Update on New Therapies With Immune Checkpoint Inhibitors.

Clin J Oncol Nurs. 2016 Aug 01;20(4):405-10

Authors: Peterson JJ, Steele-Moses SK

Abstract
BACKGROUND: Immunotherapy has had a long history in cancer treatment and, with recent breakthroughs, new drugs are available that have shown promising results.
OBJECTIVES: The current article discusses an overview of immune function, including immunoediting and the theory of immune checkpoints, as well as specific drugs that have been approved as immune checkpoint inhibitors. Additional discussion includes a review of nursing implications and administration, side effects, adverse events, and the future of immuno-oncology.
METHODS: This review of literature focused on locating, summarizing, and synthesizing data from published articles, the American Cancer Society, U.S. Food and Drug Administration, and literature from pharmaceutical manufacturers that focused on immunotherapy treatment options that use checkpoint inhibition. Search criteria included articles published from 2005-2015 and archived in CINAHL®, OVID®, and PubMed databases using the key words immunotherapy, immune checkpoint inhibition, PD-1, PD-L1, CTLA-4, and oncology.
FINDINGS: Cancer therapy targeting immune checkpoint inhibition has shown promising results and continues to evolve. Oncology nurses need to remain abreast of new immune-modulating therapies to understand their efficacy, as well as side effect management.

PMID: 27441513 [PubMed - indexed for MEDLINE]

Evaluation of a Chemotherapy and Medication Education Process for Patients Starting Cancer Treatment.

Clin J Oncol Nurs. 2016 Aug 01;20(4):364-6

Authors: Kean CC, Iverson L, Boylan A

Abstract
A cancer diagnosis, along with accompanying chemotherapy treatments and new medication regimens, can significantly affect patients' overall health, well-being, and quality of life. Chemotherapy and medication teaching that meets patients' learning needs enhances knowledge and supports adherence to instructions. These interventions promote optimal patient outcomes, satisfaction, and overall safety.

PMID: 27441506 [PubMed - indexed for MEDLINE]

FP/FORM Versus FP/SAL Within Clinical Practice: An Updated Budget Impact Analysis in Asthma.

Adv Ther. 2016 May;33(5):794-806

Authors: Farrington E, Saunders A, Heron L, Dunlop W

Abstract
INTRODUCTION: Pressurized metered-dose inhalers (pMDI) such as fluticasone propionate and salmeterol (FP/SAL) are commonly used for the treatment of asthma in the UK. Previously, a budget impact analysis demonstrated that use of FP and formoterol fumarate (FP/FORM) pMDI as an alternative to FP/SAL pMDI, would be a cost-saving option for the UK National Health Service (NHS). This budget impact analysis aimed to update the existing analysis with prescription volume data and real-world evidence since the introduction of FP/FORM to the UK market.
METHODS: Patient Data (IMS Information Solutions UK Ltd) moving annual total (MAT) August 2015 were used to ascertain the number of units of pMDI prescribed. Annual costs to the NHS in terms of drug, administration, monitoring and adverse event costs, were used to estimate the potential budget impact for FP/FORM and FP/SAL. Costs were calculated for current prescription volumes (12% FP/FORM, 88% FP/SAL), and for different prescription volume scenarios (FP/FORM at 0%, 25%, 50% and 100%). Real-world evidence and budget impact at a clinical commissioning group (CCG) level were also considered.
RESULTS: Total annual costs per person year were less with FP/FORM (£625) than with FP/SAL (£734). Annual costs to the NHS based on the current prescription volumes and clinical trial data were estimated at £210.0M, however, based on real-world evidence, costs were estimated at £179.8M. For all scenarios with increased FP/FORM prescription volumes, the annual total costs to the NHS decreased. This was reflected at a CCG level.
CONCLUSION: The use of FP/FORM as an alternative to FP/SAL can result in cost savings for the NHS when assessing drug, administration, monitoring and adverse events costs. The inclusion of data released since the launch of FP/FORM within the budget impact analysis demonstrates that the potential cost savings to the NHS that were previously published are being translated to clinical practice.
FUNDING: Mundipharma, UK.

