Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients with Advanced or Metastatic Nonhematologic Malignancies.

Target Oncol. 2019 Feb 11;:

Authors: de Jonge MJA, Steeghs N, Lolkema MP, Hotte SJ, Hirte HW, van der Biessen DAJ, Abdul Razak AR, De Vos FYFL, Verheijen RB, Schnell D, Pronk LC, Jansen M, Siu LL

Abstract
BACKGROUND: Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor.
OBJECTIVE: Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker expression, and preliminary activity.
PATIENTS AND METHODS: The study comprised a standard 3 + 3 dose-escalation phase followed by an expansion phase in patients with selected advanced, nonhematologic malignancies.
RESULTS: Thirty-three patients received BI 853520 in the dose-escalation phase; the MTD was 200 mg once daily (QD). Dose-limiting toxicities included proteinuria and fatigue, both of which were grade 3. Preliminary PK data supported QD dosing. In the expansion cohort, 63 patients received BI 853520 200 mg QD. Drug-related adverse events (AEs) in > 10% of patients included proteinuria (57%), nausea (57%), fatigue (51%), diarrhea (48%), vomiting (40%), decreased appetite (19%), and peripheral edema (16%). Most AEs were grade 1-2; grade 3 proteinuria, reported in 13 patients (21%), was generally reversible upon treatment interruption. Nineteen patients underwent dose reduction due to AEs, and three drug-related serious AEs were reported, none of which were fatal. Preliminary PD analysis indicated target engagement. Of 63 patients, 49 were evaluable; 17 (27%) achieved a best response of stable disease (4 with 150 + days), and 32 (51%) patients had progressive disease.
CONCLUSIONS: BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. CLINICALTRIALS.
GOV IDENTIFIER: NCT01335269.

PMID: 30756308 [PubMed - as supplied by publisher]

Effect of Systematic Conversion to Generic Mycophenolate Mofetil (MMF) in Kidney Transplantation: A Single-Center Clinical Experience from Japan.

Transplant Proc. 2018 Dec;50(10):3255-3257

Authors: Hirano H, Matsunaga T, Maenosono R, Taniguchi S, Uehara H, Nomi H, Kano Y, Fujiwara Y, Ichihashi A, Kobayashi D, Tsutsumi T, Komura K, Ibuki N, Inamoto T, Matsumura H, Ashida A, Azuma H

Abstract
INTRODUCTION: Recently, more and more generic drugs have been used for immunosuppressive drugs in the field of organ transplantation. Some reports have indicated that blood concentration of most generic drugs is difficult to maintain stability, and it may cause the difference in graft survival of transplanted organs between original drugs and generic drugs. In this article, we report the cases could not maintain blood concentration of generic drugs of mycophenolate mofetil (MMF).
RESULTS: In 4 cases out of 5 cases that we had to change original MMF to generic MMF, there were cases that blood concentration level was not stabilized. There were possibility that the lowered blood concentration level of MMF caused a rejection, in two cases. Mean MMF trough level was decreased from 3.6 ± 1.9 μg/mL to 0.6 ± 0.4 μg/mL. Due to the early detection, it did not become severe or failure of graft function, however, we cannot deny the possibilities that side effects were increased and rejection rose. In these cases, we discontinued to use the generic drugs thereafter due to unstable plasma concentration of MMF.
DISCUSSION: Some reports have indicated that failure to maintain plasma concentration of MMF leads to rejection. Therefore, maintenance of effective plasma concentration and prevention of rejection are essential to long-term graft survival in kidney transplant.
CONCLUSION: Generic drug formulations may exhibit differences in effects and absorption compared to the brand-name drug. If the generic drug should be used, patients should be closely monitored.

PMID: 30577194 [PubMed - indexed for MEDLINE]

Development of torsadogenic risk assessment using human induced pluripotent stem cell-derived cardiomyocytes: Japan iPS Cardiac Safety Assessment (JiCSA) update.

