Cardiovascular adverse events associated with oral antineoplastic therapy.

Rev Bras Enferm. 2018 Sep-Oct;71(5):2561-2569

Authors: Silva JMD, Lima BDS, Araújo TL, Lima FET, Cunha GHD

Abstract
OBJECTIVE: To identify in the literature the cardiovascular adverse events resulting from oral antineoplastic therapy.
METHOD: Integrative review of the literature through the SCOPUS, Scientific Electronic Library Online (SciELO), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medical Literature Analysis and Retrieval System Online (MEDLINE) databases. The antineoplastic, cardiotoxicity, cardiovascular system and adverse reaction descriptors were used in Portuguese, English and Spanish. We selected 23 articles published between 1985 and 2015.
RESULTS: Twenty studies were related to cardiac events and eleven to peripheral vascular events. The most frequent adverse cardiac events were reduced left ventricular ejection fraction, myocardial infarction, changes in the electrocardiogram, heart failure and angina, whereas peripheral vascular events were hypertension and thromboembolism.
CONCLUSION: Oral antineoplastic therapy is associated with different adverse events, including cardiac and peripheral vascular events.

PMID: 30304190 [PubMed - indexed for MEDLINE]

Toxicological study of a new doxorubicin-loaded pH-sensitive liposome: A preclinical approach.

Toxicol Appl Pharmacol. 2018 08 01;352:162-169

Authors: de Oliveira Silva J, Miranda SEM, Leite EA, de Paula Sabino A, Borges KBG, Cardoso VN, Cassali GD, Guimarães AG, Oliveira MC, de Barros ALB

Abstract
Doxorubicin (DOX) is widely used in cancer treatment, however, the use of this drug is often limited due to its cardiotoxic side effects. In order to avoid these adverse effects, the encapsulation of DOX into nanosystems has been used in the last decades. In this context, pH-sensitive liposomes have been shown promising for delivering cytotoxic agents into tumor cells, however, the lack of information about in vivo toxicity of this nanocarrier has impaired translational studies. Therefore, the aim of this work was to investigate the acute toxicity and cardiotoxicity of DOX-loading pH-sensitive liposomes (SpHL-DOX). To achieve this, female BALB/c mice, after intravenous administration, were monitored by means of clinical, laboratory, histopathological and electrocardiographic (ECG) analyses. Results indicate that SpHL was able to prevent renal toxicity and the hepatic injury was less extensive than free DOX. In addition, lower body weight loss was associated with less ECG QT interval prolongation to animals receiving SpHL-DOX (14.6 ± 5.2%) compared to animals receiving free DOX (35.7 ± 4.0%) or non-pH-sensitive liposomes (nSpHL-DOX) (47.0 ± 9.8%). These results corroborate with SpHL-DOX biodistribution studies published by our group. In conclusion, the SpHL-DOX showed less toxic effects on mice compared to free DOX or nSpHL-DOX indicating that SpHL-DOX is a promising strategy to reduce the serious cardiotoxic effects of DOX.

PMID: 29864484 [PubMed - indexed for MEDLINE]

Evolving multidimensional pharmacological approaches to CNV therapy in AMD.

Curr Eye Res. 2018 02;43(2):147-154

Authors: Ehrenberg M, Benny O

Abstract
PURPOSE: The leading cause of severe visual loss world-wide is age-related macular degeneration. Although anti-Vascular Endothelial Growth Factor agents have significantly led to the initial pharmacologic reversal of vision loss in many cases of exudative macular degeneration, there still has been recurrence of choroidal neovascularization, and/or the onset of chorioretinal atrophy with fibrosis.
MATERIALS AND METHODS: In this review we discuss the status of anti- Vascular Endothelial Growth Factor in age-related macular degeneration and describe different studies focused on new potential therapeutic targets beyond anti- Vascular Endothelial Growth Factor.
RESULTS: Further investigations have elicited that Vascular Endothelial Growth Factor is only one of many angiogenic, and pro-inflammatory factors that bring about the growth and leakage of active choroidal neovascularization. Various new multifaceted strategies, including inhibitors to down-stream targets of endothelial cell division, such as TNP-470, may lead to a more permanent inactivation of choroidal neovascularization.
CONCLUSIONS: Based on the accumulated results in the treatment of age-related macular degeneration, it is hoped that the appropriate combination of anti-Vascular Endothelial Growth Factor agents with longer-acting and multidimensional pharmaceuticals, such as Methionine Aminopeptidase-2 inhibitors, will more effectively control choroidal neovascularization, prevent atrophy and fibrosis, and reduce the burden of frequent intraocular injections in age-related macular degeneration.

