Simulating the effect of sodium channel blockage on cardiac electromechanics.

Proc Inst Mech Eng H. 2019 Oct 18;:954411919882514

Authors: Shalaby N, Zemzemi N, Elkhodary K

Abstract
There is growing interest to better understand drug-induced cardiovascular complications and to predict undesirable side effects at as early a stage in the drug development process as possible. The purpose of this paper is to investigate computationally the influence of sodium ion channel blockage on cardiac electromechanics. To do so, we implement a myofiber orientation dependent passive stress model (Holzapfel-Ogden) in the multiphysics solver Chaste to simulate an imaged physiological model of the human ventricles. A dosage of a sodium channel blocker was then applied and its inhibitory effects on the electrical propagation across ventricles were modeled. We employ the Kerckhoffs active stress model to generate electrically excited contractile behavior of myofibers. Our predictions indicate that a delay in the electrical activation of ventricular tissue caused by the sodium channel blockage translates to a delay in the mechanical biomarkers that were investigated. Moreover, sodium channel blockage was found to increase left ventricular twist. A multiphysics computational framework from the cell level to the organ level was thus used to predict the effect of sodium channel blocking drugs on cardiac electromechanics.

PMID: 31625448 [PubMed - as supplied by publisher]

Assessment of effectiveness and safety of biosimilar infliximab (CT-P13) in a real-life setting for treatment of patients with active rheumatoid arthritis or ankylosing spondylitis.

Curr Med Res Opin. 2018 10;34(10):1763-1769

Authors: Codreanu C, Šírová K, Jarošová K, Batalov A

Abstract
OBJECTIVE: To assess the effectiveness and safety of infliximab biosimilar, CT-P13, administered in a real-life setting to adult patients with active rheumatoid arthritis (RA) or ankylosing spondylitis (AS).
METHODS: This multi-center, non-interventional, observational study was conducted in Bulgaria, the Czech Republic, and Romania. A total of 151 patients with severe active RA (n = 81) or AS (n = 70) were enrolled and treated with CT-P13 for 24 weeks, according to current medical recommendations. Effectiveness was assessed using the 4-item Disease Activity Score 28 with C-reactive protein (DAS28-CRP) for RA patients, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS patients. Safety was assessed by withdrawals and adverse events (AEs).
RESULTS: A total of 129 patients (RA: 67; AS: 62) were included in the effectiveness analysis. CT-P13 treatment significantly improved DAS28-CRP scores at 12 and 24 weeks (p = .0001 vs baseline for both timepoints) in patients with RA and BASDAI scores at 12 and 24 weeks (p = .0001 vs baseline for both timepoints) in patients with AS. CRP levels were significantly reduced at 12 and 24 weeks (p = .0001 vs baseline for both timepoints). Among 713 infusions, 34 AEs were reported (4.8% of infusions), of which 11 were considered related to CT-P13 treatment. Two of seven serious AEs were considered possibly (hepatocellular injury) or definitely (dyspnoea due to allergic infusion reaction) treatment-related. Eight patients discontinued CT-P13 due to AEs and four patients were withdrawn due to therapeutic failure.
CONCLUSIONS: CT-P13 was effective and safe in a real-life setting in patients with active RA or AS.

PMID: 29439591 [PubMed - indexed for MEDLINE]

[Description of contributing factors in adverse events related to patient safety and their preventability].

Aten Primaria. 2018 10;50(8):486-492

Authors: Guerra-García MM, Campos-Rivas B, Sanmarful-Schwarz A, Vírseda-Sacristán A, Dorrego-López MA, Charle-Crespo Á

