Incidence, causes, and consequences of preventable adverse drug reactions occurring in inpatients: A systematic review of systematic reviews.

PLoS One. 2018;13(10):e0205426

Authors: Wolfe D, Yazdi F, Kanji S, Burry L, Beck A, Butler C, Esmaeilisaraji L, Hamel C, Hersi M, Skidmore B, Moher D, Hutton B

Abstract
BACKGROUND: Preventable adverse drug reactions (PADRs) in inpatients are associated with harm, including increased length of stay and potential loss of life, and result in elevated costs of care. We conducted an overview of reviews (i.e., a systematic review of systematic reviews) to determine the incidence of PADRs experienced by inpatients. Secondary review objectives were related to assessment of the effects of patient age, setting, and clinical specialty on PADR incidence.
METHODS: The protocol was registered in PROSPERO (CRD42016043220). We performed a search of Medline, Embase, and the Cochrane Library, limiting languages of publication to English and French. We included published systematic reviews that reported quantitative data on the incidence of PADRs in patients receiving acute or ambulatory care in a hospital setting. The full texts of all primary studies for which PADR data were reported in the included reviews were obtained and data relevant to review objectives were extracted. Quality of the included reviews was assessed using the AMSTAR-2 tool. Both narrative summaries of findings and meta-analyses of primary study data were undertaken.
RESULTS: Thirteen systematic reviews encompassing 37 unique primary studies were included. Across primary studies, the PADR incidence was highly varied, ranging from 0.006 to 13.3 PADRs per 100 patients, with a pooled incidence estimate of 0.59 PADRs per 100 patients. Substantial heterogeneity was present across both reviews and primary studies with respect to review/study objectives, patient age, hospital setting, medical discipline, definitions and assessment tools used, event detection methods, endpoints of interest, and units of measure. Thirteen primary studies used prospective event detection methods and had a pooled PADR incidence of 3.13 (2.87-3.38) PADRs per 100 patients; however, extreme statistical heterogeneity (I2 = 97%) indicated this finding should be considered with caution. Subgroup meta-analyses demonstrated that PADR incidence varied significantly with event detection method (prospective > retrospective > voluntary reporting methods), hospital setting (ICU > wards), and medical discipline (medical > surgical). High statistical heterogeneity (I2 > 80%) was present across all analyses, indicating results should be interpreted with caution. Effects of patient age could not be assessed due to poor reporting of age groups used in primary studies.
DISCUSSION: The method of event detection appeared to significantly influence PADR incidence, with prospective methods having the highest reported PADR rate. This finding is in agreement with the background literature. High methodological and statistical heterogeneity across primary studies evaluating adverse drug events reduces the validity of the overall PADR incidence derived from the meta-analyses of the pooled data. Data pooled from studies using only prospective methods of event detection should provide an overall estimate closest to the true PADR incidence; however, our estimate should be considered with caution due to the statistical heterogeneity found in this group of studies. Future studies should employ prospective methods of detection. This review demonstrates that the true overall incidence of PADRs is likely much greater than the overall pooled incidence estimate of 0.59 PADRs per 100 patients obtained when event detection method was not taken into consideration.

PMID: 30308067 [PubMed - indexed for MEDLINE]

Characterization of serious adverse drug reactions as cause of emergency department visit in children: a 5-years active pharmacovigilance study.

BMC Pharmacol Toxicol. 2018 04 16;19(1):16

Authors: Lombardi N, Crescioli G, Bettiol A, Marconi E, Vitiello A, Bonaiuti R, Calvani AM, Masi S, Lucenteforte E, Mugelli A, Giovannelli L, Vannacci A