PMID: 29111834 [PubMed - indexed for MEDLINE]

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Management of Male Lower Urinary Tract Symptoms in a Simulated, Over-the-Counter Setting: An Exploratory Study of Tamsulosin.

Drugs Aging. 2019 Jan 03;:

Authors: Roehrborn CG, Lowe FC, Gittelman M, Wruck JM, Verbeek AE

Abstract
BACKGROUND: Lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH) are common in men, considerably affecting quality of life.
AIMS: The self-directed use of over-the-counter (OTC) tamsulosin (0.4 mg) and potential safety risks were evaluated in an open-label, uncontrolled, exploratory, 8-week OTC-simulated study.
METHODS: Men (≥ 18 years) were recruited via mass advertising about bothersome LUTS. In a working retail environment, respondents reviewed the product and decided whether it was appropriate for them to use (self-selection phase). After purchasing the product, participants' ability to use it as directed by the proposed drug facts label (DFL) was assessed (home-use phase).
RESULTS: Of 1446 eligible men, 679 completed the self-selection phase, and 73.9% (502/679) self-selected to use tamsulosin correctly according to the DFL. Of 369 participants who purchased tamsulosin and entered the home-use phase, 321 took one or more doses of tamsulosin and participated in at least one telephone interview. In total, 85.4% (274/321) of participants adhered to the 'Stop Use' and 'Directions' instructions in the DFL. Overall, 139 (39.6%) participants experienced one or more adverse events (AEs); 65 (18.5%) were deemed drug-related, including dizziness (11 [3.1%]), ejaculation disorder (6 [1.7%]), and semen volume decrease (6 [1.7%]). No unexpected AEs were reported.
CONCLUSIONS: Of the men interested in self-managing their LUTS, a majority had moderate-to-severe LUTS of long duration. Most men were able to appropriately self-select and use tamsulosin in concordance with DFL instructions and directions. No unexpected AEs were reported during self-directed use. With further label refinement, an over-the-counter tamsulosin option might be feasible.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01726270.

PMID: 30607798 [PubMed - as supplied by publisher]

Topical doxycycline foam 4% for prophylactic management of epidermal growth factor receptor inhibitor skin toxicity: an exploratory phase 2, randomized, double-blind clinical study.

Support Care Cancer. 2019 Jan 04;:

Authors: Shacham Shmueli E, Geva R, Yarom N, Hubert A, Keynan R, Kedem TH, Eini M, Tamarkin D, Shirvan M

Abstract
PURPOSE: Acneiform rash, a common toxicity of epidermal growth factor receptor inhibitors (EGFRIs), can cause patient discomfort, warranting changes in treatment. This study investigated the safety, tolerability, and efficacy of a novel doxycycline foam, FDX104 4%, for managing EGFRI-related skin toxicity.
METHODS: This was an exploratory phase 2, randomized, double-blind, placebo-controlled study. Subjects had metastatic colorectal cancer and were being treated with either cetuximab or panitumumab plus chemotherapy. Treatment (twice-daily topical FDX104 4% on one side of the face and vehicle foam on the other for 5 weeks) was initiated 7 ± 3 days prior to EGFRI therapy. Rash severity, safety, and tolerability were evaluated at 2 and 4 weeks after EGFRI start.
RESULTS: The mean maximal rash grade was lower with FDX104 4% vs vehicle, and fewer subjects developed moderate-to-severe (grades 2-3) rash. On the Global Severity Score scale, a statistically significant difference favored FDX104 4% over vehicle (P = .047). Adverse events (AEs) (n = 68) occurred in 20 subjects; most were mild or moderate. The most common AEs were oral mucositis, nausea, and vomiting, common to chemotherapy and EGFRI treatment. Study-drug-related AEs were experienced by five subjects and consisted of mild, local skin reactions. No study-drug-related systemic side effects were reported.
CONCLUSION: Twice-daily, topical administration of FDX104 4% as an adjunct to either cetuximab or panitumumab was safe and well tolerated, and appeared to prevent the onset of rash, especially severe rash. CLINICALTRIALS.
GOV IDENTIFIER: Trial Registration NCT02239731.

