Bridging the boundaries between scientists and clinicians-mechanistic hypotheses and patient stories in risk assessment of drugs.

J Eval Clin Pract. 2017 Feb;23(1):114-120

Authors: Rocca E

Abstract
The cultural divide between scientists and clinicians has been described as undermining the advance of medical science, by hindering the production of practice-relevant research and of research-informed clinical decisions. Here, I consider the field of post-marketing risk assessment of drugs as an example of strict interdependence between basic biomedical research, clinical research, and clinical evaluation and show how it would benefit from a closer collaboration between scientists and clinicians. The risk assessment of drugs after their marketing relies on spontaneous adverse effect reports to drug agencies and on peer-reviewed case reports. I emphasize the importance of qualitative analysis of such reports for the improvement of mechanistic understanding of harmful effects of drugs. I argue that mechanistic explanations of drug effects are at least as important as determination of their frequency, in order to establish causation. An ideal risk assessment, then, verifies not only the frequency of undesired effects but also why and how the harm happens. For this purpose, the frequency or novelty of the unintended outcome, although contextually indicative, should not determine the epistemic value of a report. Details about the context that generated an unexpected outcome, instead, can offer the chance of improving causal understanding about how the intervention works. This is illustrated through examples from medical research. Mechanistic understanding is a domain of joint collaboration among (1) clinicians, in charge of detailed, qualitative reporting of patient stories about side effects, (2) qualitative clinical researchers, in charge of analyzing clinical contexts or harmful effects and formulating explanatory hypotheses, and (3) basic biomedical researchers, in charge of verifying such hypotheses. In addition, direct information flow can on one side focus clinicians' attention on knowledge gaps about drugs/effects where more research is needed, while on the other side create a more contextualized concept of mechanism among scientists.

PMID: 27538494 [PubMed - indexed for MEDLINE]

Cardiovascular Safety Assessment in Early-Phase Clinical Studies: A Meta-Analytical Comparison of Exposure-Response Models.

CPT Pharmacometrics Syst Pharmacol. 2016 Jun;5(6):324-35

Authors: Conrado DJ, Chen D, Denney WS

Abstract
Exposure-response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure-response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred drug-effect exposure-response models on vital signs and electrocardiogram (ECG) intervals, an individual-level model-based meta-analysis (39 studies and 1,291 subjects) compared 90 model structures. Models were selected to describe the data and cross-validate studies on the same drug. The most commonly selected baseline model was an unstructured model (estimation of a value at each study nominal time) for all measures but blood pressure. The unstructured model estimated a better cross-validated drug-effect when considering all markers. A linear model was the most commonly selected to characterize drug-effect on all markers. We propose these models as a starting point assisting with CV safety exposure-response assessment in nondedicated small studies with healthy subjects.

PMID: 27318037 [PubMed - indexed for MEDLINE]

The implementation of medical monitoring programs following potentially hazardous exposures: a medico-legal perspective.