Abstract
OBJECTIVE: To assess the extent of healthcare related adverse events (AEs), their effect on patients, and their seriousness. To analyse the factors leading to the development of AEs, their relationship with the damage caused, and their degree of preventability.
DESIGN: Retrospective descriptive study.
LOCATION: Porriño, Pontevedra, Spain, Primary Care Service, from January-2014 to April-2016.
PARTICIPANTS AND/OR CONTEXT: Reported AEs were entered into the Patient Safety Reporting and Learning System (SiNASP).
METHOD: The variables measured were: Near Incident (NI) an occurrence with no effect or harm on the patient; Adverse Event (AE) an occurrence that affects or harms a patient. The level of harm is classified as minimal, minor, moderate, critical, and catastrophic. Preventability was classified as little evidence of being preventable, 50% preventable, and sound evidence of being preventable.
DATA ANALYSIS: percentages and Chi-squared test for qualitative variables; P<.05 with SPSS.15.
DATA SOURCE: SiNASP. Ethical considerations: approved by the Research Ethics Committee (2016/344).
RESULTS: There were 166 recorded AEs (50.6% in males, and 46.4% in women. The mean age was 60.80years). Almost two-thirds 62.7% of AEs affected the patient, with 45.8% causing minimal damage, while 2.4% caused critical damages. Healthcare professionals were a contributing factor in 71.7% of the AEs, with the trend showing that poor communication and lack of protocols were related to the damage caused. Degree of preventability: 96.4%.
CONCLUSIONS: Most AEs affected the patient, and were related to medication, diagnostic tests, and laboratory errors. The level of harm was related to communication problems, lack of, or deficient, protocols and a poor safety culture.

PMID: 29183678 [PubMed - indexed for MEDLINE]

[Impact of medium-term outcomes of inappropriate prescribing in older patients discharged from a short stay unit].

Aten Primaria. 2018 10;50(8):467-476

Authors: Rodríguez Del Río E, Perdigones J, Fuentes Ferrer M, González Del Castillo J, González Armengol J, Borrego Hernando MI, Arias Fernández ML, Martín-Sánchez FJ

Abstract
OBJECTIVE: To study the association between the potential inappropriate prescriptions (PIP) and the 30 and 180-day adverse event rate after discharge from a Short Stay Unit (SSU).
METHODOLOGY: A retrospective cohort observational study was conducted on patients aged ≥75years discharged from an SSU from February to April, 2014. STOPP-START criteria version2 was used. The main outcome was 30 and 180-day adverse event rate after being discharged.
RESULTS: A total of 179 patients, with a mean age of 84 (SD5) years were included. The presence of ≥1PIP after being discharged was not associated with a 30 and 180-day composite adverse event. Patients with ≥1PIP related to a cerebro-cardiovascular process were at higher risk of an adverse event at 30 days after discharge (adjusted OR, 2.1; 95%CI: 1.0-3.2; P=.045), those with ≥1PIP related to neuropsychiatric process and risk of fall were at higher risk of increased 30-day functional impairment (adjusted OR, 6.3; 95%CI: 1.7-22.5; P=.005), and those with ≥1PIP related to omission of cardiovascular system were at higher risk of 180-day hospital readmission (adjusted OR, 3.6; 95%CI: 1.5-8.3; P=.003).
CONCLUSIONS: The presence of adverse events in older patients discharged from SSU may be associated with PIP, identified by STOPP-START criteria, and more specifically with drugs related to cardiovascular, neuropsychiatric disorders, and falls.

PMID: 29079010 [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 2019/10/18

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 2019/10/18

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.

Safinamide in Clinical Practice: A Spanish Multicenter Cohort Study.

Brain Sci. 2019 Oct 11;9(10):

Authors: Martí-Andrés G, Jiménez-Bolaños R, Arbelo-González JM, Pagonabarraga J, Duran-Herrera C, Valenti-Azcarate R, Luquin MR

Abstract
Background: Safinamide is an approved drug for the treatment of motor fluctuations of Parkinson's Disease (PD) patients with a potential benefit on non-motor symptoms (NMS). Methods: A retrospective multicenter cohort study was conducted, in which the clinical effect of safinamide on both motor and NMS was assessed by the Clinical Global Impression of Change scale. Furthermore, we assessed the appearance of adverse events (AEs) and its effect on dyskinesia, that were also recorded in non-fluctuating PD patients and in those previously treated with rasagiline. Results: We included 213 PD patients who received safinamide in addition to their regular levodopa therapy. Thirty-five withdrew prematurely from safinamide, mainly because of AEs. Out of 178, clinical improvement on motor and NMS was found in 76.4% and 26.2%, respectively. A total of 44 reported AEs of mild intensity. We did not find a difference concerning the clinical benefit or AEs when comparing either patients who had or had not been taking Monoamine Oxidase B Inhibitor (MAOB-I) previously or between patients with and without motor complications. Conclusions: Safinamide is an effective and safe add-on to levodopa drug for PD patients. Moreover, safinamide could elicit an additional clinical improvement in PD patients previously treated with other MAOB-I and in non- fluctuating patients with suboptimal motor control.

