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Oral glucose lowering with linagliptin and metformin compared with linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: subgroup analysis of a randomized clinical trial.

J Diabetes Investig. 2017 Sep 16;:

Authors: Ma RC, Del Prato S, Gallwitz B, Shivane VK, Lewis-D'Agostino D, Bailes Z, Patel S, Lee J, von Eynatten M, Di Domenico M, Ross SA

Abstract
AIMS/INTRODUCTION: Type 2 diabetes mellitus (T2DM) is an epidemic in Asia, yet clinical trials of glucose-lowering therapies often enrol predominantly Western populations. We explored the initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in newly diagnosed T2DM patients in Asia with marked hyperglycemia.
MATERIALS AND METHODS: This was a post-hoc subgroup analysis of a multinational, parallel-group clinical trial in which 316 newly diagnosed T2DM patients with glycated hemoglobin A1c (HbA1c) 8.5-12.0% were randomized to double-blind oral treatment with linagliptin/metformin or linagliptin monotherapy. The primary endpoint was the change from baseline in HbA1c at week 24. We evaluated data for the 125 participants from Asian countries.
RESULTS: After 24 weeks, mean ± SE reduction from baseline in HbA1c (mean 10.0%) was -2.99 ± 0.18% with linagliptin/metformin and -1.84 ± 0.18% with linagliptin; a treatment difference of -1.15% (95% CI -1.65 to -0.66, P < 0.0001). HbA1c <7.0% was achieved by 60% of participants receiving linagliptin/metformin. Mean body weight change after 24 weeks was -0.45 ± 0.41 kg and 1.33 ± 0.45 kg in the linagliptin/metformin and linagliptin groups, respectively (treatment difference: -1.78 kg [95% CI -2.99, -0.57, P = 0.0043]). Drug-related adverse events occurred in 9.7% of participants receiving linagliptin/metformin and 4.8% of those receiving linagliptin. Hypoglycemia occurred in 6.5% and 4.8% of the linagliptin/metformin and linagliptin groups, respectively, with no severe episodes. Gastrointestinal disorders occurred in 12.9% and 12.7% of the linagliptin/metformin and linagliptin groups, respectively, with no associated treatment discontinuations.
CONCLUSIONS: In people from Asia with newly diagnosed T2DM and marked hyperglycemia, the initial combination of linagliptin and metformin substantially improved glycemic control without weight gain and with infrequent hypoglycemia. Initial oral combination therapy may be a viable treatment for such individuals. This article is protected by copyright. All rights reserved.

PMID: 28921919 [PubMed - as supplied by publisher]

Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis.

Int J Cardiol. 2017 Sep 01;:

Authors: Lennerz C, Barman M, Tantawy M, Sopher M, Whittaker P

Abstract
BACKGROUND: Atrial fibrillation occurs frequently after open-heart surgery. It is associated with increased morbidity and mortality, longer hospital stays, and increased healthcare costs. Prophylactic administration of colchicine may mitigate post-operative atrial fibrillation (POAF).
METHODS: We searched PubMed, ClinicalTrials.gov and CENTRAL databases to identify randomized controlled trials (RCTs) that; (1) compared prophylactic use of colchicine to placebo, or usual care, in patients with sinus rhythm who underwent elective open-heart surgery and (2) reported POAF-incidence. We excluded trials focused on incidence of atrial fibrillation after percutaneous interventions or colchicine treatment of diagnosed pericarditis or post-pericardiotomy-syndrome. A random-effects model was used to pool data for POAF-incidence as the primary outcome and for drug-related adverse effects, major adverse events (death and stroke), and hospital length-of-stay as secondary outcomes.
RESULTS: We included five RCTs (1412 patients). Colchicine treatment reduced POAF-events by 30% versus placebo or usual care (18% vs. 27%, risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.84, p=0.0002). Adverse drug-related effects, especially gastrointestinal intolerance, increased with colchicine; (21% vs. 8.2%, RR 2.52, 95% CI 1.62 to 3.93, p<0.0001). However, major adverse events were unchanged (3.2% vs. 3.2%, RR 0.96, 95% CI 0.48 to 1.95, p=0.92). Length-of-stay decreased by 1.2days with colchicine (95% CI -1.89 to -0.44, p=0.002).
CONCLUSION: Colchicine demonstrated superior efficacy versus usual care for prevention of atrial fibrillation after cardiac surgery. Moreover, colchicine treatment was associated with shorter hospital stays. These benefits outweigh increased risk of adverse drug-related effects; although further work is needed to minimize gastrointestinal effects.