J Pharmacol Sci. 2018 Dec;138(4):233-239

Authors: Kanda Y, Yamazaki D, Osada T, Yoshinaga T, Sawada K

Abstract
Cardiac safety assessment is challenging because a better understanding of torsadogenic mechanisms beyond hERG blockade and QT interval prolongation is necessary for patient safety. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a new human cell-based platform to assess cardiac safety in non-clinical testing during drug development. The multi-electrode array (MEA) platform is a promising electrophysiological technology to assess QT interval prolongation and proarrhythmic potential of drug candidates using hiPSC-CMs. The Japan iPS Cardiac Safety Assessment (JiCSA) has established an MEA protocol to evaluate the applicability of hiPSC-CMs for assessing the torsadogenic potential of compounds and completed a large-scale validation study using 60 compounds. During our study, an international multi-site study of hiPSC-CMs was performed by the Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative using 28 compounds. We have comparatively analyzed our JiCSA datasets with those of CiPA using the CiPA logistical and ordinal linear regression model. Regardless of the protocol differences, the evaluation results of the 28 compounds were very similar and highly predictable for torsadogenic risks. Thus, an MEA-based approach using hiPSC-CMs would be a standard testing method to evaluate proarrhythmic potentials. This review paper would provide new insights into the hiPSC-CMs/MEA method required for its regulatory use.

PMID: 30415824 [PubMed - indexed for MEDLINE]

Application of the comparison approach to open TG-GATEs: A useful toxicogenomics tool for detecting modes of action in chemical risk assessment.

Food Chem Toxicol. 2018 Nov;121:115-123

Authors: Heusinkveld HJ, Wackers PFK, Schoonen WG, van der Ven L, Pennings JLA, Luijten M

Abstract
Mode of action information is one of the key components for chemical risk assessment as mechanistic insight leads to better understanding of potential adverse health effects of a chemical. This insight greatly facilitates assessment of human relevance and enhances the use of non-animal methods for risk assessment, as it ultimately enables extrapolation from initiating events to adverse effects. Recently, we reported an in vitro toxicogenomics comparison approach to categorize (non-)genotoxic carcinogens according to similarities in their proposed modes of action. The present study aimed to make this comparison approach generally applicable, allowing comparison of outcomes across different studies. The resulting further developed comparison approach was evaluated through application to toxicogenomics data on 18 liver toxicants in human and rat primary hepatocytes from the Open TG-GATEs database. The results showed sensible matches between compounds with (partial) overlap in mode of action, whilst matches for compounds with different modes of action were absent. Comparison of the results across species revealed pronounced and relevant differences between primary rat and human hepatocytes, underpinning that information on mode of action enhances assessment of human relevance. Thus, we demonstrate that the comparison approach now is generally applicable, facilitating its use as tool in mechanism-based risk assessment.

PMID: 30096367 [PubMed - indexed for MEDLINE]

Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 (BMS-936559).

Crit Care Med. 2019 Feb 08;:

Authors: Hotchkiss RS, Colston E, Yende S, Angus DC, Moldawer LL, Crouser ED, Martin GS, Coopersmith CM, Brakenridge S, Mayr FB, Park PK, Ye J, Catlett IM, Girgis IG, Grasela DM

Abstract
OBJECTIVES: To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559, Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression.
DESIGN: Randomized, placebo-controlled, dose-escalation.
SETTING: Seven U.S. hospital ICUs.
STUDY POPULATION: Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL.
INTERVENTIONS: Participants received single-dose BMS-936559 (10-900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels.
MEASUREMENTS AND MAIN RESULTS: The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1-2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1-2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days.
CONCLUSIONS: In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.

PMID: 30747773 [PubMed - as supplied by publisher]

Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial.

Lancet Oncol. 2019 Feb 07;:

Authors: de Bono JS, Concin N, Hong DS, Thistlethwaite FC, Machiels JP, Arkenau HT, Plummer R, Jones RH, Nielsen D, Windfeld K, Ghatta S, Slomovitz BM, Spicer JF, Yachnin J, Ang JE, Mau-Sørensen PM, Forster MD, Collins D, Dean E, Rangwala RA, Lassen U

Abstract
BACKGROUND: Tisotumab vedotin is a first-in-human antibody-drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor.
METHODS: InnovaTV 201 is a phase 1-2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing.
FINDINGS: Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2-22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment.
INTERPRETATIONS: Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours.
FUNDING: Genmab A/S.

PMID: 30745090 [PubMed - as supplied by publisher]

Real world study of regimen containing bevacizumab as first-line therapy in Chinese patients with advanced non-small cell lung cancer.

