Literature Watch
Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin's lymphoma.
Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin's lymphoma.
Blood. 2017 May 03;:
Authors: Kuruvilla J, Savona M, Baz R, Mau-Sorensen M, Gabrail N, Garzon R, Stone R, Wang M, Savoie L, Martin P, Flinn I, Jacoby M, Unger TJ, Saint-Martin JR, Rashal T, Friedlander S, Carlson R, Kauffman M, Shacham S, Gutierrez M
Abstract
Patients with relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B cell lymphoma (DLBCL), Richter's transformation, mantle cell lymphoma (MCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) were enrolled. In the dose escalation phase, patients received 3-80 mg/m(2) of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics and anti-tumor activity. In the dose expansion phase, patients were treated with selinexor at 35 mg/m(2) or 60 mg/m(2) The most common grade 3-4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%) and hyponatremia (10%). Tumor biopsies showed decreases in cell signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN) and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective response (OR), including 4 complete responses (CR) and 18 partial responses (PR), which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m(2) (60mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m(2) is a safe therapy with encouraging and durable anti-cancer activity in patients with R/R NHL. The trial is registered to www.clinicaltrials.gov as NCT01607892.
PMID: 28468797 [PubMed - as supplied by publisher]
Reduction of Medical Cost through Pharmaceutical Inquiries by Community Pharmacists and Relation with Iyaku Bungyo Rates: A Nationwide Survey on Prescription Inquiries.
Reduction of Medical Cost through Pharmaceutical Inquiries by Community Pharmacists and Relation with Iyaku Bungyo Rates: A Nationwide Survey on Prescription Inquiries.
Yakugaku Zasshi. 2016;136(9):1263-73
Authors: Shikamura Y, Mano Y, Komoda M, Negishi K, Sato T, Miyazaki S
Abstract
This nationwide survey aimed to evaluate reduction of drug and medical costs due to prevention of serious adverse drug reactions through pharmaceutical inquires by community pharmacist, and investigate relation with iyaku bungyo (separation of dispensing from medical practice) rates. Using the national list of pharmacies, 10% of pharmacies were randomly selected by prefecture and asked to participate in an Internet-based survey. The survey period was 7 days, from July 21 to July 27, 2015. Of the 5575 pharmacies queried, 818 responded to the survey (response rate: 14.7%). The proportion of inquiries to total prescriptions was 2.6%. Among these, the proportion of prescriptions changed in response to inquiry was 74.9%. An estimated 103 million yen was saved by reducing drug costs, and 133 million yen was saved by reducing medical costs due to prevention of serious adverse drug reactions. Comparison of prescription change rates between pharmacies with high and low iyaku bungyo rates indicated that the proportion of prescriptions changed was significantly higher in pharmacies with high iyaku bungyo rates than in those with low iyaku bungyo rates (78.2% vs. 69.9%, p<0.01). The findings suggest that inquiries about prescriptions are useful in ensuring the safety of pharmacotherapy and reducing the cost of healthcare. They also suggest that iyaku bungyo promotes prescription changes through inquiries, leading to proper use of pharmaceutical products.
PMID: 27592829 [PubMed - indexed for MEDLINE]
Safety Assessment and Power Analyses in Published Anti-Vascular Endothelial Growth Factor Randomized Controlled Trials.
Safety Assessment and Power Analyses in Published Anti-Vascular Endothelial Growth Factor Randomized Controlled Trials.
Am J Ophthalmol. 2016 Sep;169:68-72
Authors: Esen F, Alhan O, Kuru P, Sahin O
Abstract
PURPOSE: To investigate a certain set of methodological limitations in published anti-vascular endothelial growth factor (VEGF) randomized controlled trials (RCTs).
DESIGN: Descriptive methodological study.
METHODS: We did a PubMed search with the terms "bevacizumab OR ranibizumab OR pegaptanib OR aflibercept" and the limitations "humans" and "randomized controlled trials" in 15 of the highest-impact-factor general medicine and ophthalmology journals. We included only RCTs published as original articles, where an anti-VEGF agent was used to treat eye disease. Two independent observers (O.A., P.K.) read through each article and classified the articles according to a predefined set of criteria.
