Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes

PubMed Central

Löfqvist, Malin; Leinonen, Mika; Goldbach-Mansky, Raphaela; Olivecrona, Hans

2016-01-01

Objective. Anakinra is approved for the treatment of RA and cryopyrin-associated periodic syndromes (CAPS). While the anakinra safety profile is well established in RA, the long-term safety profile in severe CAPS is less well documented and will therefore be discussed in this report. Methods. A prospective, open-label, single centre, clinical cohort study was conducted at the National Institutes of Health in the USA, from 2003 to 2010, investigating the efficacy and safety of anakinra treatment for up to 5 years in 43 patients with CAPS. Safety was evaluated using adverse event (AE) reports, laboratory assessments, vital signs and diary reports. Results. In total, 1233 AEs were reported during the study, with a yearly rate of 7.7 AEs per patient. The event rate decreased over time, and dose escalation during the study did not affect AE frequency. Anakinra had similar safety profiles in adults and children. The most frequently reported AEs were typical CAPS disease symptoms such as headache and arthralgia. Injection site reactions occurred mainly during the first month of anakinra treatment. In total, 14 patients experienced 24 serious AEs (SAEs), all of which resolved during the study period. The most common types of SAEs were infections such as pneumonia and gastroenteritis. There were no permanent discontinuations of treatment due to AEs. Conclusion. In this study anakinra treatment of patients with severe CAPS for up to 5 years was safe and well tolerated both in paediatric and adult patients, with most AEs emerging during the first months after treatment initiation. Trial registration: ClincialTrials.gov, clinicaltrials.gov, NCT00069329 PMID:27143789

Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders.

PubMed

Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; De Maeyer, J H; Stanghellini, V

2012-04-01

The nonselective 5-HT(4) receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT(4) agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT(4) agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT(4) agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT(1) receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT(4) agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT(4) agonists with no hERG or 5-HT(1) affinity (renzapride, clebopride, mosapride). 5-HT(4) agonists for GI disorders differ in chemical structure and selectivity for 5-HT(4) receptors. Selectivity for 5-HT(4) over non-5-HT(4) receptors may influence the agent's safety and overall risk-benefit profile. Based on available evidence, highly selective 5-HT(4) agonists may offer improved safety to treat patients with impaired GI motility. © 2012 Blackwell Publishing Ltd.

Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders

PubMed Central

Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; Maeyer, J H; Stanghellini, V

2012-01-01

Summary Background The nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility. PMID:22356640

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

PubMed Central

Solmi, Marco; Murru, Andrea; Pacchiarotti, Isabella; Undurraga, Juan; Veronese, Nicola; Fornaro, Michele; Stubbs, Brendon; Monaco, Francesco; Vieta, Eduard; Seeman, Mary V; Correll, Christoph U; Carvalho, André F

2017-01-01

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed

Safety and bleeding profile of continuous levonorgestrel 90 mcg/ethinyl estradiol 20 mcg based on 2 years of clinical trial data in Canada.

PubMed

Reid, Robert L; Fortier, Michel P; Smith, Lynne; Mirkin, Sebastian; Grubb, Gary S; Constantine, Ginger D

2010-12-01

The study was conducted to evaluate bleeding profile and safety of continuous oral contraceptive (OC) containing levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg. Healthy women who participated at seven Canadian sites in 1-year open-label study of LNG 90 mcg/EE 20 mcg daily were eligible for this second-year extension study. Primary end points included bleeding profile and adverse events. Seventy-nine women enrolled without interrupting pill taking; 62 (78.5%) completed. Adverse events were comparable to cyclic OC regimens, except unscheduled vaginal bleeding. Amenorrhea and absence of bleeding increased to about 80% and 90%, respectively, by Pill Pack 18. Mean (median) number of bleeding days for the last two 90-day intervals was 1.1 (0) and 0.7 (0) days, respectively. Continuous LNG 90 mcg/EE 20 mcg had a safety profile similar to low-dose cyclic OCs. Short-term safety profile remained excellent, with increasing rates of amenorrhea and decreasing incidence of unscheduled bleeding and/or spotting. Copyright © 2010 Elsevier Inc. All rights reserved.

Safety culture perceptions of pharmacists in Malaysian hospitals and health clinics: a multicentre assessment using the Safety Attitudes Questionnaire.

PubMed

Samsuri, Srima Elina; Pei Lin, Lua; Fahrni, Mathumalar Loganathan

2015-11-26

To assess the safety attitudes of pharmacists, provide a profile of their domains of safety attitude and correlate their attitudes with self-reported rates of medication errors. A cross-sectional study utilising the Safety Attitudes Questionnaire (SAQ). 3 public hospitals and 27 health clinics. 117 pharmacists. Safety culture mean scores, variation in scores across working units and between hospitals versus health clinics, predictors of safety culture, and medication errors and their correlation. Response rate was 83.6% (117 valid questionnaires returned). Stress recognition (73.0±20.4) and working condition (54.8±17.4) received the highest and lowest mean scores, respectively. Pharmacists exhibited positive attitudes towards: stress recognition (58.1%), job satisfaction (46.2%), teamwork climate (38.5%), safety climate (33.3%), perception of management (29.9%) and working condition (15.4%). With the exception of stress recognition, those who worked in health clinics scored higher than those in hospitals (p<0.05) and higher scores (overall score as well as score for each domain except for stress recognition) correlated negatively with reported number of medication errors. Conversely, those working in hospital (versus health clinic) were 8.9 times more likely (p<0.01) to report a medication error (OR 8.9, CI 3.08 to 25.7). As stress recognition increased, the number of medication errors reported increased (p=0.023). Years of work experience (p=0.017) influenced the number of medication errors reported. For every additional year of work experience, pharmacists were 0.87 times less likely to report a medication error (OR 0.87, CI 0.78 to 0.98). A minority (20.5%) of the pharmacists working in hospitals and health clinics was in agreement with the overall SAQ questions and scales. Pharmacists in outpatient and ambulatory units and those in health clinics had better perceptions of safety culture. As perceptions improved, the number of medication errors reported

Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme.

PubMed

Holz, Frank G; Bandello, Francesco; Gillies, Mark; Mitchell, Paul; Osborne, Aaron; Sheidow, Tom; Souied, Eric; Figueroa, Marta S

2013-09-01

Evaluation of 1-year safety profile of intravitreal ranibizumab 0.5 mg in neovascular age-related macular degeneration (NV-AMD) within routine clinical practice. The LUMINOUS programme comprises a prospective observational study assessing ranibizumab 'real-world' safety and clinical effectiveness across licensed indications worldwide and an annual retrospective pooled safety analysis from completed NV-AMD ranibizumab registries. 1-year data from four European registries are available. This retrospective pooled safety analysis assessed 1-year incidence rates for safety events of particular interest (key ocular or systemic events possibly related to the injection procedure or vascular endothelial growth factor inhibition) together with treatment exposure. Patients were treated according to local protocols within the ranibizumab licence. Data of 4444 patients from registries in Germany (n=3470), the Netherlands (n=243), Belgium (n=260) and Sweden (n=471) were retrospectively pooled. Between 70.4% and 84.4% of enrolled patients completed 1 year of follow-up. Most frequent overall ocular events of particular interest were retinal pigment epithelial tears (27 patients; <1%) and intraocular pressure-related events (12 patients; <0.3%). Most frequent non-ocular event of particular interest was stroke (19 patients; 0.4%); annual incidence of stroke was low across all registries (0.0-0.5%). Ranibizumab demonstrated favourable 1-year safety profile for NV-AMD in this routine clinical practice sample, consistent with previous reported trial data. Additional data from a larger patient population are needed to better describe the long-term safety profile of ranibizumab in routine clinical practice and further evaluate risk for infrequent but serious events in 'real-life' settings. The 5-year LUMINOUS prospective observational study will address this need.

Safety and tolerability review of lorcaserin in clinical trials.

PubMed

Greenway, F L; Shanahan, W; Fain, R; Ma, T; Rubino, D

2016-10-01

Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three lorcaserin Phase III trials, the incidence of FDA-defined valvulopathy was similar in patients taking lorcaserin and the placebo. Here, the safety profile of lorcaserin at the FDA-approved dose of 10 mg twice daily is reviewed using data from the lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the lorcaserin Phase III clinical trial data, lorcaserin is safe and well tolerated in the indicated patient populations. © 2016 World Obesity.

Efficacy and safety profile of xanthines in COPD: a network meta-analysis.

PubMed

Cazzola, Mario; Calzetta, Luigino; Barnes, Peter J; Criner, Gerard J; Martinez, Fernando J; Papi, Alberto; Gabriella Matera, Maria

2018-06-30

Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD. Copyright ©ERS 2018.

Can Disproportionality Analysis of Post-marketing Case Reports be Used for Comparison of Drug Safety Profiles?

PubMed

Michel, Christiane; Scosyrev, Emil; Petrin, Michael; Schmouder, Robert

2017-05-01

Clinical trials usually do not have the power to detect rare adverse drug reactions. Spontaneous adverse reaction reports as for example available in post-marketing safety databases such as the FDA Adverse Event Reporting System (FAERS) are therefore a valuable source of information to detect new safety signals early. To screen such large data-volumes for safety signals, data-mining algorithms based on the concept of disproportionality have been developed. Because disproportionality analysis is based on spontaneous reports submitted for a large number of drugs and adverse event types, one might consider using these data to compare safety profiles across drugs. In fact, recent publications have promoted this practice, claiming to provide guidance on treatment decisions to healthcare decision makers. In this article we investigate the validity of this approach. We argue that disproportionality cannot be used for comparative drug safety analysis beyond basic hypothesis generation because measures of disproportionality are: (1) missing the incidence denominators, (2) subject to severe reporting bias, and (3) not adjusted for confounding. Hypotheses generated by disproportionality analyses must be investigated by more robust methods before they can be allowed to influence clinical decisions.

Brain profiling and clinical-neuroscience.

PubMed

Peled, Avi

2006-01-01

The current psychiatric diagnostic system, the diagnostic statistic manual, has recently come under increasing criticism. The major reason for the shortcomings of the current psychiatric diagnosis is the lack of a scientific brain-related etiological knowledge about mental disorders. The advancement toward such knowledge is further hampered by the lack of a theoretical framework or "language" that translates clinical findings of mental disorders to brain disturbances and insufficiencies. Here such a theoretical construct is proposed based on insights from neuroscience and neural-computation models. Correlates between clinical manifestations and presumed neuronal network disturbances are proposed in the form of a practical diagnostic system titled "Brain Profiling". Three dimensions make-up brain profiling, "neural complexity disorders", "neuronal resilience insufficiency", and "context-sensitive processing decline". The first dimension relates to disturbances occurring to fast neuronal activations in the millisecond range, it incorporates connectivity and hierarchical imbalances appertaining typically to psychotic and schizophrenic clinical manifestations. The second dimension relates to disturbances that alter slower changes namely long-term synaptic modulations, and incorporates disturbances to optimization and constraint satisfactions within relevant neuronal circuitry. Finally, the level of internal representations related to personality disorders is presented by a "context-sensitive process decline" as the third dimension. For practical use of brain profiling diagnosis a consensual list of psychiatric clinical manifestations provides a "diagnostic input vector", clinical findings are coded 1 for "detection" and 0 for "non-detection", 0.5 is coded for "questionable". The entries are clustered according to their presumed neuronal dynamic relationships and coefficients determine their relevance to the specific related brain disturbance. Relevant equations

Influenza vaccines: Evaluation of the safety profile

PubMed Central

Trombetta, Claudia Maria; Gianchecchi, Elena; Montomoli, Emanuele

2018-01-01

ABSTRACT The safety of vaccines is a critical factor in maintaining public trust in national vaccination programs. Vaccines are recommended for children, adults and elderly subjects and have to meet higher safety standards, since they are administered to healthy subjects, mainly healthy children. Although vaccines are strictly monitored before authorization, the possibility of adverse events and/or rare adverse events cannot be totally eliminated. Two main types of influenza vaccines are currently available: parenteral inactivated influenza vaccines and intranasal live attenuated vaccines. Both display a good safety profile in adults and children. However, they can cause adverse events and/or rare adverse events, some of which are more prevalent in children, while others with a higher prevalence in adults. The aim of this review is to provide an overview of influenza vaccine safety according to target groups, vaccine types and production methods. PMID:29297746

Safety profile and clinical activity of sifalimumab, a fully human anti-interferon α monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study.

PubMed

Merrill, Joan T; Wallace, Daniel J; Petri, Michelle; Kirou, Kyriakos A; Yao, Yihong; White, Wendy I; Robbie, Gabriel; Levin, Robert; Berney, Seth M; Chindalore, Vishala; Olsen, Nancy; Richman, Laura; Le, Chenxiong; Jallal, Bahija; White, Barbara

2011-11-01

Type I interferons (IFNs) appear to play a central role in disease pathogenesis in systemic lupus erythematosus (SLE), making them potential therapeutic targets. Safety profile, pharmacokinetics, immunogenicity, pharmacodynamics and clinical activity of sifalimumab, an anti-IFNα monoclonal antibody, were assessed in a phase I, multicentre, randomised, double-blind, dose-escalation study with an open-label extension in adults with moderately active SLE. received one intravenous dose of sifalimumab (n=33 blinded phase, 0.3, 1, 3, 10 or 30 mg/kg; n=17 open-label, 1, 3, 10 or 30 mg/kg) or placebo (n=17). Each phase lasted 84 days. Adverse events (AEs) were similar between groups; about 97% of AEs were grade 1 or 2. All grade 3 and 4 AEs and all serious AEs (2 placebo, 1 sifalimumab) were deemed unrelated to the study drug. No increase in viral infections or reactivation was observed. Sifalimumab caused dose-dependent inhibition of type I IFN-induced mRNAs (type I IFN signature) in whole blood and corresponding changes in related proteins in affected skin. Exploratory analyses showed consistent trends toward improvement in disease activity in sifalimumab-treated versus placebo-treated subjects. A lower proportion of sifalimumab-treated subjects required new or increased immunosuppressive treatments (12% vs 41%; p=0.03) and had fewer Systemic Lupus Erythematosus Disease Activity Index flares (3% vs 29%; p=0.014). Sifalimumab had a safety profile that supports further clinical development. This trial demonstrated that overexpression of type I IFN signature in SLE is at least partly driven by IFNα, and exploratory analyses suggest that IFNα inhibition may be associated with clinical benefit in SLE. Trial registration number NCT00299819.

Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme

PubMed Central

Holz, Frank G; Bandello, Francesco; Gillies, Mark; Mitchell, Paul; Osborne, Aaron; Sheidow, Tom; Souied, Eric; Figueroa, Marta S

2013-01-01

Purpose Evaluation of 1-year safety profile of intravitreal ranibizumab 0.5 mg in neovascular age-related macular degeneration (NV-AMD) within routine clinical practice. Methods The LUMINOUS programme comprises a prospective observational study assessing ranibizumab ‘real-world’ safety and clinical effectiveness across licensed indications worldwide and an annual retrospective pooled safety analysis from completed NV-AMD ranibizumab registries. 1-year data from four European registries are available. This retrospective pooled safety analysis assessed 1-year incidence rates for safety events of particular interest (key ocular or systemic events possibly related to the injection procedure or vascular endothelial growth factor inhibition) together with treatment exposure. Patients were treated according to local protocols within the ranibizumab licence. Results Data of 4444 patients from registries in Germany (n=3470), the Netherlands (n=243), Belgium (n=260) and Sweden (n=471) were retrospectively pooled. Between 70.4% and 84.4% of enrolled patients completed 1 year of follow-up. Most frequent overall ocular events of particular interest were retinal pigment epithelial tears (27 patients; <1%) and intraocular pressure-related events (12 patients; <0.3%). Most frequent non-ocular event of particular interest was stroke (19 patients; 0.4%); annual incidence of stroke was low across all registries (0.0–0.5%). Conclusions Ranibizumab demonstrated favourable 1-year safety profile for NV-AMD in this routine clinical practice sample, consistent with previous reported trial data. Additional data from a larger patient population are needed to better describe the long-term safety profile of ranibizumab in routine clinical practice and further evaluate risk for infrequent but serious events in ‘real-life’ settings. The 5-year LUMINOUS prospective observational study will address this need. PMID:23850682

Practice-based evidence: profiling the safety of cilostazol by text-mining of clinical notes.

PubMed

Leeper, Nicholas J; Bauer-Mehren, Anna; Iyer, Srinivasan V; Lependu, Paea; Olson, Cliff; Shah, Nigam H

2013-01-01

Peripheral arterial disease (PAD) is a growing problem with few available therapies. Cilostazol is the only FDA-approved medication with a class I indication for intermittent claudication, but carries a black box warning due to concerns for increased cardiovascular mortality. To assess the validity of this black box warning, we employed a novel text-analytics pipeline to quantify the adverse events associated with Cilostazol use in a clinical setting, including patients with congestive heart failure (CHF). We analyzed the electronic medical records of 1.8 million subjects from the Stanford clinical data warehouse spanning 18 years using a novel text-mining/statistical analytics pipeline. We identified 232 PAD patients taking Cilostazol and created a control group of 1,160 PAD patients not taking this drug using 1:5 propensity-score matching. Over a mean follow up of 4.2 years, we observed no association between Cilostazol use and any major adverse cardiovascular event including stroke (OR = 1.13, CI [0.82, 1.55]), myocardial infarction (OR = 1.00, CI [0.71, 1.39]), or death (OR = 0.86, CI [0.63, 1.18]). Cilostazol was not associated with an increase in any arrhythmic complication. We also identified a subset of CHF patients who were prescribed Cilostazol despite its black box warning, and found that it did not increase mortality in this high-risk group of patients. This proof of principle study shows the potential of text-analytics to mine clinical data warehouses to uncover 'natural experiments' such as the use of Cilostazol in CHF patients. We envision this method will have broad applications for examining difficult to test clinical hypotheses and to aid in post-marketing drug safety surveillance. Moreover, our observations argue for a prospective study to examine the validity of a drug safety warning that may be unnecessarily limiting the use of an efficacious therapy.

Safety Profile of the Newest Antiepileptic Drugs: A Curated Literature Review.

PubMed

Palleria, Caterina; Cozza, Giuseppe; Khengar, Rajeshree; Libri, Vincenzo; De Sarro, Giovambattista

2017-01-01

Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remain unsatisfactory. In addition, whilst several antiepileptic drugs (AEDs) have been approved and consequently marketed in recent years, little is known about their long-term safety and tolerability. Availability of the newest AEDs, characterized by improved pharmacokinetic profiles, has positively impacted the treatment approach for patients with partial seizures in clinical practice. However, the main cause of treatment failure is still poor patient compliance due to the occurrence of adverse drug reactions (ADRs) that lead to treatment withdrawal in about 25% of cases before achieving maximal efficacy, and is associated with increasing health care costs. In this Review, we conducted an online database search using Medline, PubMed, Embase, and the Cochrane Online Library to review the available studies highlighting the clinical relevance of side effects, pharmacological interactions, safety and tolerability of the newest AEDs: Brivaracetam (BRV), Cannabidiol (CBD), Eslicarbazepine acetate (ESL), Lacosamide (LCM), and Perampanel (PER). The principal benefit of the newest AEDs, in addition to reduced frequency and seizure severity, is the low number and severity of ADRs reported compared to more historic drugs. Early detection of ADRs could lead to an improvement in patients' quality of life, therefore it is important to monitor ADRs and to adequately perform post marketing surveillance in the clinical practice setting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Patient safety trilogy: perspectives from clinical engineering.

PubMed

Gieras, Izabella; Sherman, Paul; Minsent, Dennis

2013-01-01

This article examines the role a clinical engineering or healthcare technology management (HTM) department can play in promoting patient safety from three different perspectives: a community hospital, a national government health system, and an academic medical center. After a general overview, Izabella Gieras from Huntington Hospital in Pasadena, CA, leads off by examining the growing role of human factors in healthcare technology, and describing how her facility uses clinical simulations in medical equipment evaluations. A section by Paul Sherman follows, examining patient safety initiatives from the perspective of the Veterans Health Administration with a focus on hazard alerts and recalls. Dennis Minsent from Oregon Health & Science University writes about patient safety from an academic healthcare perspective, and details how clinical engineers can engage in multidisciplinary safety opportunities.

Practice-Based Evidence: Profiling the Safety of Cilostazol by Text-Mining of Clinical Notes

PubMed Central

Iyer, Srinivasan V.; LePendu, Paea; Olson, Cliff; Shah, Nigam H.