Clin Toxicol (Phila). 2017 Nov;55(9):956-969

Authors: Vearrier D, Greenberg MI

Abstract
CONTEXT: Clinical toxicologists may be called upon to determine the appropriateness of medical monitoring following documented or purported exposures to toxicants in the occupational, environmental, and medical settings.
METHODS: We searched the MEDLINE database using the Ovid(®) search engine for the following terms cross-referenced to the MeSH database: ("occupational exposures" OR "environmental exposures") AND ("physiologic monitoring" OR "population surveillance"). The titles and abstracts of the resulted articles were reviewed for relevance. We expanded our search to include non-peer-reviewed publications and gray literature and resources using the same terms as utilized in the MEDLINE search. There were a total of 48 relevant peer-reviewed and non-peer-reviewed publications. Publications excluded contained no information relevant to medical monitoring following potentially harmful toxicologic exposures, discussed only worker screening/surveillance and/or population biomonitoring, contained redundant information, or were superseded by more recent information. Approaches to medical monitoring: A consensus exists in the peer-reviewed medical literature, legal literature, and government publications that for medical monitoring to be a beneficial public health activity, careful consideration must be given to potential benefits and harms of the program. Characteristics of the exposure, the adverse human health effect, the screening test, and the natural history of the disease are important in determining whether an exposed population will reap a net benefit or harm from a proposed monitoring program. Broader interpretations of medical monitoring: Some have argued that medical monitoring programs should not be limited to exposure-related outcomes but should duplicate general preventive medicine efforts to improve public health outcomes although an overall reduction of morbidity, mortality and disability by modifying correctable risk factors and disease conditions. This broader approach is inconsistent with the targeted approach advocated by the Agency for Toxic Substances and Disease Registry and the United States Preventive Services Task Force and the bulk of the peer-reviewed medical literature. Medical monitoring in legal contexts: Numerous medical monitoring actions have been litigated. Legal rationales for allowing medical monitoring claims often incorporate some of the scientific criteria for the appropriateness of monitoring programs. In the majority of cases in which plaintiffs were awarded medical monitoring relief, plaintiffs were required to demonstrate both that the condition for which medical monitoring was sought could be detected early, and that early detection and treatment will improve morbidity and mortality. However, the treatment of medical monitoring claims varies significantly depending upon jurisdiction. Examples of large-scale, comprehensive medical monitoring programs: Large-scale, comprehensive medical monitoring programs have been implemented, such as the Fernald Medical Monitoring Program and the World Trade Center Health Program, both of which exceeded the scope of medical monitoring typically recommended in the peer-reviewed medical literature and the courts. The Fernald program sought to prevent death and disability due to non-exposure-related conditions in a manner similar to general preventive medicine. The World Trade Center Health Program provides comprehensive medical care for World Trade Center responders and may be viewed as a large-scale, federally--funded research effort, which distinguishes it from medical monitoring in a medico-legal context. Synthesis of public health approaches to medical monitoring: Medical monitoring may be indicated following a hazardous exposure in limited circumstances. General causation for a specific adverse health effect must be either established by scientific consensus through a formal causal analysis using a framework such as the Bradford-Hill criteria. The exposure must be characterized and must be of sufficient severity that the exposed population has a significantly elevated risk of an adverse health effect. Monitoring must result in earlier detection of the condition than would otherwise occur and must confer a benefit in the form of primary, secondary or tertiary prevention. Outcome tables may be of use in describing the potential benefits and harms of a proposed monitoring program.
CONCLUSIONS: In the context of litigation, plaintiffs may seek medical monitoring programs after documented or putative exposures. The role of the clinical toxicologist, in this setting, is to evaluate the scientific justifications and medical risks and assist the courts in determining whether monitoring would be expected to result in a net public health benefit.

PMID: 28644057 [PubMed - indexed for MEDLINE]

Trends in hospital admissions due to antidepressant-related adverse drug events from 2001 to 2011 in the U.S.

BMC Health Serv Res. 2017 Jan 19;17(1):51

Authors: Parihar HS, Yin H, Gooch JL, Allen S, John S, Xuan J

Abstract
BACKGROUND: Depression is a prevalent mental health disorder and the fourth leading cause of disability in the world as per the World Health Organization. Use of antidepressants can lead to adverse drug events (ADEs), defined as any injury resulting from medication use. This study aimed to examine changes in hospital admissions due to antidepressant-related ADEs (ArADEs) among different socio-demographic groups and changes in lengths of stay (LOS) and hospital charges in ArADE admissions from 2001 to 2011.
METHODS: The Healthcare Cost and Utilization Project database was used. ArADE admissions in different socio-demographic groups were examined including characteristics such as age, gender, rural/urban, and income. LOS and hospital charges for ArADE cases were compared between 2001 and 2011. Chi-square test and t test were used for statistical analyses.
RESULTS: There were 17,375 and 20,588 ArADE related admissions in 2001 and 2011, respectively. There was a 17.6% increase among the group of 18 to 64 years old and a 64.8% increase among the group of 65 years or older while the other age groups experienced decreased admission rates. Males and females had similar increases. Patients from the lower income areas experienced a two-fold increase while those from the higher income areas experienced a decrease. The mean LOS for all ArADE related admissions increased from 2.18 to 2.81 days and mean hospital charges increased from $8,456.2 to $21,572.5.
CONCLUSIONS: There was an increase in ArADE hospital admissions. The greater increase in ArADE admissions among elderly, urban or low-income patients should be noted and addressed by practitioners and policy makers. The large increase in hospital charges needs further research.

