Limitations in Clinical Translation of Nanoparticle-Based Gene Therapy.

Trends Biotechnol. 2017 Dec;35(12):1124-1125

Authors: Wong JKL, Mohseni R, Hamidieh AA, MacLaren RE, Habib N, Seifalian AM

Abstract
Organic nanoparticle-based (ONP) gene therapy is a potential strategy to cure human cancer. However, there are still many practical barriers before the promising results from in vitro and preclinical studies can be translated to clinical success. We discuss the reasons behind the hesitant uptake by the clinic.

PMID: 28822599 [PubMed - indexed for MEDLINE]

[Deprescription, what are we talking about?]

Farm Hosp. 2017 Jul 01;41(4):567-568

Authors: Gutiérrez-Valencia M, Martínez-Velilla N

PMID: 28683712 [PubMed - indexed for MEDLINE]

Using the diffusion of innovations theory to assess socio-technical factors in planning the implementation of an electronic health record alert across multiple primary care clinics.

J Innov Health Inform. 2016 04 15;23(1):450-8

Authors: Lin CP, Guirguis-Blake J, Keppel GA, Dobie S, Osborn J, Cole AM, Baldwin LM

Abstract
BACKGROUND: Adverse drug events (ADEs) are a leading cause of death in the United States. Patients with stage 3 and 4 chronic kidney disease (CKD) are at particular risk because many medications are cleared by the kidneys. Alerts in the electronic health record (EHR) about drug appropriateness and dosing at the time of prescription have been shown to reduce ADEs for patients with stage 3 and 4 CKD in inpatient settings, but more research is needed about the implementation and effectiveness of such alerts in outpatient settings.
OBJECTIVE: To explore factors that might inform the implementation of an electronic drug-disease alert for patients with CKD in primary care clinics, using Rogers' diffusion of innovations theory as an analytic framework.
METHODS: Interviews were conducted with key informants in four diverse clinics using various EHR systems. Interviews were audio recorded and transcribed. results Although all clinics had a current method for calculating glomerular filtration rate (GFR), clinics were heterogeneous with regard to current electronic decision support practices, quality improvement resources, and organizational culture and structure.
CONCLUSION: Understanding variation in organizational culture and infrastructure across primary care clinics is important in planning implementation of an intervention to reduce ADEs among patients with CKD.

PMID: 27348488 [PubMed - indexed for MEDLINE]

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism.

Res Pract Thromb Haemost. 2018 Jan;2(1):69-76

Authors: Albisetti M, Schlosser A, Brueckmann M, Gropper S, Glund S, Tartakovsky I, Brandão LR, Reilly PA

Abstract

Background: The incidence of venous thromboembolism (VTE) in children has been increasing. Anticoagulants are the mainstay of treatment but are associated with bleeding events that may be life-threatening. Idarucizumab is a fragment antigen-binding (fab) that provides immediate, complete, and sustained reversal of dabigatran's anticoagulant effects in adults.
Objective and Methods: This phase III, open-label, single-arm, multicenter, multinational trial will assess the safety of idarucizumab in children participating in two ongoing trials investigating dabigatran etexilate. Eligible patients will be children with VTE (aged 0-≤18 years; n = ~5) with life-threatening or uncontrolled bleeding (group A), and children who require emergency surgery/urgent procedures for a condition other than bleeding (group B). Patients will receive idarucizumab up to 5 g as two consecutive intravenous infusions over 5-10 minutes each, as two 10-15-minute drips or as two bolus injections (15 minutes apart) and will be monitored for 30 days. The primary endpoint will be the safety of idarucizumab assessed by the occurrence of drug-related adverse events (including immune reactions) and all-cause mortality. Secondary endpoints will be the reversal of dabigatran anticoagulant effects assessed by changes in diluted thrombin time and ecarin clotting time, time to achieve complete reversal and the duration of the reversal and bleeding severity (group A). The formation of antidrug antibodies at 30 days post-dose and cessation of bleeding will also be assessed.
Conclusion: This study will report the safety of idarucizumab in children with VTE who require rapid reversal of the anticoagulant effects of dabigatran. Clinical trial registration: NCT02815670.

PMID: 30046708 [PubMed]

The Experience of Management of High-Alert Medications.