Thorac Cancer. 2018 07;9(7):805-813

Authors: Xing P, Mu Y, Wang Y, Hao X, Zhu Y, Hu X, Wang H, Liu P, Lin L, Wang Z, Li J

Abstract
BACKGROUND: Large scale randomized controlled trials have demonstrated that the use of bevacizumab in addition to chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) conveys significant survival benefits. We explored the clinical impact of a first-line regimen containing bevacizumab (B+) versus a non-bevacizumab regimen (non-B) in advanced non-squamous NSCLC (NS-NSCLC) patients in a real world setting.
METHODS: The medical records of patients with advanced NS-NSCLC who received first-line therapy with or without bevacizumab were retrospectively collected. The primary outcome was progression-free survival (PFS), with secondary objectives of objective response rate (ORR), disease control rate (DCR), and safety. Exploratory analysis of EGFR and ALK status was conducted in subgroup.
RESULTS: One hundred and forty-nine patients met the selection criteria: 62 in the B+ and 87 in the non-B group. The baseline characteristics were well balanced. In the overall population, the median PFS was significantly longer in the B+ than in the non-B group (9.7 vs. 7.0 months, hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.30-0.91; P = 0.0184). Improved trends in both ORR and DCR were observed in the B+ group. In wild-type patients, the median PFS of the B+ was 11.3 compared to 5.5 months in the non-B group (HR 0.43, 95% CI 0.20-0.91; P = 0.0234). In wild type and unknown populations, the median PFS was 11.3 (B+) compared to 6.0 months (non-B) (HR 0.53; 95% CI 0.28-1.02; P = 0.0520). The safety profile was acceptable in both groups and no unexpected findings were observed.
CONCLUSION: Our analysis confirmed that a first-line regimen containing bevacizumab showed superior clinical benefits over a non-bevacizumab regimen in Chinese patients with advanced NS-NSCLC in a real world setting.

PMID: 29768721 [PubMed - indexed for MEDLINE]

Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea.

Scand J Gastroenterol. 2019 Feb 10;:1-6

Authors: Ota K, Takeuchi T, Kojima Y, Harada S, Ozaki H, Sugawara N, Hirata Y, Yamaguchi T, Terazawa T, Kakimoto K, Kii T, Goto M, Higuchi K

Abstract
BACKGROUND AND AIM: Although the fluoropyrimidines are effective chemotherapeutic agents for malignant gastrointestinal tumors, they sometimes cause enteritis with diarrhea. Severe treatment-related diarrhea may result in chemotherapy discontinuation. We investigated the relationship between diarrhea severity and fluoropyrimidine-induced small intestinal mucosal injury.
METHODS: We performed small bowel capsule endoscopy in patients undergoing chemotherapy including fluoropyrimidine for a malignant tumor between May 2017 and June 2018 and analyzed the relationship between the endoscopic findings and diarrhea severity. We also performed a cross-sectional analysis of patient factors and routes of chemotherapy to identify risk factors of fluoropyrimidine-induced small intestinal injury.
RESULTS: Small bowel capsule endoscopy was successfully completed in 16 eligible patients. The diarrhea grade (per the Common Terminology Criteria for Adverse Events, version 4.0) was significantly correlated with the percentage of patients with a small intestinal mucosal break (grade 0, 16.7%; grade 1, 57.1%; grade 2, 100%; p = .016, Cochran-Armitage trend test). Compared to patients receiving intravenous therapy, those receiving an orally administered fluoropyrimidine had a significantly greater number of small intestinal mucosal breaks (median number of breaks [range]; intravenous 5-fluorouracil, 0 [0-13]; oral fluoropyrimidine, 6.5 [1-20]; p = .0162, Mann-Whitney U test).
CONCLUSIONS: Many patients with diarrhea caused by chemotherapy including fluoropyrimidine had small intestinal mucosal breaks. Additionally, small intestinal mucosal breaks were more severe in patients receiving a regimen of oral treatment than in those receiving a regimen of intravenous therapy. These outcomes have important implications for investigations of new strategies for preventing anti-cancer drug-induced diarrhea.

PMID: 30739515 [PubMed - as supplied by publisher]

Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors.

