Clinical Effects of a Pharmacist Intervention in Acute Wards - A Randomized Controlled Trial.

Basic Clin Pharmacol Toxicol. 2017 Oct;121(4):325-333

Authors: Nielsen TRH, Honoré PH, Rasmussen M, Andersen SE

Abstract
The purpose of the study was to investigate the clinical effect of a clinical pharmacist (CP) intervention upon admission to hospital on inpatient harm and to assess a potential educational bias. Over 16 months, 593 adult patients taking ≥4 medications daily were included from three Danish acute medicine wards. Patients were randomized to either the CP intervention or the usual care (prospective control). To assess a potential educational bias, a retrospective control group was formed by randomization. The CP intervention comprised medication history, medication reconciliation, medication review and entry of proposed prescriptions into the electronic prescribing system. The primary outcome of inpatient harm was identified using triggers from the Institute of Healthcare Improvement Global Trigger Tool. Harms were validated and rated for severity by two independent and blinded outcome panels. Secondary end-points were harms per patient, length of hospital stay, readmissions and 1-year mortality. Harm affected 11% of the patients in the intervention group compared to 17% in the combined control group, odds ratio (OR) 0.57 (CI 0.32-1.02, p = 0.06). The incidence of harm was similar in the intervention and prospective control groups, OR 0.80 (CI 0.40-1.59, p = 0.52) but occurred less frequently in the intervention than in the retrospective control group OR 0.46 (CI 0.25-0.85, p = 0.01). An educational bias from the intervention to the control group might have contributed to this negative outcome. In conclusion, the CP intervention at admission to hospital had no statistically significant effect on inpatient harm.

PMID: 28457021 [PubMed - indexed for MEDLINE]

Asking the right questions to get the right answers: using cognitive interviews to review the acceptability, comprehension and clinical meaningfulness of patient self-report adverse event items in oncology patients.

Acta Oncol. 2016 Sep - Oct;55(9-10):1220-1226

Authors: Holch P, Warrington L, Potrata B, Ziegler L, Hector C, Keding A, Harley C, Absolom K, Morris C, Bamforth L, Velikova G

Abstract
BACKGROUND: Standardized reporting of treatment-related adverse events (AE) is essential in clinical trials, usually achieved by using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) reported by clinicians. Patient-reported adverse events (PRAE) may add value to clinician assessments, providing patient perspective on subjective toxicity. We developed an online patient symptom report and self-management system for real-time reporting and managing AE during cancer treatment integrated with electronic patient records (eRAPID). As part of this program we developed a patient version of the CTCAE (version 4.0), rephrasing terminology into a self-report format. We explored patient understanding of these items via cognitive interviews.
MATERIAL AND METHOD: Sixty patients (33 female, 27 male) undergoing treatment were purposively sampled by age, gender and tumor group (median age 61.5, range 35-84, 12 breast, 12 gynecological, 13 colorectal, 12 lung and 11 renal). Twenty-one PRAE items were completed on a touch-screen computer. Subsequent audio-recorded cognitive interviews and thematic analysis explored patients' comprehension of items via verbal probing techniques during three interview rounds (n = 20 patients/round).
RESULTS: In total 33 item amendments were made; 29% related to question comprehension, 68% response option and 3% order effects. These amendments to phrasing and language improved patient understanding but maintained CTCAE grading and key medical information. Changes were endorsed by members of a patient advisory group (N = 11).
CONCLUSION: Item adaptations resulted in a bank of consistently interpreted self-report AE items for use in future research program. In-depth analysis of items through cognitive interviews is an important step towards developing an internationally valid system for PRAE, thus improving patient safety and experiences during cancer treatment.

PMID: 27551774 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/01/30

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15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/01/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Eliciting adverse effects data from participants in clinical trials.

