Effect-enhancing and toxicity-reducing activity of usnic acid in ascitic tumor-bearing mice treated with bleomycin.

Int Immunopharmacol. 2017 May;46:146-155

Authors: Su ZQ, Liu YH, Guo HZ, Sun CY, Xie JH, Li YC, Chen JN, Lai XP, Su ZR, Chen HM

Abstract
Usnic acid (UA) can be found in certain lichen species. Growing evidence suggests that UA possesses antitumoral, antioxidative and anti-inflammatory activities. Bleomycin (BLM) is widely used in the treatment of malignant ascites, however, it unexpectedly causes pulmonary fibrosis (PF). Researches show that excessive inflammatory response and oxidative stress in lung tissue is conspicuous causes of BLM-induced PF. Here we investigated mechanism underlying the effect-enhancing and toxicity-reducing activity of UA on H22-bearing mice treated with BLM. UA combined with BLM was significantly more effective than BLM alone in inhibiting the tumor growth, arresting the cell cycle at G0/G1 phase, and promoting the cleaved caspase-3 and cleaved caspase-8 activities to induce cancer cellular apoptosis. The mechanism may be associated with the transcriptional regulation of p53/p21/Cyclin pathway. Furthermore, UA effectively moderated the histopathological changes, reduced the content of MDA, HYP, TNF-α, IL-1β, IL-6 and TGF-β1, and increased the level of SOD when combined with BLM in lung tissues of H22-bearing mice, which was believed to be related to the inhibition on the protein level of p-Smad2/3 and enhancement of Smad7 expression. These findings suggested that UA might be a potential effect-enhancing and toxicity-reducing candidate for BLM in the treatment of malignant ascites.

PMID: 28284148 [PubMed - indexed for MEDLINE]

Off-Label Prescribing and Polypharmacy: Minimizing the Risks.

J Psychosoc Nurs Ment Health Serv. 2017 Feb 01;55(2):17-22

Authors: Leahy LG

Abstract
Off-label prescribing and polypharmacy are commonplace in today's health care environment. Patients are treated with multiple medications obtained through multiple providers, and all too frequently, there is no collaboration amongst professionals. Nurses can address these issues by educating themselves and their patients regarding medication indications and uses, side effects, risks, and benefits. By exploring a patient's medication reconciliation, including over-the-counter agents, and identifying the U.S. Food and Drug Administration-approved indications, as well as potential off-label uses and overlapping side effects of the medications prescribed, nurses can facilitate collaboration among prescribers to reduce polypharmacy, minimize medication side effects, and alleviate drug-drug interactions, while improving patient outcomes and quality of life. [Journal of Psychosocial Nursing and Mental Health Services, 55(2), 17-22.].

PMID: 28218925 [PubMed - indexed for MEDLINE]

Supporting clinical rules engine in the adjustment of medication (SCREAM): protocol of a multicentre, prospective, randomised study.

BMC Geriatr. 2017 Jan 26;17(1):35

Authors: Mestres Gonzalvo C, de Wit HA, van Oijen BP, Hurkens KP, Janknegt R, Schols JM, Mulder WJ, Verhey FR, Winkens B, van der Kuy PM

Abstract
BACKGROUND: In the nursing home population, it is estimated that 1 in every 3 patients is polymedicated and given their considerable frailty, these patients are especially prone to adverse drug reactions. Clinical pharmacist-led medication reviews are considered successful interventions to improve medication safety in the inpatient setting. Due to the limited available evidence concerning the benefits of medication reviews performed in the nursing home setting, we propose a study aiming to demonstrate a positive effect that a clinical decision support system, as a health care intervention, may have on the target population. The primary objective of this study is to reduce the number of patients with at least one event when using the clinical decision support system compared to the regular care. These events consist of hospital referrals, delirium, falls, and/or deaths.
METHOD/DESIGN: This study is a multicentre, prospective, randomised study with a cluster group design. The randomisation will be per main nursing home physician and stratified per ward (somatic and psychogeriatric). In the intervention group the clinical decision support system will be used to screen medication list, laboratory values and medical history in order to obtain potential clinical relevant remarks. The remarks will be sent to the main physician and feedback will be provided whether the advice was followed or not. In the control group regular care will be applied.
DISCUSSION: We strongly believe that by using a clinical decision support system, medication reviews are performed in a standardised way which leads to comparable results between patients. In addition, using a clinical decision support system eliminates the time factor to perform medication reviews as the major problems related to medication, laboratory values, indications and/or established patient characteristics will be directly available. In this way, and in order to make the medication review process complete, consultation within healthcare professionals and/or the patient itself will be time effective and the medication surveillance could be performed around the clock.
TRIAL REGISTRATION: The Netherlands National Trial Register NTR5165 . Registered 2nd April 2015.