PMID: 30607677 [PubMed - as supplied by publisher]

Efficacy and Safety of Spironolactone in Patients With HFpEF and Chronic Kidney Disease.

JACC Heart Fail. 2019 Jan;7(1):25-32

Authors: Beldhuis IE, Myhre PL, Claggett B, Damman K, Fang JC, Lewis EF, O'Meara E, Pitt B, Shah SJ, Voors AA, Pfeffer MA, Solomon SD, Desai AS

Abstract
OBJECTIVES: This study investigated the association between baseline renal function and the net benefit of spironolactone in patients with heart failure (HF) with a preserved ejection fraction (HFpEF).
BACKGROUND: Guidelines recommend consideration of spironolactone to reduce HF hospitalization in HFpEF. However, spironolactone may increase risk for hyperkalemia and worsening renal function, particularly in patients with chronic kidney disease.
METHODS: This investigation analyzed data from patients enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) Americas study (N = 1,767) to examine the association between the baseline estimated glomerular filtration rate (eGFR) and the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest, as well as safety outcomes, including hyperkalemia, worsening renal function, and permanent drug discontinuation for adverse events (AEs). Variations in the efficacy and safety of spironolactone according to eGFR were examined in Cox models using interaction terms.
RESULTS: The incidence of both the primary outcome and drug-related AEs increased with declining eGFR. Compared with placebo, across all eGFR categories, spironolactone was associated with lower relative risk for the primary efficacy outcome and for hypokalemia, but higher relative risk for hyperkalemia, worsening renal function, and drug discontinuation. During 4-year follow-up, the absolute risk for AEs that prompted drug discontinuation was amplified in the lower eGFR categories, which suggested heightened risk for drug intolerance with declining renal function.
CONCLUSIONS: Although consistent efficacy of spironolactone was observed across the range of eGFR, the risk of AEs was amplified in the lower eGFR categories. These data supported use of spironolactone to treat HFpEF patients with advanced chronic kidney disease only when close laboratory surveillance is possible.

PMID: 30606484 [PubMed - in process]

Pre-operative autologous blood donation and transfusion-related adverse reactions: A 14-year experience at a university hospital.

Transfus Apher Sci. 2018 Oct;57(5):651-655

Authors: Furuta Y, Nakamura Y, Tokida M, Ichikawa K, Ohsawa T, Ohkubo M, Ohsaka A

Abstract
OBJECTIVE: The objective of this study was to determine the rate of adverse reactions to pre-operative autologous blood donation (PAD) transfusion in a single institution over a 14-year period.
STUDY DESIGN AND METHODS: Between January 2003 and December 2016, we investigated adverse reactions to PAD transfusion and compared them with those to allogeneic blood transfusion in Juntendo University Hospital. Adverse reactions were categorized according to the definition proposed by the International Society of Blood Transfusion (ISBT) Working Party on Haemovigilance.
RESULTS: A total of 178,014 blood components were transfused during the study period, of which PAD transfusions were 13,653 (8%), whereas allogeneic blood transfusions were 164,361 (92%). The number and rate of adverse reactions to PAD transfusion were 16 and 0.1%, whereas those of allogeneic blood transfusion were 1075 and 0.7%, respectively. The rate of adverse reactions to allogeneic blood transfusions excluding platelet transfusion was 0.3%, being significant (p < 0.01) against PAD transfusion. Among 16 adverse reactions to PAD transfusion, the most common was febrile non-hemolytic transfusion reaction (FNHTR) at 12 (75%), followed by allergic reaction at 4 (25%). The severity of adverse reactions to PAD transfusion was Grade 1 (non-severe) in all cases. With regard to blood component types, 16 adverse reactions involved: 12 cases of whole blood PAD, 2 of frozen PAD, and 2 of autologous fresh-frozen plasma.
CONCLUSIONS: Non-severe adverse reactions were observed on PAD transfusion at a rate of 0.1% at our institution.

PMID: 30078740 [PubMed - indexed for MEDLINE]

Defining the aetiology of paediatric community-acquired pneumonia: an unsolved problem.

