Drug-drug interactions involving CYP3A4 and p-glycoprotein in hospitalized elderly patients.

Eur J Intern Med. 2019 Jul;65:51-57

Authors: Gallo P, De Vincentis A, Pedone C, Nobili A, Tettamanti M, Gentilucci UV, Picardi A, Mannucci PM, Incalzi RA, REPOSI Investigators

Abstract
Polypharmacy is very common in older patients and may be associated with drug-drug interactions. Hepatic cytochrome P450 (notably 3A4 subtype, CYP3A4) is a key enzyme which metabolizes most drugs; P-glycoprotein (P-gp) is a transporter which significantly influences distribution and bioavailability of many drugs. In this study, we assess the prevalence and patterns of potential interactions observed in an hospitalized older cohort (Registro Politerapia Società Italiana di Medicina Interna) exposed to at least two interacting drugs involving CYP3A4 and P-gp at admission, during hospitalization and at discharge. Individuals aged 65 and older (N-4039; mean age 79.2; male 48.1%), hospitalized between 2010 and 2016, were selected. The most common combinations of interacting drugs (relative frequency > 5%) and socio-demographic and clinical factors associated with the interactions were reported. The prevalence of interactions for CYP3A4 was 7.9% on admission, 10.3% during the stay and 10.7% at discharge; the corresponding figures for P-gp interactions were 2.2%, 3.8% and 3.8%. The most frequent interactions were amiodarone-statin for CYP3A4 and atorvastatin-verapamil-diltiazem for P-gp. The prevalence of some interactions, mainly those involving cardiovascular drugs, decreased at discharge, whereas that of others, e.g. those involving neuropsychiatric drugs, increased. The strongest factor associated with interactions was polypharmacy (OR 6.7, 95% CI 5.0-9.2). In conclusion, hospital admission is associated with an increased prevalence, but also a changing pattern of interactions concerning CYP3A4 and P-gp in elderly. Educational strategies and appropriate use of dedicated software seem desirable to limit drug interactions and the inherent risk of adverse events in older patients.

PMID: 31084979 [PubMed - indexed for MEDLINE]

Risk of Major Complications After Perioperative Norepinephrine Infusion Through Peripheral Intravenous Lines in a Multicenter Study.

Anesth Analg. 2020 Oct;131(4):1060-1065

Authors: Pancaro C, Shah N, Pasma W, Saager L, Cassidy R, van Klei W, Kooij F, Vittali D, Hollmann MW, Kheterpal S, Lirk P

Abstract
BACKGROUND: Continuous infusions of norepinephrine to treat perioperative hypotension are typically administered through a central venous line rather than a peripheral venous catheter to avoid the risk of localized tissue necrosis in case of drug extravasation. There is limited literature to estimate the risk of skin necrosis when peripheral norepinephrine is used to counteract anesthesia-associated hypotension in elective surgical cases. This study aimed to estimate the rate of occurrence of drug-related adverse effects, including skin necrosis requiring surgical management when norepinephrine peripheral extravasation occurs.
METHODS: This retrospective cohort study used the perioperative databases of the University Hospitals in Amsterdam and Utrecht, the Netherlands, to identify surgical patients who received norepinephrine peripheral intravenous infusions (20 µg/mL) between 2012 and 2016. The risk of drug-related adverse effects, including skin necrosis, was estimated. Particular care was taken to identify patients who needed plastic surgical or medical attention secondary to extravasation of dilute, peripheral norepinephrine.
RESULTS: A total of 14,385 patients who received norepinephrine peripheral continuous infusions were identified. Drug extravasation was observed in 5 patients (5/14,385 = 0.035%). The 95% confidence interval (CI) for infusion extravasation was 0.011%-0.081%, indicating an estimated risk of 1-8 events per every 10,000 patients. There were zero related complications requiring surgical or medical intervention, resulting in a 95% CI of 0%-0.021% and indicating a risk of approximately 0-2 events per 10,000 patients.
CONCLUSIONS: In the current database analysis, no significant association was found between the use of peripheral intravenous norepinephrine infusions and adverse events.

PMID: 32925324 [PubMed - as supplied by publisher]

Preclinical developments of enzyme-loaded red blood cells.