Am J Med Qual. 2017 Sep/Oct;32(5):571

Authors: Peng TR, Wu TW

PMID: 28862027 [PubMed - indexed for MEDLINE]

Gingival bleeding, a possible "serious" adverse drug reaction: An observational study in the French PharmacoVigilance Database.

J Clin Periodontol. 2017 Sep;44(9):898-904

Authors: Bondon-Guitton E, Mourgues T, Rousseau V, Cousty S, Cottin J, Drablier G, Micallef J, Montastruc JL

Abstract
INTRODUCTION: Antithrombotic drugs are known to increase the risk of gingival bleeding because they affect coagulation. However, other drugs could also be involved in gingival bleeding.
AIM: We performed a pharmacoepidemiological study to identify the drugs most frequently "suspected" in the occurrence of gingival bleeding.
MATERIAL AND METHODS: We selected reports of "gingival bleeding" from 1 January 1985 to 30 September 2014 in the French PharmacoVigilance Database.
RESULTS: Among 523,808 reports of adverse drug reactions, we identified 454 reports of gingival bleeding (0.09%). Most of them were "serious" (58.4%) and occurred in females (54.6%). The frequency of gingival bleeding increased with age. The most frequently "suspected" drugs were antithrombotics (67.8%), particularly fluindione. Other drugs frequently involved were furosemide followed by paracetamol, amiodarone, amoxicillin, paroxetine, ketoprofen, zolpidem, enalapril and ramipril. Thirty-nine reports involved a drug-drug interaction with antithrombotics, mainly with anti-infectives.
CONCLUSION: Gingival bleeding can be an adverse drug reaction, often "serious" and rarely fatal. Patients older than 50 years and women are particularly at risk. Among drugs known to increase the risk of gingival bleeding, the most frequently involved were fluindione, furosemide, paracetamol, amiodarone, amoxicillin, paroxetine or ketoprofen. We also identified signal for drugs not usually known to be involved in bleeding, like zolpidem, enalapril or ramipril.

PMID: 28667742 [PubMed - indexed for MEDLINE]

Advances in hypersensitivity drug reactions.

Curr Opin Allergy Clin Immunol. 2016 08;16(4):297-9

Authors: Blanca M, Thong BY

PMID: 27327122 [PubMed - indexed for MEDLINE]

13 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")

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13 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 2018/07/26

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.

14 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 2018/07/25

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.

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 2018/07/24

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.

16 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 2018/07/22

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.

Communicating risk of medication side-effects: role of communication format on risk perception.

Pharm Pract (Granada). 2018 Apr-Jun;16(2):1174

Authors: Sawant R, Sansgiry S

Abstract
Background: Medication side-effects often arouse fear in the minds of consumers and therefore need to be communicated in a manner such that the intended message is clearly understood, without causing undue fear.
Objectives: Considering the message format and contextual factors that influence perceptions of risk, this study aimed at assessing the interaction effects of message format and contextual factors (rate of occurrence and severity) on risk perception of medication side-effects.
Methods: Using Rhormann's risk communication process model, a 2 (message format: words-only vs. words + numeric) X 2 (rate of occurrence: high vs low) X 2 (severity: mild vs severe) experimental factorial study was designed. Participants were presented with four of eight possible combinations of the three factors and were asked to indicate the risk perception with the associated side-effects. Repeated measures analysis was conducted while adjusting for control variables.
Results: A total of 196 completed surveys were collected. Communication format did not have significant main effect on risk perception (P=0.4237) but demonstrated a significant interaction with rate of occurrence (P=0.0001). As compared to words-only format, least square means for words + numeric format were lower among low-rate side-effects but were higher among high-rate side-effects. Rate of occurrence (P<0.0001) and severity (P<0.0001) had significant main effects on risk perception as well as interaction effect with each other (P<0.0001).
Conclusions: The results indicated that effect of communication format on risk perception of side-effect is dependent on the underlying rate of occurrence of side-effect. Healthcare providers should therefore carefully construct risk communication messages for effective communication with patients.

PMID: 30023029 [PubMed]

Phase 2 study of gandotinib (LY2784544) in patients with myeloproliferative neoplasms.

