An Insurer's Care Transition Program Emphasizes Medication Reconciliation, Reduces Readmissions And Costs.

Health Aff (Millwood). 2016 Jul 01;35(7):1222-9

Authors: Polinski JM, Moore JM, Kyrychenko P, Gagnon M, Matlin OS, Fredell JW, Brennan TA, Shrank WH

Abstract
Adverse drug events and the challenges of clarifying and adhering to complex medication regimens are central drivers of hospital readmissions. Medication reconciliation programs can reduce the incidence of adverse drug events after discharge, but evidence regarding the impact of medication reconciliation on readmission rates and health care costs is less clear. We studied an insurer-initiated care transition program based on medication reconciliation delivered by pharmacists via home visits and telephone and explored its effects on high-risk patients. We examined whether voluntary program participation was associated with improved medication use, reduced readmissions, and savings net of program costs. Program participants had a 50 percent reduced relative risk of readmission within thirty days of discharge and an absolute risk reduction of 11.1 percent. The program saved $2 for every $1 spent. These results represent real-world evidence that insurer-initiated, pharmacist-led care transition programs, focused on but not limited to medication reconciliation, have the potential to both improve clinical outcomes and reduce total costs of care.

PMID: 27385237 [PubMed - indexed for MEDLINE]

Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial.

Lancet Haematol. 2016 May;3(5):e217-27

Authors: Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G, International Extranodal Lymphoma Study Group (IELSG)

Abstract
BACKGROUND: Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article.
METHODS: For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920.
FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity.
INTERPRETATION: With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials.
FUNDING: Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

PMID: 27132696 [PubMed - indexed for MEDLINE]

Vibegron, a Novel Potent and Selective β3-Adrenoreceptor Agonist, for the Treatment of Patients with Overactive Bladder: A Randomized, Double-blind, Placebo-controlled Phase 3 Study.

Eur Urol. 2018 Jan 20;:

Authors: Yoshida M, Takeda M, Gotoh M, Nagai S, Kurose T

Abstract
BACKGROUND: Vibegron is a novel, potent, and selective β3-adrenoreceptor agonist for the treatment of patients with overactive bladder (OAB).
OBJECTIVE: To evaluate the efficacy and safety of vibegron versus placebo in Japanese OAB patients.
DESIGN, SETTING, AND PARTICIPANTS: Patients with OAB entered a 2-wk placebo run-in phase. Once eligibility (≥8 micturition/d and either ≥1 urgency episodes/d or ≥1 urgency incontinence episodes/d) was confirmed, patients entered a 12-wk double-blind treatment phase. The anticholinergic imidafenacin was used as an active reference.
INTERVENTION: A total of 1232 patients were randomly assigned to one of the four 12-wk treatment groups: vibegron (50mg or 100mg once daily), placebo, or imidafenacin (0.1mg twice daily).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was change in the mean number of micturitions/d at wk 12 from baseline. The secondary endpoints were changes from baselines in OAB symptom variables (daily episodes of urgency, urgency incontinence, incontinence, and nocturia, and voided volume/micturition). Quality of life (QoL) and safety were assessed. A constrained longitudinal data analysis model was used for analysis of efficacy.
RESULTS AND LIMITATIONS: Patients taking vibegron 50mg and 100mg orally for 12 wk had significant improvements over the placebo in the primary and secondary endpoints. The proportions of patients with normalization of micturition, resolution of urgency, urgency incontinence, and incontinence were significantly greater than placebo. Vibegron significantly improved QoL, with high patient satisfaction. Incidences of drug-related adverse events with vibegron 50mg and 100mg were 7.6%, 5.4%, similar to placebo (5.1%), and less than imidafenacin (10.3%). Treatment was for just 12 wk and a long-term study is needed.
CONCLUSIONS: The 12-wk treatment with vibegron is effective and well tolerated in patients with OAB.
PATIENT SUMMARY: This randomized study demonstrated that vibegron is clinically useful for treatment of patients with OAB. Trial registration ​JapicCTI-152936. http://www.clinicaltrials.jp/user/cteDetail.jsp.

PMID: 29366513 [PubMed - as supplied by publisher]

Comparison between insulin degludec/liraglutide treatment and insulin glargine/lixisenatide treatment in type 2 diabetes: a systematic review and meta-analysis.