PMID: 28125977 [PubMed - indexed for MEDLINE]

Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study.

Am J Gastroenterol. 2017 Jan;112(1):120-131

Authors: Casanova MJ, Chaparro M, García-Sánchez V, Nantes O, Leo E, Rojas-Feria M, Jauregui-Amezaga A, García-López S, Huguet JM, Arguelles-Arias F, Aicart M, Marín-Jiménez I, Gómez-García M, Muñoz F, Esteve M, Bujanda L, Cortés X, Tosca J, Pineda JR, Mañosa M, Llaó J, Guardiola J, Pérez-Martínez I, Muñoz C, González-Lama Y, Hinojosa J, Vázquez JM, Martinez-Montiel MP, Rodríguez GE, Pajares R, García-Sepulcre MF, Hernández-Martínez A, Pérez-Calle JL, Beltrán B, Busquets D, Ramos L, Bermejo F, Barrio J, Barreiro-de Acosta M, Roncedo O, Calvet X, Hervías D, Gomollón F, Domínguez-Antonaya M, Alcaín G, Sicilia B, Dueñas C, Gutiérrez A, Lorente-Poyatos R, Domínguez M, Khorrami S, Muñoz C, Taxonera C, Rodríguez-Pérez A, Ponferrada A, Van Domselaar M, Arias-Rivera ML, Merino O, Castro E, Marrero JM, Martín-Arranz M, Botella B, Fernández-Salazar L, Monfort D, Opio V, García-Herola A, Menacho M, Ramírez-de la Piscina P, Ceballos D, Almela P, Navarro-Llavat M, Robles-Alonso V, Vega-López AB, Moraleja I, Novella MT, Castaño-Milla C, Sánchez-Torres A, Benítez JM, Rodríguez C, Castro L, Garrido E, Domènech E, García-Planella E, Gisbert JP

Abstract
OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed.
METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included.
RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe.
CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

PMID: 27958281 [PubMed - indexed for MEDLINE]

Drug-induced progressive multifocal leukoencephalopathy: a case/noncase study in the French pharmacovigilance database.

Fundam Clin Pharmacol. 2017 Apr;31(2):237-244

Authors: Colin O, Favrelière S, Quillet A, Neau JP, Houeto JL, Lafay-Chebassier C, Pérault-Pochat MC, French Pharmacovigilance Network

Abstract
Progressive multifocal leukoencephalopathy (PML) is an often fatal demyelinating disease of the central nervous system. As effective treatment is unavailable, identification of all drugs that could be associated with PML is essential. The objective of this study was to investigate the putative association of reports of PML and drugs. We used the case/noncase method in the French PharmacoVigilance database (FPVD). Cases were reports of PML in the FPVD between January 2008 and December 2015. Noncases were all other reports during the same period. To assess the association between PML and drug intake, we calculated an adverse drug report odds ratio (ROR) with its 95% confidence interval. We have studied the delay of onset of PML for each drug concerned. Among the 101 cases of PML, 39 drugs were mentioned as suspect. The main therapeutic classes suspected with significant ROR were antineoplastic agents (n = 85), immunosuppressants (n = 67), and corticosteroids. A latent interval from the time of drug initiation to the development of PML is established: the median time to onset was 365 days (123-1095 days). The onset of PML is highly variable and differs among drug classes [from 1 to 96 months (IQR: 39.0-126)]. An association between PML and some immunosuppressant drugs was found as expected, but also with antineoplastic agents and glucocorticoids. An important delay of PML onset after stopping treatment is suspected and should alert prescribers. Prescribers but also patients should be informed about the potential associations with all these drugs. Monitoring could be necessary for many drugs to early detect PML.