Abstract
BACKGROUND: To describe frequency, preventability and seriousness of adverse drug reactions (ADRs) in children as cause of emergency department (ED) admission and to evaluate the association between specific factors and the reporting of ADRs.
METHODS: A retrospective analysis based on reports of suspected ADRs collected between January 1st, 2012 and December 31st, 2016 in the ED of Meyer Children's Hospital (Italy). Demographics, clinical status, suspected drugs, ADR description, and its degree of seriousness were collected. Logistic regression was used to estimate the reporting odds ratios (RORs) with 95% confidence intervals (CIs) of potential predictors of ADR seriousness.
RESULTS: Within 5 years, we observed 834 ADRs (1100 drug-ADR pairs), of whom 239 were serious; of them, 224 led to hospitalization. Patients were mostly treated with one drug. Among patients treated with more than one drug, 78 ADRs presented a potential interaction. The most frequently reported ADRs involved gastrointestinal system. The most frequently reported medication class was antinfectives. Risk of serious ADR was significantly lower in children and infants compared to adolescents (ROR 0.41 [95% CI: 0.27-0.61] and 0.47 [0.32-0.71], respectively), and it was significantly increased in subjects exposed to more than one drug (ROR 1.87 [1.33-2.62] and 3.01 [2.07-4.37] for subjects exposed to 2 and 3 or more drugs, respectively). Gender, interactions and off-label drug use did not influence the risk of serious ADRs.
CONCLUSION: Active surveillance in pharmacovigilance might represent the best strategy to estimate and characterize the clinical burden of ADRs in children.

PMID: 29661234 [PubMed - indexed for MEDLINE]

Usefulness of the Liverpool Adverse Events Profile for predicting a high risk of suicidality in people with drug-resistant epilepsy.

Seizure. 2019 Mar 19;67:65-70

Authors: Kwon OY, Park SP

Abstract
PURPOSE: Suicidality including suicidal ideation and attempt has been a critical issue in people with epilepsy, especially in people with drug-resistant epilepsy (PWDRE). Clinicians commonly ask about adverse effects of antiepileptic drugs (AEDs) using something like the Liverpool Adverse Events Profile (LAEP) at epilepsy clinics, but suicide is usually not of interest. A high risk of suicidality can increase mortality by committing suicide in PWDRE. This study aimed to investigate whether clinicians can discern a high risk of suicidality in PWDRE by referring to the LAEP.
METHODS: We recruited PWDRE, aged from 19 to 68. They completed the 21-item LAEP, the suicidality module of the Mini International Neuropsychiatric Interview, and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Through receiver operating characteristic curve analysis, we tested the usefulness of LAEP to detect a high risk of suicide. By this, we determined each cutoff point of the total LAEP score and the number of severe LAEP items, for detecting the risk.
RESULTS: A hundred forty-four PWDRE participated in this study. Among them, 36 PWDRE (25.0%) had a high risk of suicidality. Either >45 of the total LAEP score or >8 of the number of severe LAEP items was a suggested optimal cutoff point for discerning the high risk of suicidality. LAEP had a correlation with the suicidality item of the NDDI-E.
CONCLUSION: The LAEP may inform a high risk of suicidality in PWDRE. Referring to this, clinicians can discern suicidal problems in their epilepsy clinics.

PMID: 30909164 [PubMed - as supplied by publisher]

Haematological adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia: a network meta-analysis.

Br J Clin Pharmacol. 2019 Mar 25;:

Authors: Fachi MM, Tonin FS, Leonart LP, Rotta I, Fernandez-Llimos F, Pontarolo R

Abstract
AIMS: Despite their overall favourable safety profile, tyrosine kinase inhibitors (TKIs) are related to severe adverse events (AEs) including haematological toxicities such as anaemia, leukopenia, neutropenia, and thrombocytopenia. We designed a systematic review and network meta-analysis of randomised controlled trials (RCT) to compare safety among TKIs (bosutinib, dasatinib, imatinib, nilotinib, ponatinib, and radotinib) used by patients diagnosed with chronic myeloid leukemia (CML).
METHODS: We obtained data from the PubMed, Scopus, Web of Science, and SciELO databases. The Bayesian approach was used for direct and indirect comparisons, and the treatments were ranked by the surface under the cumulative ranking curve (SUCRA).
RESULTS: Seventeen studies were included in the network meta-analysis. Our data shows that dasatinib was generally considered worse than the other TKIs, with SUCRA values for 140 mg dasatinib of 90.3% for anaemia, 87.4% for leukopenia, 90.6% for neutropenia, and 97.2% for thrombocytopenia. In addition, nilotinib was shown to be safer, with SUCRA values for 600 and 800 mg doses of 21.9 and 35.8% for anaemia, 23.8 and 14.6% for leukopenia, 33.0 and 17.7% for neutropenia, and 28.7 and 32.6% for thrombocytopenia, respectively.
CONCLUSION: Dasatinib appeared as the least safe drug for CML, most likely because it binds to multiple key kinase targets, being more prone to cause serious haematological AEs. Nilotinib demonstrated a safer profile, mostly due to its selective binding capacity.

