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]

Capsaicin 8% Patch Repeat Treatment in Nondiabetic Peripheral Neuropathic Pain: A 52-Week, Open-Label, Single-Arm, Safety Study.

Clin J Pain. 2017 Oct;33(10):921-931

Authors: Gálvez R, Navez ML, Moyle G, Maihöfner C, Stoker M, Ernault E, Nurmikko TJ, Attal N

Abstract
OBJECTIVES: To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain.
METHODS: A prospective, open-label, observational study in patients with postherpetic neuralgia, posttraumatic or postsurgical nerve injury, HIV-associated distal sensory polyneuropathy, or other peripheral neuropathic pain, and average daily pain score ≥4, who received ≤6 capsaicin 8% patch treatments over 52 weeks according to clinical need (retreatment at 9 to 12 wk intervals). Sensory testing and analgesic effectiveness were assessed using "bedside tests" and Brief Pain Inventory (question 5).
RESULTS: Overall, 306 patients received treatment. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were reported by 252 (82.4%) and 207 (67.6%) patients. Application site pain was the most common drug-related TEAE (n=112, 36.6%); no drug-related serious TEAEs were reported. Sensory category shift analyses from baseline to end of study (EoS) in patients attending at least 2 sensory visits (n=278 for all tests except warm, n=277) found sensory deterioration/loss in at least 1 modality in 50.4% (n=140); deterioration/loss in 1, 2, 3, 4, or 5 modalities occurred in 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), 2.5% (n=7), and 1.4% (n=4) cases. Newly emergent hyperesthesia or allodynia was apparent in 1.1% to 3.6% of the cases (depending on modality) by EoS. Between 25.2% and 32.0% of patients reported improvement in a sensory modality by EoS. Average daily pain was 6.6 and 4.7 at baseline and month 12.
CONCLUSIONS: Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss.

PMID: 28872473 [PubMed - in process]

Evaluation of the adverse drug reaction surveillance system Kadoma City, Zimbabwe 2015.

Pan Afr Med J. 2017;27:55

Authors: Muringazuva C, Chirundu D, Mungati M, Shambira G, Gombe N, Bangure D, Juru T, Tshimanga M

Abstract
INTRODUCTION: Medicines have the potential to cause adverse drug reactions and because of this Zimbabwe monitor reactions to medicines through the Adverse Drug Reaction Surveillance System. The Medicines Control Authority of Zimbabwe monitors reactions to medicines through the Adverse Drugs Reactions Surveillance System. The system relies on health professionals to report adverse drug reactions to maximize patient safety. We report results of an evaluation of the Adverse Drugs Reactions Surveillance System in Kadoma District.
METHODS: A descriptive cross-sectional study was conducted using the updated CDC guidelines in six health facilities in Kadoma City. Data were collected using a pretested interviewer administered questionnaire, checklists and records review. Data was analyzed using Epi Info(TM) to calculate frequencies and means. Qualitative data were analyzed manually. Written informed consent was obtained from all study participants.
RESULTS: The surveillance system did not meet up to its objectives as it failed to detect the adverse drug reactions and there was no monitoring of increases in known events. Fewer than half (43%) of the participants were aware of at least 2 objectives of the surveillance system but 83% of health workers willing to participate. However the system was not acceptable, 79% did not perceive the system to be necessary with the majority saying ''why should we fill in the forms when the reactions were already known or minor''. Though the system was supposed to identify potential patient risk factors for particular types of events health workers were reluctant to participate as evidenced by only one form filled out of 20 reactions experienced in the district. The system was simple as the notification form has 16 fields which require easily obtainable information from the patient records.
CONCLUSION: The surveillance system was not useful and was not acceptable to health workers but was simple and stable. Health workers lacked knowledge. Sharing of results with the Medicines Control Authority of Zimbabwe through the Matrons facilitated training of health workers in Kadoma City. Health workers were encouraged to notify any drug reaction and to completely fill in the notification forms. Patients were also encouraged to report any drug reaction to health care workers.

PMID: 28819477 [PubMed - indexed for MEDLINE]

[A prospective multi-center trial of non-interventional and observational study of lenalidomide in Chinese patients with multiple myeloma].