PMID: 28918897 [PubMed - as supplied by publisher]

Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial.

Lancet HIV. 2017 Sep 11;:

Authors: Cahn P, Kaplan R, Sax PE, Squires K, Molina JM, Avihingsanon A, Ratanasuwan W, Rojas E, Rassool M, Bloch M, Vandekerckhove L, Ruane P, Yazdanpanah Y, Katlama C, Xu X, Rodgers A, East L, Wenning L, Rawlins S, Homony B, Sklar P, Nguyen BY, Leavitt R, Teppler H, ONCEMRK Study Group

Abstract
BACKGROUND: Once daily regimens are preferred for HIV-1 treatment, to facilitate adherence and improve quality of life. We compared a new once daily formulation of raltegravir to the currently marketed twice daily formulation.
METHODS: In this randomised, double-blind, parallel-group, phase 3, non-inferiority study, we enrolled participants aged 18 years or older with HIV-1 RNA of 1000 or more copies per mL and no previous antiretroviral treatment at 139 sites worldwide. We randomly assigned participants (2:1) via an interactive voice and web response system to raltegravir 1200 mg (two 600 mg tablets) orally once daily or raltegravir 400 mg (one tablet) orally twice daily, each with tenofovir disoproxil fumarate and emtricitabine orally once daily, for up to 96 weeks. A computer-generated allocation schedule stratified randomisation by screening HIV-1 RNA value and co-infection with hepatitis B or C. Participants, sponsor personnel, investigators, and study site personnel involved in the treatment or evaluation of the participants were unaware of the treatment group assignments. The primary endpoint was the proportion of participants with HIV-1 RNA less than 40 copies per mL at week 48 assessed with the US Food and Drug Administration Snapshot algorithm. Non-inferiority was concluded if the lower bound of the two-sided 95% CI was greater than -10%. We assessed efficacy and safety in all participants who received one dose or more of study treatment. This study is registered with ClinicalTrials.gov, number NCT02131233.
FINDINGS: Between May 26, 2014, and Dec 5, 2014, 802 participants were enrolled and randomly assigned, 533 to once daily treatment and 269 to twice daily; 797 received study therapy, 531 once daily and 266 twice daily. At week 48, 472 (89%) of 531 once daily recipients and 235 (88%) of 266 twice daily recipients achieved HIV-1 RNA less than 40 copies per mL (treatment difference 0·5%, 95% CI -4·2 to 5·2). Drug-related adverse events occurred in 130 (24%) of 531 participants in the once daily group (one of which was serious; none led to treatment discontinuation) and 68 (26%) of 266 participants in the twice daily group (two of which were serious; two led to treatment discontinuation). The most common drug-related adverse events were nausea (39 [7%] vs 18 [7%]), headache (16 [3%] vs 12 [5%]), and dizziness (12 [2%] vs eight [3%]). No treatment-related deaths were reported.
INTERPRETATION: A once daily raltegravir 1200 mg regimen was non-inferior compared with raltegravir 400 mg twice daily for initial treatment of HIV-1 infection. These results support the use of raltegravir 1200 mg once daily for first-line therapy.
FUNDING: Merck & Co, Inc.

PMID: 28918877 [PubMed - as supplied by publisher]

Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data.

