Proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in Asian patients with breast cancer: an exploratory comparison from two Phase III trials.

Future Oncol. 2017 Jul;13(16):1385-1393

Authors: Harbeck N, Gascon P, Jones CM, Nixon A, Krendyukov A, Nakov R, Li Y, Blackwell K

Abstract
AIM: This is a pooled subgroup analysis of Asian patients enrolled in two Phase III confirmatory studies comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer.
PATIENTS & METHODS: Women were randomized to LA-EP2006 (n = 90) or reference (n = 84) pegfilgrastim (Neulasta®, Amgen, Inc., CA, USA) for ≤6 cycles of TAC chemotherapy. Primary end point was duration of severe neutropenia during Cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 109/l) with equivalence confirmed if 95% CIs were within a ±1-day margin.
RESULTS: Mean duration of severe neutropenia (days) in Cycle 1 was 1.36 ± 0.98 (LA-EP2006) versus 1.35 ± 1.06 (reference) (difference 0.01 days; 95% CI: -0.30-0.32, indicating equivalence).
CONCLUSION: LA-EP2006 showed similar clinical efficacy and safety compared with reference pegfilgrastim.

PMID: 28453299 [PubMed - indexed for MEDLINE]

Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma.

Future Oncol. 2017 Jun;13(14):1263-1279

Authors: Nghiem P, Kaufman HL, Bharmal M, Mahnke L, Phatak H, Becker JC

Abstract
AIM: Merkel cell carcinoma (MCC) is a rare neuroendocrine, cutaneous malignancy with poor prognosis once metastasized. The aim of this study was to conduct a systematic literature review to assess clinical outcomes associated with chemotherapy regimens in metastatic MCC.
MATERIALS & METHODS: Embase®, MEDLINE®, MEDLINE®-In-Process and CENTRAL were searched for studies published in January 2016.
RESULTS & CONCLUSION: Overall, the literature on chemotherapy in patients with metastatic MCC is sparse, with most studies being case series/reports. Across all studies, response rates ranged from 20 to 61%, with higher response rates in first-line setting (53-61%) versus second-line setting (23-45%). Among responders, duration of response was short (≤8 months) in both first- and second-line settings. There is a need for novel agents that can induce durable responses in metastatic MCC.

PMID: 28350180 [PubMed - indexed for MEDLINE]

All medicines have side effects.

Arch Dis Child. 2016 10;101(10):951-2

Authors: Allegaert K, Choonara I

PMID: 27339166 [PubMed - indexed for MEDLINE]

Personalizing aromatase inhibitor therapy in patients with breast cancer.

Cancer Treat Rev. 2018 Jul 23;70:47-55

Authors: Hamadeh IS, Patel JN, Rusin S, Tan AR

Abstract
BACKGROUND: Aromatase inhibitors are the mainstay of therapy for patients with hormone receptor-positive breast cancer in both adjuvant and metastatic settings. Their use in clinical practice has been challenged by significant inter-individual variability in response and tolerability. Hence, the purpose of this paper is to provide a succinct review of the literature on the genetic factors contributing to this variability.
DESIGN: A systematic search in PUBMED was conducted to identify studies that investigated the association between germline polymorphisms and disposition, clinical response and toxicities of aromatase inhibitors, as well as those evaluating the implications of mutations in ESR1 on clinical response.
RESULTS: Polymorphisms in genes coding for phase I and phase II enzymes (pharmacokinetic genes) significantly modulated exposure to aromatase inhibitors; however, there is a paucity of data linking interindividual variability in drug exposure to clinical response. Furthermore, pharmacogenetic studies interrogating relationship between polymorphisms in CYP19A1 (the target site of aromatase inhibitors, i.e. a pharmacodynamic gene) and response yielded conflicting results. Acquired mutations in ESR1 receptors have been identified as the underlying mechanism of resistance to aromatase inhibitors, and likely predict drug response. Although some pharmacogenetic studies have implicated polymorphisms in CYP19A1 and ESR1 with drug-related side effects, the putative role of these genes in predicting toxicity warrants further validation.
CONCLUSION: Genetic polymorphisms in pharmacokinetic and pharmacodynamic genes appear to influence aromatase inhibitor disposition, response and/or toxicity; however, prospective interventional studies are needed to understand the application of genomics to personalize aromatase inhibitor therapy in breast cancer patients.