Zhonghua Nei Ke Za Zhi. 2017 Jul 01;56(7):500-506

Authors: Wang GM, Yang GZ, Huang ZX, Zhong YP, Jin FY, Liao AJ, Wang XM, Fu ZZ, Liu H, Li XL, Zhou JF, Zhang X, Hu Y, Meng FY, Huang XJ, Chen WM, Lu J

Abstract
Objective: To evaluate the efficacy and safety of lenalidomide in a real-world clinical practice in Chinese patients with multiple myeloma (MM). Methods: It was a prospective, multi-center, observational study. A total of 165 consecutive patients with MM treated with lenalidomide-based regimens were enrolled in 12 hospitals from June 2013 to November 2015. Relevant information was recorded, such as baseline clinical data, cytogenetic abnormalities, treatment regimens, and duration of treatment, safety, and survival. Results: (1)There were 126 relapsed and refractory MM (RRMM) patients, 25 newly diagnosed patients and 19 maintenance patients. The evaluable RRMM patients accounted for 120 cases, among which 74 cases(61.7%) reached the partial response (PR) or above, and a very good partial response (VGPR) in 16 patients (13.3%), a complete response (CR) in 14 cases (11.7%), a strictly complete response (sCR) in 4 cases (3.3%). Thus, a VGPR or above in 34 patients accounted for 28.3%. (2)The median follow-up was 13 months, the median time to progression 12 months. The median survival after receiving lenalidomide was 19 months, and the median overall survival (OS) was 62 months. (3) The univariate analysis in 120 RRMM patients suggested that prognostic factors for significant improvement in PFS included normal karyotype, international staging system (ISS) Ⅰ-Ⅱ, t(4; 14) negative (detected by fluorescence in situ hybridization), non-bortezomib resistance and response to previous regimens. As to OS, non-bortezomib resistance, response to previous regimens and non-primary refractoriness were positive factors. Multivariate analysis showed that the response to previous regimens (PR or better) was an independent good prognostic factor for progress-free survival(PFS), non-bortezomib resistance and non-primary refractoriness for OS. (4) Grade 3 or 4 adverse events that occurred in more than 10% of all enrolled patients were neutropenia (12.7%), leukocytosis(11.5%) and thrombocytopenia (12.7%). Owing to intolerance of toxic side effects, 7 cases withdrew lenalidomide. Conclusions: No matter what combination, regimens containing lenalidomide are effective to RRMM patients with overall response rate 61.7%, a time to progression 12 months and an overall survival 62 months.The toxicity is quite tolerable and manageable. In addition, the response to previous treatment (reached PR or above) is the independent good prognostic factor for PFS, non-bortezomib resistance and non-primary refractoriness for OS. Clinical trail registration: Clinicaltrials.gov, NCT01947309.

PMID: 28693058 [PubMed - indexed for MEDLINE]

[Adverse reaction caused by rabies vaccine in China: a Meta-analysis].

Zhonghua Liu Xing Bing Xue Za Zhi. 2017 Jun 10;38(6):821-827

Authors: Zhang XR, Wu ZG, Zhang WS

Abstract
Objective: To conduct a Meta-analysis on the rate of adverse reaction related to rabies vaccine, so as to provide reference for rabies vaccine immunization in China. Methods: We electronically searched databases including CNKI, VIP information resource integration service platform, WanFang Data, CBM, PubMed and The Cochrane Library, to collect studies on Chinese people who had received full rabies vaccination and recording all the adverse reactions, from January 2000 to July 2016. Inclusion and exclusion criteria were strictly followed. Meta-analysis for the adverse reaction rate was performed using the R software. Results: A total of 29 related papers had met the inclusion criteria, with no publication bias noticed. A total number of 11 020 cases had adverse reactions, among all the 94 222 respondents, with an incidence of adverse reactions as 1.04%-47.78%. The overall incidence rate of adverse reaction was 9.82% (95%CI: 7.58%-12.72%). A combined local adverse reaction rate appeared as 12.05% (95% CI: 9.26%-15.69%). The systemic adverse reaction rate was 9.06% (95%CI: 7.07%-11.61%). The overall adverse reaction rate on aqueous vaccine was 32.39% (95%CI: 21.88%-47.94%). Combined adverse reaction rate of freeze dried vaccine appeared as 8.65% (95%CI: 4.54%-16.51%). Significant differences were seen between both groups (P<0.05). Conclusions: The local adverse reaction rate caused by rabies vaccination was higher than the systemic adverse reaction rate. The adverse reaction rate of aqueous rabies vaccine was higher than that of freeze dried rabies vaccine. Our results suggested that the aqueous vaccine should gradually be eliminated.

