Frequency of Adverse Event Monitoring in Ambulatory Patients on Amiodarone or Dofetilide.

J Pharm Pract. 2018 Oct;31(5):457-461

Authors: Rickard JP, Negrelli J, Olson JL, Dick T

Abstract
BACKGROUND: Published studies state that adherence to regular laboratory assessments for anti-arrhythmic drugs is as low as 20%. Monitoring adherence is important as other studies have shown that up to 93% of patients on amiodarone experience an adverse drug event leading to a potentially lethal event.
OBJECTIVE: To determine whether patients prescribed amiodarone or dofetilide are being monitored according to package labeling and guideline recommendations for adverse events.
METHODS: Patients prescribed amiodarone or dofetilide from a 2-year period were eligible for inclusion. Patients with ventricular arrhythmias, prescribed more than 1 anti-arrhythmic agent, or received anti-arrhythmic monitoring outside the health-care system were excluded. Adherence to monitoring parameters was assessed according to labeled recommendations and published guidelines. The primary objective was to determine the frequency of baseline and follow-up monitoring recommendations for patients receiving amiodarone or dofetilide. The secondary objective was to determine rates of adverse drug events.
RESULTS: One hundred patients were evaluated (amiodarone n = 50, dofetilide n = 50). Average rates of baseline and follow-up amiodarone monitoring parameters were 55% and 57%, respectively. Average rates of baseline and follow-up dofetilide monitoring were 99.6% and 85%, respectively. There was a statistically significant difference in abnormally elevated thyroid-stimulating hormone levels (8%-30%, P ≤ .005) after patients were prescribed amiodarone. Twelve percent of patients taking dofetilide had an increase in QTc interval by >15%.
CONCLUSIONS: Amiodarone adverse event monitoring was lower than dofetilide in this cohort. Improving the monitoring of these agents may decrease morbidity risk in this population.

PMID: 28884613 [PubMed - indexed for MEDLINE]

Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria.