Int J Cancer. 2017 Sep 01;141(5):1018-1028

Authors: Wang W, Lie P, Guo M, He J

Abstract
Although existing evidence from clinical trials has demonstrated manifestation of hepatic adverse events with the use of immune checkpoint inhibitors (ICPIs), overall risks have yet to be reported. Therefore, we assessed the risk of hepatotoxicity associated with inhibitors of the immune checkpoint. We examined data from the Pubmed, Medline and Google Scholar databases. We also examined original studies and review articles for crossreferences Eligible studies included randomized Phase II to Phase III trials of cancer patients treated with nivolumab, pembrolizumab, ipilimumab, tremelimumab. The authors extracted relevant information on participants' characteristics, all-grade and high-grade hepatotoxicity and information on the methodology of the studies. In total, 17 trials were considered eligible for the meta-analysis. The odds ratio for all-grade hepatotoxicity for CTLA-4 inhibitors (Ipilimumab and tremelimumab) was 1.24 (95% confidence interval 0.75, 2.05; p = 0.39) and for high-grade hepatotoxicity was 1.93 (95% confidence interval 0.84, 4.44; p =0.12). Moreover, the odds ratio for all-grade hepatotoxicity for PD-1 inhibitors was 1.52 (95% confidence interval 1.24, 1.86; p < 0.0001) and for high-grade hepatotoxicity was 0.48 (95% confidence interval 0.29, 0.80; p =0.005). The analysis of data showed that CTLA-4 inhibitors seem to be associated with a higher risk of all- and high-grade hepatotoxicity compared with control regimens, whereas PD-1 inhibitors seem to be associated with a lower risk of all- and high-grade hepatotoxicity compared with control regimens.

PMID: 28263392 [PubMed - indexed for MEDLINE]

Italian intersociety consensus on DOAC use in internal medicine.

Intern Emerg Med. 2017 Apr;12(3):387-406

Authors: Prisco D, Ageno W, Becattini C, D'Angelo A, Davì G, De Cristofaro R, Dentali F, Di Minno G, Falanga A, Gussoni G, Masotti L, Palareti G, Pignatelli P, Santi RM, Santilli F, Silingardi M, Tufano A, Violi F, SIMI (Italian Society of Internal Medicine), FADOI (Federation of Associations of Hospital Doctors on Internal Medicine), SISET (Italian Society for the Study of Haemostasis and Thrombosis)

Abstract
The direct oral anticoagulants (DOACs) are drugs used in clinical practice since 2009 for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism. The four DOACs, including the three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and one direct thrombin inhibitor (dabigatran) provide oral anticoagulation therapy alternatives to Vitamin K antagonists (VKAs). Despite their clear advantages, the DOACs require on the part of the internist a thorough knowledge of their pharmacokinetic and pharmacodynamic characteristics to ensure their correct use, laboratory monitoring and the appropriate management of adverse events. This document represents a consensus paper on the use of DOACs by representatives of three Italian scientific societies: the Italian Society of Internal Medicine (SIMI), the Federation of the Associations of Hospital Managers (FADOI), and the Society for the Study of Haemostasis and Thrombosis (SISET). This document formulates expert opinion guidance for pragmatic managing, monitoring and reversing the anticoagulant effect of DOACs in both chronic and emergency settings. This practical guidance may help the internist to create adequate protocols for patients hospitalized ion internal medicine wards, where patients are often elderly subjects affected by poly-morbidities and renal insufficiency, and, thus, require particular attention to drug-drug interactions and peri-procedural protocols.

PMID: 28191610 [PubMed - indexed for MEDLINE]

Serious Adverse Reactions From Anti-tuberculosis Drugs Among 599 Children Hospitalized for Tuberculosis.

Pediatr Infect Dis J. 2017 Aug;36(8):720-725

Authors: Li Y, Zhu Y, Zhong Q, Zhang X, Shu M, Wan C

Abstract
BACKGROUND: The purpose of the study was to summarize the clinical characteristics of serious adverse reactions (ARs) related to anti-tuberculosis (TB) drugs in children hospitalized for TB. A comprehensive understanding of these drug-related ARs may serve to improve patient prognosis.
METHODS: Inpatients diagnosed with TB from 2008 to 2013 were enrolled retrospectively. The patients' demographics, diagnosis and ARs were recorded and analyzed for comprehensive evaluation.
RESULTS: Of the 599 enrolled patients, 3.51% (21 of 599) developed serious ARs related to anti-TB drugs. Hepatotoxicity was the most common reaction (1.84%, 11 of 599). The incidence of rash with or without fever was 1% (6 of 599), and that of auditory impairments and renal injury was 0.33% (2 of 599) and 0.17% (1 of 599), respectively. One patient experienced hepatotoxicity, rash and fever. Hospital stay of inpatients with serious ARs was significantly longer (median: 24 days; range: 8-62 days) than that of those without reactions (median: 11 days; range: 1-83 days), though no distinctions were observed between the 2 groups with regard to average age, gender or involved organs. Hepatotoxicity occurred 6-30 days after the start of anti-TB treatment (median: 6 days) and 75% of the inpatients remained asymptomatic. Hepatotoxicity was traced to the drugs isoniazid, rifampin and pyrazinamide, while fever was mainly linked to pyrazinamide. In addition, streptomycin and amikacin led to auditory impairments and renal injury, respectively. Serious ARs of all inpatients were controlled and managed successfully.
CONCLUSIONS: The incidence of serious ARs from anti-TB drugs among children inpatients was 3.5% and mainly consisted of hepatotoxicity. Inpatients with serious ARs tended to have longer hospital stays.