RESULTS: The PubMed search yielded 209 articles, and 93 were classified as eligible. In most of the studies, the study drug was bevacizumab (52.6%, n = 49), followed by ranibizumab (44.1%, n = 41), pegaptanib (7.5%, n = 7), and aflibercept (5.4%, n = 5). Basic epidemiologic data, including sex distribution (2.2%, n = 2) and mean age (3.2%, n = 3), were missing in 3.2% of the published RCTs. The power calculation for efficacy was mentioned in 48% (n = 45) of the published work, and a power calculation for safety was considered in only 1 study (1.1%). Only 6 RCTs (6.5%) reported negative results.
CONCLUSIONS: Power calculations for efficacy, an important component of an RCT, were missing in 51% of the RCTs we surveyed, while a power calculation for safety was only present in 1.1%. Around 60% of the published RCTs were labeled as an "efficacy and safety trial," and none of those studies had a power calculation for safety.
PMID: 27320058 [PubMed - indexed for MEDLINE]
Effectiveness Trials for Post-Acute Interventions and Services to Optimize Longer-term Outcomes (R01)
Pilot Effectivness Trials for Post-Acute Interventions and Services to Optimize Longer-term Outcomes (R34)
(exome OR "exome sequencing") AND disease; +12 new citations
12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
(exome OR "exome sequencing") AND disease
These pubmed results were generated on 2017/05/04
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
"systems biology"; +27 new citations
27 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2017/05/04
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects"); +12 new citations
12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")
These pubmed results were generated on 2017/05/04
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Characterization of a new Gsx2-cre line in the developing mouse telencephalon.
Characterization of a new Gsx2-cre line in the developing mouse telencephalon.
Genesis. 2016 Oct;54(10):542-549
Authors: Qin S, Madhavan M, Waclaw RR, Nakafuku M, Campbell K
Abstract
In this study, we generated a transgenic mouse line driving Cre and EGFP expression with two putative cis-regulatory modules (CRMs) (i.e., hs687 and hs678) upstream of the homeobox gene Gsx2 (formerly Gsh2), a critical gene for establishing lateral ganglionic eminence (LGE) identity. The combination of these two CRMs drives transgene expression within the endogenous Gsx2 expression domains along the anterior-posterior neuraxis. By crossing this transgenic line with the Rosa(tdTomato) (Ai14) reporter mouse line, we observed a unique recombination pattern in the lateral ventral telencephalon, namely the LGE and the dorsal half of the medial GE (MGE), but not in the septum. We found robust recombination in many cell types derived from these embryonic regions, including olfactory bulb and amygdala interneurons and striatal projection neurons from the LGE, as well as cortical interneurons from the MGE and caudal GE (CGE). In summary, this transgenic mouse line represents a new tool for genetic manipulation in the LGE/CGE and the dorsal half of MGE.
PMID: 27618396 [PubMed - indexed for MEDLINE]
Cancer stem cell (CSC) inhibitors: a review of recent patents (2012-2015).
Cancer stem cell (CSC) inhibitors: a review of recent patents (2012-2015).
Expert Opin Ther Pat. 2017 May 02;:
Authors: Kharkar PS
Abstract
INTRODUCTION: Cancer stem cells (CSCs) mediate tumor initiation and maintenance. These cells are chemoresistant and possess characteristics such as self-renewal, pluripotency, plasticity and differentiation. They have aberrant or altered signaling pathways depending on tumor microenvironment, tumor type, etc. CSCs are responsible for highly aggressive and invasive form of the disease following chemo- and/or radiotherapy. Eliminating CSCs is likely to improve the survival rate in patients. Several anti-CSC strategies and associated targets have been proposed and validated till date. Areas covered: The main emphasis is on the patent applications/patents filed/granted in the last few years (2012-2015). The anti-CSC agents are discussed under two broad headings - small- and macromolecules. Different subclasses are further elaborated, e.g., kinase inhibitors, polypeptides, etc. Expert opinion: Clinical development of small- and macromolecular anti-CSC therapeutics is underway. Few of these agents act on validated targets such as kinases. Potential problems with these agents can be envisaged based on our understanding of target biology. Other issues governing the choice of small- versus macromolecules include druggability of the target, ease its modulation and the presence of compensatory mechanisms. Drug repurposing can be attempted to discover newer anti-CSC drugs quickly.