PMID: 27084726 [PubMed - indexed for MEDLINE]

[Medication errors in a neonatal unit: One of the main adverse events].

An Pediatr (Barc). 2016 Apr;84(4):211-7

Authors: Esqué Ruiz MT, Moretones Suñol MG, Rodríguez Miguélez JM, Sánchez Ortiz E, Izco Urroz M, de Lamo Camino M, Figueras Aloy J

Abstract
INTRODUCTION: Neonatal units are one of the hospital areas most exposed to the committing of treatment errors. A medication error (ME) is defined as the avoidable incident secondary to drug misuse that causes or may cause harm to the patient. The aim of this paper is to present the incidence of ME (including feeding) reported in our neonatal unit and its characteristics and possible causal factors. A list of the strategies implemented for prevention is presented.
MATERIAL AND METHODS: An analysis was performed on the ME declared in a neonatal unit.
RESULTS: A total of 511 MEs have been reported over a period of seven years in the neonatal unit. The incidence in the critical care unit was 32.2 per 1000 hospital days or 20 per 100 patients, of which 0.22 per 1000 days had serious repercussions. The ME reported were, 39.5% prescribing errors, 68.1% administration errors, 0.6% were adverse drug reactions. Around two-thirds (65.4%) were produced by drugs, with 17% being intercepted. The large majority (89.4%) had no impact on the patient, but 0.6% caused permanent damage or death. Nurses reported 65.4% of MEs. The most commonly implicated causal factor was distraction (59%). Simple corrective action (alerts), and intermediate (protocols, clinical sessions and courses) and complex actions (causal analysis, monograph) were performed.
CONCLUSIONS: It is essential to determine the current state of ME, in order to establish preventive measures and, together with teamwork and good practices, promote a climate of safety.

PMID: 26520488 [PubMed - indexed for MEDLINE]

RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors.

Eur Respir J. 2017 Sep;50(3):

Authors: Hoeper MM, Simonneau G, Corris PA, Ghofrani HA, Klinger JR, Langleben D, Naeije R, Jansa P, Rosenkranz S, Scelsi L, Grünig E, Vizza CD, Chang M, Colorado P, Meier C, Busse D, Benza RL

Abstract
A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L·min(-1)·m(-2) and pulmonary vascular resistance >400 dyn·s·cm(-5) underwent a 1-3 day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5 mg maximum t.i.d Exploratory end-points included change in 6MWD, WHO FC, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean±sd 6MWD had increased by 31±63 m, NT-proBNP decreased by 347±1235 pg·mL(-1) and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied.

PMID: 28889107 [PubMed - in process]

Autoimmune hepatitis - update on clinical management in 2017.

Clin Res Hepatol Gastroenterol. 2017 Sep 04;:

Authors: Liwinski T, Schramm C

Abstract
Autoimmune hepatitis (AIH) is a progressive immune mediated liver disease of unknown origin. Key diagnostic features include hypergammaglobulinemia/elevated serum-IgG, characteristic circulating autoantibodies, periportal hepatitis with interface activity on liver biopsy and the exclusion of hepatotropic viruses. However, the diagnosis is challenging in cholestatic and severe presentations. It can be difficult to differentiate AIH from drug-induced liver injury. Although many patients initially respond to standard immunosuppressive therapy, a significant proportion experiences intolerable side effects or insufficient treatment response. This underlines the need for effective alternative treatment options, which are still very limited and based on rather poor evidence. This review summarises core aspects of the clinical management of AIH with focus on recent achievements and unmet needs.

PMID: 28882739 [PubMed - as supplied by publisher]

Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF (V600) mutation-positive solid tumors: a phase 1 study.

Invest New Drugs. 2017 Sep 07;:

Authors: Fujiwara Y, Yamazaki N, Kiyohara Y, Yoshikawa S, Yamamoto N, Tsutsumida A, Nokihara H, Namikawa K, Mukaiyama A, Zhang F, Tamura T

Abstract
Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF (V600E) mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF (V600) mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.