Expert Rev Respir Med. 2019 Jan 02;:1-9

Authors: Esposito S, Principi N

Abstract
INTRODUCTION: Pediatric community-acquired pneumonia (CAP) remains a significant health problem worldwide. Although knowledge in the etiology of CAP is not satisfactory, in most cases, therapy is decided following probability-based criteria that are derived from studies that report the frequency of detection of pathogens in children with CAP. Areas covered: This narrative review discusses the present knowledge on pediatric CAP etiology, the limits of the aetiological studies and the tests for differentiation of viral from bacterial infections. Expert commentary: The type of therapeutic approach in pediatric CAP is chosen considering the risk of bacterial etiology and the pathogens most frequently detected in the different pediatric ages. Fear of the potential negative course of unrecognized and untreated bacterial CAP is the main reason for the large use of antibiotics. Unfortunately, the antibiotic prescription is unnecessary in most of the cases as it can favor the emergence of resistant strains and can increase the number of drug-related adverse events. However, it is likely that a significant reduction of antibiotic prescriptions will occur when point-of-care tests with biomarkers for differentiation viral from bacterial infections become available.

PMID: 30602317 [PubMed - as supplied by publisher]

An update on the clinical consequences of polypharmacy in older adults: a narrative review.

Expert Opin Drug Saf. 2018 Dec;17(12):1185-1196

Authors: Wastesson JW, Morin L, Tan ECK, Johnell K

Abstract
INTRODUCTION: Polypharmacy, the use of multiple medications by one individual, is increasingly common among older adults. Caring for the growing number of older people with complex drug regimens and multimorbidity presents an important challenge in the coming years. Areas covered: This article reviews the international trends in the prevalence of polypharmacy, summarizes the results from previous reviews on polypharmacy and negative health outcomes, and updates a previous review on the clinical consequences of polypharmacy by focusing on studies published after 2013. This narrative review, which is based on a literature search in MEDLINE and EMBASE from January 1990 to June 2018, was undertaken to identify relevant articles. Search terms included variations of polypharmacy and multiple medications. Expert opinion: The prevalence of polypharmacy is increasing worldwide. More than half of the older population is exposed to polypharmacy in some settings. Polypharmacy is associated with a broad range of clinical consequences. However, methods to assess the dangers of polypharmacy should be refined. In our opinion, the issue of 'confounding by multimorbidity' has been underestimated and should be better accounted for in future studies. Moreover, researchers should develop more clinically relevant definitions of polypharmacy, including measures of inappropriate or problematic polypharmacy.

PMID: 30540223 [PubMed - indexed for MEDLINE]

Drug-drug interactions in patients receiving hematopoietic stem cell transplantation.

Expert Opin Drug Metab Toxicol. 2019 Jan;15(1):49-59

Authors: Pejčić A, Janković SM, Opančina V, Babić G, Milosavljević M

Abstract
INTRODUCTION: Recipients of hematopoietic stem cell transplantation (HSCT) are exposed to numerous drugs in both pre- and post-transplantation period, which creates an opportunity for drug-drug interactions (DDIs); if clinically relevant DDIs happen, the risk of adverse treatment outcomes is increased. Areas covered: This review is focused on DDIs in recipients of HSCT that were observed and published as clinical trials, case series or case reports. Relevant publications were found by the systematic search of the following online databases: MEDLINE, SCOPUS, EBSCO, and SCINDEX. Expert opinion: The most important DDIs involve cytostatic or immunosuppressant drug on one side, and antimicrobial drugs on the other. The majority of clinically relevant interactions have pharmacokinetic character, involving drug metabolizing enzymes in the liver. Antifungal azoles inhibit metabolism of many cytostatic and immunosuppressant drugs at cytochromes and increase their plasma concentrations. Macrolide antibiotics and fluoroqunolones should be avoided in HSCT recipients, as they have much larger potential for DDIs than other antibiotic groups. HSCT recipients increasingly receive new immunomodulating drugs, and further observational studies are needed to reveal unsuspected DDIs with clinical relevance.

PMID: 30479183 [PubMed - indexed for MEDLINE]

A characterization and disproportionality analysis of medication error related adverse events reported to the FAERS database.