PMID: 30907446 [PubMed - as supplied by publisher]

Synthesis, molecular modeling studies, and anticonvulsant evaluation of novel 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides and their acetate esters.

Arch Pharm (Weinheim). 2018 Dec;351(12):e1800269

Authors: Aboul-Enein MN, El-Azzouny AA, Amin KM, Aboutabl ME, Abo-Elmagd MI

Abstract
A series of 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides IXa-l and their acetate esters Xa-l were designed and synthesized as new anticovulsant agents. The evaluation of the anticonvulsant effect was performed in vivo by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) tests in mice. Further, neurotoxicity, hepatotoxicity, and acute toxicity were determined. All the new candidates displayed 100% anticonvulsant activity in the scPTZ screen in the dose range of 0.0057-0.283 mmol/kg. The most potent compounds in the scPTZ screen were Xh (ED50  = 0.0012 mmol/kg), Xd (ED50  = 0.002 mmol/kg), Xf (ED50  = 0.004 mmol/kg), IXj (ED50  = 0.0047 mmol/kg), Xl (ED50  = 0.0076 mmol/kg), and Xi (ED50  = 0.008 mmol/kg). They exhibited higher fold activity in the anticonvulsant potential than the gold standards, phenobarbital and ethosuximide. Compound Xf was active in both scPTZ and MES screens. It showed ED50 of 0.016 mmol/kg in MES screen. In the neurotoxicity screens, none of the test compounds displayed any minimal motor impairment at the maximum administered dose. The 3D pharmacophore model using Biova 1 Discovery Studio 2016 programs exhibited high fit value. The anticonvulsant evaluation results were compatible with the molecular modeling study.

PMID: 30461033 [PubMed - indexed for MEDLINE]

Problemas relacionados con medicamentos que causan ingresos por urgencias en un hospital de alta complejidad.

Farm Hosp. 2018 11 01;42(6):228-233

Authors: Calvo-Salazar RA, David M, Zapata-Mesa MI, Rodríguez-Naranjo CM, Valencia-Acosta NY

Abstract
OBJECTIVE: Determining hospital admissions prevalence associated with problems related to medicines in the emergency services of high complexity hospital; performing the pertinent pharmaceutical interventions.
METHOD: Descriptive observational cross-sectional study. The medical records of the patients admitted to the emergency services were reviewed. Those that  reported hospitalization due to problems related to medication were selected.  These were classified according to the Third Consensus of Granada adaptation. A pharma-therapeutic profile was made to hospitalized patients; performing the  necessary pharmaceutical interventions to avoid future medication related  problems.
RESULTS: 3.8% of patients were included in the study. The problems related to  medications had a preventability of 87.7% and the most frequent were those of  need with 42.2%. A pharma-therapeutic profile was done to hospitalized  patients (137). 150 pharmaceutical interventions were done, which had an  acceptance of 95.3%. The most intervened risk was administering an  unnecessary medication 62.7%.
CONCLUSIONS: Lack of supervision and analysis of problems related to medication could cause therapeutic approach failure, therefore, health and life quality improvement of the patients is not achieve. The pharmaceutical chemist  plays a fundamental role in the health care of patients, helping to the prevention  and proper use of medicines. The Pharmaceutical Care program  proves that it provides an invaluable contribution to public health service by  improving the pharmacological safety of treatments, reducing costs and public  health problems.