Expert Opin Pharmacother. 2017 Dec;18(17):1789-1798

Authors: Cai X, Gao X, Yang W, Ji L

Abstract
AIM: To evaluate the efficacy and adverse effects of IDegLira and IGlarLixi treatment and to perform a comparison between two strategies.
METHODS: The registration number is CRD42017053952. Randomized controlled trials of IGlarLixi treatment or IDegLira treatment compared with placebo or active hypoglycemic agents in type 2 diabetes were included.
RESULTS: Eight trials were included. The absolute HbA1c change relative to baseline after IGlarLixi treatment was -1.50% with significance (95% CI, -1.89% to -1.12%, p < 0.01); the absolute HbA1c change after IDegLira treatment was -1.89% with significance (95% CI, -2.04% to -1.73%, p < 0.01). Comparisons between IGlarLixi treatment and IDegLira treatment indicated no significant differences between groups. The absolute weight change after IGlarLixi treatment significantly decreased (weighted mean difference (WMD), -0.62 kg; 95% CI, -0.93 to -0.31 kg, p = < 0.01), but the absolute weight change after IDegLira treatment was not significantly changed (WMD, -0.81 kg; 95% CI, -3.26 to 1.65 kg, p = 0.52). There were no significant differences between groups.
CONCLUSION: Glucose control of IGlarLixi treatment or IDegLira treatment was significantly lower than that at baseline. Comparisons between the two treatment groups indicated no significant differences between groups in absolute HbA1c changes or body weight changes relative to baseline.

PMID: 29090600 [PubMed - indexed for MEDLINE]

Bias Against the Null Hypothesis in Retrospective Registries of Gestational Drug Exposure.

J Obstet Gynaecol Can. 2016 12;38(12):1120-1123.e1

Authors: Etwel F, Koren G

Abstract
OBJECTIVE: The findings in retrospective pregnancy registries related to prenatal drug exposure (collected after pregnancy outcome is known) are commonly reported in regulatory documents and in the medical literature. However, there is little information about the accuracy of the estimates of risk from such registries. We therefore sought to compare the rates of major congenital malformations reported in retrospective and prospective registries for the same drug to quantify the potential bias of retrospective reports.
METHODS: We searched for all fetal safety reports related to medications for which information from both prospective and retrospective registries was available. These were published either in the peer-reviewed literature or as pharmaceutical company documents between 1984 and 2011.
RESULTS: For all drugs registries studied, estimates of major congenital malformations from retrospective registries tended to be higher than the rates in prospective registries; median estimates of risk were higher by a factor of 4.18 ± 1.23 (range 2.13-5.97).
CONCLUSIONS: The present study confirms a major and consistent bias against the null hypothesis in studies of teratogenic risk using retrospective registries, and this must be considered when interpreting such data. Spontaneous reporting of outcomes after exposure to a drug is highly selective towards adverse events, which families with normal pregnancy outcomes are less likely to report.

PMID: 27986187 [PubMed - indexed for MEDLINE]

Hidden drivers of low-dose pharmaceutical pollutant mixtures revealed by the novel GSA-QHTS screening method.

Sci Adv. 2016 09;2(9):e1601272

Authors: Rodea-Palomares I, Gonzalez-Pleiter M, Gonzalo S, Rosal R, Leganes F, Sabater S, Casellas M, Muñoz-Carpena R, Fernández-Piñas F

Abstract
The ecological impacts of emerging pollutants such as pharmaceuticals are not well understood. The lack of experimental approaches for the identification of pollutant effects in realistic settings (that is, low doses, complex mixtures, and variable environmental conditions) supports the widespread perception that these effects are often unpredictable. To address this, we developed a novel screening method (GSA-QHTS) that couples the computational power of global sensitivity analysis (GSA) with the experimental efficiency of quantitative high-throughput screening (QHTS). We present a case study where GSA-QHTS allowed for the identification of the main pharmaceutical pollutants (and their interactions), driving biological effects of low-dose complex mixtures at the microbial population level. The QHTS experiments involved the integrated analysis of nearly 2700 observations from an array of 180 unique low-dose mixtures, representing the most complex and data-rich experimental mixture effect assessment of main pharmaceutical pollutants to date. An ecological scaling-up experiment confirmed that this subset of pollutants also affects typical freshwater microbial community assemblages. Contrary to our expectations and challenging established scientific opinion, the bioactivity of the mixtures was not predicted by the null mixture models, and the main drivers that were identified by GSA-QHTS were overlooked by the current effect assessment scheme. Our results suggest that current chemical effect assessment methods overlook a substantial number of ecologically dangerous chemical pollutants and introduce a new operational framework for their systematic identification.