PMID: 27736027 [PubMed - indexed for MEDLINE]

Using Rich Data on Comorbidities in Case-Control Study Design with Electronic Health Record Data Improves Control of Confounding in the Detection of Adverse Drug Reactions.

PLoS One. 2016;11(10):e0164304

Authors: Backenroth D, Chase H, Friedman C, Wei Y

Abstract
Recent research has suggested that the case-control study design, unlike the self-controlled study design, performs poorly in controlling confounding in the detection of adverse drug reactions (ADRs) from administrative claims and electronic health record (EHR) data, resulting in biased estimates of the causal effects of drugs on health outcomes of interest (HOI) and inaccurate confidence intervals. Here we show that using rich data on comorbidities and automatic variable selection strategies for selecting confounders can better control confounding within a case-control study design and provide a more solid basis for inference regarding the causal effects of drugs on HOIs. Four HOIs are examined: acute kidney injury, acute liver injury, acute myocardial infarction and gastrointestinal ulcer hospitalization. For each of these HOIs we use a previously published reference set of positive and negative control drugs to evaluate the performance of our methods. Our methods have AUCs that are often substantially higher than the AUCs of a baseline method that only uses demographic characteristics for confounding control. Our methods also give confidence intervals for causal effect parameters that cover the expected no effect value substantially more often than this baseline method. The case-control study design, unlike the self-controlled study design, can be used in the fairly typical setting of EHR databases without longitudinal information on patients. With our variable selection method, these databases can be more effectively used for the detection of ADRs.

PMID: 27716785 [PubMed - indexed for MEDLINE]

Short-term recovery of chemotherapy-induced peripheral neuropathy after treatment for pediatric non-CNS cancer.

Pediatr Blood Cancer. 2017 Jan;64(1):180-187

Authors: Gilchrist LS, Tanner LR, Ness KK

Abstract
PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect of pediatric cancer treatment. The presentation of CIPN, trajectory and completeness of recovery over the first 6 months postchemotherapy, and the influence of patient and treatment characteristics on recovery are described.
PATIENTS AND METHODS: Sixty-seven children and adolescents treated for non-CNS cancers were evaluated for CIPN using the pediatric modified total neuropathy score (ped-mTNS) while on treatment and 3 and 6 months postchemotherapy. Differences between diagnostic groups and treatment type were evaluated as well as change in scores over time. Risk factors for on-treatment and persistent CIPN at 6 months were identified.
RESULTS: Overall, ped-mTNSs were in the abnormal range for 86.5% during treatment and scores decreased over time (initial 9.3 ± 0.6, 6 months 4.3 ± 0.4; F = 38.14, P < 0.001). By 6 months posttreatment, mean scores and percentage of children with abnormal scores were reduced to 2.4 ± 0.3 and 11.5%, respectively, in the ALL group, but remained higher at 5.7 ± 0.7 and 57%, respectively, for lymphoma, and 5.2 ± 1.0 and 60%, respectively, for other solid tumors. At 6 months posttreatment, light touch deficits and foot strength deficits remained in 19.4 and 59.7%, respectively, compared with only 4.9 and 9.8% of the control population. Subjects who were older at exposure, female, or who received etoposide in addition to vincristine were at higher risk for on-treatment CIPN. On-treatment sensory abnormalities were associated with increased risk of persistent CIPN.
CONCLUSION: While CIPN improves in most pediatric patients, significant numbers, especially those treated for lymphoma or other solid tumors, have remaining neuropathic signs and symptoms 6 months posttreatment.

PMID: 27567009 [PubMed - indexed for MEDLINE]

[Cardiovascular risk of androgen deprivation therapy for treatment of hormone-dependent prostate cancer : Differences between GnRH antagonists and GnRH agonists].