Expert Opin Drug Deliv. 2020 Sep 14;:

Authors: Rossi L, Pierigè F, Bregalda A, Magnani M

Abstract
INTRODUCTION: Therapeutic enzymes are currently used in the treatment of several diseases. In most cases the benefits are limited due to a poor in vivo stability, immunogenicity and drug-induced inactivating antibodies. A partial solution to the problem is obtained by masking the therapeutic protein by chemical modifications. Unfortunately, this is not a satisfactory solution because frequent adverse events, including anaphylaxis, can arise.
AREA COVERED: Among the delivery systems, we focused on red blood cells for the delivery of therapeutic enzymes. Erythrocytes possess a long circulation time, a reduced immunogenicity, there is no need of chemical modifications and the encapsulated enzyme remains active because it is protected by the cell membrane. Here we discuss some representative applications of the preclinical developments of the field. Some of these are currently in clinic, others are approaching the clinic and others are illustrative of the development process. The selected examples are not always the most recent, but they are the most useful for a comparative approach.
EXPERT OPINION: The results discussed confirm the central role that red blood cells can play in the treatment of several conditions and suggest the benefit in using a natural cellular carrier in terms of pharmacokinetic, biodistribution, safety, and efficacy.

PMID: 32924643 [PubMed - as supplied by publisher]

Investigating the Impact of Gadolinium-Based Contrast Agents on the Corrected QT Interval.

Cureus. 2020 Aug 11;12(8):e9668

Authors: Gress KL, Gallo T, Urits I, Geng X, Viswanath O, Kaye AD, Woosley RL

Abstract
Introduction The manufacturing labels for all currently marketed gadolinium-based MRI contrast agents describe adverse cardiac events reported during post-market use. The goal of this study was to determine prolongation of the rate-corrected QT interval occurs in the immediate setting after gadolinium-based MRI contrast agent injection. Methods This study enrolled adults scheduled to have a gadolinium-based MRI contrast agent injection as part of a diagnostic MRI. A single-lead electrocardiogram was recorded using the AliveCor Kardia® ECG (Mountain View, CA) device before and after injection. The rate-corrected QT interval was subsequently measured by two independent investigators. The QT interval was corrected for rate using the two most common formulas, originally cited by Bazett and Fridericia. These rate-corrected QT intervals from before and after gadolinium-based MRI contrast agent injection were compared using the Wilcoxon signed-rank test paired analysis. Results A total of 24 consenting adults had electrocardiogram that were free of motion artifact. The mean age of the final patient cohort was 59.4 years. There was an equal split of 12 men and 12 women. The mean pre-injection, rate-corrected QT interval, corrected using Bazett's formula, was 395 msec. The mean post-injection, rate-corrected QT interval, corrected using Bazett's formula, was 396 msec. The corrections using Fridericia's formula were 384 and 381 msec, respectively. There was no statistically significant change in Bazett-corrected QT interval (QTc-B) when pre-injection and post-injection values were directly compared. Discussion The results of the present investigation support the conclusion that gadolinium-based MRI contrast agents do not commonly affect rate-corrected QT interval in routine clinical use. While the frequency of rate-corrected QT interval prolongation might be overstated, the severity of adverse events is definitively not. A role for concomitant rate-corrected QT interval-prolonging drugs or unidentified rare factors such as genetic predisposition cannot be ruled out. The limitations of this study include its relatively small size and the implementation of a single-lead electrocardiogram to measure rate-corrected QT interval. Conclusion The present investigation revealed that significant rate-corrected QT interval prolongation, while previously reported in as many as 55% of patients after gadolinium-based MRI contrast agent injection, is not a common occurrence in the routine clinical setting.

PMID: 32923263 [PubMed]

Immune-Mediated Toxic Epidermal Necrolysis.

Cureus. 2020 Aug 06;12(8):e9587

Authors: Keerty D, Koverzhenko V, Belinc D, LaPorta K, Haynes E

Abstract
The treatment of melanoma has advanced over time with the latest modalities being immune checkpoint blockade by programmed death receptor 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors. Programmed death receptor 1 inhibitors have been noted to cause multi-system adverse reactions. The dermatological adverse events can range from pruritus to severe toxic epidermal necrolysis. We report a fatal case of toxic epidermal necrolysis secondary to nivolumab therapy. Checkpoint inhibitors are becoming the standard treatment option in many malignancies. Their safety profile is still evolving as more cases are being reported. Many individuals who are immunocompromised or undergoing concomitant treatment with combination therapy could develop significant overlapping toxicities. Physicians must be vigilant for dermatological complications that lead to opportunistic infections and sepsis.

PMID: 32923193 [PubMed]

Impact of DPYD, DPYS, and UPB1 gene variations on severe drug-related toxicity in patients with cancer.

