Biochem Biophys Res Commun. 2017 May 12;:

Authors: Xu C, Ruan B, Jiang Y, Xue T, Wang Z, Lu H, Wei M, Wang S, Ye Z, Zhai D, Wang L, Lu Z

Abstract
Gut microbiota is critical for maintaining body immune homeostasis and thus affects tumor growth and therapeutic efficiency. Here, we investigated the link between microbiota and tumorgenesis in a mice model of subcutaneous melanoma cell transplantation, and explored the underlying mechanism. We found disruption of gut microbiota by pretreating mice with antibiotics promote tumor growth and remodeling the immune compartment within the primary tumor. Indeed, gut microbial dysbiosis reduced the infiltrated mature antigen-presenting cells of tumor, together with lower levels of co-stimulators, such as CD80, CD86 and MHCII, as well as defective Th1 cytokines, including IFNγ, TNFα, IL12p40, and IL12p35. Meantime, splenic APCs displayed blunted ability in triggering T cell proliferation and IFNγ secretion. However, oral administration of LPS restored the immune surveillance effects and thus inhibited tumor growth in the antibiotics induced gut microbiota dysbiosis group. Taken together, these data highly supported that antibiotics induced gut microbiota dysbiosis promotes tumor initiation, while LPS supplementation would restore the effective immune surveillance and repress tumor initiation.

PMID: 28506830 [PubMed - as supplied by publisher]

Variants of the ADRB2 Gene in COPD: Systematic Review and Meta-Analyses of Disease Risk and Treatment Response.

COPD. 2017 May 16;:1-10

Authors: Nielsen AO, Jensen CS, Arredouani MS, Dahl R, Dahl M

Abstract
The β2-adrenergic receptor (ADRB2) is an important regulator of airway smooth muscle tone in chronic obstructive pulmonary disease (COPD). Variants that impair ADRB2 function could increase disease risk or reduce the response to endogenous and inhaled adrenergic agonists in COPD. We performed a systematic review and three meta-analyses to assess whether three functional variants (Thr164Ile, Arg16Gly, and Gln27Glu) in the ADRB2 gene are associated with elevated risk of disease or reduced therapeutic response to inhaled β2-agonists in COPD. We searched the medical literature from 1966 to 2017 and found 16 relevant studies comprising 85381 study subjects. The meta-analyses found no significant association between ADRB2 genotype and COPD risk. The summary odds ratios (ORs) for COPD in Thr164Ile homozygotes and heterozygotes were 2.57 (95% confidence interval (CI): 0.54-12.4) and 1.17 (95% CI: 0.96-1.44), respectively. Corresponding summary ORs for COPD in Arg16Gly homozygotes and heterozygotes were 0.97 (95% CI: 0.76-1.22) and 1.01 (95% CI: 0.81-1.26), while summary ORs for COPD in Gln27Glu homozygotes and heterozygotes were 1.00 (95% CI: 0.80-1.25) and 0.94 (95% CI: 0.69-1.24), respectively. When stratified by ethnicity, the summary ORs for COPD did not differ from 1.0 for any of the ADRB2 variants among Asian, Caucasian, or African populations. We found no consistent associations between ADRB2 genotype and treatment response to inhaled β2-agonists in COPD. This systematic review and meta-analyses found that COPD risk and response to inhaled β2-agonists were not associated with Thr164Ile, Arg16Gly, and Gln27Glu genotypes. However, identified cases of Thr164Ile were few, and additional studies of rare ADRB2 genotypes are required.

PMID: 28506092 [PubMed - as supplied by publisher]

Determinants of bone specific metastasis in prostate cancer.

Crit Rev Oncol Hematol. 2017 Apr;112:59-66

Authors: Manca P, Pantano F, Iuliani M, Ribelli G, De Lisi D, Danesi R, Del Re M, Vincenzi B, Tonini G, Santini D

Abstract
Prostate cancer is one of the most common type of cancer in Western countries. Although the majority of patients with PCa have a minimally aggressive disease, some of them will experience relapse and formation of metastasis. Bone metastasis are a major cause of quality of life impairment and death among patients with metastatic prostate cancer. Different "bone targeted therapies" and several follow-up strategies were developed in order to optimize bone metastasis prevention and treatment. Nevertheless there is still a great clinical need of identifying patients more likely to benefit from those interventions as not all patients will develop metastatic disease and not all patients with metastatic disease will develop bone metastasis. Here we review markers predictive of bone metastasis occurrence that have been tested in clinical settings, particularly focusing on the ability of such markers to predict bone metastasis over visceral metastasis occurrence.

PMID: 28325265 [PubMed - indexed for MEDLINE]

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UGT1A1 polymorphisms with irinotecan-induced toxicities and treatment outcome in Asians with Lung Cancer: a meta-analysis.