PMID: 28060046 [PubMed - indexed for MEDLINE]

Association of nutritional status-related indices and chemotherapy-induced adverse events in gastric cancer patients.

BMC Cancer. 2016 Nov 18;16(1):900

Authors: Seo SH, Kim SE, Kang YK, Ryoo BY, Ryu MH, Jeong JH, Kang SS, Yang M, Lee JE, Sung MK

Abstract
BACKGROUND: Malnutrition in gastrectomized patients receiving chemotherapy is associated with the susceptibility to chemotherapy-related adverse events. This study evaluated pre-operative nutritional status-related indices associated with adverse events in post-operation gastric cancer patients receiving chemotherapy.
METHODS: Medical records of 234 gastrectomized patients under adjuvant tegafur/gimeracil/oteracil chemotherapy with extended lymph node dissection were analyzed. Nutritional status assessment included Patient-Generated Subjective Global Assessment (PG-SGA), body weight, body mass index, serum albumin concentration, and Nutrition Risk Index (NRI). Chemotherapy-originated adverse events were determined using Common Terminology Criteria for Adverse Events.
RESULTS: PG-SGA indicated 59% of the patients were malnourished, and 27.8% of the patients revealed serious malnutrition with PG-SGA score of ≥9. Fifteen % of patients lost ≥10% of the initial body weight, 14.5% of the patients had hypoalbuminemia (<3.5 g/dL), and 66.2% had NRI score less than 97.5 indicating moderate to severe malnutrition. Hematological adverse events were present in 94% (≥grade 1) and 16.2% (≥grade 3). Non-hematological adverse events occurred in 95.7% (≥grade1) and 16.7% (≥grade 3) of the patients. PG-SGA and NRI score was not associated with treatment-induced adverse events. Multivariate analyses indicated that female, low body mass index, and hypoalbuminemia were independent risk factors for grade 3/4 hematological adverse events. Age was an independent risk factor for grade 3/4 non-hematological adverse events. Neutropenia was the most frequently occurring adverse event, and associated risk factors were female, total gastrectomy, and hypoalbuminemia.
CONCLUSIONS: Hypoalbuminemia, not PG-SGA or NRI may predict chemotherapy-induced adverse events in gastrectomized cancer patients.

PMID: 27863481 [PubMed - indexed for MEDLINE]

Computational cardiology and risk stratification for sudden cardiac death: one of the grand challenges for cardiology in the 21st century.

J Physiol. 2016 Dec 01;594(23):6893-6908

Authors: Hill AP, Perry MD, Abi-Gerges N, Couderc JP, Fermini B, Hancox JC, Knollmann BC, Mirams GR, Skinner J, Zareba W, Vandenberg JI

Abstract
Risk stratification in the context of sudden cardiac death has been acknowledged as one of the major challenges facing cardiology for the past four decades. In recent years, the advent of high performance computing has facilitated organ-level simulation of the heart, meaning we can now examine the causes, mechanisms and impact of cardiac dysfunction in silico. As a result, computational cardiology, largely driven by the Physiome project, now stands at the threshold of clinical utility in regards to risk stratification and treatment of patients at risk of sudden cardiac death. In this white paper, we outline a roadmap of what needs to be done to make this translational step, using the relatively well-developed case of acquired or drug-induced long QT syndrome as an exemplar case.

PMID: 27060987 [PubMed - indexed for MEDLINE]

Comparison of Unintentional Exposures to Codeine and Hydrocodone Reported to Texas Poison Centers.