Eur J Med Chem. 2019 Feb 01;163:367-380

Authors: Zhao B, Xiao Z, Qi J, Luo R, Lan Z, Zhang Y, Hu X, Tang Q, Zheng P, Xu S, Zhu W

Abstract
Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.

PMID: 30530173 [PubMed - indexed for MEDLINE]

Pharmacologic Renal Therapy.

Nurs Clin North Am. 2018 12;53(4):491-497

Authors: Ruffin T

Abstract
This article discusses some of the recommended pharmacologic treatments for patients with renal drug toxicity, acute kidney injury (AKI), and chronic kidney injury (CKI). The treatment of AKI often consists of treating patients in emergency departments. Renal pharmacologic management in an acute care setting consists of identifying the cause of AKI, reviewing serum creatinine levels, administration of crystalloids, and the elimination of nephrotoxic agents.

PMID: 30388975 [PubMed - indexed for MEDLINE]

Data Mining for Adverse Drug Events With a Propensity Score-matched Tree-based Scan Statistic.

Epidemiology. 2018 11;29(6):895-903

Authors: Wang SV, Maro JC, Baro E, Izem R, Dashevsky I, Rogers JR, Nguyen M, Gagne JJ, Patorno E, Huybrechts KF, Major JM, Zhou E, Reidy M, Cosgrove A, Schneeweiss S, Kulldorff M

Abstract
The tree-based scan statistic is a statistical data mining tool that has been used for signal detection with a self-controlled design in vaccine safety studies. This disproportionality statistic adjusts for multiple testing in evaluation of thousands of potential adverse events. However, many drug safety questions are not well suited for self-controlled analysis. We propose a method that combines tree-based scan statistics with propensity score-matched analysis of new initiator cohorts, a robust design for investigations of drug safety. We conducted plasmode simulations to evaluate performance. In multiple realistic scenarios, tree-based scan statistics in cohorts that were propensity score matched to adjust for confounding outperformed tree-based scan statistics in unmatched cohorts. In scenarios where confounding moved point estimates away from the null, adjusted analyses recovered the prespecified type 1 error while unadjusted analyses inflated type 1 error. In scenarios where confounding moved point estimates toward the null, adjusted analyses preserved power, whereas unadjusted analyses greatly reduced power. Although complete adjustment of true confounders had the best performance, matching on a moderately mis-specified propensity score substantially improved type 1 error and power compared with no adjustment. When there was true elevation in risk of an adverse event, there were often co-occurring signals for clinically related concepts. TreeScan with propensity score matching shows promise as a method for screening and prioritization of potential adverse events. It should be followed by clinical review and safety studies specifically designed to quantify the magnitude of effect, with confounding control targeted to the outcome of interest.

PMID: 30074538 [PubMed - indexed for MEDLINE]

The use of mechanistic evidence in drug approval.

J Eval Clin Pract. 2018 10;24(5):1166-1176

Authors: Aronson JK, La Caze A, Kelly MP, Parkkinen VP, Williamson J

Abstract
The role of mechanistic evidence tends to be under-appreciated in current evidence-based medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies.

PMID: 29888417 [PubMed - indexed for MEDLINE]

Longitudinal assessment of chemotherapy-induced changes in brain and cognitive functioning: A systematic review.

