Gut microbiota: what is its place in pharmacology?

Expert Rev Clin Pharmacol. 2019 Oct;12(10):921-930

Authors: Tarasiuk A, Fichna J

Abstract
Introduction: In each section of the human gastrointestinal (GI) tract we may find bacteria that are adapted to local conditions and fulfill an important role in the proper functioning of the body. The gut microorganisms are crucial in human physiology in areas as diverse as the brain and the immune system functions. Therefore, there is a close relationship between the intestinal microbiota, its metabolic activity, and health of the host. Areas covered: In this review, we explore the host-microbiome interactions and characterize the role they may play in drug metabolism and toxicity. The study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect databases. Expert opinion: Increasing unhealthy eating habits, stress, antibiotic therapy, unfavorable environmental factors, and genetic predisposition contribute to imbalances in the composition and function of the GI tract microbes and the initiation and progression of disease processes. Restoration of the balanced gut microbiota composition is possible by oral administration of probiotics.

PMID: 31544557 [PubMed - indexed for MEDLINE]

Fall-risk-increasing adverse reactions-is there value in easily accessible drug information? A case-control study.

Eur J Clin Pharmacol. 2019 Jun;75(6):849-857

Authors: Schiek S, Hildebrandt K, Zube O, Bertsche T

Abstract
PURPOSE: The individual fall risk of a patient is often multifactorial. Polymedication contributes to an additional risk of fall-risk-increasing adverse reactions (FRIARs). Previous studies have not sufficiently investigated the complexity facing prescribers when balancing the therapeutic benefits of individual drugs against their potential fall risk.
METHODS: An expert panel identified drugs with FRIARs based on the Summary of Product Characteristics (SmPC). These FRIARs and other parameters (such as the total number of drugs, dosage, dose adjustments, and drug changes) were then analyzed for their impact on falls in a case-control study using logistic regression.
RESULTS: During a 1-year period, 112 (1%) of 11,481 hospital patients experienced at least one fall event. Complete data was available for evaluation from 87 of them (case group). We matched these patients to another 87 patients who had no fall events (control group). FRIAR drugs were more frequently prescribed in the case group (4.26 (Q25-Q75, 3.75-4.78) per patient; p = 0.033) than in the control group (3.48 (2.97-3.99)). Drugs with FRIARs (β = 0.137; p = 0.035) and the total number of FRIARs (β = 0.033; p = 0.031) increased the fall risk. The total number of drugs, dosage, dose adjustments, and drug changes showed no influence.
CONCLUSIONS: FRIARs were associated with a higher number of falls. To consider FRIARs offers a chance to address the complexity of the individual medication. This data can support future computerized physician order entries with clinical decision support.

PMID: 30758518 [PubMed - indexed for MEDLINE]

Associated risks of proton pump inhibitors and their influence on prescribing habits: is change truly warranted?

Dis Esophagus. 2019 Apr 01;32(4):

Authors: Dua A, Venu M

PMID: 30496546 [PubMed - indexed for MEDLINE]

A potential mechanism of the onset of acute eosinophilic pneumonia triggered by an anti-PD-1 immune checkpoint antibody in a lung cancer patient.

Immun Inflamm Dis. 2019 03;7(1):3-6

Authors: Jodai T, Yoshida C, Sato R, Kakiuchi Y, Sato N, Iyama S, Kimura T, Saruwatari K, Saeki S, Ichiyasu H, Fujii K, Tomita Y