Expert Opin Drug Saf. 2018 Dec;17(12):1161-1169

Authors: Carnovale C, Mazhar F, Pozzi M, Gentili M, Clementi E, Radice S

Abstract
OBJECTIVES: To characterize adverse reactions associated with medication errors (ME) reported in US Food and Drug Administration Adverse Event Reporting System (US-FAERS), and to identify the potential signals of disproportionate reporting (SDR) for different drugs.
METHODS: ME associated Individual Case Study Report (ICSRs) were identified. ICSRs were categorized by patient age groups, affected stages of medication process and Anatomical Therapeutic Chemical classification system. Disproportionality analyses were performed for different age groups.
RESULTS: 46,8677 ICSRs were retrieved. An increasing trend in reporting of cases of ME was observed during the studied period. Immunosuppressants and psycholeptic drugs were most frequently involved. Administration errors were reported most frequently, followed by prescribing and dispensing errors. In neonates, SDR following wrong drug administration, wrong dose, and accidental overdose were associated with methylergonovine, zidovudine, and acetaminophen. In elderlies, SDR were found for dose omission and underdose error associated with etanercept and evolocumab.
CONCLUSION: While a detailed root-cause analysis for ME characteristic can rarely be performed on such a dataset, data mining for signals in spontaneous reporting database may assist in identifying potential ME in a more standardized and objective manner. Continued use of spontaneous reporting system for identifying MEs is encouraged to prevent unnecessary patient harm.

PMID: 30451017 [PubMed - indexed for MEDLINE]

Off-Label Use of Drugs and Adverse Drug Reactions in Pediatric Units: A Prospective, Multicenter Study.

Curr Drug Saf. 2018;13(3):200-207

Authors: Pratico AD, Longo L, Mansueto S, Gozzo L, Barberi I, Tiralongo V, Salvo V, Falsaperla R, Vitaliti G, La Rosa M, Leonardi S, Rotondo A, Avola N, Sgarlata D, Damiano A, Tirantello M, Anzelmo G, Cipolla D, Rizzo A, Russo A, Ruggieri M, Salomone S, Drago F

Abstract
BACKGROUND: Given the growing use of off-label in pediatric practice, there is a growing interest on pharmacovigilance programs monitoring the occurrence of adverse drug reactions related to off-label drug prescription in childhood.
PATIENTS AND METHODS: The results of a one-year program of pharmacovigilance issued in the Sicilian Region, Italy, are herein presented. The study involved 6 pediatric and neonatal centres and prospectively reviewed the prescriptions of 5,060 patients, who were stratified for age (newborn, infant, children, adolescents).
RESULTS: A total of 14,916 prescriptions were issued for 5,060 patients. Among them, 454 patients [8.97%] received at least one off-label drug. Among the off-label treated patients, 255 [56.2%] were newborns. Anti-infective drugs were the most frequent off-label used drugs, followed by drugs for alimentary tract and metabolism and drugs for blood or blood forming organs. Ninety adverse drug reactions were recorded [1.78% of the total patients]. They occurred after an off-label prescription in 33 out of 90 [36.7%], while those occurring after an on-label prescription were 57 [63.3%]. Patients treated with an off-label drug had a significantly higher risk of adverse drug reactions [7.3% vs. 1.2%; p <0.01].
CONCLUSION: The present study indicates that children admitted to neonatal intensive care units are likely to receive an off-label medication; children who receive an off-label medication are usually more likely to be treated with more medication than the others; adverse drug reactions occur in patients admitted in neonatal intensive care and pediatrics are units are more frequently with off-label than with on-label drugs.

PMID: 29921210 [PubMed - indexed for MEDLINE]

Causality assessment of serious and severe adverse events following immunization in India: a 4-year practical experience.