2013-01-01

Background Peripheral arterial disease (PAD) is a growing problem with few available therapies. Cilostazol is the only FDA-approved medication with a class I indication for intermittent claudication, but carries a black box warning due to concerns for increased cardiovascular mortality. To assess the validity of this black box warning, we employed a novel text-analytics pipeline to quantify the adverse events associated with Cilostazol use in a clinical setting, including patients with congestive heart failure (CHF). Methods and Results We analyzed the electronic medical records of 1.8 million subjects from the Stanford clinical data warehouse spanning 18 years using a novel text-mining/statistical analytics pipeline. We identified 232 PAD patients taking Cilostazol and created a control group of 1,160 PAD patients not taking this drug using 1∶5 propensity-score matching. Over a mean follow up of 4.2 years, we observed no association between Cilostazol use and any major adverse cardiovascular event including stroke (OR = 1.13, CI [0.82, 1.55]), myocardial infarction (OR = 1.00, CI [0.71, 1.39]), or death (OR = 0.86, CI [0.63, 1.18]). Cilostazol was not associated with an increase in any arrhythmic complication. We also identified a subset of CHF patients who were prescribed Cilostazol despite its black box warning, and found that it did not increase mortality in this high-risk group of patients. Conclusions This proof of principle study shows the potential of text-analytics to mine clinical data warehouses to uncover ‘natural experiments’ such as the use of Cilostazol in CHF patients. We envision this method will have broad applications for examining difficult to test clinical hypotheses and to aid in post-marketing drug safety surveillance. Moreover, our observations argue for a prospective study to examine the validity of a drug safety warning that may be unnecessarily limiting the use of an efficacious therapy. PMID:23717437

Exploitation of molecular profiling techniques for GM food safety assessment.

PubMed

Kuiper, Harry A; Kok, Esther J; Engel, Karl-Heinz

2003-04-01

Several strategies have been developed to identify unintended alterations in the composition of genetically modified (GM) food crops that may occur as a result of the genetic modification process. These include comparative chemical analysis of single compounds in GM food crops and their conventional non-GM counterparts, and profiling methods such as DNA/RNA microarray technologies, proteomics and metabolite profiling. The potential of profiling methods is obvious, but further exploration of specificity, sensitivity and validation is needed. Moreover, the successful application of profiling techniques to the safety evaluation of GM foods will require linked databases to be built that contain information on variations in profiles associated with differences in developmental stages and environmental conditions.

Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury

PubMed Central

Kates, Steven A; Lader, Alan S; Casale, Ralph; Beeuwkes, Reinier

2014-01-01

CMX-2043 is an α-lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia–reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre-clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX-2043 did not bind to a wide range of receptors and specific targets at approximately 4 μg/mL (10 μM). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14-day repeat intravenous doses and in dogs (single intravenous dose) with a 2-week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo-controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre-clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX-2043 in a human efficacy trial. PMID:24751172

Selective estrogen receptor modulators in clinical practice: a safety overview.

PubMed

Ellis, Amanda J; Hendrick, Vicky M; Williams, Robert; Komm, Barry S

2015-06-01

Selective estrogen receptor (ER) modulators (SERMs) are a class of nonsteroidal compounds that interact with ERs, each with a distinct tissue-specific profile. Depending upon the degree of ER agonism/antagonism at the target tissue, SERMs show efficacy for various indications including osteoporosis, dyspareunia, and breast cancer, and are associated with safety risks. This review describes the safety profile of SERMs (tamoxifen, raloxifene, toremifene, bazedoxifene, lasofoxifene, and ospemifene) and fulvestrant (a pure ER antagonist) from Phase III trials, long-term extension studies, and active comparator studies. Tamoxifen, a first-generation SERM, is indicated for breast cancer prevention and treatment but is associated with serious safety concerns including endometrial cancer, venous thromboembolic events (VTE), and stroke. Toremifene, raloxifene, bazedoxifene, lasofoxifene, and ospemifene present generally improved, though distinctly different, safety profiles compared with tamoxifen, especially with endometrial cancer and stroke. However, the risk of VTE remains a concern for most SERMs. Each SERM presents a unique risk/benefit profile based on varying indications and tissue-specific ER agonist and antagonist effects, making careful patient selection and ongoing patient monitoring crucial aspects of treatment. Future research may focus on identifying new SERMs for endocrine-resistant and endocrine-responsive cancers and post-menopausal symptoms.

"Clinical brain profiling": a neuroscientific diagnostic approach for mental disorders.

PubMed

Peled, Abraham; Geva, Amir B

2014-10-01

Clinical brain profiling is an attempt to map a descriptive nosology in psychiatry to underlying constructs in neurobiology and brain dynamics. This paper briefly reviews the motivation behind clinical brain profiling (CBP) and presents some provisional validation using clinical assessments and meta-analyses of neuroscientific publications. The paper has four sections. In the first, we review the nature and motivation for clinical brain profiling. This involves a description of the key aspects of functional anatomy that can lead to psychopathology. These features constitute the dimensions or categories for a profile of brain disorders based upon pathophysiology. The second section describes a mapping or translation matrix that maps from symptoms and signs, of a descriptive sort, to the CBP dimensions that provide a more mechanistic explanation. We will describe how this mapping engenders archetypal diagnoses, referring readers to tables and figures. The third section addresses the construct validity of clinical brain profiling by establishing correlations between profiles based on clinical ratings of symptoms and signs under classical diagnostic categories with the corresponding profiles generated automatically using archetypal diagnoses. We then provide further validation by performing a cluster analysis on the symptoms and signs and showing how they correspond to the equivalent brain profiles based upon clinical and automatic diagnosis. In the fourth section, we address the construct validity of clinical brain profiling by looking for associations between pathophysiological mechanisms (such as connectivity and plasticity) and nosological diagnoses (such as schizophrenia and depression). Based upon the mechanistic perspective offered in the first section, we test some particular hypotheses about double dissociations using a meta-analysis of PubMed searches. The final section concludes with perspectives for the future and outstanding validation issues for clinical

Safety and Efficacy Profile of Commercial Veterinary Vaccines against Rift Valley Fever: A Review Study

PubMed Central

2016-01-01

Rift Valley Fever (RVF) is an infectious illness with serious clinical manifestations and health consequences in humans as well as a wide range of domestic ruminants. This review provides significant information about the prevention options of RVF along with the safety-efficacy profile of commercial vaccines and some of RVF vaccination strategies. Information presented in this paper was obtained through a systematic investigation of published data about RVF vaccines. Like other viral diseases, the prevention of RVF relies heavily on immunization of susceptible herds with safe and cost-effective vaccine that is able to confer long-term protective immunity. Several strains of RVF vaccines have been developed and are available in commercial production including Formalin-Inactivated vaccine, live attenuated Smithburn vaccine, and the most recent Clone13. Although Formalin-Inactivated vaccine and live attenuated Smithburn vaccine are immunogenic and widely used in prevention programs, they proved to be accompanied by significant concerns. Despite Clone13 vaccine being suggested as safe in pregnant ewes and as highly immunogenic along with its potential for differentiating infected from vaccinated animals (DIVA), a recent study raised concerns about the safety of the vaccine during the first trimester of gestation. Accordingly, RVF vaccines that are currently available in the market to a significant extent do not fulfill the requirements of safety, potency, and DIVA. These adverse effects stressed the need for developing new vaccines with an excellent safety profile to bridge the gap in safety and immunity. Bringing RVF vaccine candidates to local markets besides the absence of validated serological test for DIVA remain the major challenges of RVF control. PMID:27689098

Clinical efficacy and safety following dose tapering of ciclosporin in cats with hypersensitivity dermatitis.

PubMed

Roberts, Elizabeth S; Tapp, Tiffany; Trimmer, Ann; Roycroft, Linda; King, Stephen

2016-11-01

Objectives This study was designed to evaluate the efficacy and safety of reducing ciclosporin (CsA) dosing frequency from daily to every other day (EOD) or twice a week (TW) according to clinical response in cats with hypersensitivity dermatitis (HD) and treated with CsA. Methods One hundred and ninety-one cats with HD were given 7 mg/kg CsA daily for at least 4 weeks. Depending on clinical response, the dosing frequency was tapered from daily to EOD over the next 4 weeks and further to TW for an additional 4 weeks. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results The majority of cats were able to have their dose of CsA tapered to either EOD (15.5%) or TW (62.9%) according to the clinical response. Observed AEs were most frequently mild and self-limiting vomiting and diarrhea. A higher percentage of AEs occurred with daily administration (73%) compared with other dosing regimens (27%). Conclusions and relevance Following 4 weeks of daily dosing at 7 mg/kg, CsA may be tapered to EOD or TW while maintaining the desired therapeutic response in cats with HD. Additionally, CsA appears to be well tolerated with fewer AEs at EOD or TW dosing. Establishing the lowest effective dosing frequency of CsA improves the drug's safety profile.

Effect of Aripiprazole Lauroxil on Metabolic and Endocrine Profiles and Related Safety Considerations Among Patients With Acute Schizophrenia.

PubMed

Nasrallah, Henry A; Newcomer, John W; Risinger, Robert; Du, Yangchun; Zummo, Jacqueline; Bose, Anjana; Stankovic, Srdjan; Silverman, Bernard L; Ehrich, Elliot W

2016-11-01

Aripiprazole lauroxil, a long-acting injectable antipsychotic, demonstrated safety and efficacy in treating symptoms of schizophrenia in a double-blind, placebo-controlled trial. Because the metabolic profile of antipsychotics is an important safety feature, the effects of aripiprazole lauroxil on body weight, endocrine and metabolic profiles, and safety were examined in a secondary analysis. Patients with schizophrenia (DSM-IV-TR criteria) were randomly assigned to aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo intramuscularly once monthly between December 2011 and March 2014. Changes in body weight, body mass index, fasting blood glucose and serum lipids, glycosylated hemoglobin (HbA1c), and prolactin over 12 weeks were assessed. The incidence of treatment-emergent adverse events (AEs) was evaluated. Among 622 randomized patients, no clinically relevant changes from baseline to week 12 were observed for any serum lipid, lipoprotein, plasma glucose, or HbA1c value with placebo or either dose of aripiprazole lauroxil. Both doses of aripiprazole lauroxil were associated with reductions in mean prolactin levels, whereas placebo treatment was not. The mean (standard deviation) change from baseline for body weight was 0.74 (3.9) kg, 0.86 (3.7) kg, and 0.01 (3.6) kg for aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. AEs related to metabolic parameters were reported in 2.4%, 1.4%, and 2.4% of patients in the aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. Aripiprazole lauroxil was well tolerated, with a low-risk metabolic profile relative to published data for other antipsychotics. Changes similar to those observed with placebo were observed in the aripiprazole lauroxil groups for metabolic parameters, with modest weight gain in the active treatment groups over the 12-week course. ClinicalTrials.gov identifier: NCT01469039. © Copyright 2016 Physicians

Efficacy and safety of a clinically relevant foamy vector design in human hematopoietic repopulating cells.

PubMed

Everson, Elizabeth M; Hocum, Jonah D; Trobridge, Grant D

2018-06-23

Previous studies have shown that foamy viral (FV) vectors are a promising alternative to gammaretroviral and lentiviral vectors and insulators can improve FV vector safety. However, in a previous analysis of insulator effects on FV vector safety, strong viral promoters were used to elicit genotoxic events. Here we developed and analyzed the efficacy and safety of a high-titer, clinically relevant FV vector driven by the housekeeping promoter elongation factor-1α and insulated with an enhancer blocking A1 insulator (FV-EGW-A1). Human CD34 + cord blood cells were exposed to an enhanced green fluorescent protein expressing vector, FV-EGW-A1, at a multiplicity of infection of 10 and then maintained in vitro or transplanted into immunodeficient mice. Flow cytometry was used to measure engraftment and marking in vivo. FV vector integration sites were analyzed to assess safety. FV-EGW-A1 resulted in high-marking, multi-lineage engraftment of human repopulating cells with no evidence of silencing. Engraftment was highly polyclonal with no clonal dominance and a promising safety profile based on integration site analysis. An FV vector with an elongation factor-1α promoter and an A1 insulator is a promising vector design for use in the clinic. This article is protected by copyright. All rights reserved.

[Safety profile of zolpidem: two studies of 3805 patients by Swiss practitioners].

PubMed

Ganzoni, E; Gugger, M

1999-06-24

Evaluation and treatment of insomnia are frequent procedures in the physician's everyday practice, since many patients seek medical treatment for this condition. Knowledge of pharmacological therapeutical alternatives is therefore decisive, in order to identify the most efficaceous and safe therapy for the patient among the available hypnotics. The short-acting hypnotic zolpidem has been investigated in Switzerland in two multicenter safety studies in ambulatory practice. In the first study 8.9% (n = 125 of 1,972 treated patients), and in the second 7.2% of the patients (n = 175 of 1,833 treated patients) reported an adverse event. The most frequent events were related to the central nervous system (CNS) (somnolence, headache, confusion, vertigo); gastrointestinal and cutaneous symptoms were the most frequent non CNS-dependent effects. New, unknown or serious adverse events were not found and no specific risk factor or population at risk was identified. The safety profile of zolpidem is consistent with its known pharmacological properties, the results of previous clinical trials and the international experience obtained in large patients groups.

Rivaroxaban real-world evidence: Validating safety and effectiveness in clinical practice.

PubMed

Beyer-Westendorf, Jan; Camm, A John; Coleman, Craig I; Tamayo, Sally

2016-09-28

Randomised controlled trials (RCTs) are considered the gold standard of clinical research as they use rigorous methodologies, detailed protocols, pre-specified statistical analyses and well-defined patient cohorts. However, RCTs do not take into account the complexity of real-world clinical decision-making. To tackle this, real-world data are being increasingly used to evaluate the long-term safety and effectiveness of a given therapy in routine clinical practice and in patients who may not be represented in RCTs, addressing key clinical questions that may remain. Real-world evidence plays a substantial role in supporting the use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in clinical practice. By providing data on patient profiles and the use of anticoagulation therapies in routine clinical practice, real-world evidence expands the current awareness of NOACs, helping to ensure that clinicians are well-informed on their use to implement patient-tailored clinical decisions. There are various issues with current anticoagulation strategies, including under- or overtreatment and frequent monitoring with VKAs. Real-world studies have demonstrated that NOAC use is increasing (Dresden NOAC registry and Global Anticoagulant Registry in the FIELD-AF [GARFIELD-AF]), as well as reaffirming the safety and effectiveness of rivaroxaban previously observed in RCTs (XArelto on preveNtion of sTroke and non-central nervoUS system systemic embolism in patients with non-valvular atrial fibrillation [XANTUS] and IMS Disease Analyzer). This article will describe the latest updates in real-world evidence across a variety of methodologies, such as non-interventional studies (NIS), registries and database analyses studies. It is anticipated that these studies will provide valuable clinical insights into the management of thromboembolism, and enhance the current knowledge on anticoagulant use and outcomes for patients.

Safety Profile of Good Manufacturing Practice Manufactured Interferon γ-Primed Mesenchymal Stem/Stromal Cells for Clinical Trials.

PubMed

Guess, Adam J; Daneault, Beth; Wang, Rongzhang; Bradbury, Hillary; La Perle, Krista M D; Fitch, James; Hedrick, Sheri L; Hamelberg, Elizabeth; Astbury, Caroline; White, Peter; Overolt, Kathleen; Rangarajan, Hemalatha; Abu-Arja, Rolla; Devine, Steven M; Otsuru, Satoru; Dominici, Massimo; O'Donnell, Lynn; Horwitz, Edwin M

2017-10-01

Mesenchymal stem/stromal cells (MSCs) are widely studied by both academia and industry for a broad array of clinical indications. The collective body of data provides compelling evidence of the clinical safety of MSC therapy. However, generally accepted proof of therapeutic efficacy has not yet been reported. In an effort to generate a more effective therapeutic cell product, investigators are focused on modifying MSC processing protocols to enhance the intrinsic biologic activity. Here, we report a Good Manufacturing Practice-compliant two-step MSC manufacturing protocol to generate MSCs or interferon γ (IFNγ) primed MSCs which allows freshly expanded cells to be infused in patients on a predetermined schedule. This protocol eliminates the need to infuse cryopreserved, just thawed cells which may reduce the immune modulatory activity. Moreover, using (IFNγ) as a prototypic cytokine, we demonstrate the feasibility of priming the cells with any biologic agent. We then characterized MSCs and IFNγ primed MSCs prepared with our protocol, by karyotype, in vitro potential for malignant transformation, biodistribution, effect on engraftment of transplanted hematopoietic cells, and in vivo toxicity in immune deficient mice including a complete post-mortem examination. We found no evidence of toxicity attributable to the MSC or IFNγ primed MSCs. Our data suggest that the clinical risk of infusing MSCs or IFNγ primed MSCs produced by our two-step protocol is not greater than MSCs currently in practice. While actual proof of safety requires phase I clinical trials, our data support the use of either cell product in new clinical studies. Stem Cells Translational Medicine 2017;6:1868-1879. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Profiling contextual factors which influence safety in heavy vehicle industries.

PubMed

Edwards, Jason R D; Davey, Jeremy; Armstrong, Kerry A

2014-12-01

A significant proportion of worker fatalities within Australia result from truck-related incidents. Truck drivers face a number of health and safety concerns. Safety culture, viewed here as the beliefs, attitudes and values shared by an organisation's workers, which interact with their surrounding context to influence behaviour, may provide a valuable lens for exploring safety-related behaviours in heavy vehicle operations. To date no major research has examined safety culture within heavy vehicle industries. As safety culture provides a means to interpret experiences and generate behaviour, safety culture research should be conducted with an awareness of the context surrounding safety. The current research sought to examine previous health and safety research regarding heavy vehicle operations to profile contextual factors which influence health and safety. A review of 104 peer-reviewed papers was conducted. Findings of these papers were then thematically analysed. A number of behaviours and scenarios linked with crashes and non-crash injuries were identified, along with a selection of health outcomes. Contextual factors which were found to influence these outcomes were explored. These factors were found to originate from government departments, transport organisations, customers and the road and work environment. The identified factors may provide points of interaction, whereby culture may influence health and safety outcomes. Copyright © 2014. Published by Elsevier Ltd.

Temperament and character profiles of sasang typology in an adult clinical sample.

PubMed

Park, Soo Hyun; Kim, Myoung-Geun; Lee, Soo Jin; Kim, Jong Yeol; Chae, Han

2011-01-01

The purpose of this study was to examine the biopsychological personality profiles of traditional Korean Sasang typology based on the Temperament and Character Inventory (TCI) in a Korean adult clinical sample. A total of 97 adults completed the Korean version of the TCI. The participants were classified as one of three traditional Korean Sasang types (31 So-Yang, 41 Tae-Eum, 25 So-Eum) by three specialists in Sasang typology. The seven dimensions of TCI were compared between the different Sasang types using analysis of variance (ANOVA) and profile analysis. There were no significant differences in age, gender and education across the Sasang types. The TCI profile for each of the Sasang types was significantly different (profile analysis, df = 5.038, F = 3.546, P = .004). There were significant differences in the temperament dimensions of Novelty Seeking (F = 3.43, P = .036) and Harm Avoidance (F = 5.43, P = .006) among the Sasang types. The Novelty Seeking score of the So-Yang type (31.90 ± 9.87) was higher than that of the So-Eum type (25.24 ± 9.21; P = .019) while the So-Eum type (44.64 ± 8.47) scored higher on the Harm Avoidance score compared to the So-Yang type (35.16 ± 11.50; P = .003). There were no significant differences in the temperament dimension of Reward Dependence and Persistence, and the three character dimensions of Self-Directedness, Cooperativeness and Self-Transcendence. Results demonstrated distinct temperament traits associated with traditional Korean Sasang types using an objective biopsychological personality inventory. With further study, the Sasang typology may lead to enhanced clinical safety and efficacy as part of personalized medicine with traditional medicine.

Biosimilar safety considerations in clinical practice.

PubMed

Choy, Edwin; Jacobs, Ira Allen

2014-02-01

Biologics are important treatments for a number of cancers. Patents for several biologics will expire over the next decade, removing a barrier to the development and commercialization of biosimilars. As biologics differ from small-molecule drugs due to their size and complexity, multifaceted manufacturing process, and their potential for immunogenicity, biosimilars cannot be considered "generic versions" of currently approved biologics. In highly regulated markets, biosimilars can be authorized only if they are demonstrated to be highly similar to the original drug from an analytical and clinical perspective. Any differences must be justified and shown to have no clinically meaningful effect on the safety and efficacy of the biosimilar. The European Medicines Agency has approved a number of biosimilars and the recent approval of the biosimilar infliximab monoclonal antibody is another regulatory milestone. This article will provide context regarding key safety issues addressed in biosimilar development, approval, and delivery, as well as inform oncologists on matters of safety to consider when prescribing biosimilars. Pertinent issues about safety from countries or regions where biosimilars are currently in use also will be reviewed. © 2014 Elsevier Inc. All rights reserved.