PMID: 28460551 [PubMed - as supplied by publisher]
Genomes, structural biology and drug discovery: combating the impacts of mutations in genetic disease and antibiotic resistance.
Genomes, structural biology and drug discovery: combating the impacts of mutations in genetic disease and antibiotic resistance.
Biochem Soc Trans. 2017 Apr 15;45(2):303-311
Authors: Pandurangan AP, Ascher DB, Thomas SE, Blundell TL
Abstract
For over four decades structural biology has been used to understand the mechanisms of disease, and structure-guided approaches have demonstrated clearly that they can contribute to many aspects of early drug discovery, both computationally and experimentally. Structure can also inform our understanding of impacts of mutations in human genetic diseases and drug resistance in cancers and infectious diseases. We discuss the ways that structural insights might be useful in both repurposing off-licence drugs and guide the design of new molecules that might be less susceptible to drug resistance in the future.
PMID: 28408471 [PubMed - indexed for MEDLINE]
Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments.
Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments.
Curr Osteoporos Rep. 2017 May 02;:
Authors: Pacifici M
Abstract
PURPOSE OF REVIEW: Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention.
RECENT FINDINGS: Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends. HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention.
PMID: 28466453 [PubMed - as supplied by publisher]
Balloon-Occluded Retrograde Transvenous Obliteration of a Gastric Vascular Malformation: An Innovative Approach to Treatment of a Rare Condition.
Balloon-Occluded Retrograde Transvenous Obliteration of a Gastric Vascular Malformation: An Innovative Approach to Treatment of a Rare Condition.
Cardiovasc Intervent Radiol. 2017 Feb;40(2):310-314
Authors: Hansing CE, Marquardt JP, Sutton DM, York JD
Abstract
Arteriovenous malformations (AVMs) are a high-flow form of a vascular malformation, which can be found anywhere in the body. While historically treated surgically, a multidisciplinary approach utilizing multiple specialties and treatment modalities is now commonly employed. In order to effectively treat an AVM, the nidus must be targeted and eradicated, which can be done via multiple approaches. We present the case of a 43-year-old male with a gastric wall AVM, which was initially incompletely treated using a percutaneous transarterial approach. The gastric AVM was noted to have dominant drainage through a gastrorenal shunt; therefore, Balloon-occluded Retrograde Transvenous Obliteration (BRTO) was utilized to eradicate the AVM nidus. This case illustrates the utility of Interventional Radiology, specifically BRTO, as another treatment option for challenging AVMs.
PMID: 27671152 [PubMed - indexed for MEDLINE]
Preemptive Panel-Based Pharmacogenetic Testing: The Time is Now.
Preemptive Panel-Based Pharmacogenetic Testing: The Time is Now.
Pharm Res. 2017 May 02;:
Authors: Weitzel KW, Cavallari LH, Lesko LJ
Abstract
While recent discoveries have paved the way for the use of genotype-guided prescribing in some clinical environments, significant debate persists among clinicians and researchers about the optimal approach to pharmacogenetic testing in clinical practice. One crucial factor in this debate surrounds the timing and methodology of genotyping, specifically whether genotyping should be performed reactively for targeted genes when a single drug is prescribed, or preemptively using a panel-based approach prior to drug prescribing. While early clinical models that employed a preemptive approach were largely developed in academic health centers through multidisciplinary efforts, increasing examples of pharmacogenetic testing are emerging in community-based and primary care practice environments. However, educational and practice-based resources for these clinicians remain largely nonexistent. As such, there is a need for the health care system to shift its focus from debating about preemptive genotyping to developing and disseminating needed resources to equip frontline clinicians for clinical implementation of pharmacogenetics. Providing tools and guidance to support these emerging models of care will be essential to support the thoughtful, evidence-based use of pharmacogenetic information in diverse clinical practice environments. Specifically, the creation of efficient and accurate point-of-care resources, practice-based tools, and clinical models is needed, along with identification and dissemination of sustainable avenues for pharmacogenetic test reimbursement.