Cancer Sci. 2020 Sep;111(9):3359-3366

Authors: Yokoi K, Nakajima Y, Matsuoka H, Shinkai Y, Ishihara T, Maeda Y, Kato T, Katsuno H, Masumori K, Kawada K, Yoshikawa T, Ito T, Kurahashi H

Abstract
Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype-guided dose individualization of FP therapy has been proposed in western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP-related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intron regions of their DPYD, DPYS, and UPB1 genes. In total, 24 single nucleotide variants (15 in DPYD, 7 in DPYS and 2 in UPB1) were identified including 3 novel variants in DPYD and 1 novel variant in DPYS. We did not find a significant association between FP-related high toxicity and each of these individual variants, although a certain trend toward significance was observed for p.Arg181Trp and p.Gln334Arg in DPYS (P = .0813 and .087). When we focused on 7 DPYD rare variants (p.Ser199Asn, p.IIe245Phe, p.Thr305Lys, p.Glu386Ter, p.Ser556Arg, p.Ala571Asp, p.Trp621Cys) which have an allele frequency of less than 0.01% in the Japanese population and are predicted to be loss-of-function mutations by in silico analysis, the group of patients who were heterozygous carriers of at least one these rare variants showed a strong association with FP-related high toxicity (P = .003). Although the availability of screening of these rare loss-of-function variants is still unknown, our data provide useful information that may help to alleviate FP-related toxicity in Japanese patients with cancer.

PMID: 32619063 [PubMed - indexed for MEDLINE]

Leveraging Contextual Information in Extracting Long Distance Relations from Clinical Notes.

AMIA Annu Symp Proc. 2019;2019:1051-1060

Authors: Guan H, Devarakonda M

Abstract
Relation extraction from biomedical text is important for clinical decision support applications. In post-marketing pharmacovigilance, for example, Adverse Drug Events (ADE) relate medical problems to the drugs that caused them and were the focus of two recent shared challenges. While good results were reported, there was a room for improvement. Here, we studied two new improved methods for relation extraction: (1) State-of-the-art deep learning contextual representation model called BERT, Bidirectional Encoder Representations from Transformers; (2) Selection of negative training samples based on the "near-miss" hypothesis (the Edge sampling). We used the datasets from MADE and N2C2 Task-2 for performance evaluation. BERT and Edge together improved performance of ADE and Reason (indication) relations extraction by 6.4-6.7 absolute percentage (and error rate reduction of 24%-28%). ADE and Reason relations contained longer text between the entities, which BERT and Edge were able to leverage to achieve the performance improvement. While the performance improvement for medication attribute relations was smaller in absolute percentages, error rate reduction was still considerable.

PMID: 32308902 [PubMed - indexed for MEDLINE]

Mining Drugs and Indications for Suicide-Related Adverse Events.

AMIA Annu Symp Proc. 2019;2019:1011-1020

Authors: Ding T, Chen ES

Abstract
There has been a significant increase in suicide rates in the United States (U.S.) over the past two decades. Studies have highlighted the need for further exploration of suicide risk factors, particularly combinations of factors. In this study, a pharmacovigilance analysis was conducted to better understand drugs and indications as risk factors for suicide using data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and Adverse Event Open Learning through Universal Standardization (AEOLUS), a standardized version of FAERS. Association rule mining techniques were applied to 85,071 cases involving suicide-related adverse reactions and demographic subsets of these cases. Preliminary results reveal combinations of drugs and indications that may increase the likelihood of suicide, with certain combinations potentially affecting some demographic groups more than others. Further work is needed to validate the initial findings, explore subpopulations, and determine the broader implications for suicide prevention.

PMID: 32308898 [PubMed - indexed for MEDLINE]

Characterizing the Utilization of the Problem List for Pediatric Trauma Care.

AMIA Annu Symp Proc. 2019;2019:992-1001

Authors: Burkhardt HA, Subramanian D, Mower J, Cohen T

Abstract
The identification of drug-drug interactions (DDIs) is important for patient safety; yet, compared to other pharmacovigilance work, a limited amount of research has been conducted in this space. Recent work has successfully applied a method of deriving distributed vector representations from structured biomedical knowledge, known as Embedding of Semantic Predications (ESP), to the problem of predicting individual drug side effects. In the current paper we extend this work by applying ESP to the problem of predicting polypharmacy side-effects for particular drug combinations, building on a recent reconceptualization of this problem as a network of drug nodes connected by side effect edges. We evaluate ESP embeddings derived from the resulting graph on a side-effect prediction task against a previously reported graph convolutional neural network approach, using the same data and evaluation methods. We demonstrate that ESP models perform better, while being faster to train, more re-usable, and significantly simpler.

PMID: 32308896 [PubMed - indexed for MEDLINE]

Large Health System Databases and Drug Hypersensitivity.