PMID: 28103930 [PubMed - indexed for MEDLINE]

Adverse outcome pathway development from protein alkylation to liver fibrosis.

Arch Toxicol. 2017 Apr;91(4):1523-1543

Authors: Horvat T, Landesmann B, Lostia A, Vinken M, Munn S, Whelan M

Abstract
In modern toxicology, substantial efforts are undertaken to develop alternative solutions for in vivo toxicity testing. The adverse outcome pathway (AOP) concept could facilitate knowledge-based safety assessment of chemicals that does not rely exclusively on in vivo toxicity testing. The construction of an AOP is based on understanding toxicological processes at different levels of biological organisation. Here, we present the developed AOP for liver fibrosis and demonstrate a linkage between hepatic injury caused by chemical protein alkylation and the formation of liver fibrosis, supported by coherent and consistent scientific data. This long-term process, in which inflammation, tissue destruction, and repair occur simultaneously, results from the complex interplay between various hepatic cell types, receptors, and signalling pathways. Due to the complexity of the process, an adequate liver fibrosis cell model for in vitro evaluation of a chemical's fibrogenic potential is not yet available. Liver fibrosis poses an important human health issue that is also relevant for regulatory purposes. An AOP described with enough mechanistic detail might support chemical risk assessment by indicating early markers for downstream events and thus facilitating the development of an in vitro testing strategy. With this work, we demonstrate how the AOP framework can support the assembly and coherent display of distributed mechanistic information from the literature to support the use of alternative approaches for prediction of toxicity. This AOP was developed according to the guidance document on developing and assessing AOPs and its supplement, the users' handbook, issued by the Organisation for Economic Co-operation and Development.

PMID: 27542122 [PubMed - indexed for MEDLINE]

Hepatotoxicity by combination treatment of temozolomide, artesunate and Chinese herbs in a glioblastoma multiforme patient: case report review of the literature.

Arch Toxicol. 2017 Apr;91(4):1833-1846

Authors: Efferth T, Schöttler U, Krishna S, Schmiedek P, Wenz F, Giordano FA

Abstract
Glioblastoma multiforme (GBM) represents an aggressive tumor type with poor prognosis. The majority of GBM patients cannot be cured. There is high willingness among patients for the compassionate use of non-approved medications, which might occasionally lead to profound toxicity. A 65-year-old patient with glioblastoma multiforme (GBM) has been treated with radiochemotherapy including temozolomide (TMZ) after surgery. The treatment outcome was evaluated as stable disease with a tendency to slow tumor progression. In addition to standard medication (ondansetron, valproic acid, levetiracetam, lorazepam, clobazam), the patient took the antimalarial drug artesunate (ART) and a decoction of Chinese herbs (Coptis chinensis, Siegesbeckia orientalis, Artemisia scoparia, Dictamnus dasycarpus). In consequence, the clinical status deteriorated. Elevated liver enzymes were noted with peak values of 238 U/L (GPT/ALAT), 226 U/L (GOT/ASAT), and 347 U/L (γ-GT), respectively. After cessation of ART and Chinese herbs, the values returned back to normal and the patient felt well again. In the literature, hepatotoxicity is well documented for TMZ, but is very rare for ART. Among the Chinese herbs used, Dictamnus dasycarpus has been reported to induce liver injury. Additional medication included valproic acid and levetiracetam, which are also reported to exert hepatotoxicity. While all drugs alone may bear a minor risk for hepatotoxicity, the combination treatment might have caused increased liver enzyme activities. It can be speculated that the combination of these drugs caused liver injury. We conclude that the compassionate use of ART and Chinese herbs is not recommended during standard radiochemotherapy with TMZ for GBM.