PMID: 28466392 [PubMed - as supplied by publisher]
Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease.
Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease.
Respir Res. 2017 May 02;18(1):77
Authors: Weidner J, Jarenbäck L, de Jong K, Vonk JM, van den Berge M, Brandsma CA, Boezen HM, Sin D, Bossé Y, Nickle D, Ankerst J, Bjermer L, Postma DS, Faiz A, Tufvesson E
Abstract
BACKGROUND: It has been observed that mice lacking the sulfatase modifying factor (Sumf1) developed an emphysema-like phenotype. However, it is unknown if SUMF1 may play a role in Chronic Obstructive Pulmonary Disease (COPD) in humans. The aim was to investigate if the expression and genetic regulation of SUMF1 differs between smokers with and without COPD.
METHODS: SUMF1 mRNA was investigated in sputum cells and whole blood from controls and COPD patients (all current or former smokers). Expression quantitative trait loci (eQTL) analysis was used to investigate if single nucleotide polymorphisms (SNPs) in SUMF1 were significantly associated with SUMF1 expression. The association of SUMF1 SNPs with COPD was examined in a population based cohort, Lifelines. SUMF1 mRNA from sputum cells, lung tissue, and lung fibroblasts, as well as lung function parameters, were investigated in relation to genotype.
RESULTS: Certain splice variants of SUMF1 showed a relatively high expression in lung tissue compared to many other tissues. SUMF1 Splice variant 2 and 3 showed lower levels in sputum cells from COPD patients as compared to controls. Twelve SNPs were found significant by eQTL analysis and overlapped with the array used for genotyping of Lifelines. We found alterations in mRNA expression in sputum cells and lung fibroblasts associated with SNP rs11915920 (top hit in eQTL), which validated the results of the lung tissue eQTL analysis. Of the twelve SNPs, two SNPs, rs793391 and rs308739, were found to be associated with COPD in Lifelines. The SNP rs793391 was also confirmed to be associated with lung function changes.
CONCLUSIONS: We show that SUMF1 expression is affected in COPD patients compared to controls, and that SNPs in SUMF1 are associated with an increased risk of COPD. Certain COPD-associated SNPs have effects on either SUMF1 gene expression or on lung function. Collectively, this study shows that SUMF1 is associated with an increased risk of developing COPD.
PMID: 28464818 [PubMed - in process]
Functional characterization of the neuron-restrictive silencer element in the human tryptophan hydroxylase 2 gene expression.
Functional characterization of the neuron-restrictive silencer element in the human tryptophan hydroxylase 2 gene expression.
J Neurochem. 2017 May 02;:
Authors: Nawa Y, Kaneko H, Oda M, Tsubonoya M, Hiroi T, Gentile MT, Colucci-D'Amato L, Takahashi R, Matsui H
Abstract
Tryptophan hydroxylase 2 (TPH2) is the key enzyme in the synthesis of neuronal serotonin. Although previous studies suggest that TPH2 NRSE (neuron-restrictive silencer element) functions as a negative regulator dependent on NRSF (neuron-restrictive silencer factor) activity, the underlying mechanisms are yet to be fully elucidated. Here, we show a detailed analysis of the NRSE-mediated repression of the human TPH2 (hTPH2) promoter activity in RN46A cells, a cell line derived from rat raphe neurons. Quantitative real-time RT-PCR analysis revealed the expression of serotonergic marker genes (Mash1, Nkx2.2, Gata2, Gata3, Lmx1b, Pet-1, 5-Htt, and Vmat2) and Nrsf gene in RN46A cells. Tph1 mRNA is the prevalent form expressed in RN46A cells; Tph2 mRNA is also expressed but at a lower level. Electrophoretic mobility shift assays and reporter assays showed that hTPH2 NRSE is necessary for the efficient DNA binding of NRSF and for the NRSF-dependent repression of the hTPH2 promoter activity. The hTPH2 promoter activity was increased by knockdown of NRSF, or overexpression of the engineered NRSF (a dominant-negative mutant or a DNA-binding domain and activation domain fusion protein). MS-275, a class I histone deacetylase (HDAC) inhibitor, was found to be more potent than MC-1568, a class II HDAC inhibitor, in enhancing the hTPH2 promoter activity. Furthermore, treatment with the ubiquitin-specific protease 7 (USP7) deubiquitinase inhibitors, P-22077 or HBX 41108, increased the hTPH2 promoter activity. Collectively, our data demonstrate that the hTPH2 NRSE-mediated promoter repression via NRSF involves class I HDACs and is modulated by the USP7-mediated deubiquitination and stabilization of NRSF. This article is protected by copyright. All rights reserved.