PMID: 28647990 [PubMed - indexed for MEDLINE]

Characterization of Guideline Evidence for Off-label Medication Use in the Intensive Care Unit.

Ann Pharmacother. 2017 Jul;51(7):529-542

Authors: Shoulders BR, Smithburger PL, Tchen S, Buckley M, Lat I, Kane-Gill SL

Abstract
BACKGROUND: Non-Food and Drug Administration (FDA) or off-label medication prescribing occurs commonly in the intensive care unit (ICU). Off-label medication use creates a concern for untoward adverse effects; however, this worry may be alleviated by supportive literature.
OBJECTIVE: To evaluate the evidence behind off-label medication use by determining the presence of guideline support and compare graded recommendations to an online tertiary resource, DRUGDEX.
METHODS: Off-label medication use was identified prospectively over 3 months in medical ICUs in 3 academic medical centers. Literature searches were conducted in PubMed and the national guideline clearinghouse website to determine the presence of guideline support. DRUGDEX was also searched for strength-of-evidence ratings to serve as a comparator.
RESULTS: A total of 287 off-label medication indication searches resulted in 44% (126/287) without identified evidence; 253 guidelines were identified for 56% (161/287) of indications. Of the published guidelines, 89% (226/253) supported the off-label indication. In the DRUGDEX comparison, 67% (97/144) of guideline gradings disagree with DRUGDEX, whereas 33% (47/144) of the gradings matched the online database.
CONCLUSION: Because more than half of off-label medication use has the benefit of supportive guidelines recommendations and a majority of gradings are inconsistent with DRUGDEX, clinicians should consider utilizing guidelines to inform off-label medication use in the ICU. Still, there is a considerable amount of off-label medication use in the ICU that lacks supporting evidence, and use remains concerning because it may lead to inappropriate treatment and adverse events.

PMID: 28622741 [PubMed - indexed for MEDLINE]

[Promoting translational research on drug-induced liver injury].

Zhonghua Gan Zang Bing Za Zhi. 2016 Nov 20;24(11):807-809

Authors: Mao YM

Abstract
Drug-induced liver injury (DILI) is one of the most important drug-induced diseases and an important reason for failure to obtain approval, an increase in warnings, and withdrawal from market. DILI has a complex clinical phenotype and can cause almost all types of acute, subacute, and chronic liver injury, and it may cause liver failure and even death in patients with severe conditions. The diversity of drugs involved and heterogeneity of populations are the main reasons for unpredictability of most DILI cases in clinical practice. Therefore, the prediction, diagnosis, and treatment of DILI become challenging issues in the field of liver disease, and it is of great significance to strengthen clinical translational research in this aspect, so as to transform more achievements into actual diagnostic and treatment methods.

PMID: 27978924 [PubMed - indexed for MEDLINE]

Evaluating the effectiveness of a patient storytelling DVD intervention to encourage physician-patient communication about nonsteroidal anti-inflammatory drug (NSAID) use.

Patient Educ Couns. 2016 Nov;99(11):1837-1844

Authors: Miller MJ, Weech-Maldonado R, Outman RC, Ray MN, Gary LC, Chen L, Cobaugh DJ, Allison JJ, Saag KG

Abstract
OBJECTIVE: To evaluate the effectiveness of a culturally-sensitive, patient storytelling intervention to enhance physician-patient communication about NSAID risk.
METHODS: A group randomized trial of 40 medical practices in Alabama was conducted. Patients within intervention practices received a 13-minute DVD that included patient stories related to their experiences with NSAIDs, adverse effects, and importance of communication with their physicians. The proportion of patients who: (1) spoke with their physician about NSAID risk; and (2) used both prescription and over-the-counter (OTC) NSAIDS were primary outcomes. Generalized estimating equations for panel data were used for analysis.
RESULTS: Intention-to-treat analyses revealed no significant differences between intervention (n=102) and control (n=106) groups for patients speaking with their physician about NSAID risk or concomitant use of prescription/OTC NSAIDs (Odds Ratio [OR]=1.11, p=0.670; OR=0.87, p=0.632, respectively). For 54% of patients who watched the DVD, per-protocol (PP) analyses trended toward increased odds of patients speaking with their physician about prescription NSAID risk compared to the control group [OR=1.37, p=0.354] and lower odds of concomitant prescription/OTC NSAIDs use [OR=0.79, p=0.486].
CONCLUSIONS: A patient storytelling intervention in DVD format alone may not increase patient-physician interaction.
PRACTICE IMPLICATIONS: Strategies that facilitate use of patient educational materials delivered by DVD are needed.