Neurosci Biobehav Rev. 2018 09;92:304-317

Authors: Li M, Caeyenberghs K

Abstract
In addition to the burden of a life-threatening diagnosis, cancer patients are struggling with adverse side-effects from cancer treatment. Chemotherapy has been linked to an array of cognitive impairments and alterations in brain structure and function ("chemobrain"). In this review, we summarized the existing evidence that evaluate the changes in cognitive functioning and brain with chemotherapy, as assessed using structural and functional MRI-based techniques in a longitudinal design. This review followed the latest PRISMA guidelines using Embase, Medline, PsychINFO, Scopus, and Web of Science databases with date restrictions from 2012 to 2017. Fourteen research articles met the key inclusion criteria: (i) the studies involved adult cancer patients (mean age ≥ 18); (ii) the use of chemotherapy in the treatment of cancer; (iii) pre-post assessment of behavioral and brain-based outcomes; and (iv) abstracts written in English. Effect sizes of subjective and objective cognitive impairments from the reviewed studies were estimated using Cohen's d or z-scores. We calculated percentage of mean change or effect sizes for main neuroimaging findings when data were available. Strength of the correlations between brain alterations and cognitive changes was obtained using squared correlation coefficients. Small to medium effect sizes were shown? on individual tests of attention, processing speed, verbal memory, and executive control; and medium effect sizes on self-report questionnaires. Neuroimaging data showed reduced grey matter density in cancer patients in frontal, parietal, and temporal regions. Changes in brain function (brain activation and cerebral blood flow) were observed with cancer across functional networks involving (pre)frontal, parietal, occipital, temporal, and cerebellar regions. Data from diffusion-weighted MRI suggested reduced white matter integrity involving the superior longitudinal fasciculus, corpus callosum, forceps major, and corona radiate, and altered structural connectivity across the whole brain network. Finally, we observed moderate-to-strong correlations between worsening cognitive function and morphological changes in frontal brain regions. While MRI is a powerful tool for detection of longitudinal brain changes in the 'chemobrain', the underlying biological mechanisms are still unclear. Continued work in this field will hopefully detect MRI metrics to be used as biomarkers to help guide cognitive treatment at the individual cancer patient level.

PMID: 29791867 [PubMed - indexed for MEDLINE]

A new outlook on cholinergic interneurons in Parkinson's disease and L-DOPA-induced dyskinesia.

Neurosci Biobehav Rev. 2018 09;92:67-82

Authors: Conti MM, Chambers N, Bishop C

Abstract
Traditionally, dopamine (DA) and acetylcholine (ACh) striatal systems were considered antagonistic and imbalances or aberrant signaling between these neurotransmitter systems could be detrimental to basal ganglia activity and pursuant motor function, such as in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). Herein, we discuss the involvement of cholinergic interneurons (ChIs) in striatally-mediated movement in a healthy, parkinsonian, and dyskinetic state. ChIs integrate numerous neurotransmitter signals using intrinsic glutamate, serotonin, and DA receptors and convey the appropriate transmission onto nearby muscarinic and nicotinic ACh receptors to produce movement. In PD, severe DA depletion causes abnormal rises in ChI activity which promote striatal signaling to attenuate normal movement. When treating PD with L-DOPA, hyperkinetic side effects, or LID, develop due to increased striatal DA; however, the role of ChIs and ACh transmission, until recently has been unclear. Fortunately, new technology and pharmacological agents have facilitated understanding of ChI function and ACh signaling in the context of LID, thus offering new opportunities to modify existing and discover future therapeutic strategies in movement disorders.

PMID: 29782883 [PubMed - indexed for MEDLINE]

Feasibility and implementation of CYP2C19 genotyping in patients using antiplatelet therapy.

Pharmacogenomics. 2018 05;19(7):621-628

Authors: Bergmeijer TO, Vos GJ, Claassens DM, Janssen PW, Harms R, der Heide RV, Asselbergs FW, Ten Berg JM, Deneer VH

Abstract
AIM: A tailored antiplatelet strategy based on CYP2C19 genotype may reduce atherothrombotic and bleeding events. We describe our experience with CYP2C19 genotyping, using on-site TaqMan or Spartan genotyping or shipment to a central laboratory.
METHODOLOGY: Data from two ongoing projects were used: Popular Risk Score project (non-urgent percutaneous coronary intervention patients) and the Popular Genetics study (ST-segment elevation myocardial infarction patients). For both projects, the time to genotyping result was calculated.
RESULTS: In the Popular Risk Score project (n = 2556), median time from blood collection to genotyping result was 4:04 h. In the Popular Genetics study (n = 1038), median time from randomization to genotyping result was 2:24 h.
CONCLUSION: CYP2C19 genotyping is feasible in everyday clinical practice, both in the acute and non-acute settings.

PMID: 29701129 [PubMed - indexed for MEDLINE]

Application of in Vitro T Cell Assay Using Human Leukocyte Antigen-Typed Healthy Donors for the Assessment of Drug Immunogenicity.