J Emerg Med. 2016 May;50(5):744-52

Authors: Day L, Kleinschmidt K, Forrester MB, Feng SY

Abstract
BACKGROUND: Hydrocodone has recently been reclassified as a Schedule II drug by the United States Drug Enforcement Administration and Food and Drug Administration in order to curtail prescription drug abuse. There is concern that analgesic substitutes, such as codeine, will not be as safe or effective.
OBJECTIVE: The purpose of this study is to compare the demographics, adverse events, and medical outcomes of patients who had unintentional hydrocodone or codeine exposures through the use of a state's poison center database.
METHODS: The Texas Poison Center Network's database was utilized to find all reported unintentional ingestions or adverse reactions of products containing codeine or hydrocodone. Comparisons were made between the two medications by calculating the rate ratios (RR) and 95% confidence intervals (CI).
RESULTS: Children aged 5 years or younger were more exposed to codeine (51.6%). Hydrocodone exposures had more serious outcomes (11% vs. 9%; RR = 0.82; 95% CI 0.73-0.91) and had more nausea (7.1% vs. 2.8%; RR = 0.4; 95% CI 0.32-0.48) and vomiting (6.5% vs. 3.3%; RR = 0.51; 95% CI 0.43-0.62). Hydrocodone had a higher rate of intravenous fluids administration (2.4% vs. 1.7%; RR = 0.71; 95% CI 0.54-0.92) and antiemetics (0.4% vs. 0.1%; RR = 0.23; 95% CI 0.08-0.64). Codeine was more closely associated with dermal reactions and patients were given antihistamines (2.5% vs. 1.3%; RR = 1.88; 95% CI 1.46-2.41) more frequently. Cardiovascular side effects, ataxia, and headache occurred equally between the groups.
CONCLUSIONS: Both drugs had a wide array of reported side effects, but the overall incidence of serious outcomes was low.

PMID: 26899518 [PubMed - indexed for MEDLINE]

Predicting drug-induced QT prolongation and torsades de pointes.

J Physiol. 2016 May 01;594(9):2459-68

Authors: Roden DM

Abstract
Drugs used to treat cardiovascular disease as well as those used in the treatment of multiple other conditions can occasionally produce exaggerated prolongation of the QT interval on the electrocardiogram and the morphologically distinctive polymorphic ventricular tachycardia ('torsades de pointes'). This syndrome of drug-induced long QT syndrome has moved from an interesting academic exercise to become a key element in the development of any new drug entity. The prevailing view, which has driven both clinical care and drug regulation, holds that cardiac repolarization represents a balance between inward currents (primarily through calcium and sodium channels) and outward currents (primarily through rapid and slowed delayed rectifier potassium channels) and that block of the rapid delayed rectifier (IKr ) is the primary mechanism whereby drugs prolong individual action potentials, manifest on the surface electrocardiogram as QT interval prolongation. Such marked action potential prolongation in individual cardiac cells, in turn, is accompanied by arrhythmogenic afterdepolarizations thought to trigger torsades de pointes. This review describes the evidence in support of this construct, and describes the way in which clinical and whole heart experiments have informed molecular mechanisms and vice versa. New data that challenge these views and that may, as a result, lead to new clinical care and drug screening paradigms, are discussed.

PMID: 26660066 [PubMed - indexed for MEDLINE]

Bacterial Pneumonia in Older Adults.

Infect Dis Clin North Am. 2017 Sep 12;:

Authors: Henig O, Kaye KS

Abstract
The incidence of pneumonia increases with age, and is particularly high in patients who reside in long-term care facilities (LTCFs). Mortality rates for pneumonia in older adults are high and have not decreased in the last decade. Atypical symptoms and exacerbation of underlying illnesses should trigger clinical suspicion of pneumonia. Risk factors for multidrug-resistant organisms are more common in older adults, particularly among LTCF residents, and should be considered when making empiric treatment decisions. Monitoring of clinical stability and underlying comorbid conditions, potential drug-drug interactions, and drug-related adverse events are important factors in managing elderly patients with pneumonia.

PMID: 28916385 [PubMed - as supplied by publisher]

Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients.