Herz. 2016 Dec;41(8):697-705

Authors: Tschöpe C, Kherad B, Spillmann F, Schneider CA, Pieske B, Krackhardt F

Abstract
BACKGROUND: Several studies have indicated that reduction of testosterone levels in patients with prostate cancer undergoing androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists can be associated with an increased risk of cardiovascular events. The GnRH antagonists have a different mode of action compared with GnRH agonists and may be preferred in ADT for patients with cardiovascular disease.
OBJECTIVE: This review article discusses potential mechanisms underlying the development of cardiovascular events associated with ADT when using GnRH agonists and explains the differences in mode of action between GnRH agonists and GnRH antagonists. Additionally, relevant studies are presented and practical recommendations for the clinical practice are provided.
MATERIAL AND METHODS: A literature search was performed. Full publications and abstracts published in the last 10 years up to September 2015 were considered to be eligible.
RESULTS: The GnRH antagonists were associated with a decreased risk of cardiovascular events compared with GnRH agonists in prostate cancer patients undergoing ADT and particularly in patients with cardiovascular risk factors or a history of cardiovascular disease. This decrease may be due to the different mode of action of GnRH antagonists compared with GnRH agonists.
CONCLUSION: Prostate cancer patients with either cardiovascular disease or an increased risk of experiencing a cardiovascular event undergoing ADT should be preferentially treated with GnRH antagonists.

PMID: 27083586 [PubMed - indexed for MEDLINE]

Pax3- and Pax7-mediated Dbx1 regulation orchestrates the patterning of intermediate spinal interneurons.

Dev Biol. 2017 Jun 15;:

Authors: Gard C, Gonzalez-Curto G, Frarma YE, Chollet E, Duval N, Auzié V, Auradé F, Vigier L, Relaix F, Pierani A, Causeret F, Ribes V

Abstract
Transcription factors are key orchestrators of the emergence of neuronal diversity within the developing spinal cord. As such, the two paralogous proteins Pax3 and Pax7 regulate the specification of progenitor cells within the intermediate neural tube, by defining a neat segregation between those fated to form motor circuits and those involved in the integration of sensory inputs. To attain insights into the molecular means by which they control this process, we have performed detailed phenotypic analyses of the intermediate spinal interneurons (IN), namely the dI6, V0D, V0VCG and V1 populations in compound null mutants for Pax3 and Pax7. This has revealed that the levels of Pax3/7 proteins determine both the dorso-ventral extent and the number of cells produced in each subpopulation; with increasing levels leading to the dorsalisation of their fate. Furthermore, thanks to the examination of mutants in which Pax3 transcriptional activity is skewed either towards repression or activation, we demonstrate that this cell diversification process is mainly dictated by Pax3/7 ability to repress gene expression. Consistently, we show that Pax3 and Pax7 inhibit the expression of Dbx1 and of its repressor Prdm12, fate determinants of the V0 and V1 interneurons, respectively. Notably, we provide evidence for the activity of several cis-regulatory modules of Dbx1 to be sensitive to Pax3 and Pax7 transcriptional activity levels. Altogether, our study provides insights into how the redundancy within a TF family, together with discrete dynamics of expression profiles of each member, are exploited to generate cellular diversity. Furthermore, our data supports the model whereby cell fate choices in the neural tube do not rely on binary decisions but rather on inhibition of multiple alternative fates.

PMID: 28625870 [PubMed - as supplied by publisher]

Innovative approaches to treat Staphylococcus aureus biofilm-related infections.

Essays Biochem. 2017 Feb 28;61(1):61-70

Authors: Richter K, Van den Driessche F, Coenye T

Abstract
Many bacterial infections in humans and animals are caused by bacteria residing in biofilms, complex communities of attached organisms embedded in an extracellular matrix. One of the key properties of microorganisms residing in a biofilm is decreased susceptibility towards antimicrobial agents. This decreased susceptibility, together with conventional mechanisms leading to antimicrobial resistance, makes biofilm-related infections increasingly difficult to treat and alternative antibiofilm strategies are urgently required. In this review, we present three such strategies to combat biofilm-related infections with the important human pathogen Staphylococcus aureus: (i) targeting the bacterial communication system with quorum sensing (QS) inhibitors, (ii) a 'Trojan Horse' strategy to disturb iron metabolism by using gallium-based therapeutics and (iii) the use of 'non-antibiotics' with antibiofilm activity identified through screening of repurposing libraries.

PMID: 28258230 [PubMed - indexed for MEDLINE]

A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis.