PMID: 30381042 [PubMed - indexed for MEDLINE]

Hospitalisation and morbidity due to adverse drug reactions in elderly patients: a single-centre study.

Intern Med J. 2018 Oct;48(10):1192-1197

Authors: Ognibene S, Vazzana N, Giumelli C, Savoldi L, Braglia L, Chesi G

Abstract
BACKGROUND: Adverse drug reaction (ADR) is a leading but under-recognised cause of illness, particularly in frail subjects with multiple comorbidities.
AIM: To investigate the frequency, patterns and outcomes of ADR as a cause of hospitalisation in elderly patients admitted to an internal medicine ward.
METHODS: We performed a retrospective observational study including every patient aged over 65 years who was admitted to our department during a 12-month period. Patients admitted to short-stay (<24 h) observation unit were excluded.
RESULTS: ADR accounted for 106 of total 1750 recorded admissions, which constituted a proportion of 6.1% (95% confidence interval 5.0-7.3%). The median age of patients was 83.5 (78.0-87.0) years and 56.6% were on polypharmacy. A total of 170 ADR was recorded with 45.3% of subjects experiencing concomitantly more than one ADR from a single molecule. Diuretics were the most commonly imputed molecules (30 events, 17.6%), followed by antithrombotics (25 events, 14.7%) and central nervous system-active drugs (16 events, 9.4%). Interactions were judged responsible for 39 cases of ADR (36.8%). An unfavourable outcome was observed in about one-third of patients (37.7%). Among those subjects, 11 (10.4%) died and 29 (27.4%) had residual disability.
CONCLUSION: ADR are a common cause of hospital admission in elderly patients and are often associated with adverse outcomes. Our data underline the need of appropriate strategies aimed at identifying high-risk patients and avoiding potentially preventable drug toxicities.

PMID: 29740921 [PubMed - indexed for MEDLINE]

Raltegravir versus lopinavir/ritonavir for treatment of HIV-infected late-presenting pregnant women.

HIV Clin Trials. 2018 06;19(3):94-100

Authors: Brites C, Nóbrega I, Luz E, Travassos AG, Lorenzo C, Netto EM

Abstract
Background Late-presenting pregnant women pose a challenge in the prevention of HIV-1 mother-to-child-transmission. We compared the safety and efficacy of raltegravir and lopinavir/ritonavir for this population. Methods We did a single-center, pilot, open-label, randomized trial in Brazil (N = 44). We randomly allocated late-presenting HIV-infected pregnant women (older than 18 years with a plasma HIV-1 RNA >1000 copies/mL) to receive raltegravir 400 mg twice a day or lopinavir/ritonavir 400/100 mg twice a day plus zidovudine and lamivudine (1:1). The primary endpoint was virological suppression at delivery (HIV-1 RNA <50 copies per mL), in all patients who received at least one dose of study drugs (modified intention-to-treat analysis). Missing information was treated as failure. We assessed safety in all patients. Results We enrolled and randomly assigned treatment to 33 patients (17 in raltegravir group) between June 2015 and June 2017. The study was interrupted by the IRB because a significant difference between arms was detected in an interim analysis. All patients completed follow up at delivery. At delivery, virological suppression was achieved by 13/17 (76.5%) of patients in raltegravir group, versus 4/16 (25.0%) in lopinavir/ritonavir group (RR 3.1, 95% CI: 1.3-7.4). Patients in raltegravir group had significantly higher proportion of virological suppression at 2, 4, and 6 weeks than lopinavir/ritonavir group. Adverse events were most of mild intensity, but patients in lopinavir/ritonavir group had significantly more gastrointestinal adverse events. There was neither discontinuation nor deaths in this trial. Conclusion Raltegravir might be a first-line option for treatment of HIV-infected late-presenting pregnant women.

PMID: 29629852 [PubMed - indexed for MEDLINE]

Rare adverse events in clinical trials: understanding the rule of three.