Best Pract Res Clin Endocrinol Metab. 2017 Jun;31(3):349-361

Authors: Resteghini C, Cavalieri S, Galbiati D, Granata R, Alfieri S, Bergamini C, Bossi P, Licitra L, Locati LD

Abstract
Four tyrosine kinase inhibitors (TKIs) have been recently licensed in thyroid cancer (TC), sorafenib and lenvatinib for differentiated TC, vandetanib and cabozantinib for medullary TC. Others TKIs such as axitinib, pazopanib, sunitinib, have been tested within phase II trials. The toxicity burden associated to TKIs is not negligible. Drug reductions and interruptions are common, definitive drug withdrawals have also been reported as well as toxic deaths in more rare cases. In this context, the prevention of toxicities is mandatory to allow patients to stay on treatment as long as possible without dose and schedule modifications. Both physicians and patients should be educated to recognize drug-related toxicities in order to manage them in an early phase. Tools (e.g. toxicities summary booklet) for physicians and patients could be considered to improve the knowledge on side effects management. Guidelines, whenever available, should be followed.

PMID: 28911730 [PubMed - in process]

Risk of Recurrence of Adverse Events Following Immunization: A Systematic Review.

Pediatrics. 2017 Sep;140(3):

Authors: Zafack JG, De Serres G, Kiely M, Gariépy MC, Rouleau I, Top KA, Canadian Immunization Research Network

Abstract
CONTEXT: Reimmunizing patients who had an adverse event following immunization (AEFI) is sometimes a challenge because there are limited data on the risk and severity of AEFI recurrence.
OBJECTIVE: To summarize the literature on the risk of AEFI recurrence.
DATA SOURCES: PubMed, Embase, and Cochrane library.
STUDY SELECTION: We included articles in English or French published before September 30, 2016. Articles were selected if they estimated the risk of AEFI recurrence in at least 5 individuals. Studies with experimental vaccines were excluded.
DATA EXTRACTION: Data on study design, setting, population, vaccines, and AEFI recurrence were extracted.
RESULTS: Twenty-nine articles were included. Among patients with a history of hypotonic hyporesponsive episode (n = 398), anaphylaxis (n = 133), or seizures (n = 60) who were reimmunized, events recurred in 0% to 0.8%. Allergic-like events recurred in 30 of 594 reimmunized patients. Fever recurred in 0% to 84% of 836 reimmunized patients, depending on the vaccine and dose number. Among children with extensive limb swelling after the fourth dose of diphtheria-tetanus-acellular pertussis vaccine, recurrence was higher when the fifth dose was given withthe full-antigen formulation (78%) compared with the reduced-antigen formulation (53%, P = .02) LIMITATIONS: Many studies, included few patients, and those with severe AEFIs were often not reimmunized.
CONCLUSIONS: Despite vaccines being administered to millions of people annually, there are few studies in which researchers evaluated AEFI recurrence. Published studies suggest that reimmunization is usually safe. However in these studies, severe cases were often not reimmunized.

PMID: 28847985 [PubMed - indexed for MEDLINE]

Methodological and Ethical Issues in Pediatric Medication Safety Research.

Pediatrics. 2017 Sep;140(3):

Authors: Carpenter D, Gonzalez D, Retsch-Bogart G, Sleath B, Wilfond B

Abstract
In May 2016, the Eshelman School of Pharmacy at The University of North Carolina at Chapel Hill convened the PharmSci conference to address the topic of "methodological and ethical issues in pediatric medication safety research." A multidisciplinary group of experts representing a diverse array of perspectives, including those of the US Food and Drug Administration, children's hospitals, and academia, identified important considerations for pediatric medication safety research and opportunities to advance the field. This executive summary describes current challenges that clinicians and researchers encounter related to pediatric medication safety research and identifies innovative and ethically sound methodologies to address these challenges to improve children's health. This article addresses 5 areas: (1) pediatric drug development and drug trials; (2) conducting comparative effectiveness research in pediatric populations; (3) child and parent engagement on study teams; (4) improving communication with children and parents; and (5) assessing child-reported outcomes and adverse drug events.

PMID: 28778857 [PubMed - indexed for MEDLINE]

Weight Loss in Patients with Dementia: Considering the Potential Impact of Pharmacotherapy.