Abstract
INTRODUCTION: The impact of immune checkpoint blockade on immunity in cancer patients is not completely elucidated due to the complexity of the immune network. Recent studies have revealed a significant role of programed cell death-ligand 2 (PD-L2) in negatively controlling the production of CD4+ T helper type 2 (Th2) cytokines and airway hypersensitiveness, suggesting hypo-responsive Th2 cells via the PD-1/PD-L2 inhibitory pathway in lung could be reawaken by PD-1 blockade therapy.
METHODS: We describe the first report of acute eosinophilic pneumonia (AEP), which is known as Th2-associated pulmonary disease, triggered by nivolumab, an anti-PD-1 antibody, in an advanced non-small cell lung cancer patient. Based on the current case report and literature, the present study proposes a potential mechanism of the onset of AEP as an immune-related adverse event (irAE).
RESULTS: A 62-year-old man was diagnosed with lung adenocarcinoma and nivolumab was selected as the third-line regimen. After three cycles of nivolumab treatment, chest computed tomography revealed pulmonary infiltrates in both lungs. The patient was diagnosed with AEP based on the diagnostic criteria for AEP. Nivolumab was suspended and the patient was started on oral prednisolone. His symptoms and radiological findings had rapidly improved.
CONCLUSIONS: Given the increasing frequency of the use of anti-PD-1 antibodies, clinicians should be aware of the risk of AEP as a potential irAE. This study may improve our understanding of the pathophysiology underlying Th2-associated irAEs and AEP.

PMID: 30461210 [PubMed - indexed for MEDLINE]

Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events-a meta-analysis.

Ann Oncol. 2018 04 01;29(4):803-811

Authors: Trone JC, Ollier E, Chapelle C, Bertoletti L, Cucherat M, Mismetti P, Magné N, Laporte S

Abstract
Background: Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA.
Materials and methods: We searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials.
Results: The literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12-2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83-1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials.
Conclusions: Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.

PMID: 29415169 [PubMed - indexed for MEDLINE]

Comparison of the effects and side effects of misoprostol and oxytocin in the postpartum period: A systematic review.

Taiwan J Obstet Gynecol. 2019 Nov;58(6):748-756

Authors: Bilgin Z, Kömürcü N

Abstract
Follow-up of the side effects of uterotonics used for postpartum hemorrhage is one of the most important roles of health care providers. In this review, it is aimed to compare the side effects of misoprostol and oxytocin that are used to prevent postpartum hemorrhage. This systematic review was carried out in accordance with the guidelines for the Center for Reviews and Dissemination 2009 (CRD). Articles published in the PubMed, CINAHL, Wiley Interscience, Science Direct and Cochrane databases between 2010 and 2016 were examined. Finally, although 2277 articles were found to be related to misoprostol and oxytocin, only 12 randomized controlled (n = 6290) articles were included in the review. Results: In the misoprostol group, the rate of >500 mL blood loss was lower than that in the oxytocin group (p < 0.05). The groups were similar in terms of ≥500 mL blood loss were similar (p > 0.05). Although misoprostol was more effective than oxytocin in preventing PPH, the side effects of misoprostol were more. The incidence of drug-induced shivering, nausea and increase in body temperature were significantly higher in the misoprostol group than the oxytocin and placebo groups (p < 0.05). Shivering was most frequently seen in the 600 mg of sublingual misoprostol group (56.4%). Severe side effects of uterotonics used to prevent postpartum hemorrhage on maternal health were determined. Nurses and midwives should be aware of the side effects of uterotonic drugs and should develop care guidelines that explain the interventions to be performed in case of side effects.

PMID: 31759522 [PubMed - in process]

Bilateral Drug-Induced Uveitis and Epiretinal Membrane during the Treatment of a Metastatic Cutaneous Melanoma.