BMJ Evid Based Med. 2018 Feb;23(1):6

Authors: Onakpoya IJ

PMID: 29367316 [PubMed - indexed for MEDLINE]

Predictors of hepatotoxicity and pancreatitis in children and adolescents with acute lymphoblastic leukemia treated according to contemporary regimens.

Pediatr Blood Cancer. 2018 03;65(3):

Authors: Denton CC, Rawlins YA, Oberley MJ, Bhojwani D, Orgel E

Abstract
BACKGROUND: Hepatotoxicity and pancreatitis are common treatment-related toxicities (TRTs) during contemporary treatment regimens for acute lymphoblastic leukemia (ALL). Limited detailed data from Children's Oncology Group (COG) regimens has been previously reported to enable identification of patient and treatment risk factors for these toxicities and their impact on outcomes.
PROCEDURE: We analyzed a retrospective pediatric ALL cohort treated at a single institution according to COG regimens from 2008 to 2015. The primary endpoint was cumulative incidence of study-defined "severe" hepatotoxicity (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 4 transaminitis or Grade ≥ 3 hyperbilirubinemia) and clinically significant pancreatitis (any grade). Pancreatitis was additionally classified using the Ponte di Legno (PdL) toxicity criteria. Secondary endpoints were chemotherapy interruptions, early disease response (end of induction [EOI] minimal residual disease [MRD]), and event-free survival (EFS).
RESULTS: We identified 262 patients, of whom 71 (27%) and 28 (11%) developed hepatotoxicity and pancreatitis, respectively. Three cases of pancreatitis did not fulfill PdL criteria despite otherwise consistent presentations. Both TRTs occurred throughout therapy, but approximately 25% of hepatotoxicity (18/71) and pancreatitis (8/28) occurred during induction alone. Both obesity and age (≥10 years) were identified as predictors of hepatotoxicity (subdistribution hazard ratio [SHR] obesity = 1.75, 95% confidence interval [95% CI] 1.04-2.96; SHR age ≥10 = 1.9, 95% CI 1.19-3.10) and pancreatitis (SHR obesity = 2.18, 95% CI 1.01-4.67; SHR age ≥ 10 = 2.76, 95% CI 1.19-6.39, P = 0.018). Dose interruptions were common but neither toxicity influenced EOI MRD nor EFS.
CONCLUSIONS: Obese and/or older children are particularly at risk for hepatotoxicity and pancreatitis, and may benefit from toxicity surveillance and chemoprotective strategies to prevent or mitigate associated morbidity.

PMID: 29218844 [PubMed - indexed for MEDLINE]

Pharmacokinetics/pharmacodynamics, safety, and tolerability of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients.

Pediatr Blood Cancer. 2019 Mar 21;:e27690

Authors: Mora J, Valero M, DiCristina C, Jin M, Chain A, Bickham K

Abstract
BACKGROUND: Current antiemetic regimens are less effective in children than in adults. Fosaprepitant was recently approved for prevention of chemotherapy-induced nausea and vomiting (CINV) in children aged six months and older.
PROCEDURE: The pharmacokinetic (PK)/pharmacodynamic (PD) profile, safety, and tolerability of a single intravenous dose of fosaprepitant administered concomitantly with ondansetron with/without dexamethasone were evaluated in pediatric patients with cancer receiving emetogenic chemotherapy. PK/PD from three doses of fosaprepitant (3.0, 1.2, and 0.4 mg/kg, up to 150, 60, and 20 mg, respectively) were compared with placebo in 2- to 17-year-old subjects; an open-label amendment evaluated a fourth dose (5.0 mg/kg, up to 150 mg) in those under 12 years old. Historical adult PK data were used for comparison. Efficacy was measured as an exploratory endpoint.
RESULTS: PK data were evaluable for 167/234 subjects who completed cycle one. Aprepitant exposures were dose proportional; adolescents (12 to 17 years) receiving fosaprepitant 150 mg had exposures similar to adults at the same dose. Higher weight-normalized doses (5 mg/kg) were necessary for children aged < 12 years to achieve comparable adult exposures. The adverse event profile was typical of cancer patients receiving emetogenic chemotherapy. Drug-related adverse events were reported in 16 (6.8%) subjects, with hiccups being most common (n = 5; 2.1%).
CONCLUSIONS: Intravenous fosaprepitant was well tolerated by pediatric subjects with cancer, and dose-proportional exposures were observed. Subjects < 12 years old required higher doses to achieve comparable adult exposures.