PMID: 31614574 [PubMed]

Meropenem-Vaborbactam in the Treatment of Acute Bacterial Infections.

J Clin Med. 2019 Oct 11;8(10):

Authors: Lai CC, Chen CC, Tang HJ

Abstract
This study reports the integrated analysis of two phase III studies of meropenem-vaborbactam in the treatment of acute bacterial infections. Targeting Antibiotic Non-Susceptible Gram-Negative Organisms (TANGO) I compared the clinical efficacy and tolerability of meropenem-vaborbactam and piperacillin-tazobactam in the treatment of complicated urinary tract infection (cUTI)/acute pyelonephritis (APN). TANGO II compared the effect and safety of meropenem-vaborbactam and best-available therapy in the treatment confirmed/suspect carbapenem-resistant Enterobacteriaceae infections. The clinical cure rates at end of treatment (EOT) and test of cure (TOC) among the meropenem-vaborbactam group were non-inferior to those of the control group (at EOT, 92.5% versus 89.3%, risk ratio (RR) 1.27, 95% CI 0.64-2.50; at TOC, 86.2% versus 81.7%, RR 1.37, 95% CI 0.62-3.01). Meropenem-vaborbactam was non-inferior to comparators for microbiological eradication at EOT and TOC (at EOT, 93.3% versus 88.3%, RR 1.21, 95% CI 0.74-1.97; at TOC, 66.5% versus 59.9%, RR 1.12, 95% CI 0.97-1.30). In the subgroup of patients with cUTI/APN, meropenem-vaborbactam had similar overall success rate to the control group at EOT (RR 1.05, 95% CI 1.01-1.09) and at TOC (RR 1.05, 95% CI 0.93-1.19). Meropenem-vaborbactam had a similar risk of treatment-emergent adverse events, events leading to discontinuation of the study drug, any serious adverse events, life-threatening adverse events, drug-related adverse events, and risk of death to comparators. In conclusion, meropenem-vaborbactam was noninferior to comparators for clinical cure and microbiological eradication in the treatment of acute bacterial infection, particularly cUTI/APN, and meropenem-vaborbactam was as tolerable as comparators.

PMID: 31614430 [PubMed]

Frequency of low-grade adverse events and quality of life during chemotherapy determine patients' judgement about treatment in advanced-stage thoracic cancer.

Support Care Cancer. 2019 Sep;27(9):3563-3572

Authors: de Mol M, Visser S, den Oudsten BL, Lodder P, van Walree N, Belderbos H, Aerts JG

Abstract
PURPOSE: In lung cancer, the preservation of well-being is warranted given the limited prognosis. Chemotherapy may negatively influence health-related quality of life (HRQoL) due to adverse events. However, patients' judgement about this negative impact is not well understood. We examined the relationship between expectations, feelings about side effects, and satisfaction with therapy and (HR)QoL in advanced-stage thoracic cancer and investigated which of these factors has the highest impact on (HR)QoL.
METHODS: Sixty-nine patients completed the Cancer Therapy Satisfaction Questionnaire (CTSQ), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Multiple regression analyses were performed to investigate the relation of the CTSQ domains (i.e., expectations of therapy, feelings about side effects, satisfaction with therapy) with (HR)QoL and simple regression analyses to identify the factors of the CTSQ domain that was most often associated with (HR)QoL.
RESULTS: Feelings about side effects were associated with the (HR)QoL domain/scale scores (i.e., WHOQOL-BREF domains: β = 0.36 to 0.58; EORTC QLQ-C30 scales: β = 0.33 to 0.61) except social relationships of the WHOQOL-BREF. Low-grade adverse events were related to feelings about side effects (β = - 0.326; P = 0.007).
CONCLUSIONS: Patients experiencing negative feelings about side effects have worse (HR)QoL. Additional care should be provided to prevent low-grade adverse events.

PMID: 30690684 [PubMed - indexed for MEDLINE]

Prevalence of oral side effects of chemotherapy and its relationship with periodontal risk: a cross sectional study.