Ocul Immunol Inflamm. 2019 Nov 22;:1-3

Authors: Mozo Cuadrado M, Tabuenca Del Barrio L, Compains Silva E

Abstract
Purpose: To report the case of a drug-induced uveitis during the treatment of a metastatic cutaneous melanoma.Case report: A 75-year-old female treated with Dabrafenib and Trametinib due to a cutaneous melanoma stage IV presented with blurriness in both eyes. The examination revealed bilateral intraocular signs of inflammation, and fundoscopy showed bilateral changes at the posterior pole, such as chorioretinal folds and Neurosensory Retinal Detachment (NRD). Due to a worsening of Visual Acuity (VA) and persistence of intraocular inflammation in spite of topical prednisolone acetate treatment, the therapy with Dabrafenib + Trametinib was interrupted, after having been administered for 4 months, and replaced by Nivolumab. Fundus abnormalities and intraocular inflammation improved, but VA remained low due to the presence of an epiretinal membrane in the right eye. Then, a decreasing course of prednisolone eye drops was introduced for one more month and finally interrupted without the cessation of Nivolumab.Conclusion: Drug-induced uveitis has been increasing in the last few years due to the development of new biological agents for treatment of different types of tumours. The management of these adverse events should be handled in collaboration with oncologists and ophthalmologists and must be individualised and based on the risk-benefit balance. A case report of an uveitis and subsequent development of an epiretinal membrane during the treatment with Dabrafenib, Trametinib and subsequent Nivolumab for a metastatic cutaneous melanoma is reported here, in order to note the importance of an adequate follow-up of patients treated with these drugs.

PMID: 31755788 [PubMed - as supplied by publisher]

Chidamide in combination with chemotherapy in refractory and relapsed T lymphoblastic lymphoma/leukemia.

Leuk Lymphoma. 2019 Nov 22;:1-7

Authors: Guan W, Jing Y, Dou L, Wang M, Xiao Y, Yu L

Abstract
Chidamide, a novel histone deacetylase inhibitor, has exerted effects in T-cell tumors through various mechanisms. Seventeen patients with refractory or relapsed T-cell acute lymphoblastic lymphoma/leukemia (T-LBL/ALL) received Chidamide combined with chemotherapy as salvage treatment. Historical data was analyzed as comparison as chemotherapy group. Complete response (CR) rate and overall response rate (ORR) of Chidamide + chemotherapy group were higher than that of chemotherapy group after one course. Chidamide + chemotherapy group had a better progress-free survival (PFS) compared to chemotherapy group. No difference in overall survival (OS) was observed. Grade 3/4 nonhematological adverse events (>10%) of patients in Chidamide + chemotherapy group included febrile neutropenia (64.7%), drug-induced liver failure (17.6%), decreased fibrinogen (11.8%), sepsis (11.8%), pneumonitis (11.8%), and oral mucositis (11.8%). This study demonstrates that Chidamide included regimen may be a new treatment strategy with an acceptable safety profile for refractory or relapsed T-LBL/ALL patients but requires further investigation.

PMID: 31755348 [PubMed - as supplied by publisher]

Long-term safety and efficacy of lacosamide and controlled-release carbamazepine monotherapy in patients with newly diagnosed epilepsy.

Epilepsia. 2019 Nov 21;:

Authors: Ben-Menachem E, Grebe HP, Terada K, Jensen L, Li T, De Backer M, Steiniger-Brach B, Gasalla T, Brock M, Biton V