Cochrane Database Syst Rev. 2019 Jan 08;1:CD006404

Authors: Pryce J, Hine P

Abstract
BACKGROUND: The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum (P falciparum) malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine-artesunate is a novel ACT.
OBJECTIVES: To evaluate the efficacy of pyronaridine-artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine-artesunate and other pyronaridine treatments compared to alternative treatments.
SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform Search Portal, and the International Standard Randomized Controlled Trial Number (ISRCTN) registry for ongoing or recently completed trials. The date of the last search was 8 May 2018.
SELECTION CRITERIA: Efficacy analysis: randomized controlled trials (RCTs) of pyronaridine-artesunate for treating uncomplicated P falciparum malaria.Safety analysis: RCTs of pyronaridine-artesunate or pyronaridine for treating P falciparum or P vivax malaria.
DATA COLLECTION AND ANALYSIS: For this update, two review authors independently re-extracted all data and assessed certainty of evidence. We meta-analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons.
MAIN RESULTS: We included 10 relevant studies. Seven studies were co-funded by Shin Poong Pharmaceuticals which manufactures the drug. Three studies were funded by government agencies.For efficacy analysis we identified five RCTs with 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. It included 541 children aged less than five years.For polymerase chain reaction (PCR)-adjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-certainty evidence), artesunate-amodiaquine (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-certainty evidence), and mefloquine plus artesunate (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-certainty evidence).For unadjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-certainty evidence), and probably has fewer failures compared to artesunate-amodiaquine (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-certainty evidence) and mefloquine plus artesunate (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-certainty evidence).For PCR-adjusted failures at day 42, pyronaridine-artesunate may make little or no difference compared to artemether-lumefantrine (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-certainty evidence) and artesunate-amodiaquine (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low-certainty evidence), but may have higher failures than mefloquine plus artesunate (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-certainty evidence). Overall, pyronaridine-artesunate had a PCR-adjusted treatment failure rate of less than 5%.For unadjusted failures at day 42, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence), may make little or no difference compared to mefloquine plus artesunate (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low-certainty evidence), and probably makes little or no difference compared to artesunate-amodiaquine (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-certainty evidence).For the safety analysis of severe adverse events and liver function, we identified eight RCTs with 6614 participants comparing pyronaridine-artesunate to other antimalarials, four of which were not in the previous version of this review. A further two RCTs, comparing pyronaridine alone to other treatments, contributed to the synthesis of all adverse events.Raised alanine aminotransferase (ALT) greater than five times the upper limit of normal (> 5 x ULN) is more frequent with pyronaridine-artesunate compared to other antimalarials (RR 3.34, 95% CI 1.63 to 6.84; 8 RCTS, 6581 participants, high-certainty evidence). There is probably little or no difference for raised bilirubin > 2.5 x ULN between pyronaridine-artesunate and other antimalarials (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants, moderate-certainty evidence). There was one reported case in which raised ALT occurred with raised bilirubin, meeting criteria for moderate drug-induced liver injury. No study reported severe drug-induced liver injury. Electrocardiograph (ECG) abnormalities were less common with pyronaridine-artesunate compared to other antimalarials. We identified no other safety concerns.
AUTHORS' CONCLUSIONS: Pyronaridine-artesunate was efficacious against uncomplicated P falciparum malaria, achieved a PCR-adjusted treatment failure rate of less than 5% at days 28 and 42, and may be at least as good as, or better than other marketed ACTs.Pyronaridine-artesunate increases the risk of episodes of raised ALT > 5 x ULN. This meets criteria for mild drug-induced liver injury. On one instance this was linked to raised bilirubin, indicating moderate drug-induced liver injury. No episodes of severe drug-induced liver injury were reported. The findings of this review cannot fully inform a risk-benefit assessment for an unselected population. Readers should remain aware of this uncertainty when considering use of pyronaridine-artesunate in patients with known or suspected pre-existing liver dysfunction, and when co-administering with other medications which may cause liver dysfunction.

PMID: 30620055 [PubMed - as supplied by publisher]

Disabling Resting Tremors Induced by the Short-term Infusion of Valproate: A Reversible Phenomenon.

Tremor Other Hyperkinet Mov (N Y). 2018;8:615

Authors: Gupta A, Kushwaha S

Abstract
Background: Drug-induced tremors after long-term administration of anti-epileptics have been described in the literature. Such tremors are usually postural or action in nature with infrequent resting nature.
Case Report: A 23-year-old female presented in status epilepticus. Past and family histories were negative for seizures. She was managed per protocol with valproate. Within hours, she developed resting tremors. The tremors subsided on changing the anti-epileptic.
Discussion: Resting tremors have mostly been described in the literature as long-term side-effects of valproate. This case illustrates that even short-term infusion of valproate can cause resting tremors.

PMID: 30619645 [PubMed - in process]

A phase 1, first-in-human study of 18F-GP1 positron emission tomography for imaging acute arterial thrombosis.

EJNMMI Res. 2019 Jan 07;9(1):3

Authors: Chae SY, Kwon TW, Jin S, Kwon SU, Sung C, Oh SJ, Lee SJ, Oh JS, Han Y, Cho YP, Lee N, Kim JY, Koglin N, Berndt M, Stephens AW, Moon DH