Safety assessment of adjuvanted vaccines: Methodological considerations

PubMed Central

Da Silva, Fernanda Tavares; Di Pasquale, Alberta; Yarzabal, Juan P; Garçon, Nathalie

2015-01-01

Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines. PMID:26029975

Health and safety in clinical laboratories in developing countries: safety considerations.

PubMed

Ejilemele, A A; Ojule, A C

2004-01-01

Clinical laboratories are potentially hazardous work areas. Health and safety in clinical laboratories is becoming an increasingly important subject as a result of the emergence of highly infectious diseases such as hepatitis and HIV. This is even more so in developing countries where health and safety have traditionally been regarded as low priority issues, considering the more important health problems confronting the health authorities in these countries. We conducted a literature search using the medical subheadings titles on the INTERNET over a period of twenty years and summarized our findings. This article identifies hazards in the laboratories and highlights measures to make the laboratory a safer work place. It also emphasizes the mandatory obligations of employers and employees towards the attainment of acceptable safety standards in clinical laboratories in Third World countries in the face of the current HIV/AIDS epidemic in many of these developing countries especially in the sub-Saharan Africa while accommodating the increasing work load in these laboratories. Both the employer and the employee have major roles to play in the maintenance of a safe working environment. This can be achieved if measures discussed are incorporated into everyday laboratory practice.

Evaluating the Safety Profile of Non-Active Implantable Medical Devices Compared with Medicines.

PubMed

Pane, Josep; Coloma, Preciosa M; Verhamme, Katia M C; Sturkenboom, Miriam C J M; Rebollo, Irene

2017-01-01

Recent safety issues involving non-active implantable medical devices (NAIMDs) have highlighted the need for better pre-market and post-market evaluation. Some stakeholders have argued that certain features of medicine safety evaluation should also be applied to medical devices. Our objectives were to compare the current processes and methodologies for the assessment of NAIMD safety profiles with those for medicines, identify potential gaps, and make recommendations for the adoption of new methodologies for the ongoing benefit-risk monitoring of these devices throughout their entire life cycle. A literature review served to examine the current tools for the safety evaluation of NAIMDs and those for medicines. We searched MEDLINE using these two categories. We supplemented this search with Google searches using the same key terms used in the MEDLINE search. Using a comparative approach, we summarized the new product design, development cycle (preclinical and clinical phases), and post-market phases for NAIMDs and drugs. We also evaluated and compared the respective processes to integrate and assess safety data during the life cycle of the products, including signal detection, signal management, and subsequent potential regulatory actions. The search identified a gap in NAIMD safety signal generation: no global program exists that collects and analyzes adverse events and product quality issues. Data sources in real-world settings, such as electronic health records, need to be effectively identified and explored as additional sources of safety information, particularly in some areas such as the EU and USA where there are plans to implement the unique device identifier (UDI). The UDI and other initiatives will enable more robust follow-up and assessment of long-term patient outcomes. The safety evaluation system for NAIMDs differs in many ways from those for drugs, but both systems face analogous challenges with respect to monitoring real-world usage. Certain features

Anxiety and Mood Clinical Profile following Sport-related Concussion: From Risk Factors to Treatment.

PubMed

Sandel, Natalie; Reynolds, Erin; Cohen, Paul E; Gillie, Brandon L; Kontos, Anthony P

2017-08-01

Conceptual models for assessing and treating sport-related concussion (SRC) have evolved from a homogenous approach to include different clinical profiles that reflect the heterogeneous nature of this injury and its effects. There are six identified clinical profiles, or subtypes from SRC, and one such clinical profile is the anxiety/mood profile. Athletes with this profile experience predominant emotional disturbance and anxiety following SRC. The purpose of this targeted review was to present an overview of the empirical evidence to support factors contributing to the anxiety/mood profile, along with methods of evaluation and treatment of this clinical profile following SRC. We discuss the potential underlying mechanisms and risk factors for this clinical profile, describe comprehensive assessments to evaluate concussed athletes with an anxiety/mood clinical profile, and explore behavioral and other interventions for treating these athletes. Although there is limited, but growing empirical evidence for the anxiety/mood clinical profile following SRC, understanding this clinical profile is germane for clinicians who are treating athletes with emotional sequelae after SRC.

Clinical Trial Electronic Portals for Expedited Safety Reporting: Recommendations from the Clinical Trials Transformation Initiative Investigational New Drug Safety Advancement Project.

PubMed

Perez, Raymond P; Finnigan, Shanda; Patel, Krupa; Whitney, Shanell; Forrest, Annemarie

2016-12-15

Use of electronic clinical trial portals has increased in recent years to assist with sponsor-investigator communication, safety reporting, and clinical trial management. Electronic portals can help reduce time and costs associated with processing paperwork and add security measures; however, there is a lack of information on clinical trial investigative staff's perceived challenges and benefits of using portals. The Clinical Trials Transformation Initiative (CTTI) sought to (1) identify challenges to investigator receipt and management of investigational new drug (IND) safety reports at oncologic investigative sites and coordinating centers and (2) facilitate adoption of best practices for communicating and managing IND safety reports using electronic portals. CTTI, a public-private partnership to improve the conduct of clinical trials, distributed surveys and conducted interviews in an opinion-gathering effort to record investigator and research staff views on electronic portals in the context of the new safety reporting requirements described in the US Food and Drug Administration's final rule (Code of Federal Regulations Title 21 Section 312). The project focused on receipt, management, and review of safety reports as opposed to the reporting of adverse events. The top challenge investigators and staff identified in using individual sponsor portals was remembering several complex individual passwords to access each site. Also, certain tasks are time-consuming (eg, downloading reports) due to slow sites or difficulties associated with particular operating systems or software. To improve user experiences, respondents suggested that portals function independently of browsers and operating systems, have intuitive interfaces with easy navigation, and incorporate additional features that would allow users to filter, search, and batch safety reports. Results indicate that an ideal system for sharing expedited IND safety information is through a central portal used by

Safety of inhaled glycopyrronium in patients with COPD: a comprehensive analysis of clinical studies and post-marketing data.

PubMed

D'Urzo, Anthony D; Kerwin, Edward M; Chapman, Kenneth R; Decramer, Marc; DiGiovanni, Robert; D'Andrea, Peter; Hu, Huilin; Goyal, Pankaj; Altman, Pablo

2015-01-01

Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular. Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents. We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50 μg, placebo (both delivered via the Breezhaler device), or tiotropium 18 μg (delivered via the HandiHaler device). Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12 weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD). Safety comparisons were made for glycopyrronium vs tiotropium or placebo. Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events. During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA. In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated. The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo. Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo. There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies. Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data. The overall safety profile of glycopyrronium was similar to its comparators indicating no

Safety and tolerability of extended-release niacin-laropiprant: Pooled analyses for 11,310 patients in 12 controlled clinical trials.

PubMed

McKenney, James; Bays, Harold; Gleim, Gilbert; Mitchel, Yale; Kuznetsova, Olga; Sapre, Aditi; Sirah, Waheeda; Maccubbin, Darbie

2015-01-01

The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) showed that adding extended-release niacin-laropiprant (ERN-LRPT) to statin provided no incremental cardiovascular benefit vs placebo (PBO). ERN-LRPT was also associated with an excess of serious adverse experiences (AEs), some of which were unexpected (infections and bleeding). These findings led to the withdrawal of ERN-LRPT from all markets. We examined the safety profile of ERN-LRPT vs the comparators ERN alone and statins in the ERN-LRPT development program to assess whether similar safety signals were observed to those seen in HPS-THRIVE and whether these might be attributed to ERN or LRPT. Postrandomization safety data from 12 clinical studies, 12 to 52 weeks in duration and involving 11,310 patients, were analyzed across 3 treatments: (1) ERN-LRPT; (2) ERN-NSP (ERN, Merck & Co, Inc or Niaspan [NSP], Abbott Laboratories); and (3) statin-PBO (statin or PBO). The safety profiles of ERN-LRPT and ERN-NSP were similar, except for less flushing with ERN-LRPT. Nonflushing AEs reported more frequently with ERN-LRPT or ERN-NSP than with statin-PBO were mostly nonserious and typical of niacin (nausea, diarrhea, and increased blood glucose). There was no evidence for an increased risk of serious AEs related to diabetes, muscle, infection, or bleeding. Pooled data from 11,310 patients revealed that, except for reduced flushing, the safety profile of ERN-LRPT was similar to that of ERN-NSP; LRPT did not appear to adversely affect the side-effect profile of ERN. The inability to replicate the unexpected AE findings in HPS2-THRIVE could be because of the smaller sample size and substantially shorter duration of these studies. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Determining clinical benefits of drug-eluting coronary stents according to the population risk profile: a meta-regression from 31 randomized trials.

PubMed

Moreno, Raul; Martin-Reyes, Roberto; Jimenez-Valero, Santiago; Sanchez-Recalde, Angel; Galeote, Guillermo; Calvo, Luis; Plaza, Ignacio; Lopez-Sendon, Jose-Luis

2011-04-01

The use of drug-eluting stents (DES) in unfavourable patients has been associated with higher rates of clinical complications and stent thrombosis, and because of that concerns about the use of DES in high-risk settings have been raised. This study sought to demonstrate that the clinical benefit of DES increases as the risk profile of the patients increases. A meta-regression analysis from 31 randomized trials that compared DES and bare-metal stents, including overall 12,035 patients, was performed. The relationship between the clinical benefit of using DES (number of patients to treat [NNT] to prevent one episode of target lesion revascularization [TLR]), and the risk profile of the population (rate of TLR in patients allocated to bare-metal stents) in each trial was evaluated. The clinical benefit of DES increased as the risk profile of each study population increased: NNT for TLR=31.1-1.2 (TLR for bare-metal stents); p<0.001. The use of DES was safe regardless of the risk profile of each study population, since the effect of DES in mortality, myocardial infarction, and stent thrombosis, was not adversely affected by the risk profile of each study population (95% confidence interval for β value 0.09 to 0.11, -0.12 to 0.19, and -0.03 to-0.15 for mortality, myocardial infarction, and stent thrombosis, respectively). The clinical benefit of DES increases as the risk profile of the patients increases, without affecting safety. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Safety Culture and Senior Leadership Behavior: Using Negative Safety Ratings to Align Clinical Staff and Senior Leadership.

PubMed

O'Connor, Shawn; Carlson, Elizabeth

2016-04-01

This report describes how staff-designed behavior changes among senior leaders can have a positive impact on clinical nursing staff and enhance the culture of safety in a community hospital. A positive culture of safety in a hospital improves outcomes for patients and staff. Senior leaders are accountable for developing an environment that supports a culture of safety. At 1 community hospital, surveys demonstrated that staff members did not view senior leaders as supportive of or competent in creating a culture of safety. After approval from the hospital's institutional review board was obtained, clinical nurses generated and selected ideas for senior leader behavior change. The new behaviors were assessed by a convenience sample survey of clinical nurses. In addition, culture of safety survey results were compared. Risk reports and harm events were also measured before and after behavior changes. The volume of risk and near-miss reports increased, showing that clinical staff were more inclined to report events after senior leader communication, access, and visibility increased. Harm events went down. The culture of safety survey demonstrated an improvement in the senior leadership domain in 4 of 6 units. The anonymous convenience survey demonstrated that staff members recognized changes that senior leaders had made and felt that these changes positively impacted the culture of safety. By developing skills in communication, advocacy, visibility, and access, senior leaders can enhance a hospital's culture of safety and create stronger ties with clinical staff.

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies

PubMed Central

Iffland, Kerstin; Grotenhermen, Franjo

2017-01-01

Abstract Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs. Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients' compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam's side effects. Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking. PMID:28861514

Cardiovascular benefits and safety profile of acarbose therapy in prediabetes and established type 2 diabetes

PubMed Central

Hanefeld, Markolf

2007-01-01

Dysglycaemic disease is one of the most important health issues facing the world in the 21st century. Patients with type 2 diabetes and individuals with prediabetes are at risk of developing macrovascular and microvascular complications. Long-term management strategies are therefore required that are effective at controlling dysglycaemia, well tolerated and, ideally, offer additional cardiovascular disease (CVD) risk-reduction benefits. The efficacy, safety and tolerability of the α-glucosidase inhibitor acarbose have been well-established in a wide range of patient populations in both clinical and community trials. In addition, acarbose has been shown to reduce cardiovascular complications in type 2 diabetes and prevent hypertension and CVD in individuals with impaired glucose tolerance (IGT). Acarbose has a very good safety profile and, owing to its straightforward, non-systemic mode of action, avoids most adverse events. The most common side-effects of acarbose are mild-to-moderate gastrointestinal complaints that subside as treatment continues. They can be minimised through the use of an appropriate stepwise dosing regimen and careful choice of diet. Acarbose is therefore a valuable option for the management of type 2 diabetes and, as the only oral antidiabetes agent approved for the treatment of prediabetes, can help to improve clinical management across the dysglycaemic disease continuum. PMID:17697384

Safety profile of hymenoptera venom immunotherapy (VIT) in monosensitized patients: lack of new sensitization to nontreated insect venom.

PubMed

Spoerl, D; Bircher, A J; Scherer, K

2011-01-01

Venom immunotherapy (VIT) has proven to be efficacious in reducing the severity of anaphylactic reactions following field stings in patients with Hymenoptera venom allergy. Due to sequence homologies in the allergens used in Hymenoptera vaccines, there is concern that immunotherapy could lead to sensitization to allergens to which patients were not previously sensitized. The relevance of such an undesired phenomenon is unclear. To investigate the incidence of sensitization to Hymenoptera venoms other than those to which the patients were already sensitized and to assess the overall safety profile of VIT in order to compare the risk-benefit ratio in a subpopulation of monosensitized individuals. We performed a retrospective analysis of specific immunoglobulin E (sIgE) levels in patients with no prior detectable sIgE to Hymenoptera venom other than the one for which they received VIT. We assessed the safety profile of VIT using serological and clinical parameters. Of the 56 monosensitized patients who had VIT, 3 (5%) developed sIgE to the other insect with no history of field sting to explain it. This rate was similar to the rate of new sensitization due to field stings during VIT. VIT was well-tolerated and levels of serological markers improved. No patient had a systemic anaphylactic reaction after having been stung by an insect other than the one he/she was desensitized for during follow-up. VIT seems to be safe with respect to clinically significant new sensitizations.

Clinical and genomic safety of treatment with Ginkgo biloba L. leaf extract (IDN 5933/Ginkgoselect®Plus) in elderly: a randomised placebo-controlled clinical trial [GiBiEx].

PubMed

Bonassi, Stefano; Prinzi, Giulia; Lamonaca, Palma; Russo, Patrizia; Paximadas, Irene; Rasoni, Giuseppe; Rossi, Raffaella; Ruggi, Marzia; Malandrino, Salvatore; Sánchez-Flores, Maria; Valdiglesias, Vanessa; Benassi, Barbara; Pacchierotti, Francesca; Villani, Paola; Panatta, Martina; Cordelli, Eugenia

2018-01-22

Numerous health benefits have been attributed to the Ginkgo biloba leaf extract (GBLE), one of the most extensively used phytopharmaceutical drugs worldwide. Recently, concerns of the safety of the extract have been raised after a report from US National Toxicology Program (NTP) claimed high doses of GBLE increased liver and thyroid cancer incidence in mice and rats. A safety study has been designed to assess, in a population of elderly residents in nursing homes, clinical and genomic risks associated to GBLE treatment. GiBiEx is a multicentre randomized clinical trial, placebo controlled, double blinded, which compared subjects randomized to twice-daily doses of either 120-mg of IDN 5933 (also known as Ginkgoselect®Plus) or to placebo for a 6-months period. IDN 5933 is extracted from dried leaves and contains 24.3% flavone glycosides and 6.1% of terpene lactones (2.9% bilobalide, 1.38% ginkgolide A, 0.66% ginkgolide B, 1.12% ginkgolide C) as determined by HPLC. The study was completed by 47 subjects, 20 in the placebo group and 27 in the treatment group. Clinical (adverse clinical effect and liver injury) and genomic (micronucleus frequency, comet assay, c-myc, p53, and ctnnb1 expression profile in lymphocytes) endpoints were assessed at the start and at the end of the study. No adverse clinical effects or increase of liver injury markers were reported in the treatment group. The frequency of micronuclei [Mean Ratio (MR) = 1.01, 95% Confidence Intervals (95% CI) 0.86-1.18), and DNA breaks (comet assay) (MR = 0.91; 95% CI 0.58-1.43), did not differ in the two study groups. No significant difference was found in the expression profile of the three genes investigated. None of the markers investigated revealed a higher risk in the treatment group, supporting the safety of IDN 5933 at doses prescribed and for duration of six months. ClinicalTrials.gov Identifier: NCT03004508 , December 20, 2016. Trial retrospectively registered.

Comparison of the adverse event profiles of levofloxacin 500 mg and 750 mg in clinical trials for the treatment of respiratory infections.

PubMed

Khashab, Mohammed M; Xiang, Jim; Kahn, James B

2006-10-01

To compare safety data with levofloxacin 500 mg and 750 mg from clinical trials for the treatment of respiratory infections. We compared adverse event data for levofloxacin 500 mg and 750 mg from clinical trials in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia. Adverse events occurring after the initiation of therapy were classified as treatment-emergent adverse events (TEAE); drug-related adverse events (DRAE) were TEAE assessed by the clinical investigator as definitely/very likely or probably related to levofloxacin therapy. Overall, the safety profile of the two doses was similar but not identical. TEAE occurred in 49.0% (1601/3268) of those treated with 500 mg and in 45.5% (519/1141) of those treated with 750 mg (p = 0.042); the corresponding rates of DRAE were 7.6% (248/3268) and 8.0% (91/1141) (p = 0.699). There was no statistically significant difference in terms of overall TEAE and DRAE rates within each of the three infectious conditions, but there were in specific events, all of which are expected with levofloxacin therapy. The limitations of this analysis include that it utilized a subset of available safety data, that it includes data only from clinical trials, and that we report primarily on events occurring in > or = 2% of patients. Given similar adverse event profiles and the advantages of higher dose therapy, including shorter courses of therapy and potential impact on preventing resistance, clinicians should consider utilizing the 750 mg dose of levofloxacin when choosing between dosage strengths for treatment of indicated infections.

Reporting and understanding the safety and adverse effect profile of mobile apps for psychosocial interventions: An update.

PubMed

Naeem, Farooq; Gire, Nadeem; Xiang, Shuo; Yang, Megan; Syed, Yumeen; Shokraneh, Farhad; Adams, Clive; Farooq, Saeed

2016-06-22

Recent years have seen a rapidly increasing trend towards the delivery of health technology through mobile devices. Smartphones and tablet devices are thus becoming increasingly popular for accessing information and a wide range of services, including health care services. Modern mobile apps can be used for a variety of reasons, ranging from education for the patients and assistance to clinicians to delivery of interventions. Mobile phone apps have also been established to benefit patients in a scope of interventions across numerous medical specialties and treatment modalities. Medical apps have their advantages and disadvantages. It is important that clinicians have access to knowledge to make decisions regarding the use of medical apps on the basis of risk-benefit ratio. Mobile apps that deliver psycho social interventions offer unique challenges and opportunities. A number of reviews have highlighted the potential use of such apps. There is a need to describe, report and study their side effects too. The adverse effects associated with these apps can broadly be divided into: (1) those resulting from the security and safety concerns; (2) those arising from the use of a particular psycho social intervention; and (3) those due to the interaction with digital technology. There is a need to refine and reconsider the safety and adverse effects in this area. The safety profile of a mobile PSI app should describe its safety profile in: (1) privacy and security; (2) adverse effects of psychotherapy; and (3) adverse effects unique to the use of apps and the internet. This is, however, a very new area and further research and reporting is required to inform clinical decision making.

What is Clinical Safety in Electronic Health Care Record Systems?

NASA Astrophysics Data System (ADS)

Davies, George

There is mounting public awareness of an increasing number of adverse clinical incidents within the National Health Service (NHS), but at the same time, large health care projects like the National Programme for IT (NPFIT) are claiming that safer care is one of the benefits of the project and that health software systems in particular have the potential to reduce the likelihood of accidental or unintentional harm to patients. This paper outlines the approach to clinical safety management taken by CSC, a major supplier to NPFIT; discusses acceptable levels of risk and clinical safety as an end-to-end concept; and touches on the future for clinical safety in health systems software.