PMID: 27519711 [PubMed - indexed for MEDLINE]

Diarrhea in Multiple Myeloma: A Review of the Literature.

Clin J Oncol Nurs. 2016 Aug 01;20(4):E100-5

Authors: Faiman B

Abstract
BACKGROUND: One of the most common and inadequately managed symptoms that patients with multiple myeloma (MM) experience as a result of cancer treatment is diarrhea. Diarrhea in patients with MM often is severe enough to warrant dose reduction, delays, or discontinuation of chemotherapy. Short-term diarrhea can occur as a side effect of drugs, such as bortezomib (Velcade®) or panobinostat (Farydak®). Late-onset diarrhea from lenalidomide (Revlimid®) can occur 17-24 months after the start of therapy. Treatment of diarrhea is often by dose reduction and discontinuation of the offending drug. However, the symptom fails to entirely resolve with these interventions and dose reductions place the individual at risk for disease progression. Best practices for diarrhea management in MM are poorly understood, but diarrhea symptoms impede patient adherence and undermine quality of life.
OBJECTIVES: The purpose of this article is to review the etiology of the symptom of diarrhea in people with cancer, specifically MM. Management strategies also are discussed.
METHODS: A comprehensive review of CINAHL®, MEDLINE®, and PubMed databases was performed using the search terms diarrhea, chemotherapy, multiple myeloma, and cancer. Research studies, guidelines, and papers from peer-reviewed publications were considered.
FINDINGS: Although general guidelines from the American Society of Clinical Oncology and Oncology Nursing Society exist that suggest best practices in the management of chemotherapy-induced diarrhea, best practices to identify and manage diarrhea symptoms in patients with MM are lacking.

PMID: 27441522 [PubMed - indexed for MEDLINE]

Update on New Therapies With Immune Checkpoint Inhibitors.

Clin J Oncol Nurs. 2016 Aug 01;20(4):405-10

Authors: Peterson JJ, Steele-Moses SK

Abstract
BACKGROUND: Immunotherapy has had a long history in cancer treatment and, with recent breakthroughs, new drugs are available that have shown promising results.
OBJECTIVES: The current article discusses an overview of immune function, including immunoediting and the theory of immune checkpoints, as well as specific drugs that have been approved as immune checkpoint inhibitors. Additional discussion includes a review of nursing implications and administration, side effects, adverse events, and the future of immuno-oncology.
METHODS: This review of literature focused on locating, summarizing, and synthesizing data from published articles, the American Cancer Society, U.S. Food and Drug Administration, and literature from pharmaceutical manufacturers that focused on immunotherapy treatment options that use checkpoint inhibition. Search criteria included articles published from 2005-2015 and archived in CINAHL®, OVID®, and PubMed databases using the key words immunotherapy, immune checkpoint inhibition, PD-1, PD-L1, CTLA-4, and oncology.
FINDINGS: Cancer therapy targeting immune checkpoint inhibition has shown promising results and continues to evolve. Oncology nurses need to remain abreast of new immune-modulating therapies to understand their efficacy, as well as side effect management.

PMID: 27441513 [PubMed - indexed for MEDLINE]

Evaluation of a Chemotherapy and Medication Education Process for Patients Starting Cancer Treatment.

Clin J Oncol Nurs. 2016 Aug 01;20(4):364-6

Authors: Kean CC, Iverson L, Boylan A

Abstract
A cancer diagnosis, along with accompanying chemotherapy treatments and new medication regimens, can significantly affect patients' overall health, well-being, and quality of life. Chemotherapy and medication teaching that meets patients' learning needs enhances knowledge and supports adherence to instructions. These interventions promote optimal patient outcomes, satisfaction, and overall safety.