Leuk Res. 2018 Jun 30;71:82-88

Authors: Berdeja J, Palandri F, Baer MR, Quick D, Kiladjian JJ, Martinelli G, Verma A, Hamid O, Walgren R, Pitou C, Li PL, Gerds AT

Abstract
BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are associated with increases in janus kinase 2 (JAK2) signaling, often resulting from the JAK2 V617F mutation. LY2784544 (gandotinib) is a potent, selective, small-molecule inhibitor of JAK2 that has potential dose-dependent selectivity for the JAK2 V617F mutation and may inhibit additional JAK2 mutant isoforms in nonclinical testing.
METHODS: A multicenter, single-arm, outpatient phase 2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of gandotinib administered to patients (120 mg once daily) with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Between May 2012 and March 2015, 138 patients received at least one dose of study drug.
FINDINGS: Most frequent Grade 3 or 4 treatment-emergent adverse events that were considered study-drug related were anemia (11.6%), hyperuricemia (3.2%), fatigue (2.9%), diarrhea (2.2%), and thrombocytopenia (2.2%). Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2 V617F mutations had ORRs of 43.7% and 0%, respectively.
INTERPRETATIONS: LY2784544 demonstrated efficacy in JAK2 V617F-mutated MPNs, including in patients previously on ruxolitinib therapy, who had an ORR of 3.3%. At the 1-year visit, 44% of patients experienced a ≥50% improvement in the MPN-Symptom Assessment Form Total Symptom Score, and 26% of patients had a 50% reduction in Brief Fatigue Inventory score.

PMID: 30025280 [PubMed - as supplied by publisher]

Antiarrhythmic drug-induced smell and taste disturbances: A case report and literature review.

Medicine (Baltimore). 2018 Jul;97(29):e11112

Authors: Che X, Li Y, Fang Y, Reis C, Wang H

Abstract
RATIONALE: Metoprolol and amiodarone are common antiarrhythmic drugs used in clinics throughout the world. The taste and smell alterations induced by antiarrhythmic drugs remain uncommon throughout the world, with less than 10 reported cases.
PATIENT CONCERNS: In this case report, we describe a case of a 73-year-old female, diagnosed with arrhythmias, was treated for metoprolol. At the third week of metoprolol treatment, the patient noticed a qualitative change in her ability to smell, also called dysosmia. After the metoprolol was tapered, her ability to smell was recovered. However, her arrhythmia was getting worse and the patient was given amiodarone. After using amiodarone for about 2 weeks, the patient felt hypogeusia, or loss of taste sensation.
DIAGNOSES: The patient was diagnosed as dysosmia and taste disturbance induced by the antiarrhythmic drugs.
INTERVENTIONS: After noticed the side effects of the antiarrhythmic drugs, we asked the patient to abandon the drugs and have a radiofrequency ablation.
OUTCOMES: Her ability of smell and taste were recovered after withdrawing the antiarrhythmic drugs. Also, in the follow-up appointment, she reported no complaints of smell or taste anymore.
LESSONS: These rare sensory disorders induced by anti-arrhythmic drugs were less documented in past literature. Our case report describes a patient with an arrhythmia who suffered reversible dysosmia and hypogeusia after taking metoprolol and amiodarone, respectively. We conclude that smell and taste disorders should be made aware to patients during the anti-arrhythmic treatment, helping to promote the safety of patients and drug compliance.

PMID: 30024498 [PubMed - in process]

[Recording and assessment of medication errors : Experience of the Drug Commission of the German Medical Association].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2018 Jul 18;:

Authors: Köberle U, Stammschulte T, Gundert-Remy U, Pitzer M, Bräutigam K

Abstract
Adverse drug reactions (ADRs) are a common problem in daily clinical practice and they may in part result from medication errors. According to the extended interpretation in the new European pharmacovigilance guideline, medication error-related reactions are classified as ADRs. Therefore, the pharmacovigilance system needs to be adjusted to record medication errors. As a partner in the German pharmacovigilance system, the Drug Commission of the German Medical Association (DCGMA) has set up a project for developing a subsystem for the recording and assessment of medication errors within the existing spontaneous reporting system for ADRs. The aim of the project was to evaluate the feasibility of recording and assessing medication errors within the existing structures and to investigate whether it is possible to deduce risk-reducing strategies from the information obtained by the case reports. In the present narrative review, the experience of the DCGMA with the recording and assessment of medication errors is described. The conclusions and recommendations from the analysis of the reports of medication errors show how they can be used to improve medication safety. The project has closed a gap in pharmacovigilance.