PMID: 30086432 [PubMed - as supplied by publisher]

Strategies for Recognizing and Managing Immune-Mediated Adverse Events in the Treatment of Hodgkin Lymphoma with Checkpoint Inhibitors.

Oncologist. 2018 Aug 06;:

Authors: Vardhana S, Cicero K, Velez MJ, Moskowitz CH

Abstract
The programmed death-1 (PD-1) receptor checkpoint inhibitors nivolumab and pembrolizumab represent an important therapeutic advance in the treatment of relapsed or refractory classical Hodgkin lymphoma (cHL). Clinical trials have shown substantial therapeutic activity and an acceptable safety profile in heavily pretreated patients, resulting in U.S. Food and Drug Administration approval of nivolumab for the treatment of cHL that has relapsed or progressed after either autologous hematopoietic cell transplantation (auto-HCT) and brentuximab vedotin treatment or three or more lines of systemic therapy (including auto-HCT), and of pembrolizumab for adult or pediatric patients with refractory cHL or cHL that has relapsed after three or more prior therapies. Mechanistically, anti-PD-1 therapy prevents inhibitory signaling through PD-1 receptors on T cells, thereby releasing a 'block' to antitumor T-cell responses. However, this disinhibition can also lead to inappropriate T-cell activation and responses against healthy tissues, resulting in immune-mediated adverse events (IMAEs) that affect a number of organ systems. The skin, gastrointestinal, hepatic, and endocrine systems are most commonly involved, typically resulting in rash, colitis, abnormal liver enzyme levels, and thyroiditis, respectively. Notably, pneumonitis is a potentially fatal complication of checkpoint inhibitor immunotherapy. Hematologic oncologists who treat cHL with PD-1 immune checkpoint inhibitors should monitor patients for IMAEs, as early recognition and treatment can rapidly reduce morbidity and mortality. This review focuses on IMAEs during the treatment of relapsed or refractory cHL with nivolumab and pembrolizumab.
IMPLICATIONS FOR PRACTICE: This article highlights the importance of monitoring for immune-mediated adverse events (IMAEs) in patients with Hodgkin lymphoma (HL) who receive anti-programmed death-1 (anti-PD-1) therapy, with particular attention given to the recognition and management of such events. The risk of individual IMAEs differs between patients with HL and those with solid tumors, as prior treatments may predispose certain organ systems to specific IMAEs. Accurate and prompt diagnosis of IMAEs is essential for optimal management, allowing PD-1 inhibitor therapy to be restarted in order to maintain disease control. Potential difficulties, such as distinguishing disease progression from pneumonitis, or colitis from diarrhea, are highlighted to raise clinical awareness.

PMID: 30082490 [PubMed - as supplied by publisher]

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/vincristine in Relapsed/refractory Aggressive B-cell Lymphoma.

Clin Cancer Res. 2018 Aug 06;:

Authors: Kelly KR, Friedberg JW, Park SI, McDonagh KT, Hayslip J, Persky D, Ruan J, Puvvada S, Rosen PJ, Padmanabhan Iyer S, Stefanovic A, Bernstein SH, Weitman S, Karnad AB, Monohan G, VanderWalde A, Mena R, Schmelz M, Spier C, Groshen S, Venkatakrishnan K, Zhou X, Sheldon-Waniga E, Leonard EJ, Mahadevan D

Abstract
PURPOSE: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin's lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL.
EXPERIMENTAL DESIGN: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg BID days 1-7, plus IV rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3+3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) BID days 1-7 plus rituximab and vincristine (1.4 mg/m2 [maximum 2 mg] days 1, 8) for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 immunohistochemistry was performed on available archival tissue.
RESULTS: Forty-five patients participated. The alisertib RP2D for MR was 50 mg BID. For MRV (n = 32) the RP2D was determined as 40 mg BID (1 DLT at 40 mg; 2 DLTs at 50 mg). Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CRs), seven had partial responses (PRs); 9/20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) DLBCL.
CONCLUSIONS: The combination of alisertib 50 mg BID plus rituximab or alisertib 40 mg BID plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

PMID: 30082475 [PubMed - as supplied by publisher]

Prediction of Effective Drug Combinations by an Improved Naïve Bayesian Algorithm.