Drugs Aging. 2017 Jun;34(6):425-436

Authors: Franx BAA, Arnoldussen IAC, Kiliaan AJ, Gustafson DR

Abstract
Unintentional body weight loss is common in patients with dementia and is linked to cognitive impairment and poorer disease outcomes. It is proposed that some dementia medications with market approval, while aiming to improve cognitive and functional outcomes of a patient with dementia, are associated with reported body weight or body mass index loss. This review presents evidence in the published literature on body weight loss in dementia, describes selected theories behind body weight loss, evaluates the potential impact of approved dementia pharmacotherapies on body weight, considers the potential role for medical foods, understands the potential influence of treatments for neuropsychiatric symptoms and signs, and finally, summarizes this important area.

PMID: 28478593 [PubMed - indexed for MEDLINE]

Potentially Inappropriate Antihypertensive Prescriptions to Elderly Patients: Results of a Prospective, Observational Study.

Drugs Aging. 2017 Jun;34(6):453-466

Authors: Márquez PHP, Torres OH, San-José A, Vidal X, Agustí A, Formiga F, López-Soto A, Ramírez-Duque N, Fernández-Moyano A, Garcia-Moreno J, Arroyo JA, Ruiz D, Potentially Inappropriate Prescription in Older Patients in Spain (PIPOPS) Investigators’ Project

Abstract
INTRODUCTION: Previous studies of antihypertensive treatment of older patients have focused on blood pressure control, cardiovascular risk or adherence, whereas data on inappropriate antihypertensive prescriptions to older patients are scarce.
OBJECTIVES: The aim of the study was to assess inappropriate antihypertensive prescriptions to older patients.
METHODS: An observational, prospective multicentric study was conducted to assess potentially inappropriate prescription of antihypertensive drugs, in patients aged 75 years and older with arterial hypertension (HTN), in the month prior to hospital admission, using four instruments: Beers, Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert Doctors to the Right Treatment (START) and Assessing Care of Vulnerable Elders 3 (ACOVE-3). Primary care and hospital electronic records were reviewed for HTN diagnoses, antihypertensive treatment and blood pressure readings.
RESULTS: Of 672 patients, 532 (median age 85 years, 56% female) had HTN. 21.6% received antihypertensive monotherapy, 4.7% received no hypertensive treatment, and the remainder received a combination of antihypertensive therapies. The most frequently prescribed antihypertensive drugs were diuretics (53.5%), angiotensin-converting enzyme inhibitors (ACEIs) (41%), calcium antagonists (32.2%), angiotensin receptor blockers (29.7%) and beta-blockers (29.7%). Potentially inappropriate prescription was observed in 51.3% of patients (27.8% overprescription and 35% underprescription). The most frequent inappropriately prescribed drugs were calcium antagonists (overprescribed), ACEIs and beta-blockers (underprescribed). ACEI and beta-blocker underprescriptions were independently associated with heart failure admissions [beta-blockers odds ratio (OR) 0.53, 95% confidence interval (CI) 0.39-0.71, p < 0.001; ACEIs OR 0.50, 95% CI 0.36-0.70, p < 0.001].
CONCLUSION: Potentially inappropriate prescription was detected in more than half of patients receiving antihypertensive treatment. Underprescription was more frequent than overprescription. ACEIs and beta-blockers were frequently underprescribed and were associated with heart failure admissions.

PMID: 28432600 [PubMed - indexed for MEDLINE]

Clinical Relevance of Differences in Glomerular Filtration Rate Estimations in Frail Older People by Creatinine- vs. Cystatin C-Based Formulae.

Drugs Aging. 2017 Jun;34(6):445-452

Authors: Jacobs A, Benraad C, Wetzels J, Rikkert MO, Kramers C

Abstract
BACKGROUND: The risk of incorrect medication dosing is high in frail older people. Therefore, accurate assessment of the glomerular filtration rate is important.
OBJECTIVE: The objective of this study was to compare the estimated glomerular filtration rate using creatinine- and cystatin C-based formulae, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, in frail older people. We hypothesized that frailty determines the difference between the creatinine- and cystatin C-based formulae.
METHODS: The mean difference between CKD-EPI creatinine and cystatin C was determined using (cross-sectional) data of 55 patients (mean age 73 years) admitted to a psychiatric ward for older adults. The level of agreement of these estimations was assessed by a Bland-Altman analysis. In all patients, the Rockwood's Frailty Index was derived and correlated with the mean difference between CKD-EPI creatinine and cystatin C.
RESULTS: The mean difference between CKD-EPI creatinine (mean 71.2 mL/min/1.73 m(2)) and CKD-EPI cystatin C (mean 57.6 mL/min/1.73 m(2)) was 13.6 mL/min/1.73 m(2) (p < 0.0001). The two standard deviation limit in the Bland-Altman plot was large (43.2 mL/min/1.73 m(2)), which represents a low level of agreement. The Frailty Index did not correlate with the mean difference between the creatinine- and cystatin C-based glomerular filtration rate (Pearson correlation coefficient 0.182, p = 0.184).
CONCLUSIONS: There was a significant gap between a creatinine- and cystatin C-based estimation of glomerular filtration rate, irrespective of frailty. The range of differences between the commonly used estimated glomerular filtration rate formulae might result in clinically relevant differences in drug prescription and differences in chronic kidney disease staging.