PMID: 27441506 [PubMed - indexed for MEDLINE]

FP/FORM Versus FP/SAL Within Clinical Practice: An Updated Budget Impact Analysis in Asthma.

Adv Ther. 2016 May;33(5):794-806

Authors: Farrington E, Saunders A, Heron L, Dunlop W

Abstract
INTRODUCTION: Pressurized metered-dose inhalers (pMDI) such as fluticasone propionate and salmeterol (FP/SAL) are commonly used for the treatment of asthma in the UK. Previously, a budget impact analysis demonstrated that use of FP and formoterol fumarate (FP/FORM) pMDI as an alternative to FP/SAL pMDI, would be a cost-saving option for the UK National Health Service (NHS). This budget impact analysis aimed to update the existing analysis with prescription volume data and real-world evidence since the introduction of FP/FORM to the UK market.
METHODS: Patient Data (IMS Information Solutions UK Ltd) moving annual total (MAT) August 2015 were used to ascertain the number of units of pMDI prescribed. Annual costs to the NHS in terms of drug, administration, monitoring and adverse event costs, were used to estimate the potential budget impact for FP/FORM and FP/SAL. Costs were calculated for current prescription volumes (12% FP/FORM, 88% FP/SAL), and for different prescription volume scenarios (FP/FORM at 0%, 25%, 50% and 100%). Real-world evidence and budget impact at a clinical commissioning group (CCG) level were also considered.
RESULTS: Total annual costs per person year were less with FP/FORM (£625) than with FP/SAL (£734). Annual costs to the NHS based on the current prescription volumes and clinical trial data were estimated at £210.0M, however, based on real-world evidence, costs were estimated at £179.8M. For all scenarios with increased FP/FORM prescription volumes, the annual total costs to the NHS decreased. This was reflected at a CCG level.
CONCLUSION: The use of FP/FORM as an alternative to FP/SAL can result in cost savings for the NHS when assessing drug, administration, monitoring and adverse events costs. The inclusion of data released since the launch of FP/FORM within the budget impact analysis demonstrates that the potential cost savings to the NHS that were previously published are being translated to clinical practice.
FUNDING: Mundipharma, UK.

PMID: 27084726 [PubMed - indexed for MEDLINE]

[Medication errors in a neonatal unit: One of the main adverse events].

An Pediatr (Barc). 2016 Apr;84(4):211-7

Authors: Esqué Ruiz MT, Moretones Suñol MG, Rodríguez Miguélez JM, Sánchez Ortiz E, Izco Urroz M, de Lamo Camino M, Figueras Aloy J

Abstract
INTRODUCTION: Neonatal units are one of the hospital areas most exposed to the committing of treatment errors. A medication error (ME) is defined as the avoidable incident secondary to drug misuse that causes or may cause harm to the patient. The aim of this paper is to present the incidence of ME (including feeding) reported in our neonatal unit and its characteristics and possible causal factors. A list of the strategies implemented for prevention is presented.
MATERIAL AND METHODS: An analysis was performed on the ME declared in a neonatal unit.
RESULTS: A total of 511 MEs have been reported over a period of seven years in the neonatal unit. The incidence in the critical care unit was 32.2 per 1000 hospital days or 20 per 100 patients, of which 0.22 per 1000 days had serious repercussions. The ME reported were, 39.5% prescribing errors, 68.1% administration errors, 0.6% were adverse drug reactions. Around two-thirds (65.4%) were produced by drugs, with 17% being intercepted. The large majority (89.4%) had no impact on the patient, but 0.6% caused permanent damage or death. Nurses reported 65.4% of MEs. The most commonly implicated causal factor was distraction (59%). Simple corrective action (alerts), and intermediate (protocols, clinical sessions and courses) and complex actions (causal analysis, monograph) were performed.
CONCLUSIONS: It is essential to determine the current state of ME, in order to establish preventive measures and, together with teamwork and good practices, promote a climate of safety.