PLoS Negl Trop Dis. 2017 Feb;11(2):e0005373

Authors: Love MS, Beasley FC, Jumani RS, Wright TM, Chatterjee AK, Huston CD, Schultz PG, McNamara CW

Abstract
Cryptosporidiosis has emerged as a leading cause of non-viral diarrhea in children under five years of age in the developing world, yet the current standard of care to treat Cryptosporidium infections, nitazoxanide, demonstrates limited and immune-dependent efficacy. Given the lack of treatments with universal efficacy, drug discovery efforts against cryptosporidiosis are necessary to find therapeutics more efficacious than the standard of care. To date, cryptosporidiosis drug discovery efforts have been limited to a few targeted mechanisms in the parasite and whole cell phenotypic screens against small, focused collections of compounds. Using a previous screen as a basis, we initiated the largest known drug discovery effort to identify novel anticryptosporidial agents. A high-content imaging assay for inhibitors of Cryptosporidium parvum proliferation within a human intestinal epithelial cell line was miniaturized and automated to enable high-throughput phenotypic screening against a large, diverse library of small molecules. A screen of 78,942 compounds identified 12 anticryptosporidial hits with sub-micromolar activity, including clofazimine, an FDA-approved drug for the treatment of leprosy, which demonstrated potent and selective in vitro activity (EC50 = 15 nM) against C. parvum. Clofazimine also displayed activity against C. hominis-the other most clinically-relevant species of Cryptosporidium. Importantly, clofazimine is known to accumulate within epithelial cells of the small intestine, the primary site of Cryptosporidium infection. In a mouse model of acute cryptosporidiosis, a once daily dosage regimen for three consecutive days or a single high dose resulted in reduction of oocyst shedding below the limit detectable by flow cytometry. Recently, a target product profile (TPP) for an anticryptosporidial compound was proposed by Huston et al. and highlights the need for a short dosing regimen (< 7 days) and formulations for children < 2 years. Clofazimine has a long history of use and has demonstrated a good safety profile for a disease that requires chronic dosing for a period of time ranging 3-36 months. These results, taken with clofazimine's status as an FDA-approved drug with over four decades of use for the treatment of leprosy, support the continued investigation of clofazimine both as a new chemical tool for understanding cryptosporidium biology and a potential new treatment of cryptosporidiosis.

PMID: 28158186 [PubMed - indexed for MEDLINE]

A rare adult renal neuroblastoma better imaged by (18)F-FDG than by (68)Ga-dotanoc in the PET/CT scan.

Hell J Nucl Med. 2017 Jan-Apr;20(1):100-101

Authors: Jain TK, Singh SK, Sood A, Ashwathanarayama AG, Basher RK, Shukla J, Mittal BR

Abstract
Primary renal neuroblastoma is an uncommon tumor in children and extremely rare in adults. We present a case of a middle aged female having a large retroperitoneal mass involving the right kidney with features of neuroblastoma on pre-operative histopathology. Whole-body fluorine-18-fluoro-deoxyglucose positron emission tomography ((18)F-FDG PET/CT) and (68)Ga-dotanoc PET/CT scans performed for staging and therapeutic potential revealed a tracer avid mass replacing the right kidney and also pelvic lymph nodes. The (18)F-FDG PET/CT scan showed better both the primary lesion and the metastases in the pelvic lymph nodes than the (68)Ga-dotanoc scan supporting diagnosis and treatment planning.

PMID: 28315919 [PubMed - indexed for MEDLINE]

Characterization and inhibition studies of tissue nonspecific alkaline phosphatase by aminoalkanol derivatives of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5,10-trione, new competitive and non-competitive inhibitors, by capillary electrophoresis.

J Pharm Biomed Anal. 2017 Jun 01;143:285-290

Authors: Grodner B, Napiórkowska M

Abstract
The article describes the inhibitory effect of two new aminoalkanol derivatives on the enzymatic kinetic of tissue non-specific alkaline phosphatase with use of capillary zone electrophoresis to evaluate the inhibitory effect. This technique allows to investigate of the enzymatic kinetic by the measure of the amounts of the substrate and product in the presence of compound (I) or (II) in the reaction mixture. The separation process was conducted using an eCAP fused-silica capillary. The detector was set at 200nm. The best parameters for the analysis were: 25mM sodium dihydrogen phosphate adjusted to pH=2.5, temperature 25°C, and voltage -15kV. Lineweaver-Burk plots were constructed and determined by comparison of the Km, of alkaline phosphatase in the presence of inhibitor (I) or (II) with the Km in a solution without inhibitor. The influence of replacement the propylamine group by the dimethylamine group on tissue non-specific alkaline phosphatase inhibition activity of new derivatives (I) and (II) was investigated. The tested compounds (I) and (II) were found to be tissue non-specific alkaline phosphatase inhibitors. Detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase for compound (I) and non-competitive mode of inhibition for compound (II).