J Allergy Clin Immunol Pract. 2019 Sep - Oct;7(7):2125-2131

Authors: Chiriac AM, Macy E

Abstract
Large health system databases have revolutionized our understanding of the epidemiology of adverse drug reactions and immunologically mediated drug hypersensitivity. Population-based background rates of newly reported drug intolerance with each therapeutic exposure could not have been determined without large health system databases. Large databases have increased our understanding of multiple drug intolerance syndrome. Large health care systems, such as Kaiser Permanente, with a single electronic medical record system that covers all inpatient, outpatient, and pharmacy interactions, are particularly valuable in understanding the population-based incidence of severe and nonsevere adverse drug reactions, the risks of delayed-onset adverse drug reactions, such as those caused by Clostridiodes difficile, which can occur months after antibiotic exposures, and the risks and benefits associated with "allergy" delabeling, specifically penicillin allergy delabeling, which may accrue in the years after the delabeling. There currently are limitations to using electronic data, specifically billing code data, when studying adverse drug reactions. It is critical to audit electronic health records, which have temporally associated the use of a drug and an adverse reaction because of high rates of miscoding or lack of true cause and effect. Pending improvements in drug hypersensitivity coding in International Classification of Diseases, Eleventh Revision may make large databases even more useful.

PMID: 31495422 [PubMed - indexed for MEDLINE]

Drug interactions with dementia-related pathophysiological pathways worsen or prevent dementia.

Br J Pharmacol. 2019 09;176(18):3413-3434

Authors: Barus R, Béné J, Deguil J, Gautier S, Bordet R

PMID: 30714122 [PubMed - indexed for MEDLINE]

Recent updates from the BNF (BNF 80).

Drug Ther Bull. 2020 Sep 11;:

Authors:

Abstract
The BNF is jointly published by the Royal Pharmaceutical Society and BMJ. BNF is published in print twice a year and interim updates are issued and published monthly in the digital versions. The following summary provides a brief description of some recent key changes that have been made to BNF content.

PMID: 32917734 [PubMed - as supplied by publisher]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/09/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/09/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

[Emergencies in dermatology : From gonorrhea to angioedema].

Med Klin Intensivmed Notfmed. 2020 Sep 10;:

Authors: Neumayer DS, Rongisch R, Kästle J

Abstract
The spectrum of dermatological emergencies is diverse. Infections, in particular sexually transmitted infections, anaphylactic reactions, and cutaneous drug reactions are common causes for patients to present themselves to the dermatological emergency service. If a sexually transmitted infection is suspected, it is important for the physician to recognize which diseases need immediate treatment to avoid late complications. This requires a reliable diagnosis and knowledge of the appropriate therapy. Cutaneous drug reactions can take many forms. There is a spectrum of reactions that occur immediately after the administration of a medication (which manifest themselves as anaphylaxis), to those that can appear weeks after the initiation of a therapy. These reactions can be harmless and self-limiting, but also be life-threatening. It is essential for physicians in everyday clinical practice to recognize drug intolerances in time and to treat them appropriately.

PMID: 32910216 [PubMed - as supplied by publisher]

Eribulin and Confusion: A Previously Unknown Drug Side-Effect.

Eur J Case Rep Intern Med. 2020;7(9):001708

Authors: Sheikh AB, Perisetti A, Javed N, Shekhar R

Abstract
Eribulin is an antineoplastic agent used in advanced breast cancer refractory to anthracycline and taxane treatment regimens. A wide variety of side effects with unclear mechanisms have been noted, but encephalopathy has not been widely reported. Here we describe the case of a middle-aged woman treated with eribulin for advanced breast cancer who subsequently developed central nervous system drug-induced toxicity but improved promptly with steroid administration.
LEARNING POINTS: Eribulin-induced encephalopathy is a diagnosis of exclusion and should be included in the differential diagnosis of patients treated with eribulin and presenting with altered mental status.Eribulin can cross the blood-brain barrier.Steroids and drug cessation should be the mainstay of treatment in cases of eribulin-induced encephalopathy.

PMID: 32908828 [PubMed]

Safety and quality of life data from an Italian expanded access program of lenvatinib for treatment of thyroid cancer.