Genetic variation in aryl N-acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4-diaminopyridine) phosphate.

PubMed

Haroldsen, Peter E; Garovoy, Marvin R; Musson, Donald G; Zhou, Huiyu; Tsuruda, Laurie; Hanson, Boyd; O'Neill, Charles A

2015-02-01

The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl N-acetyltransferase (NAT), yet its pharmacokinetic (PK) and safety profiles, as influenced by this enzyme system, have not been investigated. The objective of this study was to assess the effect of NAT phenotype and genotype on the PK and safety profiles of amifampridine in healthy volunteers (N = 26). A caffeine challenge test and NAT2 genotyping were used to delineate subjects into slow and fast acetylators for PK and tolerability assessment of single, escalating doses of amifampridine (up to 30 mg) and in multiple daily doses (20 mg QID) of amifampridine. The results showed that fast acetylator phenotypes displayed significantly lower C max, AUC, and shorter t 1/2 for amifampridine than slow acetylators. Plasma concentrations of the N-acetyl metabolite were approximately twofold higher in fast acetylators. Gender differences were not observed. Single doses of amifampridine demonstrated dose linear PKs. Amifampridine achieved steady state plasma levels within 1 day of dosing four times daily. No accumulation or time-dependent changes in amifampridine PK parameters occurred. Overall, slow acetylators reported 73 drug-related treatment-emergent adverse events versus 6 in fast acetylators. Variations in polymorphic NAT corresponding with fast and slow acetylator phenotypes significantly affects the PK and safety profiles of amifampridine.

Atorvastatin calcium encapsulated eudragit nanoparticles with enhanced oral bioavailability, safety and efficacy profile.

PubMed

Kumar, Nagendra; Chaurasia, Sundeep; Patel, Ravi R; Khan, Gayasuddin; Kumar, Vikas; Mishra, Brahmeshwar

2017-03-01

Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation. Morphological study exhibited homogenous spherical shape of formulated nanoparticles. In vitro release study in phosphate buffer (pH 7.4) demonstrated sustained release profile over 24 h. Pharmacokinetic study in Charles Foster rats showed significant enhancement in oral bioavailability as compared to pure drug suspension. Efficacy study (lipid profile and blood glucose level) significantly justified the effectiveness of formulation having 50% less dose of ATR as compared to pure drug suspension. The effectiveness of formulation was further justified with an improved plasma safety profile of treated rats. Hence, ATR encapsulated eudragit RSPO nanoparticles can serve as potential drug delivery approach to enhance drug bioavailability, efficacy and safety profiles to alter existing marketed drug products.

7T: Physics, safety, and potential clinical applications.

PubMed

Kraff, Oliver; Quick, Harald H

2017-12-01

With more than 60 installed magnetic resonance imaging (MRI) systems worldwide operating at a magnetic field strength of 7T or higher, ultrahigh-field (UHF) MRI has been established as a platform for clinically oriented research in recent years. Profound technical and methodological developments have helped overcome the inherent physical challenges of UHF radiofrequency (RF) signal homogenization in the human body. The ongoing development of dedicated RF coil arrays was pivotal in realizing UHF body MRI, beyond mere brain imaging applications. Another precondition to clinical application of 7T MRI is the safety testing of implants and the establishment of safety concepts. Against this backdrop, 7T MRI and MR spectroscopy (MRS) recently have demonstrated capabilities and potentials for clinical diagnostics in a variety of studies. This article provides an overview of the immanent physical challenges of 7T UHF MRI and discusses recent technical solutions and safety concepts. Furthermore, recent clinically oriented studies are highlighted that span a broad application spectrum from 7T UHF brain to body MRI. 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1573-1589. © 2017 International Society for Magnetic Resonance in Medicine.

Open wide: looking into the safety culture of dental school clinics.

PubMed

Ramoni, Rachel; Walji, Muhammad F; Tavares, Anamaria; White, Joel; Tokede, Oluwabunmi; Vaderhobli, Ram; Kalenderian, Elsbeth

2014-05-01

Although dentists perform highly technical procedures in complex environments, patient safety has not received the same focus in dentistry as in medicine. Cultivating a robust patient safety culture is foundational to minimizing patient harm, but little is known about how dental teams view patient safety or the patient safety culture within their practice. As a step toward rectifying that omission, the goals of this study were to benchmark the patient safety culture in three U.S. dental schools, identifying areas for improvement. The extensively validated Medical Office Survey on Patient Safety Culture (MOSOPS), developed by the Agency for Healthcare Research and Quality, was administered to dental faculty, dental hygienists, dental students, and staff at the three schools. Forty-seven percent of the 328 invited individuals completed the survey. The "Teamwork" category received the highest marks and "Patient Care Tracking and Follow-Up" and "Leadership Support for Patient Safety" the lowest. Only 48 percent of the respondents rated systems and processes in place to prevent/catch patient problems as good/excellent. All patient safety dimensions received lower marks than in medical practices. These findings and the inherent risk associated with dental procedures lead to the conclusion that dentistry in general, and academic dental clinics in particular, stands to benefit from an increased focus on patient safety. This first published use of the MOSOPS in a dental clinic setting highlights both clinical and educational priorities for improving the safety of care in dental school clinics.

Patient Safety Culture in Slovenian out-of-hours Primary Care Clinics.

PubMed

Klemenc-Ketiš, Zalika; Deilkås, Ellen Tveter; Hofoss, Dag; Bondevik, Gunnar Tschudi

2017-10-01

Patient safety culture is a concept which describes how leader and staff interaction, attitudes, routines and practices protect patients from adverse events in healthcare. We aimed to investigate patient safety culture in Slovenian out-of-hours health care (OOHC) clinics, and determine the possible factors that might be associated with it. This was a cross-sectional study, which took place in Slovenian OOHC, as part of the international study entitled Patient Safety Culture in European Out-of-Hours Services (SAFE-EUR-OOH). All the OOHC clinics in Slovenia (N=60) were invited to participate, and 37 agreed to do so; 438 employees from these clinics were invited to participate. We used the Slovenian version of the Safety Attitudes Questionnaire - an ambulatory version (SAQAV) to measure the climate of safety. Out of 438 invited participants, 250 answered the questionnaire (57.1% response rate). The mean overall score ± standard deviation of the SAQ was 56.6±16.0 points, of Perceptions of Management 53.6±19.6 points, of Job Satisfaction 48.5±18.3 points, of Safety Climate 59.1±22.1 points, of Teamwork Climate 72.7±16.6, and of Communication 51.5±23.4 points. Employees working in the Ravne na Koroškem region, employees with variable work shifts, and those with full-time jobs scored significantly higher on the SAQ-AV. The safety culture in Slovenian OOHC clinics needs improvement. The variations in the safety culture factor scores in Slovenian OOHC clinics point to the need to eliminate variations and improve working conditions in Slovenian OOHC clinics.

Safety Analysis of Panax Ginseng in Randomized Clinical Trials: A Systematic Review

PubMed Central

Kim, Young-Sook; Woo, Jung-Yoon; Han, Chang-Kyun; Chang, Il-Moo

2015-01-01

, main results, adverse events and adverse reactions. Results: Forty-four studies met the selection criteria. These studies covered the efficacy of ginseng in areas such as cardiovascular function, glucose metabolism, sexual function, anti-oxidation, anti-fatigue and psychomotor function. Twenty-nine studies showed positive results while fifteen studies showed no effect. Sixteen studies reported adverse events while five studies had no adverse events. Twenty-three studies did not mention any adverse events. The main adverse events of ginseng reported were general symptoms such as hot flushes, insomnia and dyspepsia with no significant difference in frequency and symptoms between the ginseng and placebo groups. The symptoms were mild and temporary with no serious or severe adverse events. Conclusion: Panax ginseng showed a very safe profile in a limited number of RCTs with a small number of participants with various conditions ranging from healthy participants to patients with symptoms. However, to increase the usefulness and lower the health risk of Panax ginseng to customers, clinical trials on a larger scale and with a higher standard are necessary to define its efficacy and safety as a dietary supplement or complementary medicine. PMID:28930204

Use of the false discovery rate for evaluating clinical safety data.

PubMed

Mehrotra, Devan V; Heyse, Joseph F

2004-06-01

Clinical adverse experience (AE) data are routinely evaluated using between group P values for every AE encountered within each of several body systems. If the P values are reported and interpreted without multiplicity considerations, there is a potential for an excess of false positive findings. Procedures based on confidence interval estimates of treatment effects have the same potential for false positive findings as P value methods. Excess false positive findings can needlessly complicate the safety profile of a safe drug or vaccine. Accordingly, we propose a novel method for addressing multiplicity in the evaluation of adverse experience data arising in clinical trial settings. The method involves a two-step application of adjusted P values based on the Benjamini and Hochberg false discovery rate (FDR). Data from three moderate to large vaccine trials are used to illustrate our proposed 'Double FDR' approach, and to reinforce the potential impact of failing to account for multiplicity. This work was in collaboration with the late Professor John W. Tukey who coined the term 'Double FDR'.

Pragmatic precision oncology: the secondary uses of clinical tumor molecular profiling

PubMed Central

Thota, Ramya; Staggs, David B; Johnson, Douglas B; Warner, Jeremy L

2016-01-01

Background Precision oncology increasingly utilizes molecular profiling of tumors to determine treatment decisions with targeted therapeutics. The molecular profiling data is valuable in the treatment of individual patients as well as for multiple secondary uses. Objective To automatically parse, categorize, and aggregate clinical molecular profile data generated during cancer care as well as use this data to address multiple secondary use cases. Methods A system to parse, categorize and aggregate molecular profile data was created. A naÿve Bayesian classifier categorized results according to clinical groups. The accuracy of these systems were validated against a published expertly-curated subset of molecular profiling data. Results Following one year of operation, 819 samples have been accurately parsed and categorized to generate a data repository of 10,620 genetic variants. The database has been used for operational, clinical trial, and discovery science research. Conclusions A real-time database of molecular profiling data is a pragmatic solution to several knowledge management problems in the practice and science of precision oncology. PMID:27026612

Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials.

PubMed

Camporeale, Angelo; Porsdal, Vibeke; De Bruyckere, Katrien; Tanaka, Yoko; Upadhyaya, Himanshu; Deix, Claudia; Deberdt, Walter

2015-01-01

The safety profile of atomoxetine in the treatment of attention deficit hyperactivity disorder has been studied in many clinical trials. We performed an integrated safety analysis of 15 clinical trials in adults with attention deficit hyperactivity disorder. The analysis pooled patient data into three groups: acute placebo-controlled trials; long-term placebo-controlled trials; all trials. In total, 4829 adults (18-77 years, median: 36 years) were exposed to atomoxetine. Statistically significantly more atomoxetine-treated than placebo-treated patients experienced treatment-emergent adverse events (81.3% vs. 68.3% acute; 90.6% vs. 76.8% long term) and discontinued due to adverse events (8.9% vs. 4.0% acute; 17.9% vs. 6.3% long term). No statistically significant differences were observed in the proportion of patients experiencing serious adverse events. No previously unknown adverse events were identified. The most common adverse events included nausea, dry mouth, decreased appetite, insomnia and erectile dysfunction. Mean increases in heart rate (+5.2 beats per min) and blood pressure (systolic +2 mmHg, diastolic +1.9 mmHg) were modest. The proportion of patients experiencing clinically significant increases in blood pressure and heart rate at any time was statistically significantly higher with atomoxetine (systolic blood pressure 13-17%, diastolic blood pressure 37-40%, heart rate 42-43%) compared to placebo (systolic blood pressure 8-13%, diastolic blood pressure 29-34%, heart rate 21-26%). There was no increased risk of suicidal ideation or behaviour. Our findings confirm atomoxetine's known safety profile. From a safety perspective, atomoxetine is a useful treatment option for adults with attention deficit hyperactivity disorder. © The Author(s) 2014.

Safety profile of bilastine: 2nd generation H1-antihistamines.

PubMed

Scaglione, F

2012-12-01

Bilastine is a new H1 antagonist with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism. In addition, bilastine has proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Pharmacological studies have shown that bilastine is highly selective for the H1 receptor in both in vivo and in vitro studies, and with no apparent affinity for other receptors. The absorption of bilastine is fast, linear and dose-proportional; it appears to be safe and well tolerated at all doses levels in healthy population. Multiple administration of bilastine has confirmed the linearity of the kinetic parameters. The distribution in the brain is undetectable. The safety profile in terms of adverse effects is very similar to placebo in all Phase I, II and III clinical trials. Bilastine (20 mg), unlike cetirizine, does not increase alcohol effects on the CNS. Bilastine 20 mg does not increase the CNS depressant effect of lorazepam. Bilastine 20 mg is similar to placebo in the driving test. Therefore, it meets the current criteria for medication used in the treatment of allergic rhinitis and urticaria.

Pharmacokinetics, Clinical Efficacy, Safety Profile, and Patient-Reported Outcomes in Patients Receiving Subcutaneous Testosterone Pellets 900 mg for Treatment of Symptoms Associated With Androgen Deficiency.

PubMed

McMahon, Chris G; Shusterman, Neil; Cohen, Brian

2017-07-01

(900 mg) of testosterone pellets are generally well tolerated and could provide clinical benefit for some patients. This study provides standardized data for the implantation of 12 testosterone pellets. However, the open-label uncontrolled design of this study and its small and ethnically non-diverse patient population limit the interpretation of these data, particularly the patient-reported outcomes. Implantation of 12 testosterone pellets (900 mg) was well tolerated and provided adequate and sustained serum testosterone concentrations. Additional randomized controlled trials are needed to confirm efficacy and safety findings. McMahon CG, Shusterman N, Cohen B. Pharmacokinetics, Clinical Efficacy, Safety Profile, and Patient-Reported Outcomes in Patients Receiving Subcutaneous Testosterone Pellets 900 mg for Treatment of Symptoms Associated With Androgen Deficiency. J Sex Med 2017;14:883-890. Copyright © 2017. Published by Elsevier Inc.

Safety and Efficacy of Microinvasive Glaucoma Surgery

PubMed Central

Chen, David Z.

2017-01-01

Microinvasive glaucoma surgery (MIGS) is emerging as a new therapeutic option for glaucoma patients who wish to reduce their medication burden and avoid the postoperative complications of conventional glaucoma filtration surgery. These devices differ in terms of their efficacy and safety profile. Schlemm's canal devices have the most favorable safety profile at the compromise of modest efficacy, while subconjunctival and suprachoroidal devices are potentially more effective at lowering the intraocular pressure at the expense of a higher rate of complications. This review consolidates the latest evidence on the efficacy and safety of the MIGS devices in clinical use and provides an overview on upcoming devices which would likely also become viable treatment options in the near future. These clinical data would assist a glaucoma surgeon in selecting the most appropriate MIGS device for each patient based on the glaucoma severity and patient expectations. PMID:28512578

Clinical and Demographic Profile of Patients Receiving Fingolimod in Clinical Practice in Germany and the Benefit-Risk Profile of Fingolimod After 1 Year of Treatment: Initial Results From the Observational, Noninterventional Study PANGAEA.

PubMed

Ziemssen, Tjalf; Lang, Michael; Tackenberg, Björn; Schmidt, Stephan; Albrecht, Holger; Klotz, Luisa; Haas, Judith; Lassek, Christoph; Medin, Jennie; Cornelissen, Christian

2018-01-01

The population with multiple sclerosis receiving treatment in clinical practice differs from that in randomized controlled trials (RCTs). An assessment of the real-world benefit-risk profile of therapies is needed. This analysis used data from the large, noninterventional, observational German study Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) to assess prospectively baseline characteristics and outcomes after 12 months (± 90 days) of fingolimod treatment. Patients were divided into 2 cohorts: fingolimod starter [first received fingolimod in PANGAEA (n = 3315)] and previous study [received fingolimod before enrollment in PANGAEA in RCTs (n = 875), some of whom also had baseline data at entry into RCTs (n = 505)]. At PANGAEA baseline, patients in the fingolimod starter versus the previous study cohort had a higher annualized relapse rate [ARR (95% confidence interval): 1.79 (1.75-1.83) vs 1.32 (1.25-1.40)] and Expanded Disability Status Scale score [3.11 (3.04-3.17) vs 2.55 (2.44-2.66)]. A greater proportion in the fingolimod starter versus previous study cohort had diabetes (2.0% vs 0.7%). After 12 months of fingolimod, ARRs were lower than in the 12 months before PANGAEA enrollment in the fingolimod starter [0.386 (0.360-0.414)] and previous study [0.276 (0.238-0.320)] cohorts. Expanded Disability Status Scale scores were stable versus baseline. Adverse events were experienced by similar proportions in both cohorts during fingolimod treatment. Relevant differences exist in disease activity and comorbidities between patients receiving fingolimod in clinical practice versus RCTs. Irrespective of baseline differences indicating a higher proportion at an advanced stage of multiple sclerosis in the real world versus RCTs, fingolimod remains effective, with a manageable safety profile.

Pragmatic precision oncology: the secondary uses of clinical tumor molecular profiling.

PubMed

Rioth, Matthew J; Thota, Ramya; Staggs, David B; Johnson, Douglas B; Warner, Jeremy L

2016-07-01

Precision oncology increasingly utilizes molecular profiling of tumors to determine treatment decisions with targeted therapeutics. The molecular profiling data is valuable in the treatment of individual patients as well as for multiple secondary uses. To automatically parse, categorize, and aggregate clinical molecular profile data generated during cancer care as well as use this data to address multiple secondary use cases. A system to parse, categorize and aggregate molecular profile data was created. A naÿve Bayesian classifier categorized results according to clinical groups. The accuracy of these systems were validated against a published expertly-curated subset of molecular profiling data. Following one year of operation, 819 samples have been accurately parsed and categorized to generate a data repository of 10,620 genetic variants. The database has been used for operational, clinical trial, and discovery science research. A real-time database of molecular profiling data is a pragmatic solution to several knowledge management problems in the practice and science of precision oncology. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The clinical benefit and safety of current and future assisted reproductive technology.

PubMed

Brown, Rachel; Harper, Joyce

2012-08-01

Since the first birth by IVF was achieved in 1978, the techniques involved in assisted reproductive technology have grown at an enormous rate. However, new technology has rarely been robustly validated before clinical use and developing scientific understanding of the available techniques has done little to alter their use. Furthermore, there are inconsistencies in the available clinical studies and endpoints. The benefits of some technologies already established for routine use are currently dubious and there are clear ethical concerns with providing them to patients when their scientific basis is not clear. As the uptake of assisted reproductive technology increases and newer technologies continue to push the boundaries of science, it is important to consider the clinical benefits and safety of all assisted reproductive technologies. This review will discuss aspects of some of the more recent techniques, including sperm DNA-damage tests, intracytoplasmic morphologically selected sperm injection, amino acid and metabolomics profiling, preimplantation genetic screening and time-lapse imaging, and those that may have substantial impacts on the field of reproductive medicine in the future including artificial gametes, ovarian transplantation and gene therapy. Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Aliskiren: review of efficacy and safety data with focus on past and recent clinical trials.

PubMed

Sen, Selçuk; Sabırlı, Soner; Ozyiğit, Tolga; Uresin, Yağız

2013-09-01

Aliskiren is the newest antihypertensive drug and the first orally active direct renin inhibitor to become available for clinical use. Clinical data have substantiated that the antihypertensive effectiveness of aliskiren is similar to that of the other major antihypertensive agents. Furthermore, aliskiren has a similar safety profile to placebo. Combination treatment with aliskiren showed significant blood pressure and proteinuria reductions compared with monotherapy. Aliskiren decreases plasma renin activity in contrast to other renin-angiotensin-aldosterone related drugs. The efficacy of aliskiren in treating major cardiovascular events and the prevention of end-organ damage are being investigated in the ASPIRE HIGHER program. Although the first studies of the ASPIRE HIGHER program such as ALOFT, AVOID, AGELESS showed favorable findings, ASPIRE and AVANT-GARDE studies provided contradictory results. Subsequently, the ALTITUDE study was terminated early because of safety issues and lack of beneficial effects. Most recently, the ASTRONAUT trial showed no reduction in cardiovascular death or heart failure rehospitalization with the addition of aliskiren to standard therapy in patients who were hospitalized for heart failure and with reduced left-ventricular ejection fraction. The results of ongoing studies in other patient groups such as the ATMOSPHERE trial are awaited.

The Relationship Between the Learning and Patient Safety Climates of Clinical Departments and Residents' Patient Safety Behaviors.