Cancer Chemother Pharmacol. 2017 May 13;:

Authors: Chen X, Liu L, Guo Z, Liang W, He J, Huang L, Deng Q, Tang H, Pan H, Guo M, Liu Y, He Q, He J

Abstract
Previous studies of irinotecan pharmacogenetics have shown that the UGT1A1*28 polymorphism has an effect on irinotecan (IRI)-induced toxicities in Caucasians. Yet compared with the UGT1A1*6 mutation, the UGT1A1*28 occurs at a much lower frequency in the Asians. Whether UGT1A1*6 and UGT1A1*28 are associated with IRI-induced neutropenia, diarrhea and IRI-based chemotherapy tumor response (TR) in Asians with lung cancer remains controversial. In this meta-analysis, we found a higher risk of neutropenia and diarrhea with IRI-based chemotherapy in Asians with lung cancer carrying the UGT1A1*6 polymorphism. However, UGT1A1*28 showed a weak correlation with diarrhea, but no significant correlation with neutropenia. Neither UGT1A1*6 nor UGT1A1*28 is associated with IRI-based chemotherapy TR. These data suggest that the UGT1A1*28 polymorphism may not be a suitable biomarker to predict IRI-induced toxicities and chemotherapy TR in Asians, while UGT1A*6 polymorphism is associated with a higher risk of IRI-induced neutropenia and diarrhea, but not IRI-based chemotherapy TR.

PMID: 28502040 [PubMed - as supplied by publisher]

Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy.

J Control Release. 2017 May 11;258:43-55

Authors: Sun J, Liu Y, Chen Y, Zhao W, Zhai Q, Rathod S, Huang Y, Tang S, Kwon YT, Fernandez C, Venkataramanan R, Li S

Abstract
Two novel prodrug polymers POEG-b-PSSDas (redox-sensitive) and POEG-b-PCCDas (redox-insensitive), which consist of poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic blocks and dasatinib (DAS, an oncogenic tyrosine kinases inhibitor) conjugated hydrophobic blocks, were designed as dual-functional carriers for codelivery with doxorubicin (DOX). Both carriers retained antitumor activity of DAS and could form mixed micelles with DOX. Compared to POEG-b-PCCDas micelles, incorporation of disulfide linkage into POEG-b-PSSDas micelles facilitated efficient cleavage of DAS from prodrug micelles in tumor cells/tissues, leading to a higher level of anti-tumor activity in vitro and in vivo. In addition, DOX-loaded POEG-b-PSSDas micelles exhibited triggered DOX release under a redox environment (10mM glutathione, GSH), and demonstrated enhanced cytotoxicity against 4T1.2 and PC3 cell lines compared to DOX and DOX-loaded POEG-b-PCCDas micelles. More importantly, DOX-loaded POEG-b-PSSDas micelles were more effective in inhibiting the tumor growth and prolonging the survival rate in an aggressive murine breast cancer model (4T1.2) compared to DOX-loaded POEG-b-PCCDas micelles and a micellar formulation co-loaded with DOX and DAS. This redox-responsive prodrug micellar system provides an attractive strategy for effective combination of tumor targeted therapy and traditional chemotherapy, which warrants further investigation.

PMID: 28501705 [PubMed - as supplied by publisher]

HLA-A 31:01 is not associated with the development of methotrexate pneumonitis in the UK population: results from a genome-wide association study.

Ann Rheum Dis. 2017 May 12;:

Authors: Bluett J, Owen SA, Massey J, Alfirevic A, Pirmohamed M, Plant D, Verstappen SMM, Barton A, Pneumonitis Study Consortium

PMID: 28500057 [PubMed - as supplied by publisher]

Fundamentals of Clinical Pharmacology With Application for Pregnant Women.

J Midwifery Womens Health. 2017 May 12;:

Authors: Patil AS, Sheng J, Dotters-Katz SK, Schmoll MS, Onslow M, Pierson RC

Abstract
Medication use is common in pregnancy, yet for most medications the optimal formulation and dosage have not been described specifically for pregnant women. Often, adverse effects are only discovered anecdotally or after extensive off-label use occurs. Since pharmacologic research that includes pregnant women is sparse and animal studies are often not applicable to the human fetus, providers must use knowledge of drug behavior and normal physiologic changes of pregnancy to personalize treatment for pregnant women. In this review, we present an overview of the basic concepts of clinical pharmacology: pharmacokinetics, pharmacodynamics, and pharmacogenomics. The normal physiologic changes of pregnancy are presented as a framework to understand alterations in drug behavior. A clinical vignette that addresses 4 pregnancy scenarios involving medications-preterm birth, vaccination, herpes simplex virus infection, and codeine toxicity-is provided to illustrate application of core clinical pharmacologic concepts. Discussion of relevant literature illustrates the challenges of offering individualized pharmacologic therapy in pregnancy.