PMID: 26520488 [PubMed - indexed for MEDLINE]

RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors.

Eur Respir J. 2017 Sep;50(3):

Authors: Hoeper MM, Simonneau G, Corris PA, Ghofrani HA, Klinger JR, Langleben D, Naeije R, Jansa P, Rosenkranz S, Scelsi L, Grünig E, Vizza CD, Chang M, Colorado P, Meier C, Busse D, Benza RL

Abstract
A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L·min(-1)·m(-2) and pulmonary vascular resistance >400 dyn·s·cm(-5) underwent a 1-3 day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5 mg maximum t.i.d Exploratory end-points included change in 6MWD, WHO FC, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean±sd 6MWD had increased by 31±63 m, NT-proBNP decreased by 347±1235 pg·mL(-1) and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied.

PMID: 28889107 [PubMed - in process]

Autoimmune hepatitis - update on clinical management in 2017.

Clin Res Hepatol Gastroenterol. 2017 Sep 04;:

Authors: Liwinski T, Schramm C

Abstract
Autoimmune hepatitis (AIH) is a progressive immune mediated liver disease of unknown origin. Key diagnostic features include hypergammaglobulinemia/elevated serum-IgG, characteristic circulating autoantibodies, periportal hepatitis with interface activity on liver biopsy and the exclusion of hepatotropic viruses. However, the diagnosis is challenging in cholestatic and severe presentations. It can be difficult to differentiate AIH from drug-induced liver injury. Although many patients initially respond to standard immunosuppressive therapy, a significant proportion experiences intolerable side effects or insufficient treatment response. This underlines the need for effective alternative treatment options, which are still very limited and based on rather poor evidence. This review summarises core aspects of the clinical management of AIH with focus on recent achievements and unmet needs.

PMID: 28882739 [PubMed - as supplied by publisher]

Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF (V600) mutation-positive solid tumors: a phase 1 study.

Invest New Drugs. 2017 Sep 07;:

Authors: Fujiwara Y, Yamazaki N, Kiyohara Y, Yoshikawa S, Yamamoto N, Tsutsumida A, Nokihara H, Namikawa K, Mukaiyama A, Zhang F, Tamura T

Abstract
Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF (V600E) mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF (V600) mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.

PMID: 28879519 [PubMed - as supplied by publisher]

Safety Profile of Cough and Cold Medication Use in Pediatrics.

Pediatrics. 2017 Jun;139(6):

Authors: Green JL, Wang GS, Reynolds KM, Banner W, Bond GR, Kauffman RE, Palmer RB, Paul IM, Dart RC

Abstract
BACKGROUND AND OBJECTIVES: The safety of cough and cold medication (CCM) use in children has been questioned. We describe the safety profile of CCMs in children <12 years of age from a multisystem surveillance program.
METHODS: Cases with adverse events (AEs) after ingestion of at least 1 index CCM ingredient (brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, and pseudoephedrine) in children <12 years of age were collected from 5 data sources. An expert panel determined relatedness, dose, intent, and risk factors. Case characteristics and AEs are described.
RESULTS: Of the 4202 cases reviewed, 3251 (77.4%) were determined to be at least potentially related to a CCM, with accidental unsupervised ingestions (67.1%) and medication errors (13.0%) the most common exposure types. Liquid (67.3%), pediatric (75.5%), and single-ingredient (77.5%) formulations were most commonly involved. AEs occurring in >20% of all cases included tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. Twenty cases (0.6%) resulted in death; most were in children <2 years of age (70.0%) and none involved a therapeutic dose. The overall reported AE rate was 0.573 cases per 1 million units (ie, tablets, gelatin capsules, or liquid equivalent) sold (95% confidence interval, 0.553-0.593) or 1 case per 1.75 million units.
CONCLUSIONS: The rate of AEs associated with CCMs in children was low. Fatalities occurred even less frequently. No fatality involved a therapeutic dose. Accidental unsupervised ingestions were the most common exposure types and single-ingredient, pediatric liquid formulations were the most commonly reported products. These characteristics present an opportunity for targeted prevention efforts.