PMID: 30022236 [PubMed - as supplied by publisher]

Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3).

Mov Disord. 2017 Dec;32(12):1701-1709

Authors: Oertel W, Eggert K, Pahwa R, Tanner CM, Hauser RA, Trenkwalder C, Ehret R, Azulay JP, Isaacson S, Felt L, Stempien MJ

Abstract
BACKGROUND: The treatment of levodopa-induced dyskinesia in Parkinson's disease (PD) is an unmet need with no approved drug therapy.
OBJECTIVE: The purpose of this study was to investigate the efficacy and safety of 274 mg ADS-5102 (amantadine) extended-release capsules (equivalent to 340-mg amantadine HCl) for levodopa-induced dyskinesia in a randomized controlled trial.
METHODS: PD patients with ≥1 hour of troublesome dyskinesia and at least mild functional impact were randomized to placebo or ADS-5102 once daily at bedtime for 13 weeks. The primary efficacy analysis was based on change from baseline to week 12 on the Unified Dyskinesia Rating Scale total score in the modified intent-to-treat population. OFF time was a key secondary measure.
RESULTS: At week 12, least-squares mean change in the Unified Dyskinesia Rating Scale was -20.7 (standard error 2.2) for ADS-5102 (n = 37) and -6.3 (standard error 2.1) for placebo (n = 38; treatment difference -14.4, 95% confidence interval -20.4 to -8.3, P < .0001), indicating improvement in levodopa-induced dyskinesia. OFF time decreased 0.5 hours (standard error 0.3) for ADS-5102 from a baseline mean of 2.6 hours and increased 0.6 hours (standard error 0.3) for placebo from a baseline mean of 2.0 hours (treatment difference -1.1 hours, 95% confidence interval -2.0 to -0.2, P = .0199). The most common adverse events (ADS-5102 versus placebo) included dry mouth (13.5% versus 2.6%), nausea (13.5% versus 2.6%), decreased appetite (10.8% versus 0%), insomnia (10.8% versus 0%), orthostatic hypotension (10.8% versus 0%), constipation (8.1% versus 0%), falls (8.1% versus 5.3%), and visual hallucinations (8.1% versus 5.3%). Adverse events led to treatment discontinuation in 19% versus 8%, respectively.
CONCLUSION: ADS-5102 274 mg is an oral pharmacotherapy demonstrating a significant decrease in levodopa-induced dyskinesia and improving OFF time. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

PMID: 28833562 [PubMed - indexed for MEDLINE]

Clinical Effects of Piribedil in Adjuvant Treatment of Parkinson's Disease: A Meta-Analysis.

Open Med (Wars). 2018;13:270-277

Authors: Peihua L, Jianqin W

Abstract
OBJECTIVE: To evaluate the clinical effects of piribedil in adjuvant treatment of Parkinson's Disease (PD) by pooling previously openly published studies.
METHODS: The related electronic databases of Medline (1960~2017.5), Cochrane central register of controlled trials (CENTRAL), EMBASE (1980~2017.5) and Wanfang (1986~20175.5) were searched by two reviewers (Lu Peihua and Wang Jianqian) independently for publications including the topic of prospective randomized controlled trials about clinical effects of piribedil in adjuvant treatment of PD. The data of each included study was extracted and pooled by Stata11.0 software (for meta-analysis). The statistical heterogeneity across the studies was evaluated by I2 test and the publication bias was calculated by begg's funnel plot and Egger's line regression test.
RESULTS: After searching the related electronic databases of Medline, CENTRAL, EMBSE and Wanfang databases, 11 clinical studies were included in this meta-analysis. The pooled RR (random effect model) of clinical efficacy was 1.29 (95%CI:1.18~1.41, P=4×10-3) indicating the clinical efficacy of piribedil group was signficat higher than those of control group. The standard mean difference (SMD) for UPDRS score changed before and after treatment was pooled by random effect model. The combined SMD was -0.41 (95%CI:-0.75~-0.06). For piribedil related side effects, the combined data indicated that there was no statistical difference for nausea and vomiting (RR=0.43, 95%CI:0.41~1.69, P=0.61), mental disorders (RR=0.85, 95%CI:0.45~1.59, P=0.61) and other toxicities (RR=0.32, 95%CI:0.09~1.16, P=0.08).
CONCLUSION: Piribedil combined with Levodopa in adjuvant treatment of PD is more effective than Levodopa alone without increasing the drug related toxicity.