PMID: 27380647 [PubMed - indexed for MEDLINE]

Drug therapy problems and medication discrepancies during care transitions in super-utilizers.

J Am Pharm Assoc (2003). 2016 Nov - Dec;56(6):633-642.e1

Authors: Surbhi S, Munshi KD, Bell PC, Bailey JE

Abstract
OBJECTIVES: First, to investigate the prevalence and types of drug therapy problems and medication discrepancies among super-utilizers, and associated patient characteristics. Second, to examine the outcomes of pharmacist recommendations and estimated cost avoidance through care transitions support focused on medication management.
DESIGN: Retrospective analysis of the pharmacist-led interventions as part of the SafeMed Program.
SETTING: A large nonprofit health care system serving the major medically underserved areas in Memphis, Tennessee.
PARTICIPANTS: Three hundred seventy-four super-utilizing SafeMed participants with multiple chronic conditions and polypharmacy.
INTERVENTION: Comprehensive medication review, medication therapy management, enhanced discharge planning, home visits, telephone follow-up, postdischarge medication reconciliation, and care coordination with physicians.
MAIN OUTCOME MEASURES: Types of drug therapy problems, outcomes of pharmacist recommendations, estimated cost avoided, medication discrepancies, and self-reported medication adherence.
RESULTS: Prevalence of drug therapy problems and postdischarge medication discrepancies was 80.7% and 75.4%, respectively. The most frequently occurring drug therapy problems were enrollee not receiving needed medications (33.4%), underuse of medications (16.9%), and insufficient dose or duration (11.2%). Overall 50.8% of the pharmacist recommendations were accepted by physicians and patients, resulting in an estimated cost avoidance of $293.30 per drug therapy problem identified. Multivariate analysis indicated that participants with a higher number of comorbidities were more likely to have medication discrepancies (odds ratio 1.23 [95% CI 1.05-1.44]). Additional contributors to postdischarge medication discrepancies were difficulty picking up and paying for medications and not being given necessary prescriptions before discharge.
CONCLUSION: Drug therapy problems and medication discrepancies are common in super-utilizers with multiple chronic conditions and polypharmacy during transitions of care, and greater levels of comorbidity magnify risk. Pharmacist-led interventions in the SafeMed Program have demonstrated success in resolving enrollees' medication-related issues, resulting in substantial estimated cost savings. Preliminary evidence suggests that the SafeMed model's focus on medication management has great potential to improve outcomes while reducing costs for vulnerable super-utilizing populations nationwide.

PMID: 27720595 [PubMed - indexed for MEDLINE]

Association of anticholinergic burden with adverse effects in older people with intellectual disabilities: an observational cross-sectional study.

Br J Psychiatry. 2016 Dec;209(6):504-510

Authors: O'Dwyer M, Maidment ID, Bennett K, Peklar J, Mulryan N, McCallion P, McCarron M, Henman MC

Abstract
BACKGROUND: No studies to date have investigated cumulative anticholinergic exposure and its effects in adults with intellectual disabilities.
AIMS: To determine the cumulative exposure to anticholinergics and the factors associated with high exposure.
METHOD: A modified Anticholinergic Cognitive Burden (ACB) scale score was calculated for a representative cohort of 736 people over 40 years old with intellectual disabilities, and associations with demographic and clinical factors assessed.
RESULTS: Age over 65 years was associated with higher exposure (ACB 1-4 odds ratio (OR) = 3.28, 95% CI 1.49-7.28, ACB 5+ OR = 3.08, 95% CI 1.20-7.63), as was a mental health condition (ACB 1-4 OR = 9.79, 95% CI 5.63-17.02, ACB 5+ OR = 23.74, 95% CI 12.29-45.83). Daytime drowsiness was associated with higher ACB (P<0.001) and chronic constipation reported more frequently (26.6% ACB 5+ v. 7.5% ACB 0, P<0.001).
CONCLUSIONS: Older people with intellectual disabilities and with mental health conditions were exposed to high anticholinergic burden. This was associated with daytime dozing and constipation.

PMID: 27660331 [PubMed - indexed for MEDLINE]

Communicating information concerning potential medication harms and benefits: What gist do numbers convey?