Int J Mol Sci. 2018 Feb 05;19(2):

Authors: Bai LY, Dai H, Xu Q, Junaid M, Peng SL, Zhu X, Xiong Y, Wei DQ

Abstract
Drug combinatorial therapy is a promising strategy for combating complex diseases due to its fewer side effects, lower toxicity and better efficacy. However, it is not feasible to determine all the effective drug combinations in the vast space of possible combinations given the increasing number of approved drugs in the market, since the experimental methods for identification of effective drug combinations are both labor- and time-consuming. In this study, we conducted systematic analysis of various types of features to characterize pairs of drugs. These features included information about the targets of the drugs, the pathway in which the target protein of a drug was involved in, side effects of drugs, metabolic enzymes of the drugs, and drug transporters. The latter two features (metabolic enzymes and drug transporters) were related to the metabolism and transportation properties of drugs, which were not analyzed or used in previous studies. Then, we devised a novel improved naïve Bayesian algorithm to construct classification models to predict effective drug combinations by using the individual types of features mentioned above. Our results indicated that the performance of our proposed method was indeed better than the naïve Bayesian algorithm and other conventional classification algorithms such as support vector machine and K-nearest neighbor.

PMID: 29401735 [PubMed - indexed for MEDLINE]

Phase I clinical study of brentuximab vedotin (SGN-35) involving children with recurrent or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large cell lymphoma: rationale, design and methods of BV-HLALCL study: study protocol.

BMC Cancer. 2018 02 01;18(1):122

Authors: Sekimizu M, Iguchi A, Mori T, Koga Y, Kada A, Saito AM, Horibe K

Abstract
BACKGROUND: Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL) are the two most common tumors expressing CD30. Internationally, a clinical study that is being conducted involving adults with recurrent or refractory HL or ALCL suggests efficacy of brentuximab vedotin (SGN-35). Pediatric patients should be given medicines that have been appropriately evaluated for their use. In the past, however, new approved drugs have been used for pediatric patients without the confirmation of safety and efficacy in pediatric patients. Therefore, it is important to examine the safety and efficacy of SGN-35 in Japanese children.
METHODS: Phase I clinical study of SGN-35 involving children with recurrent or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large cell lymphoma (BV-HLALCL study) is being conducted for pediatric patients in order to evaluate the safety, feasibility and preliminary clinical effectiveness of brentuximab vedotin. SGN-35 is intravenously administered on Day 1 of each cycle (21 days/cycle). The dose of SGN-35 is calculated based on the body weight at the baseline. The primary endpoint is dose limiting toxicity and incidence of adverse events. The secondary endpoints are pharmacokinetics, response rate, complete remission rate, response duration, progression-free survival and event-free survival. The reduction rate of tumor will be calculated according to revised response criteria for malignant lymphoma for measurable tumor. Six pediatric patients will be enrolled in this study.
DISCUSSION: This study aims to expand indication of SGN-35 in Japan by assessing its safety and efficacy in pediatric patients.
TRIAL REGISTRATION: JMACCT ID: JMA-IIA00229 . Registered on 17 Nov 2015.

PMID: 29390984 [PubMed - indexed for MEDLINE]

Adjuvant treatment of resectable biliary tract cancer with cisplatin plus gemcitabine: A prospective single center phase II study.

BMC Cancer. 2018 01 11;18(1):72

Authors: Siebenhüner AR, Seifert H, Bachmann H, Seifert B, Winder T, Feilchenfeldt J, Breitenstein S, Clavien PA, Stupp R, Knuth A, Pestalozzi B, Samaras P

Abstract
BACKGROUND: Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC.
METHODS: Patients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed.
RESULTS: Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3-100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50-100) for cisplatin and 100% (IQR 75-100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0-33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8-62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts.
CONCLUSION: Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients.
TRIAL REGISTRATION: The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).

PMID: 29325521 [PubMed - indexed for MEDLINE]

Expectations, concerns, and needs of patients who start drugs for chronic conditions. A prospective observational study among community pharmacies in Serbia.