Abstract
OBJECTIVE: A large-scale, double-blind trial (SP0993; NCT01243177) demonstrated that lacosamide was noninferior to controlled-release carbamazepine (carbamazepine-CR) in terms of efficacy, and well tolerated as first-line monotherapy in patients (≥16 years of age) with newly diagnosed epilepsy. We report primary safety outcomes from the double-blind extension of the noninferiority trial (SP0994; NCT01465997) and post hoc analyses of pooled long-term safety and efficacy data from both trials.
METHODS: Patients were randomized 1:1 to lacosamide or carbamazepine-CR. Doses were escalated (lacosamide: 200/400/600 mg/d; carbamazepine-CR: 400/800/1200 mg/d) based on seizure control. Eligible patients continued randomized treatment in the extension. Primary outcomes of the extension were treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Post hoc analyses of data from combined trials included 12- and 24-month seizure freedom and TEAEs by number of comorbid conditions.
RESULTS: A total of 886 patients were treated in the initial trial and 548 in the extension; 211 of 279 patients (75.6%) on lacosamide and 180/269 (66.9%) on carbamazepine-CR completed the extension. In the extension, 181 patients (64.9%) on lacosamide and 182 (67.7%) on carbamazepine-CR reported TEAEs; in both groups, nasopharyngitis, headache, and dizziness were most common. Serious TEAEs were reported by 32 patients (11.5%) on lacosamide and 22 (8.2%) on carbamazepine-CR; 12 (4.3%) and 21 (7.8%) discontinued due to TEAEs. In the combined trials (median exposure: lacosamide 630 days; carbamazepine-CR 589 days), Kaplan-Meier estimated proportions of patients with 12- and 24-month seizure freedom from first dose were 50.8% (95% confidence interval 46.2%-55.4%) and 47.0% (42.2%-51.7%) on lacosamide, and 54.9% (50.3%-59.6%) and 50.9% (46.0%-55.7%) on carbamazepine-CR. Incidences of drug-related TEAEs and discontinuations due to TEAEs increased by number of comorbid conditions and were lower in patients on lacosamide.
SIGNIFICANCE: Long-term (median ~2 years) lacosamide monotherapy was efficacious and generally well tolerated in adults with newly diagnosed epilepsy. Seizure freedom rates were similar with lacosamide and carbamazepine-CR.

PMID: 31755090 [PubMed - as supplied by publisher]

[Selected safety-relevant medication processes in Swiss nursing homes: Current state of affairs and optimization potentials].

Z Evid Fortbild Qual Gesundhwes. 2019 Oct;146:7-14

Authors: Niederhauser A, Brühwiler LD, Fishman L, Schwappach DLB

Abstract
BACKGROUND: Reducing adverse drug events in nursing homes is a central patient safety concern. The aim of this study was to assess how often selected medication processes to increase medication safety are already implemented in Swiss nursing homes and to examine how nursing homes that have not yet implemented these processes can be characterized based on their organizational features.
METHODS: Cross-sectional survey study among directors of nursing in Swiss nursing homes.
RESULTS: 420 of 1,525 invited individuals participated in the survey (response rate: 27.5 %). Of these, 65.0 % stated that regular systematic medication reviews have been provided in their institution. 9.5 % of the nursing homes use a list to identify potentially inappropriate medication, and 6.7 % of the nursing homes have a standardized process to monitor side effects of medications. 66.0 % of the participating nursing homes have implemented at least one of these three processes, 34.0 % of the participating nursing homes have not implemented any of the three processes. Statistically significant differences in process implementation were found according to the geographical location of the nursing home, the type of documentation used for medications, the physician model, the number of external general practitioners, as well as the medication supply channel and the legal obligation to cooperate with pharmacists. No differences were found with regard to the nursing home size.
CONCLUSION: In Swiss nursing homes, central safety-relevant medication processes have not yet been implemented nationwide. In particular, implementation is not widespread in nursing homes where medical care for their residents is provided by many different external general practitioners. The organizational features need to be taken into account to successfully implement quality improvement measures.

PMID: 31375396 [PubMed - indexed for MEDLINE]

Characteristics and trends of spontaneous reporting of therapeutic ineffectiveness in South Korea from 2000 to 2016.