Expert Rev Vaccines. 2018 06;17(6):555-562

Authors: Singh AK, Wagner AL, Joshi J, Carlson BF, Aneja S, Boulton ML

Abstract
BACKGROUND: India has implemented the World Health Organization's revised Causality Assessment Protocol for adverse events following immunization (AEFI). We describe the number and types of serious/severe AEFIs, including deaths.
RESEARCH DESIGN AND METHODS: Analysis of causality classification of reported serious/severe AEFIs from 1 January 2012 to 7 January 2016 was done. Classification includes (A) consistent with causal association to immunization; (B) indeterminate; (C) coincidental association; or (D) unclassifiable. We present descriptive statistics across each category.
RESULTS: Analysis of causality assessment completed for 1037 reports of serious AEFIs: 499 (48%) were causally associated, 84 (8%) were indeterminate, 323 (31%) were coincidental, and 131 (13%) were unclassifiable. Of the 499 reports in the A category, the events were causally linked to vaccine product for 189 (18%), to immunization error for 135 (13%), and to immunization anxiety for 175 (17%). Among 279 reported deaths, more than half (55%; n = 153) were coincidental events and 37% were unclassifiable.
CONCLUSIONS: Causality assessment of AEFI cases is an important component of vaccination programs and post-marketing surveillance of vaccines. Field reporting and investigation of AEFIs can be improved for many severe or serious reports, most of which are not causally linked to the vaccination program.

PMID: 29865876 [PubMed - indexed for MEDLINE]

Improving the efficacy-safety balance of polypharmacology in multi-target drug discovery.

Expert Opin Drug Discov. 2018 02;13(2):179-192

Authors: Ravikumar B, Aittokallio T

Abstract
INTRODUCTION: Polypharmacology has emerged as an essential paradigm for modern drug discovery process. Multiple lines of evidence suggest that agents capable of modulating multiple targets in a selective manner may offer also improved balance between therapeutic efficacy and safety compared to single-targeted agents. Areas covered: Herein, the authors review the recent progress made in experimental and computational strategies for addressing the critical challenges with rational discovery of selective multi-targeted agents within the context of polypharmacological modelling. Specific focus is placed on multi-targeted mono-therapies, although examples of combinatorial polytherapies are also covered as an important part of the polypharmacology paradigm. The authors focus mainly on anti-cancer treatment applications, where polypharmacology is playing a key role in determining the efficacy-toxicity trade-off of multi-targeting strategies. Expert opinion: Even though it is widely appreciated that complex polypharmacological interactions can contribute both to therapeutic and adverse side-effects, systematic approaches for improving this balance by means of integrated experimental-computational strategies are still lacking. Future developments will be needed for comprehensive collection and harmonization of systems-wide target selectivity data, enabling better utilization and control for multi-targeted activities in the drug development process. Additional areas of future developments include model-based strategies for drug combination screening and improved pre-clinical validation options with animal models.

PMID: 29233023 [PubMed - indexed for MEDLINE]

Prediction of Drug-Related Risks Using Clinical Context Information in Longitudinal Claims Data.

Value Health. 2018 12;21(12):1390-1398

Authors: Meid AD, Groll A, Heider D, Mächler S, Adler JB, Günster C, König HH, Haefeli WE

Abstract
OBJECTIVES: To develop and internally validate prediction models for medication-related risks arising from overuse, misuse, and underuse that utilize clinical context information and are suitable for routine risk assessment in claims data (i.e., medication-based models predicting the risk for hospital admission apparent in routine claims data or MEDI-RADAR).
METHODS: Based on nationwide claims from health-insured persons in Germany between 2010 and 2012, we drew a random sample of people aged ≥65 years (N = 22,500 randomly allocated to training set, N = 7500 to validation set). Individual duration of drug supply was estimated from prescription patterns to yield time-varying drug exposure windows. Together with concurrent medical conditions (ICD-10 diagnoses), exposure to the STOPP/START (screening tool of older persons' potentially inappropriate prescriptions/screening tool to alert doctors to the right treatment) criteria was derived. These were tested as time-dependent covariates together with time-constant covariates (patient demographics, baseline comorbidities) in regularized Cox regression models.
RESULTS: STOPP/START variables were iteratively refined and selected by regularization to include 2 up to 11 START variables and 8 up to 31 STOPP variables in parsimonious and liberal selections in the prediction modeling. The models discriminated well between patients with and without all-cause hospitalizations, potentially drug-induced hospitalizations, and mortality (parsimonious model c-indices with 95% confidence intervals: 0.63 [0.62-0.64], 0.67 [0.65-0.68], and 0.78 [0.76-0.80]).
CONCLUSIONS: The STOPP/START criteria proved to efficiently predict medication-related risk in models possessing good performance. Timely detection of such risks by routine monitoring in claims data can support tailored interventions targeting these modifiable risk factors. Their impact on older peoples' medication safety and effectiveness can now be explored in future implementation studies.