PMID: 30019007 [PubMed]

Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours.

ESMO Open. 2018;3(4):e000381

Authors: Fiedler W, Stoeger H, Perotti A, Gastl G, Weidmann J, Dietrich B, Baumeister H, Danielczyk A, Goletz S, Salzberg M, De Dosso S

Abstract
Purpose: TrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco-optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab's antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX.
Patients and methods: A total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12-720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose.
Results: No dose limiting toxicity was observed, and no maximum tolerated dose was reached. Drug-related adverse events were mainly infusion-related reactions occurring during the first infusion in 51% of patients; all but two were mild-to-moderate. Compared with trastuzumab, the PK parameters were dose dependent, with a mean terminal half-life (t1/2) of 263±99 hours for the 720 mg dose. Clinical benefit in 15 out of 30 (50%) evaluable patients included one ongoing complete response, two partial remissions lasting 16 and 77 weeks and disease stabilisation (SD) in 12 patients lasting a median (range) of 17 (7-26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively.
Conclusion: TrasGEX was safe, well-tolerated and showed antitumour activity in 50% of evaluable patients, all with progressive disease at study entry. Infusions at an interval of 2-3 weeks should achieve clinically relevant trough levels for future studies (NCT01409343).

PMID: 30018811 [PubMed]

Comparison of Preoperative Administration of Pregabalin and Duloxetine on Cognitive Functions and Pain Management after Spinal Surgery: A Randomized Double-blind Placebo-controlled Study.

Clin J Pain. 2018 Jul 16;:

Authors: Altıparmak B, Güzel Ç, Gümüş Demirbilek S

Abstract
STUDY OBJECTIVE: The surgical trauma is known to induce hyperalgesia and if pain management is insufficient, it contributes to persistent pain in the postoperative period.In this study, our primary aims are to compare the effect of pregabalin and duloxetine on postoperative pain scores and cognitive functions. Our secondary aim is to determine drug-related side-effects.
DESIGN: Prospective, randomized, double-blind, placebo-controlled.
SETTINGS: Operating room, surgical ward.
PATIENTS: Nintyfour patients,18-65 years of age, ASA status I-II, scheduled for elective repair of lumbar disc herniation.
INTERVENTIONS: The patients were randomly divided into three groups; the first group orally received pregabalin 75▒mg one hour prior to the surgery and at the postoperative 12 and 24 hours. The second group orally received duloxetine 60▒mg one hour prior to the surgery. At the postoperative 12 hour, they received a placebo capsule and at the 24 hour, they received duloxetine 60▒mg again. The third group orally received placebo capsules at all timepoints.
MEASUREMENTS: Postoperative pain evaluation was conducted using visual analogue scale (VAS) at postoperative first minute, 30 minute, first hour, 12, 24 and 48 hour. The preoperative and postoperative 6 hour cognitive functions were evaluated with Montreal Cognitive Assessment (MOCA) test.
MAIN RESULTS: There was a significant reduction in mean MOCA scores postoperatively in all groups (P<0.01). The highest MOCA score reduction was in pregabalin group (1,83±1,31 point), then in duloxetine group (1,16±0,82) and least decrease was in control group (0,49±0,61). At all timepoints mean VAS scores of pregabalin and duloxetine groups were similar to each other and they were lower than control groups (P<0.05).
CONCLUSIONS: Preoperative use of duloxetine 60▒mg can be an useful alternative to pregabalin 75▒mg as it has similar analgesic effect on postoperative pain with fewer drug-related cognitive function deterioration.

PMID: 30020088 [PubMed - as supplied by publisher]