PubMed

Silkens, Milou E W M; Arah, Onyebuchi A; Wagner, Cordula; Scherpbier, Albert J J A; Heineman, Maas Jan; Lombarts, Kiki M J M H

2018-05-15

Improving residents' patient safety behavior should be a priority in graduate medical education to ensure the safety of current and future patients. Supportive learning and patient safety climates may foster this behavior. This study examined the extent to which residents' self-reported patient safety behavior can be explained by the learning climate and patient safety climate of their clinical departments. The authors collected learning climate data from clinical departments in the Netherlands that used the web-based Dutch Residency Educational Climate Test between September 2015 and October 2016. They also gathered data on those departments' patient safety climate and on residents' self-reported patient safety behavior. They used generalized linear mixed models and multivariate general linear models to test for associations in the data. In total, 1,006 residents evaluated 143 departments in 31 teaching hospitals. Departments' patient safety climate was associated with residents' overall self-reported patient safety behavior (regression coefficient (b) = 0.33; 95% confidence interval (CI) = 0.14 - 0.52). Departments' learning climate was not associated with residents' patient safety behavior (b = 0.01; 95% CI = -0.17 - 0.19), although it was with their patient safety climate (b = 0.73; 95% CI = 0.69 - 0.77). Departments should focus on establishing a supportive patient safety climate to improve residents' patient safety behavior. Building a supportive learning climate might help to improve the patient safety climate and, in turn, residents' patient safety behavior.

Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions.

PubMed

Monaco, Luca; Biagi, Chiara; Conti, Valentino; Melis, Mauro; Donati, Monia; Venegoni, Mauro; Vaccheri, Alberto; Motola, Domenico

2017-07-01

Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant. We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously. As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred. © 2017 The British Pharmacological Society.

The safety of influenza vaccine in clinically cured leprosy patients in China

PubMed Central

Zheng, Yi; Chen, Li; Zou, Jie; Zhu, Zheng-Gang; Zhu, Li; Wan, Jing; Hu, Quan

2018-01-01

ABSTRACT Background: Leprosy is an infectious disease caused by the bacterium Mycobacterium leprae. Influenza vaccine is an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. But the safety of applying influenza vaccine on the clinical cured leprosy patients is unclear. Methods: We conducted an observational clinical study, in Wuhan between November 15, 2016 and March 1, 2017. Two groups of participants ≥50 years of age received a 0.5 ml dose of the inactivated split-virion trivalent influenza vaccine and a follow-up 28 days observation of any solicited and unsolicited adverse events. Results: A total of 134 subjects were included in the study. The total rate of reactogenicity was 5.4% [2/37] in leprosy group and 15.5% [15/ 97] in control group, the difference of reactogenicity between two groups was not significant (p = 0.1522). For solicited injection-sites adverse events (AEs), 12.4% [12/ 97] participants in the control group reported of itching, pain, erythema, swelling or induration, and no participants in leprosy group reported of any solicited injection-sites AEs. For solicited systemic AEs, 7.2% [7 / 97] participants in the control group reported of fever, malaise or headache, and 2.7% [1 / 37] participants in the leprosy group reported of fever, statistic result showed that the difference was not significant (p = 0.4438). Unsolicited AEs was reported by one male aged 76, 4 hours after vaccination administration, his plantar ulcer area began bleeding. All AEs were grade 1 or grade 2, and no recurrence of lepra reaction, AEs leading to early withdrawal from the study, or deaths were reported in this study. Conclusions: To our knowledge, the present study is the first clinical study to evaluate the safety of influenza vaccine in clinically cured leprosy patients. We concluded that clinically cured leprosy patients are relatively safe for influenza vaccine. More importantly, our study make a

Methodology to assess clinical liver safety data.

PubMed

Merz, Michael; Lee, Kwan R; Kullak-Ublick, Gerd A; Brueckner, Andreas; Watkins, Paul B

2014-11-01

Analysis of liver safety data has to be multivariate by nature and needs to take into account time dependency of observations. Current standard tools for liver safety assessment such as summary tables, individual data listings, and narratives address these requirements to a limited extent only. Using graphics in the context of a systematic workflow including predefined graph templates is a valuable addition to standard instruments, helping to ensure completeness of evaluation, and supporting both hypothesis generation and testing. Employing graphical workflows interactively allows analysis in a team-based setting and facilitates identification of the most suitable graphics for publishing and regulatory reporting. Another important tool is statistical outlier detection, accounting for the fact that for assessment of Drug-Induced Liver Injury, identification and thorough evaluation of extreme values has much more relevance than measures of central tendency in the data. Taken together, systematical graphical data exploration and statistical outlier detection may have the potential to significantly improve assessment and interpretation of clinical liver safety data. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials.

Electronic clinical safety reporting system: a benefits evaluation.

PubMed

Elliott, Pamela; Martin, Desmond; Neville, Doreen

2014-06-11

Eastern Health, a large health care organization in Newfoundland and Labrador (NL), started a staged implementation of an electronic occurrence reporting system (used interchangeably with "clinical safety reporting system") in 2008, completing Phase One in 2009. The electronic clinical safety reporting system (CSRS) was designed to replace a paper-based system. The CSRS involves reporting on occurrences such as falls, safety/security issues, medication errors, treatment and procedural mishaps, medical equipment malfunctions, and close calls. The electronic system was purchased from a vendor in the United Kingdom that had implemented the system in the United Kingdom and other places, such as British Columbia. The main objective of the new system was to improve the reporting process with the goal of improving clinical safety. The project was funded jointly by Eastern Health and Canada Health Infoway. The objectives of the evaluation were to: (1) assess the CSRS on achieving its stated objectives (particularly, the benefits realized and lessons learned), and (2) identify contributions, if any, that can be made to the emerging field of electronic clinical safety reporting. The evaluation involved mixed methods, including extensive stakeholder participation, pre/post comparative study design, and triangulation of data where possible. The data were collected from several sources, such as project documentation, occurrence reporting records, stakeholder workshops, surveys, focus groups, and key informant interviews. The findings provided evidence that frontline staff and managers support the CSRS, identifying both benefits and areas for improvement. Many benefits were realized, such as increases in the number of occurrences reported, in occurrences reported within 48 hours, in occurrences reported by staff other than registered nurses, in close calls reported, and improved timelines for notification. There was also user satisfaction with the tool regarding ease of use

Temperament profiles of Sasang typology in a child clinical sample.

PubMed

Lee, Soo Jin; Park, Soo Hyun; Chae, Han

2012-12-01

Sasang typology is a personalized traditional medicine widely used in clinical diagnosis and treatment in Korea. The aim of this study was to examine the biopsychological personality profiles of traditional Korean Sasang typology in a clinical sample of Korean children. A total of 150 children were classified as one of three traditional Korean Sasang types (19 So-Yang, 118 Tae-Eum, and 13 So-Eum) by two clinical experts in Sasang typology. The childrens' mothers completed the Korean version of the Junior Temperament and Character Inventory (JTCI). The four temperament dimensions of JTCI were compared between the different Sasang types using analysis of variance (ANOVA) and profile analysis. There were no significant differences in age, gender, and parents' education levels across the Sasang types. The JTCI temperament profile for each of the child Sasang types was significantly different (profile analysis, df = 5.315, F  = 2.508, p  = 0.027). There were significant differences in novelty-seeking ( F  = 3.850, p  = 0.023) and novelty-seeking subscales, but not with other temperament dimensions. These results demonstrated distinct temperament traits associated with traditional Korean Sasang types in children using an objective biopsychological personality inventory. With further investigation into the biopsychological profiles of the children, the longitudinal stability of the Sasang typology can be examined.

Overview of phase IV clinical trials for postmarket drug safety surveillance: a status report from the ClinicalTrials.gov registry.

PubMed

Zhang, Xinji; Zhang, Yuan; Ye, Xiaofei; Guo, Xiaojing; Zhang, Tianyi; He, Jia

2016-11-23

Phase IV trials are often used to investigate drug safety after approval. However, little is known about the characteristics of contemporary phase IV clinical trials and whether these studies are of sufficient quality to advance medical knowledge in pharmacovigilance. We aimed to determine the fundamental characteristics of phase IV clinical trials that evaluated drug safety using the ClinicalTrials.gov registry data. A data set of 19 359 phase IV clinical studies registered in ClinicalTrials.gov was downloaded. The characteristics of the phase IV trials focusing on safety only were compared with those evaluating both safety and efficacy. We also compared the characteristics of the phase IV trials in three major therapeutic areas (cardiovascular diseases, mental health and oncology). Multivariable logistic regression was used to evaluate factors associated with the use of blinding and randomisation. A total of 4772 phase IV trials were identified, including 330 focusing on drug safety alone and 4392 evaluating both safety and efficacy. Most of the phase IV trials evaluating drug safety (75.9%) had enrolment <300 with 96.5% <3000. Among these trials, 8.2% were terminated or withdrawn. Factors associated with the use of blinding and randomisation included the intervention model, clinical specialty and lead sponsor. Phase IV trials evaluating drug safety in the ClinicalTrials.gov registry were dominated by small trials that might not have sufficient power to detect less common adverse events. An adequate sample size should be emphasised for phase IV trials with safety surveillance as main task. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Long-term safety and efficacy of adalimumab for intestinal Behçet's disease in the open label study following a phase 3 clinical trial.

PubMed

Inoue, Nagamu; Kobayashi, Kiyonori; Naganuma, Makoto; Hirai, Fumihito; Ozawa, Morio; Arikan, Dilek; Huang, Bidan; Robinson, Anne M; Thakkar, Roopal B; Hibi, Toshifumi

2017-07-01

Intestinal Behçet's disease (BD) is an immune-mediated inflammatory disorder. We followed up the patients and evaluated safety profile and effectiveness of adalimumab for the treatment of intestinal BD through 100 weeks rolled over from the 52 week clinical trial (NCT01243671). Patients initiated adalimumab therapy at 160 mg at week 0, followed by 80 mg at week 2, followed by 40 mg every other week until the end of the study. Long-term safety and all adverse events (AEs) were examined. The efficacy was assessed on the basis of marked improvement (MI) and complete remission (CR) using a composite efficacy index, which combined global gastrointestinal symptoms and endoscopic assessments. Twenty patients were enrolled in this study; 15 patients received adalimumab treatment until study completion. The incidence of AEs through week 100 was 544.4 events/100 person-years, which was comparable to the incidence through week 52 (560.4 events/100 person-years). No unexpected trend was observed and adalimumab was well tolerated. At weeks 52 and 100, 60.0% and 40.0% of patients showed MI, respectively, and 20.0% and 15.0% of patients showed CR, respectively. This report demonstrates 2 years safety and effectiveness of adalimumab in intestinal BD patients. Patients with intestinal BD refractory to conventional treatment receiving up to 2 years of adalimumab treatment demonstrated safety outcomes consistent with the known profile of adalimumab, and the treatment led to sustained reduction of clinical and endoscopic disease activity.

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data.

PubMed

Scavone, Cristina; Bonagura, Angela Colomba; Fiorentino, Sonia; Cimmaruta, Daniela; Cenami, Rosina; Torella, Marco; Fossati, Tiziano; Rossi, Francesco

2016-06-01

According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg. The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-β-cyclodextrin (HPβCD) and progesterone/HPβCD associations. The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPβCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPβCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the

Safety profile of methotrexate in inflammatory bowel disease.

PubMed

Gabbani, Tommaso; Deiana, Simona; Lunardi, Sarah; Manetti, Natalia; Annese, Vito

2016-10-01

Methotrexate, which was initially developed in 1948 for the treatment of leukemia, is known to be an immunomodulatory and anti-inflammatory drug. It has been widely used for over 60 years as both a low and high-dose therapy in chronic inflammatory diseases. The aim of this review was to analyze and summarize the available data specifically on the safety of this drug in the management of inflammatory bowel diseases. A structured search of articles was conducted using the PubMed database up to April 2016. All articles in English with isolated or combined keywords were included according to their relevance to the aims of this study. Numerous of studies have established the efficacy of parenteral methotrexate in the management of steroid-dependent and steroid-resistant Crohn's disease, either for inducing or maintaining remission. However, its efficacy in ulcerative colitis has not been properly investigated. Additionally, methotrexate has been shown to reduce the effect of immunization with anti-TNF agents when combined. The drug has potential advantages over thiopurines such as its weekly administration, a possible shorter time of action, low cost, decreased risk for malignancy and overall a comparable safety profile.

Spectrum of complicated migraine in children: A common profile in aid to clinical diagnosis

PubMed Central

Gupta, Surya N; Gupta, Vikash S; Fields, Dawn M

2015-01-01

Complicated migraine encompasses several individual clinical syndromes of migraine. Such a syndrome in children frequently presents with various neurological symptoms in the Emergency Department. An acute presentation in the absence of headache presents a diagnostic challenge. A delay in diagnosis and treatment may have medicolegal implication. To date, there are no reports of a common clinical profile proposed in making a clinical diagnosis for the complicated migraine. In this clinical review, we propose and describe: (1) A common clinical profile in aid to clinical diagnosis for spectrum of complicated migraine; (2) How it can be used in differentiating complicated migraine from migraine without aura, migraine with aura, and seizure; (3) We discuss the status of complicated migraine in the International Headache Society classification 2013; and (4) In addition, a common treatment strategy for the spectrum of migraine has been described. To diagnose complicated migraine clinically, it is imperative to adhere with the proposed profile. This will optimize the use of investigation and will also avoid a legal implication of delay in their management. The proposed common clinical profile is incongruent with the International Headache Society 2013. Future classification should minimize the dissociation from clinically encountered syndromes and coin a single word to address collectively this subtype of migraine with an acute presentation of a common clinical profile. PMID:25664241

Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ryan, Patricia C., E-mail: ryanp@medimmune.com; Sleeman, Matthew A.; Rebelatto, Marlon

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26 weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters othermore » than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress. - Highlights: • Mavrilimumab is a MAB targeting GM-CSFRα being developed for RA therapy. • Mavrilimumab has an acceptable safety profile in cynomolgus

Clinical, epidemiological, and therapeutic profile of dermatophytosis*

PubMed Central

Pires, Carla Andréa Avelar; da Cruz, Natasha Ferreira Santos; Lobato, Amanda Monteiro; de Sousa, Priscila Oliveira; Carneiro, Francisca Regina Oliveira; Mendes, Alena Margareth Darwich

2014-01-01

BACKGROUND The cutaneous mycoses, mainly caused by dermatophyte fungi, are among the most common fungal infections worldwide. It is estimated that 10% to 15% of the population will be infected by a dermatophyte at some point in their lives, thus making this a group of diseases with great public health importance. OBJECTIVE To analyze the clinical, epidemiological, and therapeutic profile of dermatophytosis in patients enrolled at the Dermatology service of Universidade do Estado do Pará, Brazil, from July 2010 to September 2012. METHOD A total of 145 medical records of patients diagnosed with dermatophytosis were surveyed. Data were collected and subsequently recorded according to a protocol developed by the researchers. This protocol consisted of information regarding epidemiological and clinical aspects of the disease and the therapy employed. RESULTS The main clinical form of dermatophyte infection was onychomycosis, followed by tinea corporis, tinea pedis, and tinea capitis. Furthermore, the female population and the age group of 51 to 60 years were the most affected. Regarding therapy, there was a preference for treatments that combine topical and systemic drugs, and the most widely used drugs were fluconazole (systemic) and ciclopirox olamine (topical). CONCLUSION This study showed the importance of recurrent analysis of the epidemiological profile of dermatophytosis to enable correct therapeutic and preventive management of these conditions, which have significant clinical consequences, with chronic, difficult-totreat lesions that can decrease patient quality of life and cause disfigurement. PMID:24770502

Sources of Safety Data and Statistical Strategies for Design and Analysis: Clinical Trials.

PubMed

Zink, Richard C; Marchenko, Olga; Sanchez-Kam, Matilde; Ma, Haijun; Jiang, Qi

2018-03-01

There has been an increased emphasis on the proactive and comprehensive evaluation of safety endpoints to ensure patient well-being throughout the medical product life cycle. In fact, depending on the severity of the underlying disease, it is important to plan for a comprehensive safety evaluation at the start of any development program. Statisticians should be intimately involved in this process and contribute their expertise to study design, safety data collection, analysis, reporting (including data visualization), and interpretation. In this manuscript, we review the challenges associated with the analysis of safety endpoints and describe the safety data that are available to influence the design and analysis of premarket clinical trials. We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from clinical trials compared to other sources. Clinical trials are an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. This work is a result of the efforts of the American Statistical Association Biopharmaceutical Section Safety Working Group.

Specific Safety Profile of Bevacizumab in Asian Patients With Advanced NSCLC

PubMed Central

Chen, Zhenguang; Zhong, Beilong; Lun, Xueping; Lai, Yingrong; Bella, Amos Ela; Yang, Weilin; Wu, Jiabin

2015-01-01

Abstract Randomized studies have obtained varying findings regarding the benefits and toxicities of bevacizumab in the treatment of nonsmall cell lung cancer (NSCLC). It is unclear whether the discrepancies among trials are due to ethnic/racial differences. We therefore performed a meta-analysis of all published, randomized, controlled clinical trials involving bevacizumab in patients with NSCLC to assess its effectiveness and safety in Asian and non-Asian populations. Results from the phase II JO19907 trial, the phase III AVAiL and ECOG 4599 trials, and the phase IV SAiL trials were used to calculate the benefits and toxicities of bevacizumab in Asian and non-Asian patients. Combined statistical estimates, including hazard ratios and odds ratios, were calculated using fixed-effects and random-effects models. A total of 4308 patients were evaluated. Combining bevacizumab with different chemotherapy regimens resulted in similar objective response rates, overall survival, and progression-free survival in Asian and non-Asian populations. Disease control rates, however, were only reported in Asian populations. The rates of severe bleeding (relative risk [RR], 2.17; P = 0.02) and thromboembolism (RR, 3.65; P < 0.0001) were significantly higher, while the rate of severe proteinuria was significantly lower (RR, 0.43; P < 0.0001), in non-Asian than in Asian populations. The rates of severe hypertension (P = 0.71) and hemoptysis (P = 0.66) were similar in Asian and non-Asian populations. Bevacizumab combined with chemotherapy for first-line NSCLC treatment showed similar benefits in Asian and non-Asian populations, but had specific safety profiles in each. PMID:26091469

Clinical and microbiological profile of infectious keratitis in children

PubMed Central

2013-01-01

Background Infectious keratitis is a sight-threatening condition for children. The purpose of this study was to describe the clinical profile, risk factors and microbiological profile of infectious keratitis in children. Methods Retrospective review of clinical records of patients under 16 years of age with history of microbial keratitis seen at a tertiary referral center. Clinical characteristics, risk factors, visual and surgical outcomes as well as the microbiological profile are analyzed. Results Forty-one eyes of 41 patients. Mean age was 8.7 years. Time between the onset of symptoms and ophthalmological examination was 12.7 days. Predisposing factors were found in 78%; ocular trauma was the most common (25%). Visual acuity equal or worse than 20/200 at admission correlated positively with a poorer visual outcome, p=0.002. Positivity of cultures was 34%. Gram-positive bacteria were isolated in 78.5%; Staphylococcus epidermidis (28.6%) was the most common microorganism. Conclusions Our study emphasizes the importance of a prompt diagnosis and treatment of infectious corneal ulcers in children. Trauma and contact lenses were the main predisposing factors. Gram-positive organisms were isolated in the vast majority of cases and visual outcomes are usually poor. PMID:24131681

Evaluation of the safety profile of an electronic vapour product used for two years by smokers in a real-life setting.

PubMed

Walele, Tanvir; Bush, Jim; Koch, Annelize; Savioz, Rebecca; Martin, Claire; O'Connell, Grant

2018-02-01

The safety profile of Puritane™, a closed system electronic vapour product (EVP), was evaluated when used by smokers of conventional cigarettes (CCs) for 24 months in a real-life setting. The study was a two-centre ambulatory clinical study with 209 healthy volunteers. Outcome measures included adverse events (AEs), vital signs, electrocardiogram, lung function tests, exposure to nicotine and selected smoke constituents, nicotine withdrawal effects and smoking desire. No serious AEs related to EVP use were observed. The most frequently reported AEs were headache, nasopharyngitis, sore throat and cough, reported by 28.7%, 28.7%, 19.6% and 16.7% of subjects, respectively, which dissipated over time. Small decreases in lung function were not considered clinically relevant. No clinically relevant findings were observed in the other safety parameters. From Month 2, nicotine withdrawal symptoms decreased. Smoking desire and CC consumption steadily decreased over time in all subjects. EVP use was associated with reduced exposure to cigarette smoke constituents, whereas urinary nicotine levels remained close to baseline. Body weight did not increase in CC subjects switching to the EVP. In conclusion, the aerosol of the EVP at study was well tolerated and not associated with any clinically relevant health concerns after usage for up to 24 months. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Pre-Exposure Prophylaxis for HIV Prevention: Safety Concerns.