PMID: 27617294 [PubMed - indexed for MEDLINE]

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates.

Proc Natl Acad Sci U S A. 2016 09 13;113(37):E5511-8

Authors: Ding H, Czoty PW, Kiguchi N, Cami-Kobeci G, Sukhtankar DD, Nader MA, Husbands SM, Ko MC

Abstract
Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.

PMID: 27573832 [PubMed - indexed for MEDLINE]

Interpretation of Biochemical Tests Using the Reference Change Value in Monitoring Adverse Effects of Oral Isotretinoin in 102 Ethnic Turkish Patients.

Lab Med. 2016 Aug;47(3):213-9

Authors: Bugdayci G, Polat M, Oguzman H, Cinpolat HY

Abstract
OBJECTIVES: The aim of this study was to model the use of reference change values (RCVs) for the follow-up of 4 parameters of patients using oral isotretinoin which is gaining widespread popularity for monitoring the side effects of the treatment.
METHOD: 102 patients received 30 mg/day oral isotretinoin for 24 weeks for the diagnosis of acne vulgaris.
RESULTS: Repetitive measurements of the patients were interpreted with RCVs, after comparing the first and second doses based on RCVs: TC, TG, AST and ALT results increased in 12%, 20%, 14% and 12% of the patients respectively. When the first dose was compared with the last dose, the increases were 20%, 29%, 22% and 18% respectively interpreted as significant changes based on laboratory medicine.
CONCLUSIONS: A more sensitive follow-up is possible in the monitorization of adverse effects by using RCVs method.

PMID: 27346869 [PubMed - indexed for MEDLINE]

[A Case of Fatal Interstitial Pneumonia during FOLFIRI plus Cetuximab Therapy for Liver Metastasis of Colon Cancer].

Gan To Kagaku Ryoho. 2018 Jan;45(1):51-53

Authors: Aoyagi H, Ito H, Higuchi K, Koseki K, Watanabe I, Tanaka Y, Suzuki K, Nishi N, Nihei Z, Ito M

Abstract
The patient was a 76-year-old woman who underwent sigmoidectomy in April 2011 for sigmoid colon cancer with multiple concurrent liver metastases. She was treated postoperatively with mFOLFOX6 plus cetuximab but was diagnosed with the progressive disease at the end of course 14. The patient started receiving FOLFIRI plus cetuximab therapy in May 2012. Later in August 2012, she was examined for respiratory distress on the scheduled date of receiving course 7 and was diagnosed with drug-induced interstitial pneumonia resulting from systemic chemotherapy. The patient was administered oxygen, and her symptoms improved temporarily with steroid half-pulse and endotoxin adsorption therapy, but on inpatient day 10, her respiratory condition deteriorated. She was treated with steroid pulse therapy, but died of respiratory failure on inpatient day 17. The main adverse events associated with FOLFIRI plus cetuximab therapy are gastrointestinal symptoms, hematotoxicity, peripheral nerve damage, and dermatological symptoms. However, reports of respiratory conditions such as interstitial pneumonia are rare. Although the incidence is low, interstitial pneumonia can be severe and fatal and therefore requires close attention.

PMID: 29362307 [PubMed - in process]

Interdisciplinary collaboration across secondary and primary care to improve medication safety in the elderly (IMMENSE study): study protocol for a randomised controlled trial.

BMJ Open. 2018 Jan 23;8(1):e020106

Authors: Johansen JS, Havnes K, Halvorsen KH, Haustreis S, Skaue LW, Kamycheva E, Mathiesen L, Viktil KK, Granås AG, Garcia BH

Abstract
INTRODUCTION: Drug-related problems (DRPs) are common in the elderly, leading to suboptimal therapy, hospitalisations and increased mortality. The integrated medicines management (IMM) model is a multifactorial interdisciplinary methodology aiming to optimise individual medication therapy throughout the hospital stay. IMM has been shown to reduce readmissions and drug-related hospital readmissions. Using the IMM model as a template, we have designed an intervention aiming both to improve medication safety in hospitals, and communication across the secondary and primary care interface. This paper presents the study protocol to explore the effects of the intervention with regard to healthcare use, health-related quality of life (HRQoL) and medication appropriateness in elderly patients.
METHODS AND ANALYSIS: A total of 500 patients aged ≥70 years will be included and randomised to control (standard care) or intervention group (1:1). The intervention comprises five steps mainly performed by pharmacists: (1) medication reconciliation at admission, (2) medication review during hospital stay, (3) patient counselling about the use of medicines, (4) a comprehensible and patient-friendly medication list with explanations in discharge summary and (5) postdischarge phone calls to the primary care level. The primary outcome is the difference between intervention and control patients in the rate of emergency medical visits (acute readmissions and visits to emergency department) 12 months after discharge. Secondary outcomes include length of index hospital stay, time to first readmission, mortality, hip fractures, strokes, medication changes, HRQoL and medication appropriateness. Patient inclusion started in September 2016.
ETHICS AND DISSEMINATION: The trial was approved by the Norwegian Centre for Research Data and the Norwegian Data Protection Authority. We aim to publish the results in international peer-reviewed open access journals, at national and international conferences, and as part of two PhD theses.
TRIAL REGISTRATION NUMBER: NCT02816086.