PMID: 30502782 [PubMed - indexed for MEDLINE]

Synergistic enzymatic and bioorthogonal reactions for selective prodrug activation in living systems.

Nat Commun. 2018 11 28;9(1):5032

Authors: Yao Q, Lin F, Fan X, Wang Y, Liu Y, Liu Z, Jiang X, Chen PR, Gao Y

Abstract
Adverse drug reactions (ADRs) restrict the maximum doses applicable in chemotherapy, which leads to failure in cancer treatment. Various approaches, including nano-drug and prodrug strategies aimed at reducing ADRs, have been developed, but these strategies have their own pitfalls. A renovated strategy for ADR reduction is urgently needed. Here, we employ an enzymatic supramolecular self-assembly process to accumulate a bioorthogonal decaging reaction trigger inside targeted cancer cells, enabling spatiotemporally controlled, synergistic prodrug activation. The bioorthogonally activated prodrug exhibits significantly enhanced potency against cancer cells compared with normal cells. This prodrug activation strategy further demonstrates high tumour inhibition efficacy with satisfactory biocompatibility, pharmacokinetics, and safety in vivo. We envision that integration of enzymatic and bioorthogonal reactions will serve as a general small-molecule-based strategy for alleviation of ADRs in chemotherapy.

PMID: 30487642 [PubMed - indexed for MEDLINE]

Association between medication-related adverse events and non-elective readmission in acute ischemic stroke.

BMC Neurol. 2018 Nov 19;18(1):192

Authors: Crispo JAG, Thibault DP, Fortin Y, Krewski D, Willis AW

Abstract
BACKGROUND: There is limited data on the effects of medication-related adverse events occurring during inpatient stays for stroke. The objectives of our study were to characterize reasons for acute readmission after acute ischemic stroke (AIS) and determine if medication-related adverse events occuring during AIS hospitalization were associated with 30-day readmission. Secondary objectives examined whether demographic, clinical, and hospital characterisitcs were associated with post-AIS readmission.
METHODS: We used the Nationwide Readmission Database to identify index AIS hospitalizations in the United States between January and November 2014. Inpatient records were screened for diagnostic and external causes of injury codes indicative of medication-related adverse events, including adverse effects of prescribed drugs, unintentional overdosing, and medication errors. Nationally representative estimates of AIS hospitalizations, medication-related adverse events, and acute non-elective readmissions were computed using survey weighting methods. Adjusted odds of readmission for medication-related adverse events and select characteristics were estimated using unconditional logistic regression.
RESULTS: We identified 439,682 individuals who were hospitalized with AIS, 4.7% of whom experienced a medication-related adverse event. Overall, 10.7% of hospitalized individuals with AIS were readmitted within 30 days of discharge. Reasons for readmission were consistent with those observed among older adults. Inpatients who experienced medication-related adverse events had significantly greater odds of being readmitted within 30 days (adjusted odds ratio (AOR): 1.22; 95% CI: 1.14-1.30). Medication-related adverse events were associated with readmission for non-AIS conditions (AOR, 1.26; 95% CI: 1.17-1.35), but not with readmission for AIS (AOR, 0.91; 95% CI: 0.75-1.10). Several factors, including but not limited to being younger than 40 years (AOR, 1.12; 95% CI: 1.00-1.26), Medicare insurance coverage (AOR, 1.33; 95% CI: 1.26-1.40), length of stay greater than 1 week (AOR, 1.38; 95% CI: 1.33-1.42), having 7 or more comorbidites (AOR, 2.20; 95% CI: 2.08-2.34), and receiving care at a for-profit hospital (AOR, 1.20; 95% CI: 1.12-1.29), were identified as being associated with all-cause 30-day readmission.
CONCLUSIONS: In this nationally representative sample of AIS hospitalizations, medication-related adverse events were positively associated with 30-day readmission for non-AIS causes. Future studies are necessary to determine whether medication-related adverse events and readmissions in AIS are avoidable.

PMID: 30453901 [PubMed - indexed for MEDLINE]

Cross-sectional study of perioperative drug and allergen exposure in UK practice in 2016: the 6th National Audit Project (NAP6) Allergen Survey.