Support Care Cancer. 2019 Sep;27(9):3479-3490

Authors: García-Chías B, Figuero E, Castelo-Fernández B, Cebrián-Carretero JL, Cerero-Lapiedra R

Abstract
PURPOSE: To determine the prevalence of professionally reported oral side effects of chemotherapy and the self-reported oral side effects and whether both prevalences could be related to the periodontal risk of the patients.
METHODS: A cross-sectional study with patients undergoing chemotherapy treatment was carried out. Demographic, oral hygiene habits, and cancer-related data were collected while the patient was receiving the chemotherapy infusion. Patient's oral status, measured according to the oral-assessment guide for patients in hospital environments, patient-related outcomes (PROMs), measured by a visual analogue scale, and patient's periodontal risk were analyzed using validated questionnaires. Data was reported in means and standard deviations (SD) in quantitative variables and in counts, prevalence, and 95% confidence intervals (CI) in qualitative variables. ANOVA test and chi-squared tests were used to compare oral side effects among different periodontal risk groups.
RESULTS: Three hundred sixty-nine patients were included in the study. The prevalence of professionally reported oral side effects was 86.99% (95% confidence interval CI 83.54%; 90.44%). The prevalence of self-reported oral side effects was 89.70% (95% CI 86.59; 92.82). The most common oral side effects were xerostomia (73.4%), dysgeusia (61.8%), and dry lips (54.2%). More oral alterations were found in patients with worse periodontal risk (p < 0.001).
CONCLUSIONS: The prevalence of oral side effects (professional or self-reported) is higher than 85% in patients undergoing chemotherapy. This prevalence increases as the risk of developing periodontal disease does.

PMID: 30675665 [PubMed - indexed for MEDLINE]

Bulgarian Experience with Adverse Drug Reaction Reports from Patients and Consumers - Retrospective Data-base Study.

Folia Med (Plovdiv). 2018 Sep 01;60(3):447-453

Authors: Getova VI, Georgiev SR, Stoimenova AH, Petkova-Georgieva ES

Abstract
BACKGROUND: Since 2012, in compliance with the changes in the European legislation, the Bulgarian Drug Agency (BDA) has been receiving adverse drug reaction (ADR) reports directly from patients as well as from healthcare professionals and marketing authorization holders (MAH). Adverse reaction reports from patients and consumers have different characteristics from those sent by healthcare professionals. Moreover, they may require specific algorithm and assessment methods in order to be informative and beneficial to the pharmacovigilance system.
AIM: The study aims to analyze the data-base of consumer reports in Bulgaria in order to distinguish and classify the main characteristics of the ADR reports from non-healthcare professionals.
MATERIALS AND METHODS: In-depth analysis of the Bulgarian data-base of consumer ADR reports for 2012-2016 was conducted. The criteria include patient demographic characteristics, preferred method of reporting, seriousness and expectedness criteria and most frequently reported pharmacological groups.
RESULTS: The data showed the current trends in patient reporting in the country. It also marked new courses for development of the spontaneous reporting system and collection of safety data. The analysis of the data-base showed a rather stable level of patient reporting with a tendency for constant growth every year. Bulgaria follows the world tendencies for high number of reports for insufficiently studied ADRs which meet the seriousness criteria. The review of the most frequently reported ATC codes could lead to the conclusion that the current pharmacovigi-lance methods are not sensitive enough for specific groups of medicines.
CONCLUSIONS: The results from the conducted study confirm the importance of patient reporting as a valuable source of information on adverse drug reactions. Moreover, it draws the attention to the lack of more sensitive methods for evaluation of drug safety in specific pharmacological groups. Maintenance of consumer-friendly ADR reporting system and innovative assessment algorithms should be the future directions for development in post-marketing surveillance.

PMID: 30355838 [PubMed - indexed for MEDLINE]

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Comparative Study From Sudan.