PMID: 29362276 [PubMed - in process]

Derisking Drug-Induced Carcinogenicity for Novel Therapeutics.

Trends Cancer. 2016 Aug;2(8):398-408

Authors: Moggs JG, MacLachlan T, Martus HJ, Bentley P

Abstract
Assessing the carcinogenic potential of innovative drugs spanning diverse therapeutic modalities and target biology represents a major challenge during drug development. Novel modalities, such as cell and gene therapies that involve intrinsic genetic modification of the host genome, require distinct approaches for identification of cancer hazard. We emphasize the need for customized weight-of-evidence cancer risk assessments based on mode of action that balance multiple options for preclinical identification of cancer hazard with appropriate labeling of clinical products and risk management plans. We review how advances in molecular carcinogenesis can enhance mechanistic interpretation and preclinical indicators of neoplasia, and recommend that drug targets be systematically assessed for potential association with tumorigenic phenotypes via genetic models and cancer genome resources.

PMID: 28741493 [PubMed - indexed for MEDLINE]

Adverse Events Associated with Treatment of Multidrug-Resistant Tuberculosis in China: An Ambispective Cohort Study.

Med Sci Monit. 2017 May 18;23:2348-2356

Authors: Zhang Y, Wu S, Xia Y, Wang N, Zhou L, Wang J, Fang R, Sun F, Chen M, Zhan S

Abstract
BACKGROUND Adverse events are under-appreciated negative consequences that are significant clinical problems for patients undergoing anti-MDR-TB treatment due to longer duration of treatment and more need for concurrent use of multiple second-line drugs. The aim of this study was to determine the incidence of adverse events and their impact on MDR-TB therapy and treatment outcome, and to identify possible drug-event pairs in China. MATERIAL AND METHODS An ambispective cohort study was conducted based on hospital medical records, which included a retrospective study that enrolled 751 MDR-TB patients receiving standardized regimen between May 2009 and July 2013, and a follow-up investigation of treatment outcome conducted in December 2016 in China. Adverse events were determined according to laboratory results or clinical criteria. Cox's proportional hazards regression models were used for evaluating associations. RESULTS There were 681(90.7%) patients experienced at least 1 type of adverse event and 55.2% of them required a changed MDR-TB treatment; 51(6.8%) patients required permanent discontinuation of the offending drug due to adverse events. The occurrence of adverse events was associated with poor treatment outcome (adjusted hazard ratio, 1.54; 95% CI 1.21, 1.87). A total of 10 different drug-event pairs were identified. CONCLUSIONS Adverse events occurred commonly during MDR-TB treatment in China, and often resulted in MDR-TB treatment change. The occurrence of adverse events affected MDR-TB poor outcome after treatment.

PMID: 28520704 [PubMed - indexed for MEDLINE]

Estimation of the prevalence of adverse drug reactions from social media.

Int J Med Inform. 2017 Jun;102:130-137

Authors: Nguyen T, Larsen ME, O'Dea B, Phung D, Venkatesh S, Christensen H

Abstract
This work aims to estimate the degree of adverse drug reactions (ADR) for psychiatric medications from social media, including Twitter, Reddit, and LiveJournal. Advances in lightning-fast cluster computing was employed to process large scale data, consisting of 6.4 terabytes of data containing 3.8 billion records from all the media. Rates of ADR were quantified using the SIDER database of drugs and side-effects, and an estimated ADR rate was based on the prevalence of discussion in the social media corpora. Agreement between these measures for a sample of ten popular psychiatric drugs was evaluated using the Pearson correlation coefficient, r, with values between 0.08 and 0.50. Word2vec, a novel neural learning framework, was utilized to improve the coverage of variants of ADR terms in the unstructured text by identifying syntactically or semantically similar terms. Improved correlation coefficients, between 0.29 and 0.59, demonstrates the capability of advanced techniques in machine learning to aid in the discovery of meaningful patterns from medical data, and social media data, at scale.