PMID: 28405944 [PubMed - indexed for MEDLINE]

Adapting Cancer Immunotherapy Models for the Real World.

Trends Immunol. 2016 Jun;37(6):354-63

Authors: Klevorn LE, Teague RM

Abstract
Early experiments in mice predicted the success of checkpoint blockade immunotherapy in cancer patients. However, these same animal studies failed to accurately predict many of the limitations and toxicities of treatment. One of the likely reasons for this discrepancy is the nearly universal use of young healthy mice, which stand in stark contrast to diverse patient populations varying in age, weight, diet, and hygiene. Because these variables impact immunity and metabolism, they also influence outcomes during immunotherapy and should be incorporated into the study design of preclinical experiments. Here, we discuss recent findings that highlight how efficacy and toxicity of cancer immunotherapy are affected by patient variation, and how distinct host environments can be better modeled in animal studies.

PMID: 27105824 [PubMed - indexed for MEDLINE]

Polyethylene Glycol 3350 With Electrolytes vs Polyethylene Glycol 4000 for Constipation: A Randomized, Controlled Trial.

J Pediatr Gastroenterol Nutr. 2017 Sep 12;:

Authors: Bekkali NLH, Hoekman DR, Liem O, Bongers MEJ, van Wijk MP, Zegers B, Pelleboer RA, Verwijs W, Koot BGP, Voropaiev M, Benninga MA

Abstract
OBJECTIVES: The long-term efficacy and safety of polyethylene glycol (PEG) in constipated children are unknown, and a head-to-head comparison of the different PEG formulations is lacking. We aimed to investigate non-inferiority of PEG3350 with electrolytes (PEG3350+E) compared to PEG4000 without electrolytes (PEG4000).
METHODS: In this double-blind trial, children aged 0.5 - 16 years with constipation, defined as a defecation frequency of < 3 times per week, were randomized to receive either PEG3350 + E or PEG4000. Primary outcomes were change in total sum score (TSS) at week 52 compared to baseline, and dose range determination. TSS was the sum of the severity of 5 constipation-symptoms rated on a 4-point scale (0 - 3). Non-inferiority margin was a difference in TSS of ≤1.5 based on a 95%-CI. Treatment success was defined as a defecation frequency of ≥3 per week with < 1 episode of fecal incontinence.
RESULTS: Ninety-seven subjects were included, of whom 82 completed the study. Mean reduction in TSS was -3.81 (95%-CI:-4.96 - -2.65) and -3.74 (95%-CI:-5.08 - -2.40), for PEG3350 + E and PEG4000, respectively. Non-inferiority criteria were not met (maximum difference between groups: -1.81 - 1.68). Daily sachet use was: 0 - 2 years: 0.4 - 2.3 and 0.9 - 2.1; 2 - 4y 0.1 - 3.5 and 1.2 - 3.2; 4 - 8y 1.1 - 2.8 and 0.7 - 3.8; 8 - 16y 0.6 - 3.7 and 1.0 - 3.7, in PEG3350 + E and PEG4000, respectively. Treatment success after 52 weeks was achieved in 50% and 45% of children, respectively (p = 0.69). Rates of adverse events were similar between groups, and no drug-related serious adverse events occurred.
CONCLUSIONS: Non-inferiority regarding long-term constipation-related symptoms of PEG3350 + E compared to PEG4000 was not demonstrated. However, analysis of secondary outcomes suggests similar efficacy and safety of these agents.

PMID: 28906317 [PubMed - as supplied by publisher]