Chem Res Toxicol. 2018 03 19;31(3):165-167

Authors: Usui T, Faulkner L, Farrell J, French NS, Alfirevic A, Pirmohamed M, Park BK, Naisbitt DJ

Abstract
It is unclear whether priming of naïve T cells to drugs is detectable in healthy human donors expressing different human leukocyte antigen (HLA) alleles. Thus, we examined T cell priming with drugs associated with HLA risk alleles and control compounds in 14 HLA-typed donors. Nitroso sulfamethoxazole and piperacillin activated T cells from all donors, whereas responses to carbamazepine and oxypurinol were only seen in donors expressing HLA-B*15:02 and HLA-B*58:01, respectively. Weak flucloxacillin-specific T cell responses were detected in donors expressing HLA-B*57:01 and HLA-B*58:01. These data show that the priming of T cells with certain drugs is skewed toward donors expressing specific HLA alleles.

PMID: 29436218 [PubMed - indexed for MEDLINE]

Modification of cardiovascular pharmacotherapy in palliative care patients with cancer: a narrative review.

Pol Arch Intern Med. 2017 10 31;127(10):687-693

Authors: Pasierski T

Abstract
Palliative care patients with cancer are treated with many drugs, especially at the end of life. Limiting polypharmacy decreases the risk of associated adverse effects, medical errors, and harmful drug interactions. The time lag to benefit from the use of many medications used for cardiovascular diseases or their risk factors, such as hypertension and hypercholesterolemia, is frequently longer than the life expectancy of palliative care patients with cancer. It is ethically appropriate to modify, and even to discontinue, cardiovascular pharmacotherapy when there is no prospect of benefit. The decision to discontinue lipid‑lowering drugs and antihypertensive drugs is rather straightforward. Antithrombotic therapy may be stopped in low‑risk primary prevention but not in high‑risk group. Discontinuation of drugs for heart failure may provoke exacerbation of symptoms and should be considered only in the last weeks of life.

PMID: 28918428 [PubMed - indexed for MEDLINE]

Efficacy and Safety of Ruzasvir 60 mg and Uprifosbuvir 450 mg for 12 Weeks in Adults With Chronic Hepatitis C Virus Genotype 1, 2, 3, 4, or 6 Infection.

J Viral Hepat. 2019 Feb 09;:

Authors: Lawitz E, Poordad F, Anderson LJ, Vesay M, Kelly MM, Liu H, Gao W, Fernsler D, Asante-Appiah E, Robertson MN, Hanna GJ, Barr E, Butterton J, Kowdley KV, Hassanein T, Sahota A, Gordon SC, Yeh WW

Abstract
In clinical trials, the three-drug regimen of ruzasvir (RZR) 60 mg, uprifosbuvir (UPR) 450 mg, and grazoprevir 100 mg, with or without ribavirin has demonstrated promising efficacy and excellent tolerability across a wide range of hepatitis C virus (HCV)-infected individuals. The present study assessed the efficacy and safety of the two-drug combination of RZR 60 mg plus UPR 450 mg administered for 12 weeks in participants with HCV genotype (GT) 1-6 infection. In this open-label clinical trial, treatment-naive or -experienced and cirrhotic or noncirrhotic participants with chronic HCV GT1-6 infection received RZR 60 mg plus UPR 450 mg orally once daily for 12 weeks (NCT02759315/protocol PN035). The primary efficacy endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). One hundred and sixty participants were enrolled. SVR12 rates were 96% (52/54) in participants with GT1a infection; 100% (15/15) in those with GT1b infection; 97% (28/29) in those with GT2 infection; 77% (30/39) in those with GT3 infection; 90% (18/20) in those with GT4 infection; and 67% (2/3) in those with GT6 infection. Drug-related adverse events (AEs) reported by >5% of participants were fatigue (n=10, 6.3%) and diarrhea (n=9, 5.6%). Five participants reported a total of 11 serious AEs, none considered drug-related. One participant experienced on-treatment alanine aminotransferase/aspartate aminotransferase elevations that resolved without intervention. Data from the present study indicate that the combination of RZR 60 mg plus UPR 450 mg once daily for 12 weeks was well-tolerated overall but was effective only for certain genotypes. This article is protected by copyright. All rights reserved.

PMID: 30739366 [PubMed - as supplied by publisher]

Acute tubulointerstitial nephritis caused by rifampicin: An increasing and often overlooked side effect in elderly patients
.