Br J Anaesth. 2018 Jul;121(1):146-158

Authors: Marinho S, Kemp H, Cook TM, Farmer L, Farooque S, Lucas DN, Garcez T, Floss K, Torevell H, Thomas M, Warner A, Hitchman J, Ferguson K, Egner W, Nasser S, Karanam S, Kong KL, McGuire N, Bellamy M, Harper NJN

Abstract
BACKGROUND: Details of the current UK drug and allergen exposure were needed for interpretation of reports of perioperative anaphylaxis to the 6th National Audit Project (NAP6).
METHODS: We performed a cross-sectional survey of 356 NHS hospitals determining anaesthetic drug usage in October 2016. All cases cared for by an anaesthetist were included.
RESULTS: Responses were received from 342 (96%) hospitals. Within-hospital return rates were 96%. We collected 15 942 forms, equating to an annual caseload of 3.1 million, including 2.4 million general anaesthetics. Propofol was used in 74% of all cases and 90% of general anaesthetics. Maintenance included a volatile agent in 95% and propofol in 8.7%. Neuromuscular blocking agents were used in 47% of general anaesthetics. Analgesics were used in 88% of cases: opioids, 82%; paracetamol, 56%; and non-steroidal anti-inflammatory drugs, 28%. Antibiotics were administered in 57% of cases, including 2.5 million annual perioperative administrations; gentamicin, co-amoxiclav, and cefuroxime were most commonly used. Local anaesthetics were used in 74% cases and 70% of general anaesthetics. Anti-emetics were used in 73% of cases: during general anaesthesia, ondansetron in 78% and dexamethasone in 60%. Blood products were used in ≈3% of cases, gelatin <2%, starch very rarely, and tranexamic acid in ≈6%. Chlorhexidine and povidone-iodine exposures were 74% and 40% of cases, and 21% reported a latex-free environment. Exposures to bone cement, blue dyes, and radiographic contrast dye were each reported in 2-3% of cases.
CONCLUSIONS: This survey provides insights into allergen exposures in perioperative care, which is important as denominator data for the NAP6 registry.

PMID: 29935566 [PubMed - indexed for MEDLINE]

Prevalence, risk factors and adverse outcomes of anticholinergic burden in patients with advanced chronic conditions at hospital admission.

Geriatr Gerontol Int. 2018 Aug;18(8):1159-1165

Authors: Sevilla-Sánchez D, Molist-Brunet N, González-Bueno J, Solà-Bonada N, Espaulella-Panicot J, Codina-Jané C

Abstract
AIM: To evaluate the anticholinergic burden (ACB), the risk factors associated with its onset and the clinical consequences for patients with advanced chronic conditions.
METHODS: A 10-month cross-sectional study was carried out in an acute hospital care geriatric unit. Patients with advanced chronic conditions were identified by the NECessity of PALliative care (NECPAL) test. The ACB was established using the Anticholinergic Drug Scale and Drug Burden Index (DBI) tools. Demographic, pharmacological and clinical patient data were collected with the objective of determining risk factors related to ACB. Measured clinical outcomes were the presence of acute confusional state, bone fractures, length of stay, mortality and 12-month survival rate.
RESULTS: A total of 235 patients were recruited (mean age 86.80 years, SD 5.37 years; 65.50% women), and 82.10% (DBI) and 93.6% (Anticholinergic Drug Scale) of the patients were treated with anticholinergic medications. Excessive polypharmacy (≥10 drugs) was identified as a risk factor for the presence of anticholinergic medication (Anticholinergic Drug Scale: OR 6.26, 95% CI 1.38-28.42; DBI: OR 3.44, 95% CI 1.60-7.38). High anticholinergic burden (by DBI >2 points) was an independent risk factor for the presence of acute confusional state on hospital admission (OR 2.98, 95% CI 1.04-8.50). However, ACB was not related to bone fractures on admission, length of stay, mortality or survival.
CONCLUSIONS: Patients with advanced chronic conditions are frequently treated with anticholinergic drugs, with excessive polypharmacy as a risk factor. Anticholinergic drugs are a risk factor for the presence of acute confusional state on hospital admission, but have no other effect in terms of morbimortality. Geriatr Gerontol Int 2018; 18: 1159-1165.

PMID: 29644803 [PubMed - indexed for MEDLINE]