Eur J Gen Pract. 2018 Dec;24(1):19-25

Authors: Vučićević KM, Miljković BR, Golubović BC, Jovanović MN, Vezmar Kovačević SD, Ćulafić MD, Kovačević MM, de Gier JJ

Abstract
BACKGROUND: During the initiation of treatment of a chronic disease, patients may have varying interests, expectations, concerns, and reasons to stop treatment, influencing compliance with prescribed treatment. Thus, healthcare professionals are expected to integrate these needs into medicines management.
OBJECTIVES: To determine what information is important to patients; assess predictors of patients' interests, expectations, concerns, reasons to stop therapy; evaluate drug-related problems following initiation of therapy and summarize how pharmacists resolve them during patient-pharmacist counselling.
METHODS: In 2014, a four-month study was performed in Serbian community pharmacies, as part of the Pharmaceutical Care Quality Indicators Project led by the European Directorate for the Quality of Medicines & Healthcare. Seventy community pharmacists were asked to participate in the study. Pharmacists recruited adult patients who consented to participate in the study and who initiated treatment, lasting at least six months. Patients completed an open-ended questions form. After two-to-four weeks, a patient-pharmacist consultation was performed.
RESULTS: Forty-four community pharmacists (response rate 62.9%) sent back the completed forms from 391 patients (response rate 67.1%). The total number of dispensed drugs was 403. In terms of drug safety, 29.4% of patients sought information, 32.5% expressed concerns, and 28.1% of patients cited it as a reason to discontinue treatment. During the first weeks of therapy, 18% of patients experienced practical problems, while 27.3% reported adverse drug reactions.
CONCLUSION: Safety issues are a major focus of patients' prescribed new medicines for long-term treatment.

PMID: 29164957 [PubMed - indexed for MEDLINE]

An assessment of pregnant women's knowledge and use of the Internet for medication safety information and purchase.

J Adv Nurs. 2018 Jan;74(1):137-147

Authors: Sinclair M, Lagan BM, Dolk H, McCullough JEM

Abstract
AIM: The aim of this study was to assess pregnant women's Internet searching activity about medication safety, knowledge and perceptions of medication risk and willingness to take prescribed and non-prescribed medication or make online medication purchases.
BACKGROUND: Online medication advice for pregnant women is complex. The quality and veracity of this data is increasingly important as more midwives report women are bringing retrieved online information to clinical appointments. Pregnant women's use of the Internet for seeking medication advice and purchasing medications has not yet been fully investigated.
DESIGN: Online survey conducted from January - March 2013.
FINDINGS: Of the 284 respondents, 39% were taking a medication when they became pregnant and 76% had searched the Internet for medication safety information. Analgesics were the most commonly searched category (41%). Health service sites were the most common online source and regarded as the most helpful and trusted. Regardless of age and education level, 90% of women agreed that if trying to become pregnant they would reconsider taking any medications because of the potential risk to their unborn baby. Forty-six percent of women with higher levels of education consider buying medication online as safe, a greater proportion than those of lower education. Five percent of women reported buying medication online.
CONCLUSION: The lack of specific recommendations for medication use during pregnancy is challenging for healthcare staff and pregnant women who need robust evidence to make informed treatment decisions. The Internet is a recognized, commonly accessed, source of medication information for pregnant women.

PMID: 28880394 [PubMed - indexed for MEDLINE]

Cancer-induced cognitive impairment: practical solutions to reduce and manage the challenge.

Future Oncol. 2017 04;13(9):767-771

Authors: Vardy JL, Bray VJ, Dhillon HM

PMID: 28266247 [PubMed - indexed for MEDLINE]

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Host genetic profiling to increase drug safety in colorectal cancer from discovery to implementation.

Drug Resist Updat. 2018 Jul;39:18-40

Authors: Cecchin E, De Mattia E, Ecca F, Toffoli G

Abstract
Adverse events affect the pharmacological treatment of approximately 90% of colorectal cancer (CRC) patients at any stage of the disease. Chemotherapy including fluoropyrimidines, irinotecan, and oxaliplatin is the cornerstone of the pharmacological treatment of CRC. The introduction of novel targeted agents, as anti-EGFR (i.e. cetuximab, panitumumab) and antiangiogenic (i.e. bevacizumab, ziv-aflibercept, regorafenib, and ramucirumab) molecules, into the oncologist's toolbox has led to significant improvements in the life expectancy of advanced CRC patients, but with a substantial increase in toxicity burden. In this respect, pharmacogenomics has largely been applied to the personalization of CRC chemotherapy, focusing mainly on the study of inhered polymorphisms in genes encoding phase I and II enzymes, ATP-binding cassette (ABC)/solute carrier (SLC) membrane transporters, proteins involved in DNA repair, folate pathway and immune response. These research efforts have led to the identification of some validated genetic markers of chemotherapy toxicity, for fluoropyrimidines and irinotecan. No validated genetic determinants of oxaliplatin-specific toxicity, as peripheral neuropathy, has thus far been established. The contribution of host genetic markers in predicting the toxicity associated with novel targeted agents' administration is still controversial due to the heterogeneity of published data. Pharmacogenomics guidelines have been published by some international scientific consortia such as the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) strongly suggesting a pre-treatment dose adjustment of irinotecan based on UGT1A1*28 genotype and of fluoropyrimidines based on some DPYD genetic variants, to increase treatment safety. However, these recommendations are still poorly applied at the patient's bedside. Several ongoing projects in the U.S. and Europe are currently evaluating how pharmacogenomics can be implemented successfully in daily clinical practice. The majority of drug-related adverse events are still unexplained, and a great deal of ongoing research is aimed at improving knowledge of the role of pharmacogenomics in increasing treatment safety. In this review, the issue of pre-treatment identification of CRC patients at risk of toxicity via the analysis of patients' genetic profiles is addressed. Available pharmacogenomics guidelines with ongoing efforts to implement them in clinical practice and new exploratory markers for clinical validation are described.