PMID: 28628862 [PubMed - as supplied by publisher]

The COMT Val(108/158)Met Genetic Polymorphism can not be Recommended as a Biomarker of Prediction of Venlafaxine Efficacy in Patients treated in Psychiatric settings.

Basic Clin Pharmacol Toxicol. 2017 Jun 19;:

Authors: Taranu A, Asmar KE, Colle R, Ferreri F, Polosan M, David D, Becquemont L, Corruble E, Verstuyft C

Abstract
The antidepressant venlafaxine is known to increase the turn-over of cerebral monoamines, which are catabolized by the cathecol-O-methyltransferase (COMT). The COMT (Val108/158Met, rs4680) genetic polymorphism affects the cerebral COMT activity. But whether this genetic polymorphism is associated with response to venlafaxine remains unclear. We assessed the impact of the COMT Val(108/158)Met, rs4680 genetic polymorphism on the efficacy of venlafaxine in depressed patients. This study was nested in the METADAP cohort, a real-world naturalistic treatment study in psychiatric settings. 206 Caucasian patients with a unipolar Major Depressive Episode (DSM-IVTR) treated with venlafaxine and evaluated with the Hamilton Depression Rating Scale (HDRS) were studied. 180 patients were genotyped for the COMT Val(108/158)Met, rs4680 genetic polymorphism and classified into 3 genotype subgroups: Val/Val, Val/Met, Met/Met. The COMT genotype was the explanatory variable and the variables to be explained were the HDRS score, the HDRS score improvement over time, response and remission rates. Venlafaxine had a trend to higher efficacy in the Val/Val patients as compared to Met/Met carriers, as shown by the HDRS score improvement after 3 months of treatment but this result was not significant in mixed models (Val/Val: 59.78% (±22.4); Val/Met: 51.64% (±26.3); Met/Met: 39.52% (±27.6). The percentage of responders and remitters after 3 months of treatment were not significantly different in the 3 genotype groups, although coherent trends were shown. The COMT Val(108/158)Met, rs4680 genetic polymorphism can not be recommended as a biomarker of prediction of venlafaxine efficacy in patients treated in psychiatric settings. This article is protected by copyright. All rights reserved.

PMID: 28627776 [PubMed - as supplied by publisher]

Impact of fixation artifacts and threshold selection on high resolution melting analysis for KRAS mutation screening.

Mol Cell Probes. 2017 Jun 13;:

Authors: Pérez-Báez W, Garcia-Latorre EA, Maldonado-Martinez HA, Coronado-Martinez I, Flores-Garcia L, Taja-Chayeb L

Abstract
INTRODUCTION: Treatment in the metastatic colorectal cancer has expanded with monoclonal antibodies targeting Epidermal Growth Factor Receptor, but is restricted to patients with a wild-type (WT) KRAS mutational status. The most sensitive assays for KRAS mutation detection in formalin-fixed paraffin embedded (FFPE) tissues are based on Real-time PCR. Among them, high resolution melting analysis (HRMA), is a simple, fast, highly sensitive, specific and cost-effective method, proposed as adjunct for KRAS mutation detection. However the method to categorize WT vs mutants sequences in HRMA is not clearly specified in available studies, besides the impact of FFPE artifacts on HRMA performance hasn't been addressed either.
METHODS: Avowedly adequate samples from 104 consecutive metastatic CRC patients were tested for KRAS mutations by Therascreen™ (FDA Validated test), HRMA, and HRMA with UDG pre-treatment to reverse FFPE fixation artifacts. Comparisons of KRAS status allocation among the three methods were done. Focusing on HRMA as screening test, ROC curve analyses were performed for HRMA and HMRA-UDG against Therascreen™, in order to evaluate their discriminative power and to determine the threshold of profile concordance between WT control and sample for KRAS status determination.
RESULTS: Comparing HRMA and HRMA-UDG against Therascreen™ as surrogate gold standard, sensitivity was 1 for both HRMA and HRMA-UDG; and specificity and positive predictive values were respectively 0.838 and 0.939; and 0.777 and 0.913. As evaluated by the McNemar test, HRMA-UDG allocate samples to a WT/mutated genotype in a significatively different way from HRMA (p > 0.001). On the other hand HRMA-UDG does not differ from Therascreen™ (p = 0.125). ROC-curve analysis showed a significant discriminative power for both HRMA and HRMA-UDG against Therascreen™ (respectively, AUC of 0.978, p > 0.0001, CI 95% 0.957-0.999; and AUC of 0.98, p > 0.0001, CI 95% 0.000-1.0). For HRMA as a screening tool, the best threshold (degree of concordance between sample curves and WT control) was attained at 92.14% for HRMA (specificity of 0.887), and at 92.55% for HRMA-UDG (specificity of 0.952).
CONCLUSIONS: HRMA is a highly sensitive method for KRAS mutation detection, with apparently adequate and statistically significant discriminative power. FFPE sample fixation artifacts have an impact on HRMA results, so for HRMA on FFPE samples pre-treatment with UDG should be strongly suggested. The choice of the threshold for melting curve concordance has also great impact on HRMA performance. A threshold of 93% or greater might be adequate if using HRMA as a screening tool. Further validation of this threshold is required.