PMID: 28495341 [PubMed - indexed for MEDLINE]

Review Article: The Role of Molecular Pathological Epidemiology in the Study of Neoplastic and Non-neoplastic Diseases in the Era of Precision Medicine.

Epidemiology. 2016 Jul;27(4):602-11

Authors: Ogino S, Nishihara R, VanderWeele TJ, Wang M, Nishi A, Lochhead P, Qian ZR, Zhang X, Wu K, Nan H, Yoshida K, Milner DA, Chan AT, Field AE, Camargo CA, Williams MA, Giovannucci EL

Abstract
Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases, such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity-related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical/radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational/systems biology, there are wide open opportunities in MPE to contribute to public health.

PMID: 26928707 [PubMed - indexed for MEDLINE]

Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury.

Clin Sci (Lond). 2018 Jan 22;:

Authors: Tang J, Shi Y, Liu N, Xu L, Zang X, Li P, Zhang J, Zheng X, Qiu A, Zhuang S

Abstract
Histone deacetylase 6 (HDAC6) has been shown to be involved in various pathological conditions, including cancer, neurodegenerative disorders and inflammatory diseases. Nonetheless, its specific role in drug-induced nephrotoxicity is poorly understood. Cisplatin (dichlorodiamino platinum) belongs to an inorganic platinum-fundamental chemotherapeutic drug utilized in the therapy of various solid malignant tumors. However, the use of cisplatin is limited by obvious side effects. In this study, we utilized a murine model of cisplatin-induced acute kidney injury (AKI) and a highly selective inhibitor of HDAC6, tubastatin A (TA), to assess the role of HDAC6 in nephrotoxicity and its associated mechanisms. Cisplatin-induced AKI was accompanied by increased expression and activation of HDAC6; blocking HDAC6 with TA lessened renal dysfunction, attenuated renal pathological changes, reduced expression of neutrophil gelatinase-associated lipocalin and Kim-1, and decreased tubular cell apoptosis. In cultured human epithelial cells, TA or HDAC6 siRNA treatment also inhibited cisplatin-induced apoptosis. Mechanistic studies demonstrated that cisplatin induced phosphorylation of AKT and loss of E-cadherin in the nephrotoxic kidney, and administration of TA enhanced AKT phosphorylation and preserved E-cadherin expression. HDAC6 inhibition also potentiated autophagy as evidenced by increased expression of Atg7, Beclin-1, and decreased renal oxidative stress as demonstrated by upregulation of superoxide dismutase activity and downregulation of malondialdehyde levels. Moreover, TA was effective in inhibiting NF-κB phosphorylation and suppressing the expression of tumor necrosis factor-a and interleukin-6. Collectively, these data provide strong evidence that HDAC6 inhibition is protective against cisplatin-induced AKI and suggest that HDAC6 may be a potential therapeutic target for AKI treatment.

PMID: 29358506 [PubMed - as supplied by publisher]

Drug-induced liver and skin reactions: In need of a consensus definition.

Hepatology. 2017 01;65(1):391

Authors: Medina-Cáliz I, Robles-Díaz M, Lucena MI, Andrade RJ

PMID: 27618725 [PubMed - indexed for MEDLINE]

Detrimental Side Effects of Repeated Ketamine Infusions in the Brain.

Am J Psychiatry. 2016 10 01;173(10):1044-1045

Authors: Hashimoto K

PMID: 27690555 [PubMed - indexed for MEDLINE]

Trends in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.