PMID: 30075835 [PubMed - in process]

Association of Oral Contraceptives With Drug-Induced QT Interval Prolongation in Healthy Nonmenopausal Women.

JAMA Cardiol. 2018 Aug 01;:

Authors: Salem JE, Dureau P, Bachelot A, Germain M, Voiriot P, Lebourgeois B, Trégouët DA, Hulot JS, Funck-Brentano C

Abstract
Importance: Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial.
Objective: To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills.
Design, Setting, and Participants: A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018.
Main Outcomes and Measures: Electrocardiographic changes 3 hours after sotalol administration.
Results: A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P = .005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P = .005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n = 13 of 61 [21.0%]) than those taking levonorgestrel (n = 20 of 137 [14.6%]) or women taking no OCs (n = 24 of 207 [11.6%]; P = .01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P = .01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P < .001).
Conclusions and Relevance: Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.

PMID: 30073300 [PubMed - as supplied by publisher]

[Method for MEA Data Analysis of Drug-treated Rat Primary Neurons and Human iPSC-derived Neurons to Evaluate the Risk of Drug-induced Seizures].

Yakugaku Zasshi. 2018;138(6):823-828

Authors: Ojima A, Miyamoto N

Abstract
　Use of the microelectrode array (MEA) system to record spontaneous neuron activity from networks of cultured neurons has potential as a good risk evaluation method for drug-induced seizure events. Spontaneous electrical activity in neural networks consists of action potential spikes and organized patterns of action potential bursts. In both potentiated rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons, an epileptogenic response pattern manifests as a synchronized burst from spatially separated neurons. Here, we delineate how to perform MEA experiments using cultured neurons, and how to analyze the MEA data to detect drug-induced seizurogenic abnormalities. Usually, a drug's effects, as shown by MEA data, include changes in spike frequency, inter-spike intervals (ISI), burst frequency, burst duration, spikes in a burst, etc. Subsequently, seizurogenic events are evidenced by changes in synchronized burst phenotypes from spatially separated multiple channels in an MEA probe, such as a change in the cross correlation of the spike events from all channels in an MEA probe, or a change in histogram from the sum of ISI for all channels in a probe, etc. We attempted to depict an epileptogenic marker using a histogram of the sum of spikes for all channels in an MEA probe. Verification of these metrics for drug induced abnormalities is ongoing in various collaboration organizations, including the Consortium for Safety Assessment using Human iPS Cells (CSAHi), iPS Non-clinical Experiments for the Nervous System (iNCENS). Collaboration networks for the utilization of iPSC-derived cells during drug development are also summarized here.

PMID: 29863054 [PubMed - indexed for MEDLINE]

[Machine Learning-based Prediction of Seizure-inducing Action as an Adverse Drug Effect].

Yakugaku Zasshi. 2018;138(6):809-813

Authors: Gao M, Sato M, Ikegaya Y

Abstract
　During the preclinical research period of drug development, animal testing is widely used to help screen out a drug's dangerous side effects. However, it remains difficult to predict side effects within the central nervous system. Here, we introduce a machine learning-based in vitro system designed to detect seizure-inducing side effects before clinical trial. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices that were bath-perfused with each of 14 different drugs, and at 5 different concentrations of each drug. For each of these experimental conditions, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events, and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which have indeed been reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to pre-clinically detect seizure-inducing side effects of drugs.