J Glob Oncol. 2018 09;4:1-9

Authors: Osman AAM, Elhassan MMA, AbdElrahim BHA, Ahmed FHA, Yousif JBH, Ahmed MAM, Abdelhafeez RHA, Ahmed UMY

Abstract
PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a distressing adverse effect. Neurokinin-1 receptor antagonist (NK1RA)-containing regimens are the standard regimens for CINV prophylaxis in patients with cancer receiving highly or moderately emetogenic chemotherapy (HEC or MEC). NK1RA agents are expensive and were not registered in Sudan. Recently, regimens containing olanzapine, the available and affordable medication in Sudan, were introduced as another option. This study aimed to compare the efficacy of an olanzapine-containing regimen with the antiemetic regimen that was currently used in our institute for CINV prophylaxis in HEC/MEC settings.
PATIENTS AND METHODS: The study prospectively compared an olanzapine-containing regimen (acute phase: olanzapine, ondansetron, dexamethasone; delayed phase: olanzapine, ondansetron) with an ondansetron/dexamethasone regimen (acute phase: ondansetron, dexamethasone; delayed phase: ondansetron) in adult patients with cancer receiving HEC or MEC. The study outcomes were complete response (CR; no emesis and no rescue medications) and nausea control (no nausea), which were assessed in the acute (0 to 24 hours), delayed (24 to 120 hours), and overall (0 to 120 hours) phases.
RESULTS: The study included 131 patients (olanzapine-containing: 50 patients; ondansetron/dexamethasone: 81 patients). CR and nausea control were higher in the olanzapine-containing than in the ondansetron/dexamethasone regimen (CR: acute phase, 86% v 71.6%; P = .086; delayed phase, 72% v 30.9%; P < .001; overall phase, 66% v 25.9%; P < .001; nausea control: acute phase, 86% v 74.1%; P = .127; delayed phase, 76% v 34.6%; P < .001; overall phase, 72% v 29.6%; P < .001). The major toxicity of olanzapine was grade 1 and 2 sedation or drowsiness (25 patients).
CONCLUSION: An olanzapine-containing regimen has better efficacy for prevention of CINV in the HEC/MEC setting. Oncologists working in a limited-resource setting should be familiar with olanzapine-containing regimens, because NK1RA agents are not affordable and not easily available.

PMID: 30241275 [PubMed - indexed for MEDLINE]

Efficacy/toxicity dose-finding using hierarchical modeling for multiple populations.

Contemp Clin Trials. 2018 08;71:162-172

Authors: Cunanan KM, Koopmeiners JS

Abstract
Traditionally, Phase I oncology trials evaluate the safety profile of a novel agent and identify a maximum tolerable dose based on toxicity alone. With the development of biologically targeted agents, investigators believe the efficacy of a novel agent may plateau or diminish before reaching the maximum tolerable dose while toxicity continues to increase. This motivates dose-finding based on the simultaneous evaluation of toxicity and efficacy. Previously, we investigated hierarchical modeling in the context of Phase I dose-escalation studies for multiple populations and found borrowing strength across populations improved operating characteristics. In this article, we discuss three hierarchical extensions to commonly used probability models for efficacy and toxicity in Phase I-II trials and adapt our previously proposed dose-finding algorithm for multiple populations to this setting. First, we consider both parametric and non-parametric bivariate models for binary outcomes and, in addition, we consider an under-parameterized model that combines toxicity and efficacy into a single trinary outcome. Our simulation results indicate hierarchical modeling increases the probability of correctly identifying the optimal dose and increases the average number of patients treated at the optimal dose, with the under-parameterized hierarchical model displaying desirable and robust operating characteristics.

PMID: 29936124 [PubMed - indexed for MEDLINE]

11 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 2019/10/16

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.

11 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 2019/10/16

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.

The frequency and nature of clinician identified medication-related rapid response system calls.

Resuscitation. 2019 Oct 11;:

Authors: Levkovich BJ, Bingham G, Orosz J, Cooper DJJ, Kirkpatrick CM, Dooley MJ, Jones DA

Abstract
AIM: The contribution of adverse medication events to clinical deterioration is unknown. This study aimed to determine the frequency and nature of rapid response system (RRS) calls that clinicians perceived were medication-related using RRS quality arm data.
METHODS: Analysis of routine data prospectively collected by clinicians responding to RRS calls in an Australian acute tertiary academic hospital.
RESULTS: Between January 2013 and June 2017, 12,221 adult patients triggered the RRS for 25,906 medical emergency team (MET) and 512 code blue calls. Clinicians identified 433 medication-related RRS calls (1.6%) involving 406 patients (3.3%). These included 418 MET calls (1.3 medication-related MET calls per 1000 admissions) and 15 code blue calls (0.045 medication-related code blue calls per 1000 admissions). Medication-related calls occurred earlier in the admission (p = 0.002) and were more common for patients triggering multiple calls during the same admission (p < 0.001), compared to non-medication-related calls. Medication-related calls most commonly were triggered by low blood pressure (38.3%) and involved cardiovascular (43.0%) and nervous system medications (36.0%). Dose-related toxicity (n = 178) was the most frequent adverse medication event contributing to medication-related calls.
CONCLUSION: One in 30 patients triggering a RRS call experienced medication-related clinical deterioration, most often due to dose related toxicity of cardiovascular system medications. The perceived frequency and potential preventability of this medication-related harm suggest further research is required to increase recognition of medication-related RRS calls by responding clinicians and to reduce the incidence.