PMID: 28498553 [PubMed - as supplied by publisher]

Application of metabolomics: Focus on the quantification of organic acids in healthy adults.

Int J Mol Med. 2017 May 10;:

Authors: Tsoukalas D, Alegakis A, Fragkiadaki P, Papakonstantinou E, Nikitovic D, Karataraki A, Nosyrev AE, Papadakis EG, Spandidos DA, Drakoulis N, Tsatsakis AM

Abstract
Metabolomics, a 'budding' discipline, may accurately reflect a specific phenotype which is sensitive to genetic and epigenetic interactions. This rapidly evolving field in science has been proposed as a tool for the evaluation of the effects of epigenetic factors, such as nutrition, environment, drug and lifestyle on phenotype. Urine, being sterile, is easy to obtain and as it contains metabolized or non‑metabolized products, is a favored study material in the field of metabolomics. Urine organic acids (OAs) reflect the activity of main metabolic pathways and have been used to assess health status, nutritional status, vitamin deficiencies and response to xenobiotics. To date, a limited number of studies have been performed which actually define reference OA values in a healthy population and as reference range for epigenetic influences, and not as a reference to congenital metabolic diseases. The aim of the present study was thus the determination of reference values (RVs) for urine OA in a healthy adult population. Targeted metabolomics analysis of 22 OAs in the urine of 122 healthy adults by gas chromatography‑mass spectrometry, was conducted. Percentile distributions of the OA concentrations in urine, as a base for determining the RVs in the respective population sample, were used. No significant differences were detected between female and male individuals. These findings can facilitate the more sensitive determination of OAs in pathological conditions. Therefore, the findings of this study may contribute or add to the information already available on urine metabolite databases, and may thus promote the use of targeted metabolomics for the evaluation of OAs in a clinical setting and for pathophysiological evaluation. However, further studies with well‑defined patients groups exhibiting specific symptoms or diseases are warranted in order to discern between normal and pathological values.

PMID: 28498405 [PubMed - as supplied by publisher]

Association of NPR3 polymorphism with risk of essential hypertension in a Chinese population.

J Clin Pharm Ther. 2017 May 11;:

Authors: Kuang DB, Zhou JP, Li MP, Tang J, Chen XP

Abstract
WHAT IS KNOWN AND OBJECTIVE: Essential hypertension (EH) is a common disease exhibiting large individual difference in occurrence, development and treatment response. Genetic factors are implicated in the development and progression of EH. This study aimed to explore the association between NPR3 single nucleotide polymorphism rs2270915 (A/G, Asn521Asp) and the risk of EH in a Chinese Han population by a case-control study.
METHODS: The study was a single-centre, case-control trial, in which a total of 287 EH patients and 289 age- and sex-matched healthy controls were enrolled. The inclusion criteria were as follows: Han Chinese origin, male or female patients, systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg. The healthy controls were subjects without histories of cardiovascular or cerebrovascular diseases. NPR3 rs2270915 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In addition, primary human umbilical vein endothelial cells (HUVECs) were isolated from 19 fresh human umbilical cords and cultured. Atrial natriuretic peptide (ANP) concentration in cell medium was determined by enzyme-linked immunosorbent assay (ELISA). NPR3 mRNA expression was determined by real-time semi-quantitative PCR.
RESULTS AND DISCUSSION: No significant difference in genotype distribution of NPR3 rs2270915 polymorphism was observed between cases and controls (P>.05). Patients carrying the rs2270915 G allele showed decreased SBP, and the difference was marginal. As compared with cells carrying the rs2270915 AA genotype, those with the AG genotype showed significantly lower NPR3 mRNA expression levels (P<.05) and lower medium ANP concentration (P<.001).
WHAT IS NEW AND CONCLUSION: This study suggested that NPR3 rs2270915 polymorphism was associated with decreased SBP level marginally in EH patients in a Chinese Han population, and the polymorphism may function through decreasing NPR3 mRNA expression and ANP level.

PMID: 28497617 [PubMed - as supplied by publisher]

A computational algorithm for personalized medicine in schizophrenia.

Schizophr Res. 2017 May 08;:

Authors: Lee BS, McIntyre RS, Gentle JE, Park NS, Chiriboga DA, Lee Y, Singh S, McPherson MA