PMID: 28464229 [PubMed - as supplied by publisher]
Evaluating the association of single-nucleotide polymorphisms with tenofovir exposure in a diverse prospective cohort of women living with HIV.
Evaluating the association of single-nucleotide polymorphisms with tenofovir exposure in a diverse prospective cohort of women living with HIV.
Pharmacogenomics J. 2017 May 02;:
Authors: Baxi SM, Greenblatt RM, Bacchetti P, Cohen M, DeHovitz JA, Anastos K, Gange SJ, Young MA, Aouizerat BE
Abstract
Higher exposure to tenofovir (TFV) increases the risk for kidney function decline, but the impact of genetic factors on TFV exposure is largely unknown. We investigated whether single-nucleotide polymorphisms (SNPs, n=211) in 12 genes are potentially involved in TFV exposure. Participants (n=91) from the Women's Interagency HIV Study, underwent a 24 h intensive pharmacokinetic sampling of TFV after witnessed dose and TFV area under the time-concentration curves (AUCs) were calculated for each participant. SNPs were assayed using a combination of array genotyping and Sanger sequencing. Linear regression models were applied to logarithmically transformed AUC. Those SNPs that met an a priori threshold of P<0.001 were considered statistically associated with TFV AUC. ABCG2 SNP rs2231142 was associated with TFV AUC with rare allele carriers displaying 1.51-fold increase in TFV AUC (95% confidence interval: 1.26, 1.81; P=1.7 × 10(-5)). We present evidence of a moderately strong effect of the rs2231142 SNP in ABCG2 on a 24 h TFV AUC.The Pharmacogenomics Journal advance online publication, 2 May 2017; doi:10.1038/tpj.2017.3.
PMID: 28462920 [PubMed - as supplied by publisher]
Short DNA Hairpins Compromise Recombinant Adeno-Associated Virus Genome Homogeneity.
Short DNA Hairpins Compromise Recombinant Adeno-Associated Virus Genome Homogeneity.
Mol Ther. 2017 Apr 24;:
Authors: Xie J, Mao Q, Tai PWL, He R, Ai J, Su Q, Zhu Y, Ma H, Li J, Gong S, Wang D, Gao Z, Li M, Zhong L, Zhou H, Gao G
Abstract
Short hairpin (sh)RNAs delivered by recombinant adeno-associated viruses (rAAVs) are valuable tools to study gene function in vivo and a promising gene therapy platform. Our data show that incorporation of shRNA transgenes into rAAV constructs reduces vector yield and produces a population of truncated and defective genomes. We demonstrate that sequences with hairpins or hairpin-like structures drive the generation of truncated AAV genomes through a polymerase redirection mechanism during viral genome replication. Our findings reveal the importance of genomic secondary structure when optimizing viral vector designs. We also discovered that shDNAs could be adapted to act as surrogate mutant inverted terminal repeats (mTRs), sequences that were previously thought to be required for functional self-complementary AAV vectors. The use of shDNAs as artificial mTRs opens the door to engineering a new generation of AAV vectors with improved potency, genetic stability, and safety for both preclinical studies and human gene therapy.
PMID: 28462820 [PubMed - as supplied by publisher]
Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD.
Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD.