PLoS One. 2019;14(2):e0212905

Authors: Kim HJ, Jeong HE, Bae JH, Baek YH, Shin JY

Abstract
Therapeutic ineffectiveness involves drug-related therapeutic failure, inefficacy or resistance and has not been sufficiently studied. Objective of our study was to evaluate reporting trends in therapeutic ineffectiveness by year and describe factors affecting therapeutic ineffectiveness using the Korea Adverse Event Reporting System. Proportion of therapeutic ineffectiveness reports was based on total submitted reports between 2000 and 2016. Utilizing 2016 alone, we compared the characteristics of therapeutic ineffectiveness with age group and gender matching by random extraction. We conducted a logistic regression analysis to estimate reporting odds ratios (ROR) and its 95% confidence intervals (CI) for reports by type of reporters, e.g., doctors, pharmacists, or consumers. We presented most frequent reports by the anatomical main groups and therapeutic subgroups according to the Anatomical Therapeutic Chemical (ATC) classification system. For the 17-years, the proportion of therapeutic ineffectiveness adverse drug reactions reporting ranged from 0.0% to 3.7% between 2000 and 2016. Of 228,939 reports, 2,797 (1.2%) were submitted in 2016. Consumers accounted for 6.92% of reports and doctors accounted for 45.49%, in which, consumers were more likely to report therapeutic ineffectiveness than doctors (adjusted ROR 3.98; 95% CI, 2.92 to 5.41). According to the ATC classification system, "nervous system" was the most frequently reported anatomical group (18.7%) and "parathyroid hormones and analogues" was reported most frequently in the pharmacological subgroup (23.7%). Teriparatide, a drug used to treat osteoporosis, had the most reports (11.0%). Therapeutic ineffectiveness reports may be used as a scientific tool for the reevaluation of respective drugs in order to confirm of its therapeutic effects.

PMID: 30817781 [PubMed - indexed for MEDLINE]

Drug allergy in children and adults: Is it the double X chromosome?

Ann Allergy Asthma Immunol. 2019 02;122(2):148-155

Authors: Eaddy Norton A, Broyles AD

Abstract
OBJECTIVE: This article reviews the latest science and epidemiologic studies related to drug allergy in children and adults to explore possible mechanisms related to female propensity for drug allergy.
DATA SOURCES: PubMed literature review, focusing primarily on the last 5 years.
STUDY SELECTIONS: Articles reviewing the science behind female predisposition to atopic and asthmatic conditions and epidemiologic studies reviewing drug allergy and drug-induced anaphylaxis.
RESULTS: Despite adult female predilection for atopic conditions, few laboratory studies explore sex-specific mechanisms in atopic/allergic diseases, and most are focused on autoimmunity and asthma. Drug allergy is more frequently reported in adult females compared with adult males. Adult females are also more likely to have drug-induced anaphylaxis (DIA), although no clear sex predominance has been reported in fatal or severe DIA. Studies in children suggest the reverse picture, with prepubertal males more likely to have drug allergy and DIA than prepubertal girls.
CONCLUSION: Possible explanations for female predisposition for drug allergy are multifactorial and include disproportionate utilization of health care with more exposure to antibiotics or medications, genetic factors related to the X chromosome, epigenetic changes, and discrepant hormonal interactions with immune cells.

PMID: 30465863 [PubMed - indexed for MEDLINE]

Improvement of Adequate Digoxin Dosage: An Application of Machine Learning Approach.

J Healthc Eng. 2018;2018:3948245

Authors: Hu YH, Tai CT, Tsai CF, Huang MW

Abstract
Digoxin is a high-alert medication because of its narrow therapeutic range and high drug-to-drug interactions (DDIs). Approximately 50% of digoxin toxicity cases are preventable, which motivated us to improve the treatment outcomes of digoxin. The objective of this study is to apply machine learning techniques to predict the appropriateness of initial digoxin dosage. A total of 307 inpatients who had their conditions treated with digoxin between 2004 and 2013 at a medical center in Taiwan were collected in the study. Ten independent variables, including demographic information, laboratory data, and whether the patients had CHF were also noted. A patient with serum digoxin concentration being controlled at 0.5-0.9 ng/mL after his/her initial digoxin dosage was defined as having an appropriate use of digoxin; otherwise, a patient was defined as having an inappropriate use of digoxin. Weka 3.7.3, an open source machine learning software, was adopted to develop prediction models. Six machine learning techniques were considered, including decision tree (C4.5), k-nearest neighbors (kNN), classification and regression tree (CART), randomForest (RF), multilayer perceptron (MLP), and logistic regression (LGR). In the non-DDI group, the area under ROC curve (AUC) of RF (0.912) was excellent, followed by that of MLP (0.813), CART (0.791), and C4.5 (0.784); the remaining classifiers performed poorly. For the DDI group, the AUC of RF (0.892) was the best, followed by CART (0.795), MLP (0.777), and C4.5 (0.774); the other classifiers' performances were less than ideal. The decision tree-based approaches and MLP exhibited markedly superior accuracy performance, regardless of DDI status. Although digoxin is a high-alert medication, its initial dose can be accurately determined by using data mining techniques such as decision tree-based and MLP approaches. Developing a dosage decision support system may serve as a supplementary tool for clinicians and also increase drug safety in clinical practice.