PMID: 28879519 [PubMed - as supplied by publisher]

Safety Profile of Cough and Cold Medication Use in Pediatrics.

Pediatrics. 2017 Jun;139(6):

Authors: Green JL, Wang GS, Reynolds KM, Banner W, Bond GR, Kauffman RE, Palmer RB, Paul IM, Dart RC

Abstract
BACKGROUND AND OBJECTIVES: The safety of cough and cold medication (CCM) use in children has been questioned. We describe the safety profile of CCMs in children <12 years of age from a multisystem surveillance program.
METHODS: Cases with adverse events (AEs) after ingestion of at least 1 index CCM ingredient (brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, and pseudoephedrine) in children <12 years of age were collected from 5 data sources. An expert panel determined relatedness, dose, intent, and risk factors. Case characteristics and AEs are described.
RESULTS: Of the 4202 cases reviewed, 3251 (77.4%) were determined to be at least potentially related to a CCM, with accidental unsupervised ingestions (67.1%) and medication errors (13.0%) the most common exposure types. Liquid (67.3%), pediatric (75.5%), and single-ingredient (77.5%) formulations were most commonly involved. AEs occurring in >20% of all cases included tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. Twenty cases (0.6%) resulted in death; most were in children <2 years of age (70.0%) and none involved a therapeutic dose. The overall reported AE rate was 0.573 cases per 1 million units (ie, tablets, gelatin capsules, or liquid equivalent) sold (95% confidence interval, 0.553-0.593) or 1 case per 1.75 million units.
CONCLUSIONS: The rate of AEs associated with CCMs in children was low. Fatalities occurred even less frequently. No fatality involved a therapeutic dose. Accidental unsupervised ingestions were the most common exposure types and single-ingredient, pediatric liquid formulations were the most commonly reported products. These characteristics present an opportunity for targeted prevention efforts.

PMID: 28562262 [PubMed - indexed for MEDLINE]

Adverse Health Events Related to Self-Medication Practices Among Elderly: A Systematic Review.

Drugs Aging. 2017 May;34(5):359-365

Authors: Locquet M, Honvo G, Rabenda V, Van Hees T, Petermans J, Reginster JY, Bruyère O

Abstract
BACKGROUND: Older adults often resort to self-medication to relieve symptoms of their current illnesses; however, the risks of this practice are multiplied in old age. In particular, this age group is more vulnerable to adverse drug events because of the physiological changes that occur due to senescence.
OBJECTIVE: The aim of the study was to obtain an overview of the adverse health events related to self-medication among subjects aged 60 years and over through a systematic review of the literature.
METHODS: A study of relevant articles was conducted among databases (MEDLINE, PsycINFO, and EBM Reviews-Cochrane Database of Systematic Reviews). Eligibility criteria were established and applied by two investigators to include suitable studies. The results and outcomes of interest were detailed in a descriptive report.
RESULTS: The electronic search identified 4096 references, and the full texts of 74 were reviewed, of which four were retained in the analysis: three had a cross-sectional design and one prospectively followed elderly subjects. The first study showed a 26.7% prevalence of adverse drug reactions (ADRs) among elders, the second study found a 75% prevalence of side effects, and, finally, a prospective study showed an ADR incidence of 4.5% among self-medicated elders. These studies showed that adverse health events related to self-medication are relatively frequently reported. They also highlighted that analgesics and anti-inflammatory drugs are the most self-medicated products, while vitamins and dietary supplements also appear to be frequently self-administered, but by older individuals.
CONCLUSIONS: Studies on self-medication in the elderly and its adverse health effects are clearly lacking. There is a need to perform prospective studies on this topic to gain a clear understanding of the extent of this problem and to enhance the awareness of health professionals to better inform seniors.

PMID: 28247317 [PubMed - indexed for MEDLINE]

Efficacy and safety of daclatasvir plus asunaprevir therapy for chronic hepatitis C patients with renal dysfunction.