PubMed

Tetteh, Raymond A; Yankey, Barbara A; Nartey, Edmund T; Lartey, Margaret; Leufkens, Hubert G M; Dodoo, Alexander N O

2017-04-01

Available evidence supports the efficacy of pre-exposure prophylaxis (PrEP) in decreasing the incidence of human immunodeficiency virus (HIV) infection among high-risk individuals, especially when used in combination with other behavioural preventive methods. Safety concerns about PrEP present challenges in the implementation and use of PrEP. The aim of this review is to discuss safety concerns observed in completed clinical trials on the use of PrEP. We performed a literature search on PrEP in PubMed, global advocacy for HIV prevention (Aids Vaccine Advocacy Coalition) database, clinical trials registry " http://www.clinicaltrials.gov " and scholar.google, using combination search terms 'pre-exposure prophylaxis', 'safety concerns in the use of pre-exposure prophylaxis', 'truvada use as PrEP', 'guidelines for PrEP use', 'HIV pre-exposure prophylaxis' and 'tenofovir' to identify clinical trials and literature on PrEP. We present findings associated with safety issues on the use of PrEP based on a review of 11 clinical trials on PrEP with results on safety and efficacy as at April 2016. We also reviewed findings from routine real-life practice reports. The pharmacological intervention for PrEP was tenofovir disoproxil fumarate/emtricitabine in a combined form as Truvada ® or tenofovir as a single entity. Both products are efficacious for PrEP and seem to have a good safety profile. Regular monitoring is recommended to prevent long-term toxic effects. The main adverse effects observed with PrEP are gastrointestinal related; basically mild to moderate nausea, vomiting and diarrhea. Other adverse drug effects worth monitoring are liver enzymes, renal function and bone mineral density. PrEP as an intervention to reduce HIV transmission appears to have a safe benefit-risk profile in clinical trials. It is recommended for widespread use but adherence monitoring and real-world safety surveillance are critical in the post-marketing phase to ensure that the benefits

Single-cell genomic profiling of acute myeloid leukemia for clinical use: A pilot study

PubMed Central

Yan, Benedict; Hu, Yongli; Ban, Kenneth H.K.; Tiang, Zenia; Ng, Christopher; Lee, Joanne; Tan, Wilson; Chiu, Lily; Tan, Tin Wee; Seah, Elaine; Ng, Chin Hin; Chng, Wee-Joo; Foo, Roger

2017-01-01

Although bulk high-throughput genomic profiling studies have led to a significant increase in the understanding of cancer biology, there is increasing awareness that bulk profiling approaches do not completely elucidate tumor heterogeneity. Single-cell genomic profiling enables the distinction of tumor heterogeneity, and may improve clinical diagnosis through the identification and characterization of putative subclonal populations. In the present study, the challenges associated with a single-cell genomics profiling workflow for clinical diagnostics were investigated. Single-cell RNA-sequencing (RNA-seq) was performed on 20 cells from an acute myeloid leukemia bone marrow sample. Putative blasts were identified based on their gene expression profiles and principal component analysis was performed to identify outlier cells. Variant calling was performed on the single-cell RNA-seq data. The present pilot study demonstrates a proof of concept for clinical single-cell genomic profiling. The recognized limitations include significant stochastic RNA loss and the relatively low throughput of the current proposed platform. Although the results of the present study are promising, further technological advances and protocol optimization are necessary for single-cell genomic profiling to be clinically viable. PMID:28454300

Modeling for influenza vaccines and adjuvants profile for safety prediction system using gene expression profiling and statistical tools

PubMed Central

Sasaki, Eita; Momose, Haruka; Hiradate, Yuki; Furuhata, Keiko; Takai, Mamiko; Asanuma, Hideki; Ishii, Ken J.

2018-01-01

Historically, vaccine safety assessments have been conducted by animal testing (e.g., quality control tests and adjuvant development). However, classical evaluation methods do not provide sufficient information to make treatment decisions. We previously identified biomarker genes as novel safety markers. Here, we developed a practical safety assessment system used to evaluate the intramuscular, intraperitoneal, and nasal inoculation routes to provide robust and comprehensive safety data. Influenza vaccines were used as model vaccines. A toxicity reference vaccine (RE) and poly I:C-adjuvanted hemagglutinin split vaccine were used as toxicity controls, while a non-adjuvanted hemagglutinin split vaccine and AddaVax (squalene-based oil-in-water nano-emulsion with a formulation similar to MF59)-adjuvanted hemagglutinin split vaccine were used as safety controls. Body weight changes, number of white blood cells, and lung biomarker gene expression profiles were determined in mice. In addition, vaccines were inoculated into mice by three different administration routes. Logistic regression analyses were carried out to determine the expression changes of each biomarker. The results showed that the regression equations clearly classified each vaccine according to its toxic potential and inoculation amount by biomarker expression levels. Interestingly, lung biomarker expression was nearly equivalent for the various inoculation routes. The results of the present safety evaluation were confirmed by the approximation rate for the toxicity control. This method may contribute to toxicity evaluation such as quality control tests and adjuvant development. PMID:29408882

Improving diabetic foot care in a nurse-managed safety-net clinic.

PubMed

Peterson, Joann M; Virden, Mary D

2013-05-01

This article is a description of the development and implementation of a Comprehensive Diabetic Foot Care Program and assessment tool in an academically affiliated nurse-managed, multidisciplinary, safety-net clinic. The assessment tool parallels parameters identified in the Task Force Foot Care Interest Group of the American Diabetes Association's report published in 2008, "Comprehensive Foot Examination and Risk Assessment." Review of literature, Silver City Health Center's (SCHC) 2009 Annual Report, retrospective chart review. Since the full implementation of SCHC's Comprehensive Diabetic Foot Care Program, there have been no hospitalizations of clinic patients for foot-related complications. The development of the Comprehensive Diabetic Foot Assessment tool and the implementation of the Comprehensive Diabetic Foot Care Program have resulted in positive outcomes for the patients in a nurse-managed safety-net clinic. This article demonstrates that quality healthcare services can successfully be developed and implemented in a safety-net clinic setting. ©2012 The Author(s) Journal compilation ©2012 American Association of Nurse Practitioners.

Pharmacological and clinical profile of bivalirudin in the treatment of patients with acute coronary syndrome.

PubMed

White, Harvey D

2009-05-01

Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over heparin. It has been studied extensively in non-ST elevation acute 60 coronary syndromes (NSTE-ACS) and in percutaneous coronary intervention. Bivalirudin has also recently been investigated in patients with ST-elevation myocardial infarction (STEMI) treated with primary angioplasty and stenting. More than 27,000 patients were randomized in these trials. To provide an overview of the pharmacological properties of bivalirudin and its efficacy and safety profile in patients across the spectrum of acute coronary syndromes (ACS). All published, peer-reviewed clinical trials were reviewed and as relevant were included. Bivalirudin with provisional IIb/IIIa antagonists provides consistent results across the full spectrum of ACS, with similar or non-inferior protection from ischemic events and significantly reduces bleeding complications compared with heparin and IIb/IIIa antagonists. In STEMI, mortality at 30 days and 1 year is significantly reduced. The unique pharmacokinetic profile of bivalirudin allows for simultaneous reductions in both ischemic and hemorrhagic events and makes it an appropriate alternative to heparin.

Establishment of a New Quality Control and Vaccine Safety Test for Influenza Vaccines and Adjuvants Using Gene Expression Profiling

PubMed Central

Momose, Haruka; Mizukami, Takuo; Kuramitsu, Madoka; Takizawa, Kazuya; Masumi, Atsuko; Araki, Kumiko; Furuhata, Keiko; Yamaguchi, Kazunari; Hamaguchi, Isao

2015-01-01

We have previously identified 17 biomarker genes which were upregulated by whole virion influenza vaccines, and reported that gene expression profiles of these biomarker genes had a good correlation with conventional animal safety tests checking body weight and leukocyte counts. In this study, we have shown that conventional animal tests showed varied and no dose-dependent results in serially diluted bulk materials of influenza HA vaccines. In contrast, dose dependency was clearly shown in the expression profiles of biomarker genes, demonstrating higher sensitivity of gene expression analysis than the current animal safety tests of influenza vaccines. The introduction of branched DNA based-concurrent expression analysis could simplify the complexity of multiple gene expression approach, and could shorten the test period from 7 days to 3 days. Furthermore, upregulation of 10 genes, Zbp1, Mx2, Irf7, Lgals9, Ifi47, Tapbp, Timp1, Trafd1, Psmb9, and Tap2, was seen upon virosomal-adjuvanted vaccine treatment, indicating that these biomarkers could be useful for the safety control of virosomal-adjuvanted vaccines. In summary, profiling biomarker gene expression could be a useful, rapid, and highly sensitive method of animal safety testing compared with conventional methods, and could be used to evaluate the safety of various types of influenza vaccines, including adjuvanted vaccine. PMID:25909814

The effect of safety factor profile on transport in steady-state, high-performance scenarios

DOE PAGES

Holcomb, C. T.; Ferron, J. R.; Luce, T. C.; ...

2012-03-09

In this study, an analysis of the dependence of transport on the safety factor profile in high-performance, steady-state scenario discharges is presented. This is based on experimental scans of q 95 and q min taken with fixed β N, toroidal field, double-null plasma shape, divertor pumping, and electron cyclotron current drive input. The temperature and thermal diffusivity profiles were found to vary considerably with the q-profile, and these variations were significantly different for electrons and ions. With fixed q 95, both temperature profiles increase and broaden as q min is increased and the magnetic shear becomes low or negative inmore » the inner half radius, but these temperature profile changes are stronger for the electrons. Power balance calculations show the peak in the ion thermal diffusivity (χ i) at ρ – 0.6 – 0.8 increases with q 95 or q min.« less

Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

PubMed

Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

2014-11-01

Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Undergraduate medical students' perceptions and intentions regarding patient safety during clinical clerkship.

PubMed

Lee, Hoo-Yeon; Hahm, Myung-Il; Lee, Sang Gyu

2018-04-04

The purpose of this study was to examine undergraduate medical students' perceptions and intentions regarding patient safety during clinical clerkships. Cross-sectional study administered in face-to-face interviews using modified the Medical Student Safety Attitudes and Professionalism Survey (MSSAPS) from three colleges of medicine in Korea. We assessed medical students' perceptions of the cultures ('safety', 'teamwork', and 'error disclosure'), 'behavioural intentions' concerning patient safety issues and 'overall patient safety'. Confirmatory factor analysis and Spearman's correlation analyses was performed. In total, 194(91.9%) of the 211 third-year undergraduate students participated. 78% of medical students reported that the quality of care received by patients was impacted by teamwork during clinical rotations. Regarding error disclosure, positive scores ranged from 10% to 74%. Except for one question asking whether the disclosure of medical errors was an important component of patient safety (74%), the percentages of positive scores for all the other questions were below 20%. 41.2% of medical students have intention to disclose it when they saw a medical error committed by another team member. Many students had difficulty speaking up about medical errors. Error disclosure guidelines and educational efforts aimed at developing sophisticated communication skills are needed. This study may serve as a reference for other institutions planning patient safety education in their curricula. Assessing student perceptions of safety culture can provide clerkship directors and clinical service chiefs with information that enhances the educational environment and promotes patient safety.

Clinical symptoms in fibromyalgia are associated to overweight and lipid profile.

PubMed

Cordero, Mario D; Alcocer-Gómez, Elísabet; Cano-García, Francisco J; Sánchez-Domínguez, Benito; Fernández-Riejo, Patricia; Moreno Fernández, Ana M; Fernández-Rodríguez, Ana; De Miguel, Manuel

2014-03-01

In order to analyze the association between body mass index (BMI), lipid profile and clinical symptoms in patients with fibromyalgia, we assessed BMI levels, lipid profile and its association with clinical symptoms in 183 patients with fibromyalgia. The patients were evaluated using tender points, FIQ and Visual Analogue Scales of pain (VAS). Serum lipid profile analysis (total cholesterol, triglyceride, HDL, LDL and VLDL), and biochemical parameters were measured in the biochemistry laboratory. The BMI distribution of the nonobese, overweight and obese patients' groups were relatively even with 37.7, 35.5 and 26.8%, respectively, with a mean BMI of 27.3 ± 4.9. The number of tender points showed significantly positive correlation with higher BMI (P < 0.05). A total of 57.9% of patients showed increased levels of total cholesterol, 63.4 % increased levels of LDL cholesterol and 19.9% high levels of triglycerides. BMI, total cholesterol and triglycerides showed high association with some clinical parameters. Overweight and lipid profile could be associated with fibromyalgia symptoms. A treatment program with weight loss strategies, and control in diet and increased physical activity is advised to patients.

Clinically relevant safety issues associated with St. John's wort product labels.

PubMed

Clauson, Kevin A; Santamarina, Marile L; Rutledge, Jennifer C

2008-07-17

St. John's wort (SJW), used to treat depression, is popular in the USA, Canada, and parts of Europe. However, there are documented interactions between SJW and prescription medications including warfarin, cyclosporine, indinavir, and oral contraceptives. One source of information about these safety considerations is the product label. The aim of this study was to evaluate the clinically relevant safety information included on labeling in a nationally representative sample of SJW products from the USA. Eight clinically relevant safety issues were identified: drug interactions (SJW-HIV medications, SJW-immunosupressants, SJW-oral contraceptives, and SJW-warfarin), contraindications (bipolar disorder), therapeutic duplication (antidepressants), and general considerations (phototoxicity and advice to consult a healthcare professional (HCP)). A list of SJW products was identified to assess their labels. Percentages and totals were used to present findings. Of the seventy-four products evaluated, no product label provided information for all 8 evaluation criteria. Three products (4.1%) provided information on 7 of the 8 criteria. Four products provided no safety information whatsoever. Percentage of products with label information was: SJW-HIV (8.1%), SJW-immunosupressants (5.4%), SJW-OCPs (8.1%), SJW-warfarin (5.4%), bipolar (1.4%), antidepressants (23.0%), phototoxicity (51.4%), and consult HCP (87.8%). Other safety-related information on labels included warnings about pregnancy (74.3%), lactation (64.9%), discontinue if adverse reaction (23.0%), and not for use in patients under 18 years old (13.5%). The average number of a priori safety issues included on a product label was 1.91 (range 0-8) for 23.9% completeness. The vast majority of SJW products fail to adequately address clinically relevant safety issues on their labeling. A few products do provide an acceptable amount of information on clinically relevant safety issues which could enhance the quality of

Clinically relevant safety issues associated with St. John's wort product labels

PubMed Central

Clauson, Kevin A; Santamarina, Marile L; Rutledge, Jennifer C

2008-01-01

Background St. John's wort (SJW), used to treat depression, is popular in the USA, Canada, and parts of Europe. However, there are documented interactions between SJW and prescription medications including warfarin, cyclosporine, indinavir, and oral contraceptives. One source of information about these safety considerations is the product label. The aim of this study was to evaluate the clinically relevant safety information included on labeling in a nationally representative sample of SJW products from the USA. Methods Eight clinically relevant safety issues were identified: drug interactions (SJW-HIV medications, SJW-immunosupressants, SJW-oral contraceptives, and SJW-warfarin), contraindications (bipolar disorder), therapeutic duplication (antidepressants), and general considerations (phototoxicity and advice to consult a healthcare professional (HCP)). A list of SJW products was identified to assess their labels. Percentages and totals were used to present findings. Results Of the seventy-four products evaluated, no product label provided information for all 8 evaluation criteria. Three products (4.1%) provided information on 7 of the 8 criteria. Four products provided no safety information whatsoever. Percentage of products with label information was: SJW-HIV (8.1%), SJW-immunosupressants (5.4%), SJW-OCPs (8.1%), SJW-warfarin (5.4%), bipolar (1.4%), antidepressants (23.0%), phototoxicity (51.4%), and consult HCP (87.8%). Other safety-related information on labels included warnings about pregnancy (74.3%), lactation (64.9%), discontinue if adverse reaction (23.0%), and not for use in patients under 18 years old (13.5%). The average number of a priori safety issues included on a product label was 1.91 (range 0–8) for 23.9% completeness. Conclusion The vast majority of SJW products fail to adequately address clinically relevant safety issues on their labeling. A few products do provide an acceptable amount of information on clinically relevant safety issues

Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease.

PubMed

Balwani, Manisha; Breen, Catherine; Enns, Gregory M; Deegan, Patrick B; Honzík, Tomas; Jones, Simon; Kane, John P; Malinova, Vera; Sharma, Reena; Stock, Eveline O; Valayannopoulos, Vassili; Wraith, J Edmond; Burg, Jennifer; Eckert, Stephen; Schneider, Eugene; Quinn, Anthony G

2013-09-01

Cholesteryl ester storage disease (CESD), an inherited deficiency of lysosomal acid lipase (LAL), is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once-weekly infusions (0.35, 1, or 3 mg·kg(-1) ) in LAL-CL01, which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received four once-weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg(-1) ) before transitioning to long-term every-other-week infusions (1 or 3 mg·kg(-1) ). Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In seven patients receiving ongoing sebelipase alfa treatment in LAL-CL04, the mean ± standard deviation (SD) decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46 ± 21 U/L (-52%) and 21 ± 14 U/L (-36%), respectively (P ≤ 0.05). Through week 12 of LAL-CL04, these seven patients also showed mean decreases from baseline in total cholesterol of 44 ± 41 mg/dL (-22%; P = 0.047), low density lipoprotein-cholesterol of 29 ± 31 mg/dL (-27%; P = 0.078), and triglycerides of 50 ± 38 mg/dL (-28%, P = 0.016) and increases in high density lipoprotein-cholesterol of 5 mg/dL (15%; P = 0.016). These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long-term dosing and are accompanied by improvements in serum lipid profile. Copyright © 2013 American Association for the

Clinical Effect and Safety Profile of Recombinant Human Lysosomal Acid Lipase in Patients with Cholesteryl Ester Storage Disease

PubMed Central

Balwani, Manisha; Breen, Catherine; Enns, Gregory M; Deegan, Patrick B; Honzík, Tomas; Jones, Simon; Kane, John P; Malinova, Vera; Sharma, Reena; Stock, Eveline O; Valayannopoulos, Vassili; Wraith, J Edmond; Burg, Jennifer; Eckert, Stephen; Schneider, Eugene; Quinn, Anthony G

2013-01-01

Background & Aims Cholesteryl Ester Storage Disease, an inherited deficiency of lysosomal acid lipase, is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. Methods To assess the clinical effects and safety of the recombinant human lysosomal acid lipase, sebelipase alfa, 9 patients received 4 once-weekly infusions (0.35, 1, or 3 mg·kg−1) in LAL-CL01 which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received 4 once-weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg−1) before transitioning to long term every other week infusions (1 or 3 mg·kg−1). Results Sebelipase alfa was well-tolerated with mostly mild adverse events unrelated sebelipase alfa. No anti-drug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In 7 patients receiving ongoing sebelipase alfa treatment in LAL-CL04, mean±SD decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46±21U/L (-52%) and 21±14U/L (-36%), respectively (p<0.05). Through week 12 of LAL-CL04, these 7 patients also showed mean decreases from baseline in total cholesterol of 44±41mg/dL (-22%; p=0.047), low density lipoprotein-cholesterol of 29±31mg/dL (-27%; p=0.078), and triglycerides of 50±38mg/dL (-28%, p=0.016) and increases in high density lipoprotein-cholesterol of 5mg/dL (15%; p=0.016). Conclusions These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with Cholesteryl Ester Storage Disease is well tolerated, rapidly decreases serum transaminases and that these improvements are sustained with long term dosing and are accompanied by improvements in serum lipid profile. PMID:23348766

[Clinical governance and patient safety culture in clinical laboratories in the Spanish National Health System].

PubMed

Giménez-Marín, Á; Rivas-Ruiz, F

To conduct a situational analysis of patient safety culture in public laboratories in the Spanish National Health System and to determine the clinical governance variables that most strongly influence patient safety. A descriptive cross-sectional study was carried out, in which a Survey of Patient Safety in Clinical Laboratories was addressed to workers in 26 participating laboratories. In this survey, which consisted of 45 items grouped into 6 areas, scores were assigned on a scale from 0 to 100 (where 0 is the lowest perception of patient safety). Laboratory managers were asked specific questions about quality management systems and technology. The mean scores for the 26 participating hospitals were evaluated, and the following results observed: in 4of the 6areas, the mean score was higher than 70 points. In the third area (equipment and resources) and the fourth area (working conditions), the scores were lower than 60 points. Every hospital had a digital medical record system. This 100% level of provision was followed by that of an electronic request management system, which was implemented in 82.6% of the hospitals. The results obtained show that the culture of security is homogeneous and of high quality in health service laboratories, probably due to the steady improvement observed. However, in terms of clinical governance, there is still some way to go, as shown by the presence of weaknesses in crucial dimensions of safety culture, together with variable levels of implementation of fail-safe technologies and quality management systems. Copyright © 2017 SECA. Publicado por Elsevier España, S.L.U. All rights reserved.