PMID: 30900392 [PubMed - as supplied by publisher]

Adverse Reactions to Medications: Concept Analysis and Development of a New Risk Nursing Diagnosis.

Int J Nurs Knowl. 2019 Mar 21;:

Authors: Monteiro Mantovani V, Moorhead S, de Abreu Almeida M, Rabelo-Silva ER

Abstract
PURPOSE: To analyze the concept of adverse reaction to medications and to develop the new nursing diagnosis Risk for Adverse Reactions to Medications.
METHODS: Concept analysis using Walker and Avant's eight step method.
FINDINGS: Thirty-three articles indexed in four databases were included. The components of the new nursing diagnosis were determined, including possible nursing outcomes and interventions.
CONCLUSIONS: The concept analysis supported the development of the new nursing diagnosis Risk for Adverse Reactions to Medications, which may help nurses to evaluate and identify patients susceptible to adverse reactions.
IMPLICATIONS FOR NURSING PRACTICE: The establishment of this nursing diagnosis will provide nurses an opportunity to implement interventions to anticipate and effectively intervene with patients at risk for this condition.

PMID: 30900386 [PubMed - as supplied by publisher]

Management of high cholesterol levels in older people.

Geriatr Gerontol Int. 2019 Mar 22;:

Authors: Bertolotti M, Lancellotti G, Mussi C

Abstract
The management of hypercholesterolemia in older adults still represents a challenge in clinical medicine. The pathophysiological alterations of cholesterol metabolism associated with aging are still incompletely understood, even if epidemiological evidence suggests that serum cholesterol levels increase with ongoing age, possibly with a plateau after the age of 80 years. Age is also one of the main determinants of cardiovascular disease, according to all cardiovascular risk estimate tools. Cholesterol-lowering treatment, therefore, would be expected to bring significant protection, even in these patients. Unfortunately, direct experimental evidence is extremely limited, particularly in the very old age strata of the population; a clinical benefit still seems to be present, but the risk for drug-related adverse events is clearly higher. At any rate, at the present time, definite guidelines for the correct management of hypercholesterolemia in older patients are not available. Therefore, the decision whether or not a pharmacological treatment should be set up, and the choice of the drug, need to be tailored to the individual patient, and requires accurate clinical judgment. The specific aspects of frailty and disability, along with the actual age of the patients, have to be considered together, with a comprehensive assessment approach. The present review summarizes the evidence regarding the modifications of cholesterol metabolism in older patients, the impact of lipid-lowering drugs on cardiovascular outcomes and focuses on the considerations that can help to define the most appropriate treatment strategy, in view of the individual functional profile. Geriatr Gerontol Int 2019; ••: ••-••.

PMID: 30900369 [PubMed - as supplied by publisher]

Novel Neural Network Approach to Predict Drug-Target Interactions Based on Drug Side Effects and Genome-Wide Association Studies.

Hum Hered. 2018;83(2):79-91

Authors: Prinz J, Koohi-Moghadam M, Sun H, Kocher JA, Wang J

Abstract
AIMS: We propose a novel machine learning approach to expand the knowledge about drug-target interactions. Our method may help to develop effective, less harmful treatment strategies and to enable the detection of novel indications for existing drugs.
METHODS: We developed a novel machine learning strategy to predict drug-target interactions based on drug side effects and traits from genome-wide association studies. We integrated data from the databases SIDER and GWASdb and utilized them in a unique way by a neural network approach.
RESULTS: We validate our method using drug-target interactions from the STITCH database. In addition, we compare the chemical similarity of the predicted target to known targets of the drug under consideration and present literature-based evidence for predicted interactions. We find drug combination warnings for drugs we predict to target the same protein, hinting to synergistic effects aggravating harmful events. This substantiates the translational value of our approach, because we are able to detect drugs that should be taken together with care due to common mechanisms of action.
CONCLUSION: Taken together, we conclude that our approach is able to generate a novel and clinically applicable insight into the molecular determinants of drug action.