Abstract
Despite advances in sequencing candidate genes and whole genomes, no method has accurately predicted who will or will not benefit from a specific antipsychotic medication among patients with schizophrenia. We propose a computational algorithm that utilizes a person-centered approach that directly identifies individual patients who will respond to a specific antipsychotic medication. The algorithm was applied to the data obtained from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. The predictors were either (1) 13 single-nucleotide polymorphisms (SNPs) and 53 baseline variables or (2) 25 SNPs and the same 53 baseline variables, depending on the existing findings and data availability. The outcome variables were either (1) improvement in the Positive and Negative Syndrome Scale (PANSS) (Yes/No) or (2) completion of phase 1/1A (Yes/No). Each of those four predictor-outcome combinations was tried for each of the five antipsychotic medications (Perphenazine, Olanzapine, Quetiapine, Risperidone, and Ziprasidone), leading to 20 prediction experiments. For 18 out of 20 experiments, all three performance measures were greater than 0.50 (sensitivity 0.51-0.79, specificity 0.52-0.79, accuracy 0.52-0.74). Notably, the model provided a promising prediction for Ziprasidone for the case involving completion of phase 1/1A (Yes/No) predicted by 13 SNPs and 53 baseline variables (sensitivity 0.75, specificity 0.74, accuracy 0.74). The proposed algorithm simultaneously used both genetic information and clinical profiles to predict individual patients' response to antipsychotic medications. As the method is not disease-specific but a general algorithm, it can be easily adopted in many other clinical practices for personalized medicine.

PMID: 28495491 [PubMed - as supplied by publisher]

Comprehensive analysis of treatment response phenotypes in rheumatoid arthritis for pharmacogenetic studies.

Arthritis Res Ther. 2017 May 12;19(1):90

Authors: Standish KA, Huang CC, Curran ME, Schork NJ

Abstract
BACKGROUND: An individual patient's response to a particular drug is influenced by multiple factors, which may include genetic predisposition. Pharmacogenetic studies attempt to discover and estimate the contributions of genetic variants to the variability in response to a drug treatment. The task of identifying the genetic contribution is often complicated by response phenotypes that are based on imprecise or subjective clinical observations. Because the success of a pharmacogenetic study depends on the analysis of a heritable phenotype, it is important to identify phenotypes with a significant heritable component to ensure reliable and reproducible results in subsequent genetic association studies.
METHODS: We retrospectively analyzed data collected from 436 rheumatoid arthritis patients treated with golimumab during the phase III GO-FURTHER study. We investigated the reliability of several potential response outcomes after golimumab treatment. Using whole-genome sequencing of the clinical trial cohort, we estimated the heritability of each potential outcome measure. We further performed a longitudinal analysis of the clinical data to estimate variability of outcome measures over time and the degree to which each response metric could be confounded by placebo response.
RESULTS: We determined that the high degree of within-patient variation over time makes a single follow-up visit insufficient to assess an individual patient's response to golimumab treatment. We found that different potential response outcomes had varying degrees of heritability and that averaging across multiple follow-up visits yielded higher heritability estimates than single follow-up estimates. Importantly, we found that the change in swollen and tender joint counts were the most heritable outcome metrics we tested; however, we showed that they are also more likely to be confounded by a placebo response than objective phenotypes like the change in C-reactive protein levels.
CONCLUSIONS: Our rigorous approach to finding robust and heritable response phenotypes could be beneficial to all pharmacogenetic studies and may lead to more reliable and reproducible results.
TRIAL REGISTRATION: Clinicaltrials.gov NCT00973479 . Registered 4 September 2009.

PMID: 28494788 [PubMed - in process]

ABCB1 2677G>T/A variant enhances chemosensitivity to anti-cancer agents acting on microtubule dynamics through LAMP1 inhibition.

Biochem Pharmacol. 2017 Jan 01;123:73-84

Authors: Kwon WS, Rha SY, Jeung HC, Ahn JB, Jung JJ, Ki DH, Kim TS, Chung HC

Abstract
Overexpression of ABCB1 associated with single nucleotide variants in cancers was reported to encode a protein responsible for drug resistance. We studied chemosensitivity-related genes associated with ABCB1 2677G>T/A variant. The associated genes were identified based on the results of the significance analysis of microarray, and then prediction accuracy was evaluated using the prediction analysis of microarray. Functional assay of the selected gene was performed by using siRNA and drug accumulation study. A higher frequency of chemoresistance to microtubule-modulating agents was found in cell lines with wild-type ABCB1 compared to cell lines with 2677G>T/A ABCB1 variant. Based on the pharmacogenetic association study with 2677 variant, we identified seven genes that could predict chemosensitivity to microtubule dynamics modulators. The classification accuracy with these seven genes was 90.0%, and the predicted probability was 0.73. LAMP1 was the only gene that was commonly related to chemosensitivity. LAMP1 expression levels were relatively higher in chemoresistant ABCB1 wild-type compared to chemosensitive polymorphic cells. But, there was no difference in ABCB1 expression levels between the two groups. Following LAMP1 siRNA, chemosensitivity was restored due to increased intracellular drug accumulation in wild type cell line. In conclusion, ABCB1 2677G>T/A variant enhances chemosensitivity on microtubule dynamics through LAMP1 inhibition.

PMID: 27832934 [PubMed - indexed for MEDLINE]