Cochrane Database Syst Rev. 2018 Jan 16;1:MR000039

Authors: Allen EN, Chandler CI, Mandimika N, Leisegang C, Barnes K

Abstract
BACKGROUND: Analysis of drug safety in clinical trials involves assessing adverse events (AEs) individually or by aggregate statistical synthesis to provide evidence of likely adverse drug reactions (ADR). While some AEs may be ascertained from physical examinations or tests, there is great reliance on reports from participants to detect subjective symptoms, where he/she is often the only source of information. There is no consensus on how these reports should be elicited, although it is known that questioning methods influence the extent and nature of data detected. This leaves room for measurement error and undermines comparisons between studies and pooled analyses. This review investigated comparisons of methods used in trials to elicit participant-reported AEs. This should contribute to knowledge about the methodological challenges and possible solutions for achieving better, or more consistent, AE ascertainment in trials.
OBJECTIVES: To systematically review the research that has compared methods used within clinical drug trials (or methods that would be specific for such trials) to elicit information about AEs defined in the protocol or in the planning for the trial.
SEARCH METHODS: Databases (searched to March 2015 unless indicated otherwise) included: Embase; MEDLINE; MEDLINE in Process and Other Non-Indexed Citations; Cochrane Methodology Register (July 2012); Cochrane Central Register of Controlled Trials (February 2015); Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects (January 2015); Health Technology Assessment database (January 2015); CINAHL; CAB Abstracts; BIOSIS (July 2013); Science Citation Index; Social Science Citation Index; Conference Proceedings Citation Index - Science. The search used thesaurus headings and synonyms for the following concepts: (A): Adverse events AND measurement; (B): Participants AND elicitation (also other synonyms for extraction of information about adverse effects from people); (C): Participants AND checklists (also other synonyms as for B). Pragmatic ways were used to limit the results whilst trying to maintain sensitivity. There were no date or sample size restrictions but only reports published in English were included fully, because of resource constraints as regards translation.
SELECTION CRITERIA: Two types of studies were included: drug trials comparing two or more methods within- or between-participants to elicit participant-reported AEs, and research studies performed outside the context of a trial to compare methods which could be used in trials (evidenced by reference to such applicability). Primary outcome data included AEs elicited from participants taking part in any such clinical trial. We included any participant-reported data relevant for an assessment of drug-related harm, using the original authors' terminology (and definition, where available), with comment on whether the data were likely to be treatment-emergent AEs or not.
DATA COLLECTION AND ANALYSIS: Titles and abstracts were independently reviewed for eligibility. Full texts of potentially eligible citations were independently reviewed for final eligibility. Relevant data were extracted and subjected to a 100% check. Disagreements were resolved by discussion, involving a third author. The risk of bias was independently assessed by two authors. The Cochrane 'Risk of bias' tool was used for reports comparing outcomes between participants, while for within-participant comparisons, each study was critically evaluated in terms of potential impact of the design and conduct on findings using the framework of selection, performance, detection, attrition, reporting, and other biases. An attempt was made to contact authors to retrieve protocols or specific relevant missing information. Reports were not excluded on the basis of quality unless data for outcomes were impossible to compare (e.g. where denominators differed). A narrative synthesis was conducted because differences in study design and presentation meant that a quantitative meta-analysis was not possible.
MAIN RESULTS: The 33 eligible studies largely compared open questions with checklist-type questions or rating scales. Two included participant interviews. Despite different designs, populations and details of questioning methods, the narrative review showed that more specific questioning of participants led to more AEs detected compared to a more general enquiry. A subset of six studies suggested that more severe, bothersome, or otherwise clinically relevant AEs were reported when an initial open enquiry was used, while some less severe, bothersome, or clinically relevant AEs were only reported with a subsequent specific enquiry. However, two studies showed that quite severe or debilitating AEs were only detected by an interview, while other studies did not find a difference in the nature of AEs between elicitation methods. No conclusions could be made regarding the impact of question method on the ability to detect a statistically significant difference between study groups. There was no common statistical rubric, but we were able to represent some effect measures as a risk ratio of the proportion of participants with at least one AE. This showed a lower level of reporting for open questions (O) compared to checklists (CL), with a range for the risk ratios of 0.12 to 0.64.
AUTHORS' CONCLUSIONS: This review supports concerns that methods to elicit participant-reported AEs influence the detection of these data. There was a risk for under-detection of AEs in studies using a more general elicitation method compared to those using a comprehensive method. These AEs may be important from a clinical perspective or for patients. This under-detection could compromise ability to pool AE data. However, the impact on the nature of the AE detected by different methods is unclear. The wide variety and low quality of methods to compare elicitation strategies limited this review. Future studies would be improved by using and reporting clear definitions and terminology for AEs (and other important variables), frequency and time period over which they were ascertained, how they were graded, assessed for a relationship to the study drug, coded, and tabulated/reported. While the many potential AE endpoints in a trial may preclude the development of general AE patient-reported outcome measurement instruments, much could also be learnt from how these employ both quantitative and qualitative methods to better understand data elicited. Any chosen questioning method needs to be feasible for use by both staff and participants.