PMID: 30347404 [PubMed - indexed for MEDLINE]

2015 Beers criteria medication review in assisted living facilities.

J Am Assoc Nurse Pract. 2018 Nov;30(11):648-654

Authors: Chun JC, Appel SJ, Simmons S

Abstract
BACKGROUND AND PURPOSE: The elderly population is expected to double by 2050 with falls and hospitalizations due to adverse drug events having a major effect on health and quality of life. With the release of the revised 2015 American Geriatrics Society (AGS) Beers criteria, usage of potentially inappropriate medications (PIMs) should be studied to determine their effect on falls and hospitalizations in frail populations such as those in assisted living facilities.
METHODS: This quality improvement project used a retrospective chart review on residents from a purposive sample of two assisted living facilities in Northern Virginia. Residents were aged ≥65 and lived at the facility for at least 6 months and were not enrolled in hospice and/or palliative care or living in the dementia unit. The 2015 AGS Beers criteria were used to evaluate the effect of PIMs on falls and hospitalization rates.
CONCLUSIONS: This project did not find statistical significance between PIMs and falls (p = .276). A favorable, but not statistically significant trend, was noted between PIMs and hospitalizations (p = .079).
IMPLICATIONS FOR PRACTICE: Understanding the effect of PIMs on falls and hospitalizations could help providers improve prescribing practices for the elderly population who are at the greatest risk for potential adverse effects from polypharmacy.

PMID: 30234687 [PubMed - indexed for MEDLINE]

Antidepressant-Induced Activation in Children and Adolescents: Risk, Recognition and Management.

Curr Probl Pediatr Adolesc Health Care. 2018 02;48(2):50-62

Authors: Luft MJ, Lamy M, DelBello MP, McNamara RK, Strawn JR

Abstract
The tolerability of antidepressants is poorly characterized in children and adolescents with depressive and anxiety disorders. Among adverse events that affect the tolerability of antidepressants in youth is activation, a cluster of symptoms that represent a hyperarousal event characterized by impulsivity, restlessness, and/or insomnia. This cluster of symptoms was first identified as a side effect of selective serotonin and selective serotonin norepinephrine inhibitors (SSRIs and SSNRIs) in the early 1990s; however, activation remains poorly characterized in terms of prevalence, risk factors, and pathophysiology. This article describes the pathophysiology of antidepressant-related activation, predictors of activation and its clinical management in youth with depressive and anxiety disorders who are treated with antidepressant medications.

PMID: 29358037 [PubMed - indexed for MEDLINE]

Antidepressant Response and Dissociative Effects After Ketamine Treatment: Two Sides of the Same Coin?

J Clin Psychiatry. 2017 Nov/Dec;78(9):e1318

Authors: Bartoli F, Clerici M, Carrà G

PMID: 29345870 [PubMed - indexed for MEDLINE]

Effect of rifabutin on the pharmacokinetics of oral cabotegravir in healthy subjects.