PMID: 28562262 [PubMed - indexed for MEDLINE]

Adverse Health Events Related to Self-Medication Practices Among Elderly: A Systematic Review.

Drugs Aging. 2017 May;34(5):359-365

Authors: Locquet M, Honvo G, Rabenda V, Van Hees T, Petermans J, Reginster JY, Bruyère O

Abstract
BACKGROUND: Older adults often resort to self-medication to relieve symptoms of their current illnesses; however, the risks of this practice are multiplied in old age. In particular, this age group is more vulnerable to adverse drug events because of the physiological changes that occur due to senescence.
OBJECTIVE: The aim of the study was to obtain an overview of the adverse health events related to self-medication among subjects aged 60 years and over through a systematic review of the literature.
METHODS: A study of relevant articles was conducted among databases (MEDLINE, PsycINFO, and EBM Reviews-Cochrane Database of Systematic Reviews). Eligibility criteria were established and applied by two investigators to include suitable studies. The results and outcomes of interest were detailed in a descriptive report.
RESULTS: The electronic search identified 4096 references, and the full texts of 74 were reviewed, of which four were retained in the analysis: three had a cross-sectional design and one prospectively followed elderly subjects. The first study showed a 26.7% prevalence of adverse drug reactions (ADRs) among elders, the second study found a 75% prevalence of side effects, and, finally, a prospective study showed an ADR incidence of 4.5% among self-medicated elders. These studies showed that adverse health events related to self-medication are relatively frequently reported. They also highlighted that analgesics and anti-inflammatory drugs are the most self-medicated products, while vitamins and dietary supplements also appear to be frequently self-administered, but by older individuals.
CONCLUSIONS: Studies on self-medication in the elderly and its adverse health effects are clearly lacking. There is a need to perform prospective studies on this topic to gain a clear understanding of the extent of this problem and to enhance the awareness of health professionals to better inform seniors.

PMID: 28247317 [PubMed - indexed for MEDLINE]

Efficacy and safety of daclatasvir plus asunaprevir therapy for chronic hepatitis C patients with renal dysfunction.

J Med Virol. 2017 Apr;89(4):665-671

Authors: Nakamura Y, Imamura M, Kawakami Y, Teraoka Y, Daijo K, Honda F, Morio K, Kobayashi T, Nakahara T, Nagaoki Y, Kawaoka T, Tsuge M, Hiramatsu A, Aikata H, Hayes CN, Miki D, Ochi H, Chayama K

Abstract
Chronic hepatitis C virus (HCV) infection is associated with renal dysfunction. Daclatasvir and asunaprevir combination therapy showed a high virological response for genotype 1 chronic HCV-infected patients with renal dysfunction on hemodialysis. However, the safety and efficacy of the therapy for patients with renal dysfunction who are not on hemodialysis are not well-known. In total, 147 patients with chronic HCV genotype 1 infection were treated with 24 weeks of daclatasvir plus asunaprevir therapy. Among these patients, 126 had normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 ml/min/1.73 m(2) ) and 21 had renal dysfunction (eGFR < 50 ml/min/1.73 m(2) ). Plasma concentrations of daclatasvir and asunaprevir after 5 days of treatment were the same in the normal renal function and renal dysfunction groups. Early virological response (4, 8, 48, 96, and 168 hr after the start of the therapy) was similar between the two groups. End-of-treatment response was achieved in 122 (96.8%) and 20 (95.2%) patients with normal renal function and with renal dysfunction, respectively, and sustained virological response was achieved in 119 (94.4%) and 20 (95.2%) patients. The frequency of adverse events was also comparable between the two groups. Treatment discontinuation due to adverse events was required for only one patient in each group. Renal function did not change either during or after treatment in both groups. In conclusion, renal function is unlikely to have a significant impact on blood kinetics of daclatasvir and asunaprevir. This combination therapy was effective and safe for patients without hemodialysis. J. Med. Virol. 89:665-671, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 27602542 [PubMed - indexed for MEDLINE]

[The impact of adverse events on health primary care professionals and institutions].