J Med Virol. 2017 Apr;89(4):665-671

Authors: Nakamura Y, Imamura M, Kawakami Y, Teraoka Y, Daijo K, Honda F, Morio K, Kobayashi T, Nakahara T, Nagaoki Y, Kawaoka T, Tsuge M, Hiramatsu A, Aikata H, Hayes CN, Miki D, Ochi H, Chayama K

Abstract
Chronic hepatitis C virus (HCV) infection is associated with renal dysfunction. Daclatasvir and asunaprevir combination therapy showed a high virological response for genotype 1 chronic HCV-infected patients with renal dysfunction on hemodialysis. However, the safety and efficacy of the therapy for patients with renal dysfunction who are not on hemodialysis are not well-known. In total, 147 patients with chronic HCV genotype 1 infection were treated with 24 weeks of daclatasvir plus asunaprevir therapy. Among these patients, 126 had normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 ml/min/1.73 m(2) ) and 21 had renal dysfunction (eGFR < 50 ml/min/1.73 m(2) ). Plasma concentrations of daclatasvir and asunaprevir after 5 days of treatment were the same in the normal renal function and renal dysfunction groups. Early virological response (4, 8, 48, 96, and 168 hr after the start of the therapy) was similar between the two groups. End-of-treatment response was achieved in 122 (96.8%) and 20 (95.2%) patients with normal renal function and with renal dysfunction, respectively, and sustained virological response was achieved in 119 (94.4%) and 20 (95.2%) patients. The frequency of adverse events was also comparable between the two groups. Treatment discontinuation due to adverse events was required for only one patient in each group. Renal function did not change either during or after treatment in both groups. In conclusion, renal function is unlikely to have a significant impact on blood kinetics of daclatasvir and asunaprevir. This combination therapy was effective and safe for patients without hemodialysis. J. Med. Virol. 89:665-671, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 27602542 [PubMed - indexed for MEDLINE]

[The impact of adverse events on health primary care professionals and institutions].

Aten Primaria. 2016 Mar;48(3):143-6

Authors: Torijano-Casalengua ML, Astier-Peña P, Mira-Solves JJ, grupo de seguridad del paciente de la Sociedad Española de Medicina Familiar y Comunitaria, semFYC, Grupo de Investigación en Segundas y Terceras Víctimas

PMID: 26968621 [PubMed - indexed for MEDLINE]

Clinical Practice Guideline: Safe Medication Use in the ICU.

Crit Care Med. 2017 Sep;45(9):e877-e915

Authors: Kane-Gill SL, Dasta JF, Buckley MS, Devabhakthuni S, Liu M, Cohen H, George EL, Pohlman AS, Agarwal S, Henneman EA, Bejian SM, Berenholtz SM, Pepin JL, Scanlon MC, Smith BS

Abstract
OBJECTIVE: To provide ICU clinicians with evidence-based guidance on safe medication use practices for the critically ill.
DATA SOURCES: PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, and ISI Web of Science for relevant material to December 2015.
STUDY SELECTION: Based on three key components: 1) environment and patients, 2) the medication use process, and 3) the patient safety surveillance system. The committee collectively developed Population, Intervention, Comparator, Outcome questions and quality of evidence statements pertaining to medication errors and adverse drug events addressing the key components. A total of 34 Population, Intervention, Comparator, Outcome questions, five quality of evidence statements, and one commentary on disclosure was developed.
DATA EXTRACTION: Subcommittee members were assigned selected Population, Intervention, Comparator, Outcome questions or quality of evidence statements. Subcommittee members completed their Grading of Recommendations Assessment, Development, and Evaluation of the question with his/her quality of evidence assessment and proposed strength of recommendation, then the draft was reviewed by the relevant subcommittee. The subcommittee collectively reviewed the evidence profiles for each question they developed. After the draft was discussed and approved by the entire committee, then the document was circulated among all members for voting on the quality of evidence and strength of recommendation.
DATA SYNTHESIS: The committee followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation system to determine quality of evidence and strength of recommendations.
CONCLUSIONS: This guideline evaluates the ICU environment as a risk for medication-related events and the environmental changes that are possible to improve safe medication use. Prevention strategies for medication-related events are reviewed by medication use process node (prescribing, distribution, administration, monitoring). Detailed considerations to an active surveillance system that includes reporting, identification, and evaluation are discussed. Also, highlighted is the need for future research for safe medication practices that is specific to critically ill patients.