Antivir Ther. 2019 Mar 21;:

Authors: Ford SL, Lou Y, Lewis N, Michalis K, D'Amico R, Spreen W, Patel P

Abstract
BACKGROUND: Cabotegravir (CAB) is an integrase strand transfer inhibitor in development as a long-acting injectable formulation, with an oral formulation used during a safety lead-in period. Tuberculosis (TB)/HIV co-infection is common, often requiring simultaneous treatment. Rifabutin (RBT) is an alternative antimycobacterial agent for TB and a moderate inducer of cytochrome P450 and UDP-glucuronosyltransferase isoenzymes. This study evaluated the impact of RBT on the pharmacokinetics (PK) of oral CAB.
METHODS: In this Phase 1, single-center, open-label, two-period, fixed-sequence, drug interaction study, subjects received oral CAB 30mg once daily (QD) for 14 days in Period 1, and oral CAB plus RBT 300mg QD for 14 days in Period 2. Serial PK sampling was performed on Days 14 and 28. Geometric least squares (GLS) mean ratios with associated 90% CIs were calculated to compare CAB noncompartmental PK parameters following CAB+RBT vs. CAB alone. Safety was also assessed.
RESULTS: Fifteen male subjects were enrolled and 12 completed all treatments. Comparing CAB+RBT with CAB alone, the GLS mean ratios (90% CIs) for CAB AUC0-τ, Cmax, and Cτ were 0.79 (0.74, 0.83), 0.83 (0.76, 0.90), and 0.74 (0.70, 0.78), respectively. Eleven subjects reported 24 adverse events (AEs); 22 were reported with CAB+RBT (three drug-related), and two with CAB alone (not drug-related). All AEs resolved by study end.
CONCLUSIONS: RBT had a modest impact on plasma CAB exposure following oral co-administration, resulting in overall plasma CAB trough exposures above the 10mg oral dose shown to maintain viral suppression in HIV-1-infected subjects. Oral CAB can be co-administered with RBT without dosage adjustment.

PMID: 30896438 [PubMed - as supplied by publisher]

Adverse Event Circumstances and the Case of Drug Interactions.

Healthcare (Basel). 2019 Mar 19;7(1):

Authors: Soldatos TG, Jackson DB

Abstract
Adverse events are a common and for the most part unavoidable consequence of therapeutic intervention. Nevertheless, available tomes of such data now provide us with an invaluable opportunity to study the relationship between human phenotype and drug-induced protein perturbations within a patient system. Deciphering the molecular basis of such adverse responses is not only paramount to the development of safer drugs but also presents a unique opportunity to dissect disease systems in search of novel response biomarkers, drug targets, and efficacious combination therapies. Inspired by the potential applications of this approach, we first examined adverse event circumstances reported in FAERS and then performed a molecular level interrogation of cancer patient adverse events to investigate the prevalence of drug-drug interactions in the context of patient responses. We discuss avoidable and/or preventable cases and how molecular analytics can help optimize therapeutic use of co-medications. While up to one out of three adverse events in this dataset might be explicable by iatrogenic, patient, and product/device related factors, almost half of the patients in FAERS received multiple drugs and one in four may have experienced effects attributable to drug interactions.

PMID: 30893930 [PubMed]

A Brief Introduction to Antibody-Drug Conjugates for Toxicologic Pathologists.

Toxicol Pathol. 2018 10;46(7):746-752

Authors: Mecklenburg L

Abstract
Antibody-drug conjugates (ADCs) are an emerging class of anticancer therapeutics, delivering highly cytotoxic molecules directly to cancer cells. ADCs are composed of an antibody, a small molecule drug, and a linker attaching one to another. Antibodies are directed to a large variety of antigens overexpressed on tumor cells, tumor vasculature, or tumor-supporting stroma. After internalization, the ADC is transferred to lysosomes where the cytotoxic component is released, finally killing the target cell. All ADCs are administered via intravenous injection. Once in the circulation, linker stability in plasma is of high importance. In vivo studies in animals address the release of payload over time and typically measure total antibody, conjugated ADC, and free drug. ADC development is driven by ICH (International Council for Harmonisation) guidelines S6(R1) and S9. Dose-limiting toxicities of current ADCs are mainly associated with the payload and correlate well between clinical trials and nonclinical studies in rodents and nonrodents. This mini review is intended to provide general information about ADCs in oncology and shall assist the toxicologic pathologist in correctly interpreting morphological findings acquired in toxicity studies with this entity.

PMID: 30295169 [PubMed - indexed for MEDLINE]