Third year nursing students' viewpoints about circumstances which threaten safety in the clinical setting.

PubMed

Montgomery, Phyllis; Killam, Laura; Mossey, Sharolyn; Heerschap, Corey

2014-02-01

Evidence emphasizes that learners, educators, clinicians, programs, and organizations share the responsibility for establishing and maintaining safety throughout undergraduate nursing education. Increased knowledge about students' perceptions of threats to safety in the clinical setting may guide educators' efforts to promote the development of safe novice practitioners while preserving patient safety. The purpose of this study was to describe third year nursing students' viewpoints of the circumstances which threaten safety in the clinical setting. Using Q methodology, 34 third year Bachelor of Science in Nursing students sorted 43 theoretical statement cards. Each card identified a statement describing a threat to safety in the clinical setting. These statements were generated through a review of nursing literature and consultation with experts in nursing education. Centroid factor analysis and varimax rotation identified viewpoints regarding circumstances that most threaten safety. Three discrete viewpoints and one consensus perspective constituted students' description of threatened safety. The discrete viewpoints were labeled lack of readiness, misdirected practices, and negation of professional boundaries. There was consensus that it is most unsafe in the clinical setting when novices fail to consolidate an integrated cognitive, behavioral, and ethical identity. This unifying perspective was labeled non-integration. Third year nursing students and their educators are encouraged to be mindful of the need to ensure readiness prior to entry into the clinical setting. In the clinical setting, the learning of prepared students must be guided by competent educators. Finally, both students and their educators must respect professional boundaries to promote safety for students and patients. © 2013.

[A new method for safety monitoring of natural dietary supplements--quality profile].

PubMed

Wang, Juan; Wang, Li-Ping; Yang, Da-Jin; Chen, Bo

2008-07-01

A new method for safety monitoring of natural dietary supplements--quality profile was proposed. It would convert passive monitoring of synthetic drug to active, and guarantee the security of natural dietary supplements. Preliminary research on quality profile was completed by high performance liquid chromatography (HPLC) and mass spectrometry (MS). HPLC was employed to analyze chemical constituent profiles of natural dietary supplements. The separation was completed on C18 column with acetonitrile and water (0.05% H3PO4) as mobile phase, the detection wavelength was 223 nm. Based on HPLC, stability of quality profile had been studied, and abnormal compounds in quality profile had been analyzed after addition of phenolphthalein, sibutramine, rosiglitazone, glibenclamide and gliclazide. And by MS, detector worked with ESI +, capillary voltage: 3.5 kV, cone voltage: 30 V, extractor voltage: 4 V, RF lens voltage: 0.5 V, source temperature: 105 degrees C, desolvation temperature: 300 degrees C, desolvation gas flow rate: 260 L/h, cone gas flow rate: 50 L/h, full scan mass spectra: m/z 100-600. Abnormal compound in quality profile had been analyzed after addition of N-mono-desmethyl sibutramine. Quality profile based on HPLC had good stability (Similarity > 0.877). Addition of phenolphthalein, sibutramine, rosiglitazone, glibenclamide and gliclazide in natural dietary supplements could be reflected by HPLC, and addition of N-mono-desmethyl sibutramine in natural dietary supplements could be reflected by MS. Quality profile might monitor adulteration of natural dietary supplements, and prevent addition of synthetic drug after "approval".

Safety Profile of Biologic Drugs in the Therapy of Ulcerative Colitis: A Systematic Review and Network Meta-Analysis.

PubMed

Moćko, Paweł; Kawalec, Paweł; Pilc, Andrzej

2016-08-01

We compared the safety profile of biologic drugs in patients with moderately to severely active ulcerative colitis (UC). A systematic literature search was performed using Medline (PubMed), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases through February 9, 2016. We included randomized controlled trials (RCTs) that compared the safety of biologic drugs (infliximab, adalimumab, golimumab, and vedolizumab) with one another or with placebo in patients with UC. Two reviewers independently conducted the search and selection of studies and rated the risk of bias in each trial. The network meta-analysis (NMA) was conducted for an induction phase (6-8 weeks) and maintenance phase (52-54 weeks) with a Bayesian hierarchical random effects model in Aggregate Data Drug Information System (ADDIS) software. The PROSPERO registration number was CRD42016032607. Seven RCTs were included in the systematic review with NMA. In the case of the induction phase, the NMA could be conducted for the assessment of the relative safety profile of adalimumab, golimumab, and vedolizumab, and in the case of the maintenance phase of infliximab, adalimumab, golimumab, and vedolizumab. The methodological quality of the included RCTs was evaluated as low risk of bias, but high risk of bias in the case of attrition bias (incomplete outcome data) according to the Cochrane criteria. No significant differences were found in the rate of adverse events in patients treated with the reviewed biologics. Vedolizumab was most likely to have the most favorable safety profile in the induction phase as was infliximab for the maintenance phase. The assessment of the relative safety profile revealed no significant differences between the biologic drugs. Further studies are needed to confirm our findings including head-to-head comparisons between the analyzed biologics. © 2016 Pharmacotherapy Publications, Inc.

The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV- and CMV-seropositive patients

PubMed Central

Jung, Donald; AbdelHameed, Magdy H; Hunter, John; Teitelbaum, Philip; Dorr, Albert; Griffy, Kay

1999-01-01

Aims We investigated the pharmacokinetics and safety profile of oral ganciclovir coadministered with trimethoprim in HIV-and CMV-seropositive patients. Methods In an open-label, randomized, 3-way crossover study, 12 adult males received oral ganciclovir 1000 mg every 8h, oral trimethoprim 200 mg once daily, or both drugs concomitantly in a sequence of three 7-day treatment periods. Pharmacokinetic parameters were determined and adverse events recorded for each treatment. Results The presence of trimethoprim significantly decreased CLr (12.9%, P = 0.0068) and increased t1/2 (18.1%, P = 0.0378) of ganciclovir. However, these changes are unlikely to be clinically meaningful. There were no statistically significant changes in trimethoprim pharmacokinetic parameters in the presence of ganciclovir, with the exception of a 12.7% increase in Cmin. Ganciclovir was well tolerated when administered alone or in combination with trimethoprim. Conclusions There was no clinically significant pharmacokinetic interaction between oral ganciclovir and trimethoprim when coadministered. PMID:10215748

Clinical Trials of Precision Medicine through Molecular Profiling: Focus on Breast Cancer.

PubMed

Zardavas, Dimitrios; Piccart-Gebhart, Martine

2015-01-01

High-throughput technologies of molecular profiling in cancer, such as gene-expression profiling and next-generation sequencing, are expanding our knowledge of the molecular landscapes of several cancer types. This increasing knowledge coupled with the development of several molecularly targeted agents hold the promise for personalized cancer medicine to be fully realized. Moreover, an expanding armamentarium of targeted agents has been approved for the treatment of specific molecular cancer subgroups in different diagnoses. According to this paradigm, treatment selection should be dictated by the specific molecular aberrations found in each patient's tumor. The classical clinical trials paradigm of patients' eligibility being based on clinicopathologic parameters is being abandoned, with current clinical trials enrolling patients on the basis of specific molecular aberrations. New, innovative trial designs have been generated to better tackle the multiple challenges induced by the increasing molecular fragmentation of cancer, namely: (1) longitudinal cohort studies with or without downstream trials, (2) studies assessing the clinical utility of molecular profiling, (3) master or umbrella trials, (4) basket trials, (5) N-of-1 trials, and (6) adaptive design trials. This article provides an overview of the challenges for clinical trials in the era of molecular profiling of cancer. Subsequently, innovative trial designs with respective examples and their potential to expedite efficient clinical development of targeted anticancer agents is discussed.

Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis

PubMed Central

Cuffari, Carmen; Pierce, David; Korczowski, Bartosz; Fyderek, Krzysztof; Van Heusen, Heather; Hossack, Stuart; Wan, Hong; Edwards, Alena YZ; Martin, Patrick

2016-01-01

Background Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC). Aim To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC. Methods Participants (5–17 years of age; 18–82 kg, stratified by weight) with UC received multi-matrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model. Results Fifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%–45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified. Conclusion Children and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844. PMID:26893546

Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis.

PubMed

Cuffari, Carmen; Pierce, David; Korczowski, Bartosz; Fyderek, Krzysztof; Van Heusen, Heather; Hossack, Stuart; Wan, Hong; Edwards, Alena Y Z; Martin, Patrick

2016-01-01

Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC). To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC. Participants (5-17 years of age; 18-82 kg, stratified by weight) with UC received multi-matrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model. Fifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%-45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified. Children and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844.

Conducting Clinically Based Intimate Partner Violence Research: Safety Protocol Recommendations.

PubMed

Anderson, Jocelyn C; Glass, Nancy E; Campbell, Jacquelyn C

Maintaining safety is of utmost importance during research involving participants who have experienced intimate partner violence (IPV). Limited guidance on safety protocols to protect participants is available, particularly information related to technology-based approaches to informed consent, data collection, and contacting participants during the course of a study. The purpose of the article is to provide details on the safety protocol developed and utilized with women receiving care at an urban HIV clinic and who were taking part in an observational study of IPV, mental health symptoms, and substance abuse and their relationship to HIV treatment adherence. The protocol presents the technological strategies to promote safety and allow autonomy in participant decision-making throughout the research process, including Voice over Internet Protocol telephone numbers, and tablet-based eligibility screening and data collection. Protocols for management of participants at risk for suicide and/or intimate partner homicide that included automated high-risk messaging to participants and research staff and facilitated disclosure of risk to clinical staff based on participant preferences are discussed. Use of technology and partnership with clinic staff helped to provide an environment where research regarding IPV could be conducted without undue burden or risk to participants. Utilizing tablet-based survey administration provided multiple practical and safety benefits for participants. Most women who screened into high-risk categories for suicide or intimate partner homicide did not choose to have their results shared with their healthcare providers, indicating the importance of allowing participants control over information sharing whenever possible.

[Establish research model of post-marketing clinical safety evaluation for Chinese patent medicine].

PubMed

Zheng, Wen-ke; Liu, Zhi; Lei, Xiang; Tian, Ran; Zheng, Rui; Li, Nan; Ren, Jing-tian; Du, Xiao-xi; Shang, Hong-cai

2015-09-01

The safety of Chinese patent medicine has become a focus of social. It is necessary to carry out work on post-marketing clinical safety evaluation for Chinese patent medicine. However, there have no criterions to guide the related research, it is urgent to set up a model and method to guide the practice for related research. According to a series of clinical research, we put forward some views, which contained clear and definite the objective and content of clinical safety evaluation, the work flow should be determined, make a list of items for safety evaluation project, and put forward the three level classification of risk control. We set up a model of post-marketing clinical safety evaluation for Chinese patent medicine. Based this model, the list of items can be used for ranking medicine risks, and then take steps for different risks, aims to lower the app:ds:risksrisk level. At last, the medicine can be managed by five steps in sequence. The five steps are, collect risk signal, risk recognition, risk assessment, risk management, and aftereffect assessment. We hope to provide new ideas for the future research.

Clinical risk management and patient safety education for nurses: a critique.

PubMed

Johnstone, Megan-Jane; Kanitsaki, Olga

2007-04-01

Nurses have a pivotal role to play in clinical risk management (CRM) and promoting patient safety in health care domains. Accordingly, nurses need to be prepared educationally to manage clinical risk effectively when delivering patient care. Just what form the CRM and safety education of nurses should take, however, remains an open question. A recent search of the literature has revealed a surprising lack of evidence substantiating models of effective CRM and safety education for nurses. In this paper, a critical discussion is advanced on the question of CRM and safety education for nurses and the need for nurse education in this area to be reviewed and systematically researched as a strategic priority, nationally and internationally. It is a key contention of this paper that without 'good' safety education research it will not be possible to ensure that the educational programs that are being offered to nurses in this area are evidence-based and designed in a manner that will enable nurses to develop the capabilities they need to respond effectively to the multifaceted and complex demands that are inherent in their ethical and professional responsibilities to promote and protect patient safety and quality care in health care domains.

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies.

PubMed

Okamoto, Isamu; Schuette, Wolfgang H W; Stinchcombe, Thomas E; Rodrigues-Pereira, José; San Antonio, Belén; Chen, Jian; Liu, Jingyi; John, William J; Zinner, Ralph G

2017-05-01

This meta-analysis compared safety profiles (selected drug-related treatment-emergent adverse events [TEAEs]) of first-line pemetrexed plus carboplatin (PCb) area under the concentration-time curve 5 mg/min•mL (PCb5) or 6 mg/min•mL (PCb6), two widely used regimens in clinical practice for advanced non-squamous non-small cell lung cancer. All patients received pemetrexed 500 mg/m 2 every 21 days with either of two carboplatin doses for up to 4-6 cycles. Safety profiles of PCb doses were compared using three statistical analysis methods: frequency table analysis (FTA), generalized linear mixed effect model (GLMM), and the propensity score method. Efficacy outcomes of PCb5 and PCb6 regimens were summarized. A total of 486 patients mainly from the US, Europe, and East Asia were included in the analysis; 22% (n = 105) received PCb5 in one trial and 78% (n = 381) received PCb6 in four trials. The FTA comparison demonstrated that PCb5 vs PCb6 was associated with a statistically significantly lower incidence of TEAEs, including all-grade thrombocytopenia, anemia, fatigue, and vomiting, and grade 3/4 thrombocytopenia. In the GLMM analysis, PCb5 patients were numerically less likely to experience all-grade and grade 3/4 neutropenia, anemia, and thrombocytopenia. The propensity score regression analysis showed PCb5 group patients were significantly less likely than PCb6 group patients to experience all-grade hematologic TEAEs and grade 3/4 thrombocytopenia and anemia. After applying propensity score 1:1 matching, FTA analysis showed that the PCb5 group had significantly less all-grade and grade 3/4 hematologic toxicities. Overall efficacy outcomes, including overall survival, progression-free survival, and response rate, were similar between the two carboplatin doses. Acknowledging the limitations of this meta-analysis of five trials, heterogeneous in patient's characteristics and trial designs, the results show that the PCb5 regimen was generally associated

[Clinical assessment of drug safety].

PubMed

Imbs, J-L; Welsch, M

2007-09-01

The environment of drug safety is changing. In addition to the current system of pharmacovigilance based on spontaneous report of adverse events, clinical data observed in a given patient with a given symptom is taken into consideration and compared with information coming from pharmacovigilance data bases, which is then analyzed for causality by the experts of both the promotor and the public network. Such information is integrated into a risk management strategy, defined together by the French drug agency (Afssaps) and the marketing authorization holder. This strategy includes a pharmacovigilance plan and, if possible, a risk minimisation plan.

[The safety profile of escitalopram in pregnancy and breastfeeding].

PubMed

Bellantuono, Cesario; Orsolini, Laura; Bozzi, Francesca

2013-01-01

Escitalopram (ESC) is considered one of the most effective selective serotonin reuptake inhibitors (SSRI) for the treatment of major depression disorder. However, little is known on its potential risk of inducing major malformations (MM) and/or perinatal complications (PC). Aim of the present study is to provide a review of the available literature on the safety profile of ESC during pregnancy and breastfeeding and to compare data with the maternal and neonatal outcomes of 8 cases of the DEGRA Center. MEDLINE and PubMed databases were searched for English language articles by using the following keywords: "escitalopram", "selective serotonin reuptake inhibitors", "major malformations", "perinatal complications", "pregnancy", "breastfeeding". We also reported 8 cases of women treated with ESC during their pregnancy and breastfeeding at the Clinic of Affective Disorders in Pregnancy and Postpartum of the United Hospital of Ancona (DEGRA Center). Although some cases of MM have been reported in the literature after maternal exposure to ESC during early pregnancy, the rate of MM is substantially in the range of those reported in unexposed women. ESC exposure seems to be significantly associated with some PC such as lower rates of live births and higher rates of newborns with low birth weight. On the contrary, no short-term adverse effects in newborns were reported in the 5 studies evaluating the safety of ESC during breastfeeding. Data coming from DEGRA Center are consistent with the literature: all pregnancy were full term, all newborns were healthy and obtained normal APGAR score; no MM or miscarriage were reported. Only one case of mild withdrawal syndrome was reported in a newborn who was also exposed to benzodiazepines and paroxetine late in pregnancy. Two infants exposed to ESC also during the lactation did not reported any adverse effects at short-term. Data coming from published studies and from our cases seem to support the notion that ESC might be considered

A patient safety objective structured clinical examination.

PubMed

Singh, Ranjit; Singh, Ashok; Fish, Reva; McLean, Don; Anderson, Diana R; Singh, Gurdev

2009-06-01

There are international calls for improving education for health care workers around certain core competencies, of which patient safety and quality are integral and transcendent parts. Although relevant teaching programs have been developed, little is known about how best to assess their effectiveness. The objective of this work was to develop and implement an objective structured clinical examination (OSCE) to evaluate the impact of a patient safety curriculum. The curriculum was implemented in a family medicine residency program with 47 trainees. Two years after commencing the curriculum, a patient safety OSCE was developed and administered at this program and, for comparison purposes, to incoming residents at the same program and to residents at a neighboring residency program. All 47 residents exposed to the training, all 16 incoming residents, and 10 of 12 residents at the neighboring program participated in the OSCE. In a standardized patient case, error detection and error disclosure skills were better among trained residents. In a chart-based case, trained residents showed better performance in identifying deficiencies in care and described more appropriate means of addressing them. Third year residents exposed to a "Systems Approach" course performed better at system analysis and identifying system-based solutions after the course than before. Results suggest increased systems thinking and inculcation of a culture of safety among residents exposed to a patient safety curriculum. The main weaknesses of the study are its small size and suboptimal design. Much further investigation is needed into the effectiveness of patient safety curricula.

Safety Studies for Use of Adipose Tissue‐Derived Mesenchymal Stromal/Stem Cells in a Rabbit Model for Osteoarthritis to Support a Phase I Clinical Trial

PubMed Central

Riester, Scott M.; Denbeigh, Janet M.; Lin, Yang; Jones, Dakota L.; de Mooij, Tristan; Lewallen, Eric A.; Nie, Hai; Paradise, Christopher R.; Radel, Darcie J.; Dudakovic, Amel; Camilleri, Emily T.; Larson, Dirk R.; Qu, Wenchun; Krych, Aaron J.; Frick, Matthew A.; Im, Hee‐Jeong; Dietz, Allan B.; Smith, Jay

2016-01-01

Abstract Adipose‐derived mesenchymal stem cells (AMSCs) offer potential as a therapeutic option for clinical applications in musculoskeletal regenerative medicine because of their immunomodulatory functions and capacity for trilineage differentiation. In preparation for a phase I clinical trial using AMSCs to treat patients with osteoarthritis, we carried out preclinical studies to assess the safety of human AMSCs within the intra‐articular joint space. Culture‐expanded human AMSCs grown in human platelet‐lysate were delivered via intra‐articular injections into normal healthy rabbit knees and knees at risk for the development of osteoarthritis after bilateral medial anterior hemimeniscectomy. Treatment outcomes and safety were evaluated by assessing the general health, function, and behavior of the animals. Joint tissues were analyzed by x‐ray, magnetic resonance imaging, and histopathology. Intra‐articular AMSC therapy was well tolerated in this study. We did not observe adverse systemic reactions, nor did we find evidence of damage to intra‐articular joint tissues. Thus, the data generated in this study show a favorable safety profile for AMSCs within the joint space in support of a phase I clinical trial evaluating the clinical utility of AMSCs to treat osteoarthritis. Stem Cells Translational Medicine 2017;6:910–922 PMID:28297568

Safety and Side Effect Profile of Liposome Bupivacaine (Exparel) in Peripheral Nerve Blocks.