PMID: 30210752 [PubMed - indexed for MEDLINE]

Reduced Effectiveness of Interruptive Drug-Drug Interaction Alerts after Conversion to a Commercial Electronic Health Record.

J Gen Intern Med. 2018 11;33(11):1868-1876

Authors: Wright A, Aaron S, Seger DL, Samal L, Schiff GD, Bates DW

Abstract
BACKGROUND: Drug-drug interaction (DDI) alerts in electronic health records (EHRs) can help prevent adverse drug events, but such alerts are frequently overridden, raising concerns about their clinical usefulness and contribution to alert fatigue.
OBJECTIVE: To study the effect of conversion to a commercial EHR on DDI alert and acceptance rates.
DESIGN: Two before-and-after studies.
PARTICIPANTS: 3277 clinicians who received a DDI alert in the outpatient setting.
INTERVENTION: Introduction of a new, commercial EHR and subsequent adjustment of DDI alerting criteria.
MAIN MEASURES: Alert burden and proportion of alerts accepted.
KEY RESULTS: Overall interruptive DDI alert burden increased by a factor of 6 from the legacy EHR to the commercial EHR. The acceptance rate for the most severe alerts fell from 100 to 8.4%, and from 29.3 to 7.5% for medium severity alerts (P < 0.001). After disabling the least severe alerts, total DDI alert burden fell by 50.5%, and acceptance of Tier 1 alerts rose from 9.1 to 12.7% (P < 0.01).
CONCLUSIONS: Changing from a highly tailored DDI alerting system to a more general one as part of an EHR conversion decreased acceptance of DDI alerts and increased alert burden on users. The decrease in acceptance rates cannot be fully explained by differences in the clinical knowledge base, nor can it be fully explained by alert fatigue associated with increased alert burden. Instead, workflow factors probably predominate, including timing of alerts in the prescribing process, lack of differentiation of more and less severe alerts, and features of how users interact with alerts.

PMID: 29766382 [PubMed - indexed for MEDLINE]

Non-alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor.

J Gastroenterol Hepatol. 2019 Nov 21;:

Authors: Sawada K, Hayashi H, Nakajima S, Hasebe T, Fujiya M, Okumura T

Abstract
BACKGROUND AND AIM: Because of their survival benefits, immune checkpoint inhibitors (ICIs) are widely administered to patients with various advanced-stage malignancies. During ICI treatment, drug-induced liver injury (DILI) occasionally occurs. In particular, hepatic immune-related adverse events (irAEs) are rare but serious and fatal. In patients with hepatic irAEs, immediate steroid treatment is generally recommended; however, the risk factors for ICI-associated DILI remain unknown. In the present study, we identified a risk factor for ICI-associated DILI.
METHODS: We retrospectively analyzed 135 patients treated with anti-programmed cell death-1 (PD-1) antibodies, such as nivolumab and pembrolizumab, at Asahikawa Medical University Hospital. We investigated grade ≥ 2 hepatotoxic AEs during anti-PD-1 therapy, and PD-1 inhibitor-associated DILI was then diagnosed according to the Digestive Disease Week Japan (DDW-J) 2004 scale. The risk factors for PD-1 inhibitor-associated DILI were identified by Cox hazard analysis.
RESULTS: Thirty-six patients developed grade ≥ 2 hepatic AEs during anti-PD-1 therapy. Among them, eight patients were diagnosed with PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. Cox hazard analysis revealed that non-alcoholic fatty liver disease (NAFLD) was a risk factor for PD-1 inhibitor-associated DILI. In addition, we revealed that the outcomes of patients with the DDW-J 2004 score = 3 were improved without steroid treatment.
CONCLUSIONS: NAFLD is a potential risk factor for PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. The DDW-J 2004 scale might be useful for determining whether steroid treatment is required in patients with PD-1 inhibitor-associated DILI.