PMID: 29372930 [PubMed - as supplied by publisher]

Capecitabine/cisplatin versus 5-fluorouracil/cisplatin in Chinese patients with advanced and metastatic gastric cancer: Re-analysis of efficacy and safety data from the ML17032 phase III clinical trial.

Asia Pac J Clin Oncol. 2018 Jan 26;:

Authors: Chen J, Xiong J, Wang J, Zheng L, Gao Y, Guan Z

Abstract
AIM: To confirm non-inferiority and test potential superiority of capecitabine/cisplatin (XP) over 5-fluorouracil (5-FU)/cisplatin (FP) as first-line treatment for advanced gastric cancer (AGC) in Chinese patients.
METHODS: In open-label phase III ML17032 trial, AGC (stage IIIA-IV) patients with or without metastases were randomized 1:1 to receive cisplatin (80 mg/m2 /day intravenous [IV] day 1) with either capecitabine (1000 mg/m2 /day oral [PO] twice daily [BID], days 1-14; XP) or 5-FU (800 mg/m2 /day continuous IV days 1-5; FP) every 3 weeks. The primary objective was to confirm the non-inferiority of XP over FP for progression-free survival (PFS).
RESULTS: The intent-to-treat (ITT) population included 126 Chinese patients (XP-62, FP-64; 67.5% male, mean age 54.7 years). The primary analysis was performed on the per-protocol (PP) population (105 patients; XP-51, FP-54; 65.7% male). Median PFS in the XP and FP groups was 7.2 and 4.5 months, respectively. The adjusted hazard ratio (HR) for PFS was 0.52 (95% confidence interval [CI]: 0.32-0.83, P = 0.006). Unadjusted HR for PFS in the ITT population was 0.63 (95% CI, 0.42-0.94, P = 0.022). The most frequent drug-related grade 3/4 adverse events (AEs) were neutropenia (XP-20.7%, FP-17.7%) and gastrointestinal disorders (XP-19.0%, FP-19.4%). The overall incidence of grade 3/4 AEs (XP-43.1%, FP-46.8%), serious AEs (XP-1.7%, FP-3.2%), and AEs related to treatment discontinuation (XP-10.3%, FP-16.1%) were comparable.
CONCLUSION: XP had a similar safety profile and may demonstrate superiority for PFS compared to FP as first-line treatment of Chinese patients with AGC (NCT02563054).

PMID: 29372626 [PubMed - as supplied by publisher]

Methodological Considerations for Comparison of Brand Versus Generic Versus Authorized Generic Adverse Event Reports in the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Clin Drug Investig. 2017 Dec;37(12):1143-1152

Authors: Rahman MM, Alatawi Y, Cheng N, Qian J, Peissig PL, Berg RL, Page DC, Hansen RA

Abstract
BACKGROUND: The US Food and Drug Administration Adverse Event Reporting System (FAERS), a post-marketing safety database, can be used to differentiate brand versus generic safety signals.
OBJECTIVE: To explore the methods for identifying and analyzing brand versus generic adverse event (AE) reports.
METHODS: Public release FAERS data from January 2004 to March 2015 were analyzed using alendronate and carbamazepine as examples. Reports were classified as brand, generic, and authorized generic (AG). Disproportionality analyses compared reporting odds ratios (RORs) of selected known labeled serious adverse events stratifying by brand, generic, and AG. The homogeneity of these RORs was compared using the Breslow-Day test. The AG versus generic was the primary focus since the AG is identical to brand but marketed as a generic, therefore minimizing generic perception bias. Sensitivity analyses explored how methodological approach influenced results.
RESULTS: Based on 17,521 US event reports involving alendronate and 3733 US event reports involving carbamazepine (immediate and extended release), no consistently significant differences were observed across RORs for the AGs versus generics. Similar results were obtained when comparing reporting patterns over all time and just after generic entry. The most restrictive approach for classifying AE reports yielded smaller report counts but similar results.
CONCLUSION: Differentiation of FAERS reports as brand versus generic requires careful attention to risk of product misclassification, but the relative stability of findings across varying assumptions supports the utility of these approaches for potential signal detection.

PMID: 28933038 [PubMed - indexed for MEDLINE]

General practitioners' views on (long-term) prescription and use of problematic and potentially inappropriate medication for oldest-old patients-A qualitative interview study with GPs (CIM-TRIAD study).