PMID: 28816851 [PubMed - indexed for MEDLINE]

Medication Harmony: A Framework to Save Time, Improve Accuracy and Increase Patient Activation.

AMIA Annu Symp Proc. 2016;2016:1959-1966

Authors: Pandolfe F, Crotty BH, Safran C

Abstract
Incompletely reconciled medication lists contribute to prescribing errors and adverse drug events. Providers expend time and effort at every point of patient contact attempting to curate a best possible medication list, and yet often the list is incomplete or inaccurate. We propose a framework that builds upon the existing infrastructure of a health information exchange (HIE), centralizes data and encourages patient activation. The solution is a constantly accessible, singular, patient-adjudicated medication list that incorporates useful information and features into the list itself. We aim to decrease medication errors across transitions of care, increase awareness of potential drug-drug interactions, improve patient knowledge and self-efficacy regarding medications, decrease polypharmacy, improve prescribing safety and ultimately decrease cost to the health-care system.

PMID: 28269955 [PubMed - indexed for MEDLINE]

Classification-by-Analogy: Using Vector Representations of Implicit Relationships to Identify Plausibly Causal Drug/Side-effect Relationships.

AMIA Annu Symp Proc. 2016;2016:1940-1949

Authors: Mower J, Subramanian D, Shang N, Cohen T

Abstract
An important aspect of post-marketing drug surveillance involves identifying potential side-effects utilizing adverse drug event (ADE) reporting systems and/or Electronic Health Records. These data are noisy, necessitating identified drug/ADE associations be manually reviewed - a human-intensive process that scales poorly with large numbers of possibly dangerous associations and rapid growth of biomedical literature. Recent work has employed Literature Based Discovery methods that exploit implicit relationships between biomedical entities within the literature to estimate the plausibility of drug/ADE connections. We extend this work by evaluating machine learning classifiers applied to high-dimensional vector representations of relationships extracted from the literature as a means to identify substantiated drug/ADE connections. Using a curated reference standard, we show applying classifiers to such representations improves performance (+≈37%AUC) over previous approaches. These trained systems reproduce outcomes of the manual literature review process used to create the reference standard, but further research is required to establish their generalizability.

PMID: 28269953 [PubMed - indexed for MEDLINE]

Literature-Based Discovery of Confounding in Observational Clinical Data.

AMIA Annu Symp Proc. 2016;2016:1920-1929

Authors: Malec SA, Wei P, Xu H, Bernstam EV, Myneni S, Cohen T

Abstract
Observational data recorded in the Electronic Health Record (EHR) can help us better understand the effects of therapeutic agents in routine clinical practice. As such data were not collected for research purposes, their reuse for research must compensate for additional information that may bias analyses and lead to faulty conclusions. Confounding is present when factors aside from the given predictor(s) affect the response of interest. However, these additional factors may not be known at the outset. In this paper, we present a scalable literature-based confounding variable discovery method for biomedical research applications with pharmacovigilance as our use case. We hypothesized that statistical models, adjusted with literature-derived confounders, will more accurately identify causative drug-adverse drug event (ADE) relationships. We evaluated our method with a curated reference standard, and found a pattern of improved performance ~ 5% in two out of three models for gastrointestinal bleeding (pre-adjusted Area Under Curve ≥ 0.6).

PMID: 28269951 [PubMed - indexed for MEDLINE]

Interrater agreement of two adverse drug reaction causality assessment methods: A randomised comparison of the Liverpool Adverse Drug Reaction Causality Assessment Tool and the World Health Organization-Uppsala Monitoring Centre system.