PMID: 31752049 [PubMed - as supplied by publisher]

Guidance for Using Tafenoquine for Prevention and Antirelapse Therapy for Malaria - United States, 2019.

MMWR Morb Mortal Wkly Rep. 2019 Nov 22;68(46):1062-1068

Authors: Haston JC, Hwang J, Tan KR

Abstract
An estimated 219 million cases of malaria occurred worldwide in 2017, causing approximately 435,000 deaths (1). Malaria is caused by intraerythrocytic protozoa of the genus Plasmodium transmitted to humans through the bite of an infective Anopheles mosquito. Five Plasmodium species that regularly cause illness in humans are P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi (2). The parasite first develops in the liver before infecting red blood cells. Travelers to areas with endemic malaria can prevent malaria by taking chemoprophylaxis. However, most antimalarials do not kill the liver stages of the parasite, including hypnozoites that cause relapses of disease caused by P. vivax or P. ovale. Therefore, patients with these relapsing species must be treated with two medications: one for the acute infection, and another to treat the hypnozoites (antirelapse therapy). Until recently, primaquine was the only drug available worldwide to kill hypnozoites. Tafenoquine, a long-acting 8-aminoquinoline drug related to primaquine, was approved by the Food and Drug Administration (FDA) on July 20, 2018, for antirelapse therapy (Krintafel) and August 8, 2018, for chemoprophylaxis (Arakoda) (3,4). This report reviews evidence for the efficacy and safety of tafenoquine and provides CDC guidance for clinicians who prescribe chemoprophylaxis for travelers to areas with endemic malaria and treat malaria.

PMID: 31751320 [PubMed - in process]

Bevacizumab in Combination with TAS-102 Improves Clinical Outcomes in Patients with Refractory Metastatic Colorectal Cancer: A Retrospective Study.

Oncologist. 2019 Nov 20;:

Authors: Fujii H, Matsuhashi N, Kitahora M, Takahashi T, Hirose C, Iihara H, Yamada Y, Watanabe D, Ishihara T, Suzuki A, Yoshida K

Abstract
OBJECTIVE: TAS-102 is effective for treating patients with metastatic colorectal cancer (mCRC). This study determined whether combining bevacizumab (Bmab) with TAS-102 improves clinical outcomes in refractory mCRC.
PATIENTS AND METHODS: We retrospectively analyzed data from Japanese patients with refractory mCRC who received TAS-102 (35 mg/m2, twice a day) with (T-B group) or without Bmab (TAS-102 monotherapy; T group) between July 2014 and December 2018. The primary endpoint was median overall survival (OS), and secondary endpoints were median time to treatment failure, overall response rate, and the incidence of adverse events. Clinical outcomes were compared using propensity score matched analysis.
RESULTS: Data from 57 patients were analyzed (T-B group: 21 patients, T group: 36 patients). Median OS was significantly longer in the T-B group than the T group (14.4 months vs. 4.5 months, p < .001). Cox proportional hazard analysis showed that combination therapy with Bmab was significantly correlated with OS. Propensity score matched analysis confirmed that the median OS was significantly longer in the T-B group than the T group (14.4 months vs. 6.1 months, p = .006) and that there was a significant correlation between Bmab and OS. The incidence of hypertension (grade ≥2) as an adverse event was significantly higher in the T-B group than the T group (23.8% vs. 0.0%, p = .005), whereas other adverse events were comparable between the two groups.
CONCLUSION: Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC refractory to standard therapies.
IMPLICATIONS FOR PRACTICE: Combining bevacizumab (Bmab) with TAS-102 significantly improved overall survival and several prognostic indicators in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, with manageable toxicities. Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC.