Thyroid. 2020 Sep 10;:

Authors: Giani C, Valerio L, Bongiovanni A, Durante C, Grani G, Ibrahim T, Mariotti S, Massa M, Pani F, Pellegriti G, Porcelli T, Salvatore D, Tavarelli M, Torlontano M, Locati L, Molinaro E, Elisei R

Abstract
BACKGROUND: Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were a) to evaluate, and compared to other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and b) to evaluate their QoL during treatment with lenvatinib.
METHODS: To evaluate the safety we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients to that reported in the SELECT and TUTHYREF network studies. Moreover, we evaluated the QoL in our series by using the EORTC QLQ-C30 questionnaire and the pain visual analogue scale (VAS). Results The most frequent AEs among our 39 RR-DTC patients were hypertension(80.5%), fatigue(58.3%), diarrhea(36.1%), stomatitis(33.3%), Hand-Foot Syndrome(33.3%) and weight loss(30.5%). The most prevalent grade 3/4 AE was hypertension(25%). When compared with previous studies (i.e., SELECT and TUTHYREF) a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria and weight-loss. No statistically significant differences in the QoL of our patients evaluated before, during and at the end of follow-up (6 months after starting the therapy) were found. However, a slightly improvement of the general health, emotional and cognitive status associated to a slightly worsening of physical role and social functioning were observed during these 6 months. Pain, dyspnea, insomnia and constipation moved toward better values while fatigue, nausea-vomiting, appetite-loss and diarrhea worsened. By comparing the pain VAS scale, an overall reduction of the level of pain was found.
CONCLUSIONS: The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the general health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.

PMID: 32907501 [PubMed - as supplied by publisher]

Management of Cardiac Toxicity Induced by Chemotherapy.

J Clin Med. 2020 Sep 07;9(9):

Authors: Trapani D, Zagami P, Nicolò E, Pravettoni G, Curigliano G

Abstract
Cardiotoxicity encompasses a spectrum of adverse cardiological effects experienced by cancer patients during and after receiving antineoplastic treatments. The intersection of cancer care with the management of the multiple comorbid non-communicable diseases carried by patients or related to cancer treatments motivates the need for an integrated and multidisciplinary approach to therapeutic clinical decision-making. This present review aimed to provide a perspective and an update of the current pharmacotherapy approaches for the prevention and management of cardiotoxicity from antiblastic chemotherapy; as such, it addresses myocardial, vascular, and arrhythmic disorders associated to chemotherapy, by navigating the current knowledge and clinical indications in support of the medical interventions. Clinical scenarios of pharmacological interventions take place with patients receiving anthracycline and, by extrapolation, other agents with cardiotoxic potentials and non-chemotherapy agents, including various small molecules and immunotherapy agents. Analysis of these scenarios aims to provide practical evidence-based guidance for the management of drug-induced cardiac dysfunctions. The possible role of new biomarkers for the early recognition of cardiotoxicity is mentioned across the clinical studies, with reference to the pharmacological biomarker-driven interventions delivered. To best inform survivorship care, the management and context of cardio-oncology services are discussed within the broader network of providers and settings of care.

PMID: 32906611 [PubMed]

[Thalidomide in refractory Crohn's disease: long-term efficacy and safety].

Zhonghua Nei Ke Za Zhi. 2020 Jun 01;59(6):445-450

Authors: Xu S, Zu XM, Feng R, Zhang SH, Qiu Y, Chen BL, Zeng ZR, Chen MH, He Y

Abstract
Objective: To analyze the long-term efficacy and safety of thalidomide on refractory Crohn's disease (CD). Methods: A total of 79 patients with refractory CD in the First Affiliated Hospital of Sun Yat-sen University treated with thalidomide were enrolled in this retrospective study from September 2005 to July 2018. Clinical effects and adverse drug reactions were recorded and assessed. Results: In this cohort,69 patients were treated with thalidomide for ≥6 months. Sixty-eight patients among the 69 patients achieved complete clinical remission and were followed up for a median 33.5 months (range, 7-110 months). Seventeen cases relapsed during follow-up. The cumulative probabilities of remaining in remission at 12, 24, 60 months were 88.6% (95%CI 80.6%-96.6%), 80.7% (95%CI 70.3%-91.1%), 53.7% (95%CI 32.1%-75.3%) respectively. Disease activity was the only variable associated with relapse risk, with a hazard ratio (HR) of 3.559 for Crohn's disease activity index (CDAI) ≥220(95%CI 1.213-10.449, P<0.05). Adverse reactions were recorded in 42 (53.2%) patients including12 (15.2%) leading to discontinuation of thalidomide. No serious side effects were observed in all subjects. Conclusions: This study suggests a long-term benefit of maintenance treatment with thalidomide in refractory CD.Moderate to severe patients have an increased risk of relapse. The high incidence of drug adverse reactions may restrain the clinical application of thalidomide.

PMID: 32486585 [PubMed - indexed for MEDLINE]

[Molecular Pathway-based Prediction of Adverse Events in OECD etc.]

Yakugaku Zasshi. 2020;140(4):479-480

Authors: Tanabe S, Yamada T

PMID: 32238627 [PubMed - indexed for MEDLINE]