PLoS One. 2017;12(2):e0172830

Authors: Mouton JP, Mehta U, Rossiter DP, Maartens G, Cohen K

Abstract
INTRODUCTION: A new method to assess causality of suspected adverse drug reactions, the Liverpool Adverse Drug Reaction Causality Assessment Tool (LCAT), showed high interrater agreement when used by its developers. Our aim was to compare the interrater agreement achieved by LCAT to that achieved by another causality assessment method, the World Health Organization-Uppsala Monitoring Centre system for standardised case causality assessment (WHO-UMC system), in our setting.
METHODS: Four raters independently assessed adverse drug reaction causality of 48 drug-event pairs, identified during a hospital-based survey. A randomised design ensured that no washout period was required between assessments with the two methods. We compared the methods' interrater agreement by calculating agreement proportions, kappa statistics, and the intraclass correlation coefficient. We identified potentially problematic questions in the LCAT by comparing raters' responses to individual questions.
RESULTS: Overall unweighted kappa was 0.61 (95% CI 0.43 to 0.80) on the WHO-UMC system and 0.27 (95% CI 0.074 to 0.46) on the LCAT. Pairwise unweighted Cohen kappa ranged from 0.33 to 1.0 on the WHO-UMC system and from 0.094 to 0.71 on the LCAT. The intraclass correlation coefficient was 0.86 (95% CI 0.74 to 0.92) on the WHO-UMC system and 0.61 (95% CI 0.39 to 0.77) on the LCAT. Two LCAT questions were identified as significant points of disagreement.
DISCUSSION: We were unable to replicate the high interrater agreement achieved by the LCAT developers and instead found its interrater agreement to be lower than that achieved when using the WHO-UMC system. We identified potential reasons for this and recommend priority areas for improving the LCAT.

PMID: 28235001 [PubMed - indexed for MEDLINE]

Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics.

J Lipid Res. 2017 Apr;58(4):783-797

Authors: Dunbar RL, Goel H, Tuteja S, Song WL, Nathanson G, Babar Z, Lalic D, Gelfand JM, Rader DJ, Grove GL

Abstract
Though cardioprotective, niacin monotherapy is limited by unpleasant cutaneous symptoms mimicking dermatitis: niacin-associated skin toxicity (NASTy). Niacin is prototypical of several emerging drugs suffering off-target rubefacient properties whereby agonizing the GPR109A receptor on cutaneous immune cells provokes vasodilation, prompting skin plethora and rubor, as well as dolor, tumor, and calor, and systemically, heat loss, frigor, chills, and rigors. Typically, NASTy effects are described by subjective patient-reported perception, at best semi-quantitative and bias-prone. Conversely, objective, quantitative, and unbiased methods measuring NASTy stigmata would facilitate research to abolish them, motivating development of several objective methods. In early drug development, such methods might better predict clinical tolerability in larger clinical trials. Measuring cutaneous stigmata may also aid investigations of vasospastic, ischemic, and inflammatory skin conditions. We present methods to measure NASTy physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception. We gave niacin orally and measured rubor by colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, and calor/frigor by thermometry. Surprisingly, each stigma's abruptness predicted symptom perception, whereas peak intensity did not. These methods are adaptable to study other rubefacient drugs or dermatologic and vascular disorders.

PMID: 28119443 [PubMed - indexed for MEDLINE]

Predicting potential drug-drug interactions by integrating chemical, biological, phenotypic and network data.