PMID: 31610227 [PubMed - as supplied by publisher]

Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener. 2019 Oct 14;:1-9

Authors: Babu S, Macklin EA, Jackson KE, Simpson E, Mahoney K, Yu H, Walker J, Simmons Z, David WS, Barkhaus PE, Simionescu L, Dimachkie MM, Pestronk A, Salameh JS, Weiss MD, Brooks BR, Schoenfeld D, Shefner J, Aggarwal S, Cudkowicz ME, Atassi N

Abstract
Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (-0.80 vs. -0.84 T40, -0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

PMID: 31608711 [PubMed - as supplied by publisher]

Long-term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy.

Epilepsia. 2019 Oct 13;:

Authors: Desloovere J, Boon P, Larsen LE, Merckx C, Goossens MG, Van den Haute C, Baekelandt V, De Bundel D, Carrette E, Delbeke J, Meurs A, Vonck K, Wadman W, Raedt R

Abstract
OBJECTIVE: More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy.
METHODS: Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored.
RESULTS: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals.
SIGNIFICANCE: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

PMID: 31608439 [PubMed - as supplied by publisher]

Efficacy and Safety of 12-week Interferon-based Danoprevir Regimen in Patients with Genotype 1 Chronic Hepatitis C.

J Clin Transl Hepatol. 2019 Sep 28;7(3):221-225

Authors: Wei L, Shang J, Ma Y, Xu X, Huang Y, Guan Y, Duan Z, Zhang W, Gao Z, Zhang M, Li J, Jia J, Yang Y, Wen X, Wang M, Jia Z, Ning B, Chen Y, Qi Y, Du J, Jiang J, Tong L, Xie Y, Wu JJ

Abstract
Background and Aims: Genotype (GT) 1 remains the predominant hepatitis c virus (HCV) GT in Chinese patients. Over 80% of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860, which is favorable for interferon-based treatment regimens. This phase III clinical trial aimed to evaluate the efficacy and safety of the ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin regimen for 12 weeks in treatment-naïve mainland Chinese patients infected with HCV GT1 without cirrhosis. Methods: One hundred and forty-one treatment-naïve, non-cirrhotic HCV GT1 Chinese patients (age ≥18 years) were enrolled for this single-arm, multicenter, phase III MANASA study (NCT03020082). Patients received a combination of ritonavir-boosted danoprevir (100 mg/100 mg) twice a day plus subcutaneous injection of weekly pegylated-interferon α-2a (180 μg) and oral ribavirin (1000/1200 mg/day body weight <75/≥75 kg) for 12 weeks. The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment. The secondary end-points were safety outcomes, tolerability, virologic response over time and relapse rate. Results: All enrolled patients were HCV GT1-infected, and most among them (97.9%, 123/141) had the HCV GT1b subtype. Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype (87.2%, 123/141). Overall, 140 patients completed the 12-week treatment, and 97.1% (136/140) patients achieved sustained virologic response at 12 weeks (per protocol population group, 95% confidence interval: 92.9-99.2%). Only drug-related serious adverse event occurred. Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction. One patient discontinued treatment because of severe head injury in a car accident. Conclusions: The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin produced a sustained virologic response rate of 97.1% after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients, and was safe and well tolerated. Trial Registration Clinical-Trials.gov Identifier: NCT03020082.

PMID: 31608213 [PubMed]

A Diagnostically Challenging Infusion Reaction-Kounis, Takotsubo, or the ATAK!

JAMA Intern Med. 2019 Jan 01;179(1):99-100

Authors: Mustehsan MH, Jahufar F, Arora S

PMID: 30398531 [PubMed - indexed for MEDLINE]