BMC Fam Pract. 2017 Feb 17;18(1):22

Authors: Pohontsch NJ, Heser K, Löffler A, Haenisch B, Parker D, Luck T, Riedel-Heller SG, Maier W, Jessen F, Scherer M

Abstract
BACKGROUND: Potentially inappropriate medication (PIM) is defined as medication with uncertain therapeutic effects and/or potential adverse drug reactions outweighing the clinical benefits. The prescription rate of PIM for oldest-old patients is high despite the existence of lists of PIM (e.g. the PRISCUS list) and efforts to raise awareness. This study aims at identifying general practitioners' views on PIM and aspects affecting the (long-term) use of PIM.
METHODS: As part of the CIM-TRIAD study, we conducted semi-structured, qualitative interviews with 47 general practitioners, discussing 25 patients with and 22 without PIM (according to the PRISCUS list). The interview guideline included generic and patient-specific questions. Interviews were digitally recorded and transcribed verbatim. We content analyzed the interviews using deductive and inductive category development.
RESULTS: The majority of the general practitioners were not aware of the PRISCUS list. Agents deemed potentially inappropriate from the general practitioners' point of view and the PRISCUS list are not completely superimposable. General practitioners named their criteria to identify appropriate medication for elderly patients (e.g. renal function, cognitive state) and emphasized the importance of monitoring. We identified prescription- (e.g. benzodiazepines on alternative private prescription), medication- (e.g. subjective perception that PIM has no alternative), general practitioner- (e.g. general practitioner relies on specialists), patient- (e.g. "demanding high-user", positive subjective benefit-risk-ratio) and system-related aspects (e.g. specialists lacking holistic view, interface problems) related to the (long term) use of PIM.
CONCLUSIONS: While the PRISCUS list does not seem to play a decisive role in general practice, general practitioners are well aware of risks associated with PIM. Our study identifies some starting points for a safer handling of PIM, e.g. stronger dissemination of the PRISCUS list, better compensation of medication reviews, "positive lists", adequate patient information, multifaceted interventions and improved communication between general practitioners and specialists.

PMID: 28212616 [PubMed - indexed for MEDLINE]

Ezetimibe-Statin Combination Therapy.

Dtsch Arztebl Int. 2016 Jul 01;113(26):445-53

Authors: Nußbaumer B, Glechner A, Kaminski-Hartenthaler A, Mahlknecht P, Gartlehner G

Abstract
BACKGROUND: To date, most clinical comparisons of ezetimibe-statin combination therapy versus statin monotherapy have relied entirely on surrogate variables. In this systematic review, we study the efficacy and safety of ezetimibe-statin combination therapy in comparison to statin monotherapy in terms of the prevention of cardiovascular events in hyperlipidemic patients with atherosclerosis and/or diabetes mellitus.
METHODS: This review is based on a systematic literature search (1995 to July 2015) in PubMed, the Excerpta Medica Database (EMBASE), the Cochrane Library, and the ClinicalTrials.gov registry.
RESULTS: Nine randomized, controlled trials with data from a total of 19 461 patients were included. Ezetimibe-statin combination therapy was associated with a lower risk of cardiovascular events than statin monotherapy: 33% of the patients treated with ezetimibe and a statin, and 35% of those treated with a statin alone, had a cardiovascular event within seven years (number needed to treat [NNT]: 50 over 7 years). Combination therapy was also significantly more effective in preventing a composite endpoint consisting of death due to cardiovascular disease, nonfatal myocardial infarction, unstable angina pectoris, coronary revascularization, and nonfatal stroke (hazard ratio [HR] 0.94, 95% confidence interval [0,89; 0,99]; p = 0.016). Diabetic patients benefited from combination therapy rather than monotherapy with respect to cardiovascular morbidity (HR 0.87 [0.78; 0.94]). On the other hand, the addition of ezetimibe to statin therapy did not lessen either cardiovascular or overall mortality. Serious undesired events occurred in 38% of the patients taking ezetimibe and a statin nd in 39% of the patients taking a statin alone (relative risk 1.09 [0.77; 1.55]).
CONCLUSION: In high-risk patients with an acute coronary syndrome, combination therapy with ezetimibe and a statin lowered the risk of cardiovascular events in comparison to statin monotherapy. The risk of dying or suffering an adverse drug effect was similar in the two treatment groups.

PMID: 27412989 [PubMed - indexed for MEDLINE]

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]