Patient Educ Couns. 2016 Dec;99(12):1964-1970

Authors: Blalock SJ, Sage A, Bitonti M, Patel P, Dickinson R, Knapp P

Abstract
OBJECTIVES: Fuzzy trace theory was used to examine the effect of information concerning medication benefits and side-effects on willingness to use a hypothetical medication.
METHODS: Participants (N=999) were recruited via Amazon Mechanical Turk. Using 3×5 experimental research design, each participant viewed information about medication side effects in 1 of 3 formats and information about medication benefits in 1 of 5 formats. For both side-effects and benefits, one format presented only non-numeric information and the remaining formats presented numeric information.
RESULTS: Individuals in the non-numeric side-effect condition were less likely to take the medication than those in the numeric conditions (p<0.0001). In contrast, individuals in the non-numeric benefit condition were more likely to take the medication than those in the numeric conditions (p<0.0001).
CONCLUSIONS: Our findings suggest that non-numeric side-effect information conveys the gist that the medication can cause harm, decreasing willingness to use the medication; whereas non-numeric benefit information has the opposite effect.
PRACTICE IMPLICATIONS: Presenting side-effect and benefit information in non-numeric format appears to bias decision-making in opposite directions. Providing numeric information for both benefits and side-effects may enhance decision-making. However, providing numeric benefit information may decrease adherence, creating ethical dilemmas for providers.

PMID: 27444232 [PubMed - indexed for MEDLINE]

Drugs as Possible Triggers of Takotsubo Cardiomyopathy: A Comprehensive Literature Search - Update 2015.

Curr Clin Pharmacol. 2016;11(2):95-109

Authors: Amariles P, Cifuentes L

Abstract
BACKGROUND: In 2011 a list of 20 drugs linked to drug-induced Tako-Tsubo cardiomyopathy (TCM) was published. Thus, the objectives were both to identify cases of drug-induced TCM, and update the 2011 list of drugs as possible triggers of this cardiomyopathy.
METHOD: As the 2011 report of drug-induced TCM, case reports of drug-induced TCM were identified by a comprehensive search in Medline/PubMed database. From December 2010 to March 2015 search terms were Takotsubo cardiomyopathy, Takotsubo cardiomyopathy, stress cardiomyopathy, transient-left-ventricular ballooning syndrome, ampulla cardiomyopathy, apical ballooning syndrome, OR broken heart syndrome; together with "iatrogenic", "drug-induced", OR "induced by". Publications limited to English, Spanish, and French, in humans, and with full texts were retrieved. Articles that recognized any drug as a possible trigger of TCM were selected.
RESULTS: Overall, 405 different references were retrieved and 67 were selected (62 case reports and 5 case series) involving 78 patient cases with TCM possibly associated to drugs were reviewed. At total of 44 drugs were recognized as possible drug-induced TCM, mainly with sympathetic effect, and 37 (84.1%) were different to those 20 identified in the 2011 review; therefore, a list of 57 drugs associated to TCM was obtained.
CONCLUSION: There are new case reports that linked drug-use with the development of TCM. The list of 57 drugs obtained is principally integrated by drugs that generate sympathetic overstimulation. Consequently, the recommendation "drug-induced TCM would be considered in patients with TCM, particularly those in which no clear emotional or stress trigger could be identified" is endorsed.

PMID: 27049039 [PubMed - indexed for MEDLINE]

Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor.

Br J Clin Pharmacol. 2017 Sep 02;:

Authors: Jin Y, Regev A, Kam J, Phipps K, Smith C, Henck J, Campanale K, Hu L, Hall DG, Yang XY, Nakano M, McNearney TA, Uetrecht J, Landschulz W

Abstract
AIM: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety, and tolerability profile.
METHODS: Healthy subjects were randomised to receive LY3031207 (25, 75, and 275 mg), placebo, or celecoxib (400 mg) once daily for 28 days. The safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated.
RESULTS: The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing.
CONCLUSIONS: This study emphasised the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.

PMID: 28865237 [PubMed - as supplied by publisher]

The efficacy of (+)-Naltrexone on alcohol preference and seeking behaviour is dependent on light-cycle.

Brain Behav Immun. 2017 Aug 29;:

Authors: Jacobsen JHW, Buisman-Pijlman FT, Mustafa S, Rice KC, Hutchinson MR

Abstract
Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug-induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol-induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a biased TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice.

PMID: 28864261 [PubMed - as supplied by publisher]