Int J Clin Pharmacol Ther. 2019 Feb 10;:

Authors: Nagata M, Ohji G, Iwata K

Abstract
BACKGROUND: There are many side effects of antituberculous drugs, however, renal failure is relatively rare. Therefore, this side effect is thought to be unrecognized by most physicians. We experienced one case of acute renal failure caused by antituberculous therapy (rifampicin).
CASE REPORT: A 64-year-old Japanese male developed tuberculous pleuritis. Six weeks after starting isoniazid (INH), rifampicin (RFP), and ethambutol (EB), his renal function worsened. We temporarily stopped antituberculous therapy, but the patient's renal failure did not improve, and he was admitted to our hospital for renal biopsy. Renal pathology indicated a diagnosis of acute interstitial nephritis. After starting prednisolone, his renal function slowly improved while INH was continued. A drug-induced lymphocyte stimulation test (DLST) of the antituberculous drugs did not reveal the causative agent. However, we consider RFP to be the most likely culprit.
CONCLUSION: In recent reports, renal failure is not a rare complication during antituberculous treatment in the elderly population. Physicians who are involved with the administration of antituberculous therapy have to be aware of this side effect. DLST is not useful for identifying the causative agent of antituberculous drug side effects. Leukocyte migration test may be more useful than DLST for this purpose, but further clinical studies are necessary to verify effectiveness.
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PMID: 30738495 [PubMed - as supplied by publisher]

Safety and efficacy of glecaprevir/pibrentasvir in patients with chronic hepatitis C genotypes 1-6 receiving opioid substitution therapy.

Int J Drug Policy. 2019 Feb 05;66:73-79

Authors: Grebely J, Dore GJ, Alami NN, Conway B, Dillon JF, Gschwantler M, Felizarta F, Hézode C, Tomasiewicz K, Fredrick LM, Dumas EO, Mensa FJ

Abstract
BACKGROUND: International guidelines recommend treatment of hepatitis C virus (HCV) infection in people who inject drugs (PWID), including those on opioid substitution therapy (OST). The pangenotypic combination of glecaprevir and pibrentasvir has shown high sustained virologic response at post-treatment Week 12 (SVR12) in clinical trials. Herein, we evaluate the safety and efficacy of glecaprevir/pibrentasvir in patients receiving OST.
METHODS: Pooled data from patients with HCV genotypes 1-6 who were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight Phase 2 and 3 trials were categorized by use of OST. Treatment completion, treatment adherence, SVR12, adverse events (AEs), and laboratory abnormalities were evaluated for patients receiving and not receiving OST.
RESULTS: Among 2256 patients, 157 (7%) were receiving OST. Compared with patients not receiving OST, OST patients were younger (mean age, 46.8 vs 52.8 years), male (69% vs 54%), white (93% vs 80%), HCV treatment-naïve (86% vs 72%), had HCV genotype 3 (60% vs 26%), and had a history of depression or bipolar disorder (43% vs 19%). Most patients completed (OST: 98% [n/N = 154/157]; non-OST: 99% [n/N = 2070/2099]) and were adherent (received ≥90% of study drug doses) to glecaprevir/pibrentasvir treatment (OST: 98% [n/N = 121/123]; non-OST: 99% [n/N = 1884/1905] among patients with available data). In the intention-to-treat population, SVR12 rates in OST and non-OST patients were 96.2% (n/N = 151/157; 95% CI 93.2-99.2) and 97.9% (n/N = 2055/2099; 95% CI 97.3-98.5), respectively. For OST patients, reasons for nonresponse included virologic relapse (<1%; n = 1), premature study drug discontinuation (<1%; n = 1), and loss to follow-up (3%; n = 4). AEs occurring in ≥10% of OST patients were headache, fatigue, and nausea. Drug-related serious AEs, AEs leading to study drug discontinuation, and Grade 3 or higher laboratory abnormalities were infrequent in both groups (<1%). No HCV reinfections occurred through post-treatment Week 12.
CONCLUSION: Glecaprevir/pibrentasvir is highly efficacious and well tolerated in HCV-infected patients receiving OST.

PMID: 30735896 [PubMed - as supplied by publisher]