Am J Prev Med. 2016 Aug;51(2):151-160

Authors: Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK

Abstract
INTRODUCTION: Although many clinical guidelines caution against the combined use of opioids and benzodiazepines, overdose deaths and emergency department visits involving the co-ingestion of these drugs are increasing.
METHODS: In this ecologic time series study, the IMS Health Total Patient Tracker was used to describe nationally projected trends of patients receiving opioids and benzodiazepines in the U.S. outpatient retail setting between January 2002 and December 2014. The IMS Health Data Extract Tool was used to examine trends in the concomitant prescribing of these two medication classes among 177 million individuals receiving opioids during this period. The annual proportion of opioid recipients who were prescribed benzodiazepines concomitantly was calculated and stratified by gender, age, duration of opioid use, immediate-release versus extended-release/long-acting opioids, and benzodiazepine molecule. The proportion of patients with concomitancy receiving opioids and benzodiazepines from the same prescriber was also analyzed. Analyses were conducted from April to June 2015.
RESULTS: The nationally projected number of patients receiving opioids and benzodiazepines increased by 8% and 31%, respectively, from 2002 to 2014. During this period, the annual proportion of opioid recipients dispensed a benzodiazepine concomitantly increased from 6.8% to 9.6%, which corresponded to a relative increase of 41%. Approximately half of these patients received both prescriptions from the same prescriber on the same day. Concomitancy was more common in patients receiving opioids for ≥90 days, women, and the elderly.
CONCLUSIONS: Concomitant prescribing of opioids and benzodiazepines is increasing and may play a growing role in adverse patient outcomes related to these medications.

PMID: 27079639 [PubMed - indexed for MEDLINE]

Synergy evaluation of anti-Herpes Simplex Virus type 1 and 2 compounds acting on different steps of virus life cycle.

Antiviral Res. 2018 Jan 18;:

Authors: Criscuolo E, Clementi N, Mancini N, Burioni R, Miduri M, Castelli M, Clementi M

Abstract
Despite the clinical need of novel and safe anti-herpetic compounds effective for treating both primary infections and reactivations of Herpes Simplex Virus type 1 (HSV-1) and type 2 (HSV-2), the development of novel antivirals approved for clinical administration has been limited in the last decades to improvements of nucleoside analogues compounds. In this context, targeting different steps of the herpesvirus life cycle, including entry and cell-to-cell infection, can represent an important starting point for obtaining more efficient infection inhibition, and for overcoming both drug resistance and toxicity. Under these perspectives, testing possible synergy between drugs currently in clinical use and novel immunotherapeutics, such as neutralizing human monoclonal antibodies, represents a fascinating option. In the study here described we tested for the first-time possible combinations of inhibitors of Herpesvirus DNA synthesis and a human neutralizing IgG able to block also cell-to-cell infection, by analysing experimental results with different mathematical models. The present study clearly highlights the synergism between all anti-herpetic drugs tested in combination with the mAb; this strongly suggests possible reduction of anti-herpetic drugs combined with the IgG for overcoming drug-related side effects, as indicated by Drug Reduction Index.

PMID: 29357297 [PubMed - as supplied by publisher]

Moxifloxacin in Pediatric Patients with Complicated Intra-Abdominal Infections: Results of the MOXIPEDIA Randomized Controlled Study.

Pediatr Infect Dis J. 2018 Jan 18;:

Authors: Wirth S, Emil SGS, Engelis A, Digtyar V, Criollo M, DiCasoli C, Stass H, Willmann S, Nkulikiyinka R, Grossmann U, MOXIPEDIA Study Group

Abstract
BACKGROUND: This study was designed to evaluate primarily the safety and also the efficacy of moxifloxacin (MXF) in children with complicated intra-abdominal infections (cIAIs).
METHODS: In this multicenter, randomized, double-blind, controlled study, 451 pediatric patients aged 3 months to 17 years with cIAIs were treated with intravenous/oral MXF (N = 301) or comparator (COMP, intravenous ertapenem followed by oral amoxicillin/clavulanate; N = 150) for 5 to 14 days. Doses of MXF were selected based on the results of a Phase 1 study in pediatric patients (NCT01049022). The primary endpoint was safety, with particular focus on cardiac and musculoskeletal safety; clinical and bacteriological efficacy at test of cure were also investigated.
RESULTS: The proportion of patients with adverse events (AEs) was comparable between the two treatment arms (MXF: 58.1% and COMP: 54.7%). The incidence of drug-related AEs was higher in the MXF arm than the COMP arm (14.3% and 6.7%, respectively). No cases of QTc interval prolongation-related morbidity or mortality were observed. The proportion of patients with musculoskeletal AEs was comparable between treatment arms; no drug-related events were reported. Clinical cure rates were 84.6% and 95.5% in the MXF and COMP arms, respectively, in patients with confirmed pathogen(s) at baseline.
CONCLUSIONS: MXF treatment was well tolerated in children with cIAIs. However, a lower clinical cure rate was observed with MXF treatment compared with COMP. This study does not support a recommendation of MXF for children with cIAIs when alternative more efficacious antibiotics with better safety profile are available.

PMID: 29356761 [PubMed - as supplied by publisher]