BMC Bioinformatics. 2017 Jan 05;18(1):18

Authors: Zhang W, Chen Y, Liu F, Luo F, Tian G, Li X

Abstract
BACKGROUND: Drug-drug interactions (DDIs) are one of the major concerns in drug discovery. Accurate prediction of potential DDIs can help to reduce unexpected interactions in the entire lifecycle of drugs, and are important for the drug safety surveillance.
RESULTS: Since many DDIs are not detected or observed in clinical trials, this work is aimed to predict unobserved or undetected DDIs. In this paper, we collect a variety of drug data that may influence drug-drug interactions, i.e., drug substructure data, drug target data, drug enzyme data, drug transporter data, drug pathway data, drug indication data, drug side effect data, drug off side effect data and known drug-drug interactions. We adopt three representative methods: the neighbor recommender method, the random walk method and the matrix perturbation method to build prediction models based on different data. Thus, we evaluate the usefulness of different information sources for the DDI prediction. Further, we present flexible frames of integrating different models with suitable ensemble rules, including weighted average ensemble rule and classifier ensemble rule, and develop ensemble models to achieve better performances.
CONCLUSIONS: The experiments demonstrate that different data sources provide diverse information, and the DDI network based on known DDIs is one of most important information for DDI prediction. The ensemble methods can produce better performances than individual methods, and outperform existing state-of-the-art methods. The datasets and source codes are available at https://github.com/zw9977129/drug-drug-interaction/ .

PMID: 28056782 [PubMed - indexed for MEDLINE]

Analysis of Hemorrhage Volumes After Angiogram-Negative Subarachnoid Hemorrhage.

World Neurosurg. 2016 Oct;94:453-457

Authors: Bray DP, Ellis JA, Lavine SD, Meyers PM, Connolly ES

Abstract
BACKGROUND: Antiplatelet medication use is associated with worsened outcome after angiogram-negative subarachnoid hemorrhage (SAH). It has been hypothesized that these worsened outcomes may be the result of an association between antiplatelet medication use and increased hemorrhage volumes after angiogram-negative SAH. To test this hypothesis, we performed volumetric analysis of computed tomography (CT)-defined hemorrhage after angiogram-negative SAH.
METHODS: This was a retrospective analysis of patients presenting with nontraumatic, angiogram-negative SAH in the Columbia University Subarachnoid Hemorrhage Outcomes database between 2000 and 2013. SAH volumes on admission head CT scans were measured using the MIPAV software package, version 7.20 in a semiautomated fashion.
RESULTS: A total of 108 presenting CT scans from patients with angiogram-negative SAH were analyzed. The mean hemorrhage volume was 14.3 mL in the patients with a history of antiplatelet medication use, compared with 6.8 mL in those with no history of antiplatelet use. This difference was found to be significant (P = 0.0029).
CONCLUSIONS: Antiplatelet medication use is associated with increased SAH volumes in patients with angiogram-negative SAH. Increased hemorrhage volumes may contribute to poor outcomes in this patient population. Prospective studies are warranted to confirm this association.

PMID: 27424475 [PubMed - indexed for MEDLINE]

Updates in the management of brain metastases.

Neuro Oncol. 2016 Aug;18(8):1043-65

Authors: Arvold ND, Lee EQ, Mehta MP, Margolin K, Alexander BM, Lin NU, Anders CK, Soffietti R, Camidge DR, Vogelbaum MA, Dunn IF, Wen PY

Abstract
The clinical management/understanding of brain metastases (BM) has changed substantially in the last 5 years, with key advances and clinical trials highlighted in this review. Several of these changes stem from improvements in systemic therapy, which have led to better systemic control and longer overall patient survival, associated with increased time at risk for developing BM. Development of systemic therapies capable of preventing BM and controlling both intracranial and extracranial disease once BM are diagnosed is paramount. The increase in use of stereotactic radiosurgery alone for many patients with multiple BM is an outgrowth of the desire to employ treatments focused on local control while minimizing cognitive effects associated with whole brain radiotherapy. Complications from BM and their treatment must be considered in comprehensive patient management, especially with greater awareness that the majority of patients do not die from their BM. Being aware of significant heterogeneity in prognosis and therapeutic options for patients with BM is crucial for appropriate management, with greater attention to developing individual patient treatment plans based on predicted outcomes; in this context, recent prognostic models of survival have been extensively revised to incorporate molecular markers unique to different primary cancers.

PMID: 27382120 [PubMed - indexed for MEDLINE]