Aten Primaria. 2016 Mar;48(3):143-6

Authors: Torijano-Casalengua ML, Astier-Peña P, Mira-Solves JJ, grupo de seguridad del paciente de la Sociedad Española de Medicina Familiar y Comunitaria, semFYC, Grupo de Investigación en Segundas y Terceras Víctimas

PMID: 26968621 [PubMed - indexed for MEDLINE]

Clinical Practice Guideline: Safe Medication Use in the ICU.

Crit Care Med. 2017 Sep;45(9):e877-e915

Authors: Kane-Gill SL, Dasta JF, Buckley MS, Devabhakthuni S, Liu M, Cohen H, George EL, Pohlman AS, Agarwal S, Henneman EA, Bejian SM, Berenholtz SM, Pepin JL, Scanlon MC, Smith BS

Abstract
OBJECTIVE: To provide ICU clinicians with evidence-based guidance on safe medication use practices for the critically ill.
DATA SOURCES: PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, and ISI Web of Science for relevant material to December 2015.
STUDY SELECTION: Based on three key components: 1) environment and patients, 2) the medication use process, and 3) the patient safety surveillance system. The committee collectively developed Population, Intervention, Comparator, Outcome questions and quality of evidence statements pertaining to medication errors and adverse drug events addressing the key components. A total of 34 Population, Intervention, Comparator, Outcome questions, five quality of evidence statements, and one commentary on disclosure was developed.
DATA EXTRACTION: Subcommittee members were assigned selected Population, Intervention, Comparator, Outcome questions or quality of evidence statements. Subcommittee members completed their Grading of Recommendations Assessment, Development, and Evaluation of the question with his/her quality of evidence assessment and proposed strength of recommendation, then the draft was reviewed by the relevant subcommittee. The subcommittee collectively reviewed the evidence profiles for each question they developed. After the draft was discussed and approved by the entire committee, then the document was circulated among all members for voting on the quality of evidence and strength of recommendation.
DATA SYNTHESIS: The committee followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation system to determine quality of evidence and strength of recommendations.
CONCLUSIONS: This guideline evaluates the ICU environment as a risk for medication-related events and the environmental changes that are possible to improve safe medication use. Prevention strategies for medication-related events are reviewed by medication use process node (prescribing, distribution, administration, monitoring). Detailed considerations to an active surveillance system that includes reporting, identification, and evaluation are discussed. Also, highlighted is the need for future research for safe medication practices that is specific to critically ill patients.

PMID: 28816851 [PubMed - indexed for MEDLINE]

Medication Harmony: A Framework to Save Time, Improve Accuracy and Increase Patient Activation.

AMIA Annu Symp Proc. 2016;2016:1959-1966

Authors: Pandolfe F, Crotty BH, Safran C

Abstract
Incompletely reconciled medication lists contribute to prescribing errors and adverse drug events. Providers expend time and effort at every point of patient contact attempting to curate a best possible medication list, and yet often the list is incomplete or inaccurate. We propose a framework that builds upon the existing infrastructure of a health information exchange (HIE), centralizes data and encourages patient activation. The solution is a constantly accessible, singular, patient-adjudicated medication list that incorporates useful information and features into the list itself. We aim to decrease medication errors across transitions of care, increase awareness of potential drug-drug interactions, improve patient knowledge and self-efficacy regarding medications, decrease polypharmacy, improve prescribing safety and ultimately decrease cost to the health-care system.

PMID: 28269955 [PubMed - indexed for MEDLINE]