Abstract
BACKGROUND: 18F-GP1 is a novel positron emission tomography (PET) tracer that targets glycoprotein IIb/IIIa receptors on activated platelets. The study objective was to explore the feasibility of directly imaging acute arterial thrombosis (AAT) with 18F-GP1 PET/computed tomography (PET/CT) and to quantitatively assess 18F-GP1 uptake. Safety, biodistribution, pharmacokinetics and metabolism were also evaluated.
METHODS: Adult patients who had signs or symptoms of AAT or had recently undergone arterial intervention or surgery within 14 days prior to 18F-GP1 PET/CT were eligible for inclusion. The AAT focus was demonstrated by conventional imaging within the 5 days prior to 18F-GP1 administration. Whole-body dynamic 18F-GP1 PET/CT images were acquired for up to 140 min after injection of 250 MBq of 18F-GP1. Venous plasma samples were analysed to determine 18F-GP1 clearance and metabolite formation.
RESULTS: Among the ten eligible patients assessed, underlying diseases were abdominal aortic aneurysm with endovascular repair (n = 6), bypass surgery and stent placement (n = 1), endarterectomy (n = 1), arterial dissection (n = 1) and acute cerebral infarction (n = 1). 18F-GP1 administration and PET/CT procedures were well tolerated, with no drug-related adverse events. All patients showed high initial 18F-GP1 uptake in the spleen, kidney and blood pool, followed by rapid clearance. Unmetabolised plasma 18F-GP1 levels peaked at 4 min post-injection and decreased over time until 120 min. The overall image quality was sufficient for diagnosis in all patients and AAT foci were detected in all participants. The 18F-GP1 uptake in AAT foci remained constant from 7 min after injection and began to separate from the blood pool after 20 min. The median standardised uptake value of AAT was 5.0 (range 2.4-7.9) at 120 min post-injection. The median ratio of standardised uptake value of AAT foci to the mean blood pool activity was 3.4 (range 2.0-6.3) at 120 min.
CONCLUSIONS: 18F-GP1 is a safe and promising novel PET tracer for imaging AAT with a favourable biodistribution and pharmacokinetic profile.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02864810 , Registered August 3, 2016.

PMID: 30617563 [PubMed]

Integrated safety summary of phase II and III studies comparing oral nemonoxacin and levofloxacin in community-acquired pneumonia.

J Microbiol Immunol Infect. 2018 Dec 21;:

Authors: Cheng SL, Wu RG, Chuang YC, Perng WC, Tsao SM, Chang YT, Chang LW, Hsu MC

Abstract
BACKGROUND: Nemonoxacin, a novel nonfluorinated quinolone, has broad-spectrum antibacterial activity, including activity against antibiotic-resistant strains, and was developed for treating community-acquired pneumonia (CAP). This report provides an integrated safety summary of oral nemonoxacin from two phase II and one phase III clinical studies.
METHODS: Patients with mild CAP were randomized for treatment with nemonoxacin 500 mg (NEMO-500MG), nemonoxacin 750 mg (NEMO-750MG), or levofloxacin 500 mg (LEVO), orally, once daily, for 7-10 days. Hematological, gastrointestinal, and hepatic disorders; electrocardiography abnormalities; and reported quinolone-associated clinical concerns were included in this analysis.
RESULTS: A total of 520, 155, and 320 subjects were assigned to receive NEMO-500MG, NEMO-750MG, and LEVO, respectively. The incidence of adverse events (AEs) was the highest (54.8%) in the NEMO-750MG group (NEMO-500MG, 36.9%; NEMO-750MG, 54.8%; LEVO, 39.7%) and that of drug-related AEs was comparable between the three groups (NEMO-500MG, 22.9%; NEMO-750MG, 31.0%; LEVO, 22.5%). The majority (>80%) of the patients showed mild drug-related AEs and the distribution based on severity was similar between the groups. The most commonly reported drug-related AEs included neutropenia (NEMO-500MG, 2.5%; NEMO-750MG, 8.4%; LEVO, 4.4%), nausea (NEMO-500MG, 2.5%; NEMO-750MG, 7.1%; LEVO, 2.5%), leukopenia (NEMO-500MG, 2.3%; NEMO-750MG, 4.5%; LEVO, 3.1%), and increased alanine aminotransferase level (NEMO-500MG, 4.4%; NEMO-750MG, 0%; LEVO, 2.5%).
CONCLUSION: Nemonoxacin was well tolerated and no clinically significant safety concerns were identified, suggesting that it possesses a desirable safety and tolerability profile similar to that of levofloxacin, and may be a suitable alternative to fluoroquinolones for treating patients with CAP.

PMID: 30616912 [PubMed - as supplied by publisher]

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]