Mol Psychiatry. 2017 May 02;:
Authors: da Silva BS, Cupertino RB, Rovaris DL, Schuch JB, Kappel DB, Müller D, Bandeira CE, Victor MM, Karam RG, Mota NR, Rohde LA, Contini V, Grevet EH, Bau CHD
Abstract
Experimental studies have demonstrated that methylphenidate (MPH) modulates the synaptic vesicle trafficking and synaptotagmin-1 (SytI) mRNA levels. SytI is a regulatory protein of the SNARE complex, a neurotransmitter exocytosis mediator. Despite this evidence, most SNARE complex-related genes have never been evaluated in attention-deficit/hyperactivity disorder (ADHD) pharmacogenetics. This study evaluates, for we believe the first time, polymorphisms on the SNARE complex-related genes STX1A (rs2228607), VAMP2 (26bp Ins/Del) and SYT1 (rs1880867 and rs2251214) on the response to immediate-release methylphenidate (IR-MPH) in a naturalistic sample of adults with ADHD. The sample comprised 433 subjects, of which 272 (62.8%) have completed the short-term IR-MPH treatment (at least 30 days). The main outcome measure was the categorical variable of short-term response to IR-MPH based on the Swanson, Nolan and Pelham Rating Scale version 4 (SNAP-IV), and on the clinical global impression-improvement scale. Additional analyses evaluated the percentage of SNAP-IV symptom reduction for each dimension as well as short- and long- (7 years) term treatment persistence. SYT1-rs2251214 was associated with the categorical short-term response to IR-MPH (P=0.006, PFDR=0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction (P=0.007, PFDR=0.028 and P=0.017, PFDR=0.048, respectively). SYT1-rs2251214 was also associated with short-term treatment persistence (P=0.018, PFDR=0.048), and with months of treatment (P=0.002, PFDR=0.016) in the long-term protocol. Our findings suggest that SYT1-rs2251214 presents a broad influence in IR-MPH response variability in adults with ADHD, being involved with both symptom response and treatment persistence. If such findings are replicated, SytI could represent a key element in MPH pharmacodynamics in adults with ADHD.Molecular Psychiatry advance online publication, 2 May 2017; doi:10.1038/mp.2017.90.
PMID: 28461697 [PubMed - as supplied by publisher]
Development and validation of UHPLC-MS/MS methods for the quantification of colistin in plasma and dried plasma spots.
Development and validation of UHPLC-MS/MS methods for the quantification of colistin in plasma and dried plasma spots.
J Pharm Biomed Anal. 2016 Sep 10;129:551-7
Authors: Cangemi G, Barco S, Castagnola E, Tripodi G, Favata F, D'Avolio A
Abstract
Quantification of colistin in plasma samples may be very useful in optimizing therapy especially in special patients' population. Nevertheless, therapeutic drug monitoring of colistin is still limited probably for the low number of laboratories which perform this analysis and for high shipment costs. We developed and validated new UHPLC-MS/MS methods to quantify colistin in plasma and in dried plasma spots (DPS) collected on dried sample spots devices (DSSD). Colistin A, Colistin B and polimixin B, used as internal standard, were detected using multiple reaction monitoring (MRM) of the following specific transitions: 585.5→534.9; 576, 578.5→527.9; 568.9 and 602.5→100.9, 551.9, 592.8, respectively. Colistin A and B were extracted from plasma using protein precipitation and from DSSD using an extraction basic solution. Both methods were validated, and the mean intra and inter-day accuracies and precisions were in accordance with FDA and EMA guidelines. Colistin in DPS was found to be stable for at least one week at room temperature (20-25°C). A statistically significant linear correlation was found between colistin extracted from plasma and from DPS [r(2) 0.9864 (P<0.0001, 95% CI 0.9699-0.9939) for colistin A and 0.9695 (P<0.0001, 95% CI 0.9310-0.9866) for colistin B, respectively]. DPS on DSSD represents a safe and cheap strategy to store and ship at room temperature plasma samples. Thus, it is suited for pharmacokinetic studies and therapeutic drug monitoring of colistin.
PMID: 27505127 [PubMed - indexed for MEDLINE]
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