PMID: 31748337 [PubMed - as supplied by publisher]

[Update in the management of drug poisonings].

Rev Prat. 2019 Apr;69(4):359-361

Authors: Azzouz R, Duburcq T, Mathieu D

PMID: 31626480 [PubMed - indexed for MEDLINE]

Precision Medicine Goes Microscopic: Engineering the Microbiome to Improve Drug Outcomes.

Cell Host Microbe. 2019 Jul 10;26(1):22-34

Authors: Lam KN, Alexander M, Turnbaugh PJ

Abstract
Despite the recognition, nearly a century ago, that the human microbiome plays a clinically relevant role in drug disposition, mechanistic insights, and translational applications are still limited. Here, we highlight the recent re-emergence of "pharmacomicrobiomics," which seeks to understand how inter-individual variations in the microbiome shape drug efficacy and side effect profiles. Multiple bacterial species, genes, and enzymes have already been implicated in the direct biotransformation of drugs, both from targeted case studies and from systematic computational and experimental analyses. Indirect mechanisms are also at play; for example, microbial interactions with the host immune system can have broad effects on immunomodulatory drugs. Finally, we discuss multiple emerging strategies for the precise manipulation of complex microbial communities to improve treatment outcomes. In the coming years, we anticipate a shift toward a more comprehensive view of precision medicine that encompasses our human and microbial genomes and their combined metabolic activities.

PMID: 31295421 [PubMed - indexed for MEDLINE]

Relationship between food behavior and taste and smell alterations in cancer patients undergoing chemotherapy: A structured review.

Semin Oncol. 2019 04;46(2):160-172

Authors: Drareni K, Dougkas A, Giboreau A, Laville M, Souquet PJ, Bensafi M

Abstract
INTRODUCTION: Taste and smell alteration is a frequent side effect of chemotherapy. However, little is known about their influence on patients' food behavior and the mechanisms underpinning their occurrence. This lack of clarity is likely due to a series of factors among which heterogeneity in chemotherapy-induced taste and smell modifications may play a prominent role. The present review provides a critical overview of the evidence on the association between taste and smell alterations and food behavior modifications in cancer patients undergoing chemotherapy.
DESIGN: The literature search was performed using PubMed and Google Scholar databases and restricted to literature for English-language articles published between 1990 and June 2018. Sensory-related terms were combined with food behavior-related terms to identify the studies that examined the association between these two terms. The retrieved studies were grouped based on the taste and smell assessment outcomes.
RESULTS: Thirteen eligible articles were included in the review. The studies varied in design, length, methodology of assessment, and studied population. The categorization of studies depending on taste and smell assessment outcomes allowed the definition of three patient profiles: unaltered, hypo- and hyperchemosensation (taste and/or smell). Alterations were significantly correlated with patients' energy intake and macronutrient preferences suggesting that sensitivity of each patient to olfactory and gustatory stimuli is likely to play a role in food behavior modulation during cancer and chemotherapy.
CONCLUSION: The review summarizes and provides relevant associations between taste/smell alterations and food behavior while receiving chemotherapy considering existing individual variations. Given the sensory influence on food behavior modulation, a better characterization of smell and taste alterations before the launch of chemotherapy seems important for a better understanding and management of patients' food behavior trajectory over the treatment.

PMID: 31204004 [PubMed - indexed for MEDLINE]