PMID: 28627450 [PubMed - as supplied by publisher]

Evaluation of CYP2D6 Protein Expression and Activity in the Small Intestine to Determine its Metabolic Capability in the Japanese Population.

Biol Pharm Bull. 2017 Jun 14;:

Authors: Kawakami M, Takenoshita-Nakaya S, Takeba Y, Nishimura Y, Oda M, Watanabe M, Ohta Y, Kobayashi S, Ohtsubo T, Kobayashi S, Uchida N, Matsumoto N

Abstract
CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the first-pass metabolism of orally administered drugs. Several CYP enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals. Normal jejunal tissues were obtained from 31 patients who had undergone pancreaticoduodenectomy, and the CYP2D6*10 variant was identified in these tissues. CYP2D6 mRNA and CYP2D6 protein levels were analyzed using real-time reverse transcription-polymerase chain reaction and Western blotting, respectively. Bufuralol 1'-hydroxylation, a marker of CYP2D6 activity, was analyzed using high-performance liquid chromatography. Frequencies of the CYP2D6*1/*1, *1/*10, and *10/*10 genotypes in the jejunal tissue were 29.0% (n = 9), 35.5% (n = 11), and 35.5% (n = 11), respectively. CYP2D6 protein and activity levels did not differ significantly between the genotypes. A positive correlation was found between CYP2D6 protein and activity levels. Furthermore, CYP2D6 protein levels and activity in the small intestine were significantly lower than those in the liver. These findings suggest that the metabolic capacity of CYP2D6 in the small intestine of the Japanese population has a relatively small effect on drug metabolism.

PMID: 28626197 [PubMed - as supplied by publisher]

Pitfalls and Opportunities for Epigenomic Analyses Focused on Disease Diagnosis, Prognosis, and Therapy.

Trends Pharmacol Sci. 2017 Jun 15;:

Authors: Lauschke VM, Ivanov M, Ingelman-Sundberg M

PMID: 28625497 [PubMed - as supplied by publisher]

Pharmacogenetics in obstetric anesthesia.

Best Pract Res Clin Anaesthesiol. 2017 Mar;31(1):23-34

Authors: Landau R, Smiley R

Abstract
The 21st century has been billed as the era of "precision/personalized medicine." Genetic investigation of clinical syndromes may guide therapy as well as reveal previously unknown biological or pharmacological pathways that may result in novel drug therapies. Several clinical issues in obstetrics and obstetric anesthesiology have been targets for genetic investigations. These include evaluation of the genetic effects on preterm labor and the progression of labor, spinal anesthesia-induced hypotension and the response to medications used to treat hypotension, and the effect of gene variants on pain and analgesic responses. Most studies have examined specific single nucleotide polymorphisms. Findings have revealed modest effects of genetic variation without tangible impact on current clinical practice. Over the next decade, increased availability of whole exome and genome sequencing, epigenetics, large genetic databases, computational biology and other information technology, and more rapid methods of real-time genotyping may increase the impact of genetics in the clinical arena of obstetrics and obstetric anesthesia.

PMID: 28625302 [PubMed - in process]