PMID: 29863052 [PubMed - indexed for MEDLINE]

[A Clinical Pathway Based on Medical and Nursing Teamwork in Drug Management Facilitates Integrated Community Care for Elderly Patients with Chronic Heart Failure].

Yakugaku Zasshi. 2018;138(6):797-806

Authors: Watanabe N, Morikawa G, Kubota K, Okazawa K, Tanaka C, Horiuchi M

Abstract
　Chronic heart failure (CHF) is a critical disease in the aging population. Conventional therapy in hospitals cannot cure elderly patients with CHF at the end of life. Patients and their families experience anxiety and need comfortable care at home or in a nursing facility. To improve chronic cardiovascular disease management, we developed a simplified but integrated clinical pathway to facilitate medical and nursing care teamwork in the local community. Our institution is a central hospital in the North Shinshu district, which has an approximate population of 100000. We developed a pathway for both clinical program and information provision between our hospital and neighboring clinics. A hospital team evaluates and shares patient information with a homecare medical team every 6 months using the medical staff pathway. To maintain the efficacy and security of pharmacotherapy, a hospital clinical pharmacist reviews the prescriptions and prepares a drug profile book to share drug information between patients and all medical staff. These efforts have resulted in preventing adverse effects of drugs and reduced the cost of medications. Physical activity evaluation and nutrient guidance are also useful for patients to maintain their personal lifestyles. We initiated use of the pathway from 2009 and have followed up over 500 patients since then. We have also established a community partnership council to promote face-to-face communication among multiple categories of institutions and government agencies. Members of the council collaborate to help patients with cardiovascular disease to manage their own lives at home.

PMID: 29863050 [PubMed - indexed for MEDLINE]

A review on adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in nonsmall cell lung cancer patients.

Indian J Cancer. 2017 Dec;54(Supplement):S55-S64

Authors: Biswas B, Ghadyalpatil N, Krishna MV, Deshmukh J

Abstract
The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-mutant nonsmall cell lung cancer (NSCLC). These EGFR TKIs demonstrate a different adverse event (AE) profile as compared to conventional chemotherapy agents. They are more commonly associated with cutaneous AEs and diarrhea while hematological AEs occurred commonly with chemotherapy agents. These AEs are the extension of pharmacological effect and occur as a result of blockade of EGFR-regulated pathways in the skin and gastrointestinal tract. This review article sheds light on the safety profile of first-, second-, and third-generation EGFR TKIs based on data obtained from several clinical trials conducted in NSCLC patients and highlights trials comparing these agents with the conventional chemotherapy agents. The strategies to manage EGFR TKI-related AEs are also reviewed.

PMID: 29292709 [PubMed - indexed for MEDLINE]

Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats.

Biomed Pharmacother. 2018 Jan;97:233-239

Authors: Mehrzadi S, Fatemi I, Esmaeilizadeh M, Ghaznavi H, Kalantar H, Goudarzi M

Abstract
Hepatotoxicity is one of the major side effects of methotrexate (MTX), which restricts the clinical use of this drug. Berberine (BBR) is a natural compound with multiple pharmacological activities such as antioxidant, antiapoptotic and anti-inflammatory effects. In this study, the effect of BBR on MTX-induced hepatotoxicity was studied. A total number of 28 male Wistar rats were randomly divided into four experimental groups. Rats were pretreated with BBR orally with dose of 100mg/kg for 10 consecutive days and MTX (20mg/kg, intraperitoneally) was administrated on the 9th day. Then on day 11, blood samples were collected to determine serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The extracted livers were used for histological examination, biochemical assays and real time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed in hepatic tissue. In addition, the expression of SOD and PGx was measured using real-time PCR method in hepatic tissue. Results showed that MTX administration significantly increases AST, ALT and ALP levels (all p<0.001). It also, increases MDA, PC, NO levels and MPO activity (p<0.001, p<0.01, p<0.05 and p<0.01 respectively). Moreover, MTX decreases hepatic GSH level, SOD, GPx and CAT activities (all p<0.001). Pre-treatment with BBR for 10days prevented some of these changes. Serum levels of AST and ALT decreased (all p<0.001). Hepatic MDA level decreased (p<0.001) and GSH level as well as GPx activity increased (p<0.05 and p<0.01 respectively). Our results indicated that BBR might be useful for prevention of the hepatotoxicity induced by MTX via ameliorative effects on biochemical and oxidative stress indices.

PMID: 29091871 [PubMed - indexed for MEDLINE]