PubMed

Ilfeld, Brian M; Viscusi, Eugene R; Hadzic, Admir; Minkowitz, Harold S; Morren, Michael D; Lookabaugh, Janice; Joshi, Girish P

2015-01-01

Liposome bupivacaine (Exparel) is a multivesicular liposomal formulation of bupivacaine currently approved in the United States for single-dose administration into the surgical site to provide postsurgical analgesia. This retrospective analysis examined safety data from clinical trials involving the off-label use of this formulation in peripheral nerve blocks. Data from 6 controlled (phases I-III) studies were compiled involving single-injection ankle, femoral nerve, and intercostal nerve blocks (2 each). Adverse events (AEs) were monitored for 1 to 30 days after study drug administration. Of 575 subjects, 335 received liposome bupivacaine (2-310 mg), 33 received bupivacaine HCl (75-125 mg), and 207 received normal saline (placebo). Overall, 76% of subjects receiving liposome bupivacaine experienced 1 or more AEs compared with 61% receiving bupivacaine HCl and 76% receiving placebo. The most frequently reported AEs among subjects receiving liposome bupivacaine were nausea, pyrexia, pruritus, constipation, and vomiting. The most common treatment-related AE was hypesthesia among subjects treated with liposome bupivacaine or bupivacaine HCl. Incidence of nervous system AEs for liposome bupivacaine, bupivacaine HCl, and placebo was 21%, 27%, and 21%, respectively. Similarly, incidence of cardiac AEs was 9%, 0%, and 12%, respectively. At least 1 serious AE occurred in 8% of subjects receiving liposome bupivacaine compared with 10% of those receiving placebo (none assessed by investigators as related to study medication). Liposome bupivacaine has a similar safety and side effect profile to bupivacaine HCl and normal saline, suggesting that most of the more common AEs are related to either opioid rescue or the surgical procedure itself.

Clinical safety and professional liability claims in Ophthalmology.

PubMed

Dolz-Güerri, F; Gómez-Durán, E L; Martínez-Palmer, A; Castilla Céspedes, M; Arimany-Manso, J

2017-11-01

Patient safety is an international public health priority. Ophthalmology scientific societies and organisations have intensified their efforts in this field. As a tool to learn from errors, these efforts have been linked to the management of medical professional liability insurance through the analysis of claims. A review is performed on the improvements in patient safety, as well as professional liability issues in Ophthalmology. There is a high frequency of claims and risk of economic reparation of damage in the event of a claim in Ophthalmology. Special complaints, such as wrong surgery or lack of information, have a high risk of financial compensation and need strong efforts to prevent these potentially avoidable events. Studies focused on pathologies or specific procedures provide information of special interest to sub-specialists. The specialist in Ophthalmology, like any other doctor, is subject to the current legal provisions and appropriate mandatory training in the medical-legal aspects of health care is essential. Professionals must be aware of the fundamental aspects of medical professional liability, as well as specific aspects, such as defensive medicine and clinical safety. The understanding of these medical-legal aspects in the routine clinical practice can help to pave the way towards a satisfactory and safe professional career, and help in increasing patient safety. The aim of this review is to contribute to this training, for the benefit of professionals and patients. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

Measuring patient safety in a UK dental hospital: development of a dental clinical effectiveness dashboard.

PubMed

Pemberton, M N; Ashley, M P; Shaw, A; Dickson, S; Saksena, A

2014-10-01

Patient safety is an important marker of quality for any healthcare organisation. In 2008, the British Government white paper entitled High quality care for all, resulting from a review led by Lord Darzi, identified patient safety as a key component of quality and discussed how it might be measured, analysed and acted upon. National and local clinically curated metrics were suggested, which could be displayed via a 'clinical dashboard'. This paper explains the development of a clinical effectiveness dashboard focused on patient safety in an English dental hospital and how it has helped us identify relevant patient safety issues in secondary dental care.

ProFile Vortex and Vortex Blue Nickel-Titanium Rotary Instruments after Clinical Use.

PubMed

Shen, Ya; Zhou, Huimin; Coil, Jeffrey M; Aljazaeri, Bassim; Buttar, Rene; Wang, Zhejun; Zheng, Yu-feng; Haapasalo, Markus

2015-06-01

The aim of this study was to analyze the incidence and mode of ProFile Vortex and Vortex Blue instrument defects after clinical use in a graduate endodontic program and to examine the impact of clinical use on the instruments' metallurgical properties. A total of 330 ProFile Vortex and 1136 Vortex Blue instruments from the graduate program were collected after each had been used in 3 teeth. The incidence and type of instrument defects were analyzed. The lateral surfaces and fracture surfaces of the fractured files were examined by using scanning electron microscopy. Unused and used instruments were examined by full and partial differential scanning calorimetry. No fractures were observed in the 330 ProFile Vortex instruments, whereas 20 (6.1%) revealed bent or blunt defects. Only 2 of the 1136 Vortex Blue files fractured during clinical use. The cause of fracture was shear stress. The fractures occurred at the tip end of the spirals. Only 1.8% (21 of 1136) of the Vortex Blue files had blunt tips. Austenite-finish temperatures were very similar for unused and used ProFile Vortex files and were all greater than 50°C. The austenite-finish temperatures of used and unused Vortex Blue files (38.5°C) were lower than those in ProFile Vortex instruments (P < .001). However, the transformation behavior of Vortex Blue files had an obvious 2-stage transformation, martensite-to-R phase and R-to-austenite phase. The trends of differential scanning calorimetry plots of unused Vortex Blue instruments and clinically used instruments were very similar. The risk of ProFile Vortex and Vortex Blue instrument fracture is very low when instruments are discarded after clinical use in the graduate endodontic program. The Vortex Blue files have metallurgical behavior different from ProFile Vortex instruments. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

New geometric design consistency model based on operating speed profiles for road safety evaluation.

PubMed

Camacho-Torregrosa, Francisco J; Pérez-Zuriaga, Ana M; Campoy-Ungría, J Manuel; García-García, Alfredo

2013-12-01

To assist in the on-going effort to reduce road fatalities as much as possible, this paper presents a new methodology to evaluate road safety in both the design and redesign stages of two-lane rural highways. This methodology is based on the analysis of road geometric design consistency, a value which will be a surrogate measure of the safety level of the two-lane rural road segment. The consistency model presented in this paper is based on the consideration of continuous operating speed profiles. The models used for their construction were obtained by using an innovative GPS-data collection method that is based on continuous operating speed profiles recorded from individual drivers. This new methodology allowed the researchers to observe the actual behavior of drivers and to develop more accurate operating speed models than was previously possible with spot-speed data collection, thereby enabling a more accurate approximation to the real phenomenon and thus a better consistency measurement. Operating speed profiles were built for 33 Spanish two-lane rural road segments, and several consistency measurements based on the global and local operating speed were checked. The final consistency model takes into account not only the global dispersion of the operating speed, but also some indexes that consider both local speed decelerations and speeds over posted speeds as well. For the development of the consistency model, the crash frequency for each study site was considered, which allowed estimating the number of crashes on a road segment by means of the calculation of its geometric design consistency. Consequently, the presented consistency evaluation method is a promising innovative tool that can be used as a surrogate measure to estimate the safety of a road segment. Copyright © 2012 Elsevier Ltd. All rights reserved.

Gene expression profiling of immunomagnetically separated cells directly from stabilized whole blood for multicenter clinical trials

PubMed Central

2014-01-01

Background Clinically useful biomarkers for patient stratification and monitoring of disease progression and drug response are in big demand in drug development and for addressing potential safety concerns. Many diseases influence the frequency and phenotype of cells found in the peripheral blood and the transcriptome of blood cells. Changes in cell type composition influence whole blood gene expression analysis results and thus the discovery of true transcript level changes remains a challenge. We propose a robust and reproducible procedure, which includes whole transcriptome gene expression profiling of major subsets of immune cell cells directly sorted from whole blood. Methods Target cells were enriched using magnetic microbeads and an autoMACS® Pro Separator (Miltenyi Biotec). Flow cytometric analysis for purity was performed before and after magnetic cell sorting. Total RNA was hybridized on HGU133 Plus 2.0 expression microarrays (Affymetrix, USA). CEL files signal intensity values were condensed using RMA and a custom CDF file (EntrezGene-based). Results Positive selection by use of MACS® Technology coupled to transcriptomics was assessed for eight different peripheral blood cell types, CD14+ monocytes, CD3+, CD4+, or CD8+ T cells, CD15+ granulocytes, CD19+ B cells, CD56+ NK cells, and CD45+ pan leukocytes. RNA quality from enriched cells was above a RIN of eight. GeneChip analysis confirmed cell type specific transcriptome profiles. Storing whole blood collected in an EDTA Vacutainer® tube at 4°C followed by MACS does not activate sorted cells. Gene expression analysis supports cell enrichment measurements by MACS. Conclusions The proposed workflow generates reproducible cell-type specific transcriptome data which can be translated to clinical settings and used to identify clinically relevant gene expression biomarkers from whole blood samples. This procedure enables the integration of transcriptomics of relevant immune cell subsets sorted directly from

Safety profile and long-term engraftment of human CD31+ blood progenitors in bone tissue engineering.

PubMed

Zigdon-Giladi, Hadar; Elimelech, Rina; Michaeli-Geller, Gal; Rudich, Utai; Machtei, Eli E

2017-07-01

Endothelial progenitor cells (EPCs) participate in angiogenesis and induce favorable micro-environments for tissue regeneration. The efficacy of EPCs in regenerative medicine is extensively studied; however, their safety profile remains unknown. Therefore, our aims were to evaluate the safety profile of human peripheral blood-derived EPCs (hEPCs) and to assess the long-term efficacy of hEPCs in bone tissue engineering. hEPCs were isolated from peripheral blood, cultured and characterized. β tricalcium phosphate scaffold (βTCP, control) or 10 6 hEPCs loaded onto βTCP were transplanted in a nude rat calvaria model. New bone formation and blood vessel density were analyzed using histomorphometry and micro-computed tomography (CT). Safety of hEPCs using karyotype analysis, tumorigenecity and biodistribution to target organs was evaluated. On the cellular level, hEPCs retained their karyotype during cell expansion (seven passages). Five months following local hEPC transplantation, on the tissue and organ level, no inflammatory reaction or dysplastic change was evident at the transplanted site or in distant organs. Direct engraftment was evident as CD31 human antigens were detected lining vessel walls in the transplanted site. In distant organs human antigens were absent, negating biodistribution. Bone area fraction and bone height were doubled by hEPC transplantation without affecting mineral density and bone architecture. Additionally, local transplantation of hEPCs increased blood vessel density by nine-fold. Local transplantation of hEPCs showed a positive safety profile. Furthermore, enhanced angiogenesis and osteogenesis without mineral density change was found. These results bring us one step closer to first-in-human trials using hEPCs for bone regeneration. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

TEXTINFO: a tool for automatic determination of patient clinical profiles using text analysis.

PubMed Central

Borst, F.; Lyman, M.; Nhàn, N. T.; Tick, L. J.; Sager, N.; Scherrer, J. R.

1991-01-01

The clinical data contained in narrative patient documents is made available via grammatical and semantic processing. Retrievals from the resulting relational database tables are matched against a set of clinical descriptors to obtain clinical profiles of the patients in terms of the descriptors present in the documents. Discharge summaries of 57 Dept. of Digestive Surgery patients were processed in this manner. Factor analysis and discriminant analysis procedures were then applied, showing the profiles to be useful for diagnosis definitions (by establishing relations between diagnoses and clinical findings), for diagnosis assessment (by viewing the match between a definition and observed events recorded in a patient text), and potentially for outcome evaluation based on the classification abilities of clinical signs. PMID:1807679

Considerations for automated machine learning in clinical metabolic profiling: Altered homocysteine plasma concentration associated with metformin exposure.

PubMed

Orlenko, Alena; Moore, Jason H; Orzechowski, Patryk; Olson, Randal S; Cairns, Junmei; Caraballo, Pedro J; Weinshilboum, Richard M; Wang, Liewei; Breitenstein, Matthew K

2018-01-01

With the maturation of metabolomics science and proliferation of biobanks, clinical metabolic profiling is an increasingly opportunistic frontier for advancing translational clinical research. Automated Machine Learning (AutoML) approaches provide exciting opportunity to guide feature selection in agnostic metabolic profiling endeavors, where potentially thousands of independent data points must be evaluated. In previous research, AutoML using high-dimensional data of varying types has been demonstrably robust, outperforming traditional approaches. However, considerations for application in clinical metabolic profiling remain to be evaluated. Particularly, regarding the robustness of AutoML to identify and adjust for common clinical confounders. In this study, we present a focused case study regarding AutoML considerations for using the Tree-Based Optimization Tool (TPOT) in metabolic profiling of exposure to metformin in a biobank cohort. First, we propose a tandem rank-accuracy measure to guide agnostic feature selection and corresponding threshold determination in clinical metabolic profiling endeavors. Second, while AutoML, using default parameters, demonstrated potential to lack sensitivity to low-effect confounding clinical covariates, we demonstrated residual training and adjustment of metabolite features as an easily applicable approach to ensure AutoML adjustment for potential confounding characteristics. Finally, we present increased homocysteine with long-term exposure to metformin as a potentially novel, non-replicated metabolite association suggested by TPOT; an association not identified in parallel clinical metabolic profiling endeavors. While warranting independent replication, our tandem rank-accuracy measure suggests homocysteine to be the metabolite feature with largest effect, and corresponding priority for further translational clinical research. Residual training and adjustment for a potential confounding effect by BMI only slightly modified

Factors shaping effective utilization of health information technology in urban safety-net clinics.

PubMed

George, Sheba; Garth, Belinda; Fish, Allison; Baker, Richard

2013-09-01

Urban safety-net clinics are considered prime targets for the adoption of health information technology innovations; however, little is known about their utilization in such safety-net settings. Current scholarship provides limited guidance on the implementation of health information technology into safety-net settings as it typically assumes that adopting institutions have sufficient basic resources. This study addresses this gap by exploring the unique challenges urban resource-poor safety-net clinics must consider when adopting and utilizing health information technology. In-depth interviews (N = 15) were used with key stakeholders (clinic chief executive officers, medical directors, nursing directors, chief financial officers, and information technology directors) from staff at four clinics to explore (a) nonhealth information technology-related clinic needs, (b) how health information technology may provide solutions, and (c) perceptions of and experiences with health information technology. Participants identified several challenges, some of which appear amenable to health information technology solutions. Also identified were requirements for effective utilization of health information technology including physical infrastructural improvements, funding for equipment/training, creation of user groups to share health information technology knowledge/experiences, and specially tailored electronic billing guidelines. We found that despite the potential benefit that can be derived from health information technologies, the unplanned and uninformed introduction of these tools into these settings might actually create more problems than are solved. From these data, we were able to identify a set of factors that should be considered when integrating health information technology into the existing workflows of low-resourced urban safety-net clinics in order to maximize their utilization and enhance the quality of health care in such settings.

Quality Assurance of RNA Expression Profiling in Clinical Laboratories

PubMed Central

Tang, Weihua; Hu, Zhiyuan; Muallem, Hind; Gulley, Margaret L.

2012-01-01

RNA expression profiles are increasingly used to diagnose and classify disease, based on expression patterns of as many as several thousand RNAs. To ensure quality of expression profiling services in clinical settings, a standard operating procedure incorporates multiple quality indicators and controls, beginning with preanalytic specimen preparation and proceeding thorough analysis, interpretation, and reporting. Before testing, histopathological examination of each cellular specimen, along with optional cell enrichment procedures, ensures adequacy of the input tissue. Other tactics include endogenous controls to evaluate adequacy of RNA and exogenous or spiked controls to evaluate run- and patient-specific performance of the test system, respectively. Unique aspects of quality assurance for array-based tests include controls for the pertinent outcome signatures that often supersede controls for each individual analyte, built-in redundancy for critical analytes or biochemical pathways, and software-supported scrutiny of abundant data by a laboratory physician who interprets the findings in a manner facilitating appropriate medical intervention. Access to high-quality reagents, instruments, and software from commercial sources promotes standardization and adoption in clinical settings, once an assay is vetted in validation studies as being analytically sound and clinically useful. Careful attention to the well-honed principles of laboratory medicine, along with guidance from government and professional groups on strategies to preserve RNA and manage large data sets, promotes clinical-grade assay performance. PMID:22020152

Five-year safety and performance results from the Argus II Retinal Prosthesis System clinical trial

PubMed Central

da Cruz, Lyndon; Dorn, Jessy D.; Humayun, Mark S.; Dagnelie, Gislin; Handa, James; Barale, Pierre-Olivier; Sahel, José-Alain; Stanga, Paulo E.; Hafezi, Farhad; Safran, Avinoam B.; Salzmann, Joel; Santos, Arturo; Birch, David; Spencer, Rand; Cideciyan, Artur V.; de Juan, Eugene; Duncan, Jacque L.; Eliott, Dean; Fawzi, Amani; Olmos de Koo, Lisa C.; Ho, Allen C.; Brown, Gary; Haller, Julia; Regillo, Carl; Del Priore, Lucian V.; Arditi, Aries; Greenberg, Robert J.

2016-01-01

Purpose The Argus® II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) was developed to restore some vision to patients blind from retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception due to end-stage RP. Design The study is a prospective, multicenter, single-arm, clinical trial. Within-patient controls included the non-implanted fellow eye and patients' native residual vision compared to their vision when using the System. Subjects There were 30 subjects in 10 centers in the U.S. and Europe. Methods The worse-seeing eye of blind patients was implanted with the Argus II System. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. Main Outcome Measures The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by three computer-based, objective tests. Secondary measures included functional vision performance on objectively-scored real-world tasks. Results Twenty-four out of 30 patients remained implanted with functioning Argus II Systems at 5 years post-implant. Only one additional serious adverse event was experienced since the 3-year time point. Patients performed significantly better with the System ON than OFF on all visual function tests and functional vision tasks. Conclusions The five-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada. PMID:27453256

Five-Year Safety and Performance Results from the Argus II Retinal Prosthesis System Clinical Trial.

PubMed

da Cruz, Lyndon; Dorn, Jessy D; Humayun, Mark S; Dagnelie, Gislin; Handa, James; Barale, Pierre-Olivier; Sahel, José-Alain; Stanga, Paulo E; Hafezi, Farhad; Safran, Avinoam B; Salzmann, Joel; Santos, Arturo; Birch, David; Spencer, Rand; Cideciyan, Artur V; de Juan, Eugene; Duncan, Jacque L; Eliott, Dean; Fawzi, Amani; Olmos de Koo, Lisa C; Ho, Allen C; Brown, Gary; Haller, Julia; Regillo, Carl; Del Priore, Lucian V; Arditi, Aries; Greenberg, Robert J

2016-10-01

The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP. Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients' native residual vision compared with their vision with the Argus II. Thirty participants in 10 centers in the United States and Europe. The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Recent RF Experiments and Application of RF Waves to Real-Time Control of Safety Factor Profile in JT-60U

NASA Astrophysics Data System (ADS)

Suzuki, T.; Isayama, A.; Ide, S.; Fujita, T.; Oikawa, T.; Sakata, S.; Sueoka, M.; Hosoyama, H.; JT-60 Team

2005-09-01

Two topics of applications of RF waves to current profile control in JT-60U are presented; application of lower-hybrid (LH) waves to safety factor profile control and electron cyclotron (EC) waves to neo-classical tearing mode (NTM) control. A real-time control system of safety factor (q) profile was developed. This system, for the first time, enables 1) real time evaluation of q profile using local magnetic pitch angle measurement by motional Stark effect (MSE) diagnostic and 2) control of current drive (CD) location (ρCD) by controlling the parallel refractive index N∥ of LH waves through control of phase difference (Δφ) of LH waves between multi-junction launcher modules. The method for real-time q profile evaluation was newly developed, without time-consuming reconstruction of equilibrium, so that the method requires less computational time. Safety factor profile by the real-time calculation agrees well with that by equilibrium reconstruction with MSE. The control system controls ρCD through Δφ in such a way to decrease the largest residual between the real-time evaluated q profile q(r) and its reference profile qref(r). The real-time control system was applied to a positive shear plasma (q(0)˜1). The reference q profile was set to monotonic positive shear profile having qref(0)=1.3. The real-time q profile approached to the qref(r) during application of real-time control, and was sustained for 3s, which was limited by the duration of the injected LH power. Temporal evolution of current profile was consistent with relaxation of inductive electric field induced by theoretical LH driven current. An m/n=3/2 NTM that appeared at βN˜3 was completely stabilized by ECCD applied to a fully-developed NTM. Precise ECCD at NTM island was essential for the stabilization. ECCD that was applied to resonant rational surface (q=3/2) before an NTM onset suppressed appearance of NTM. In order to keep NTM intensity below a level, ECCD before the mode onset was more

2011 Annual Meeting of the Safety Pharmacology Society: an overview.

PubMed

Cavero, Icilio

2012-03-01

The keynote address of 2011 Annual Meeting of the Safety Pharmacology Society examined the known and the still to be known on drug-induced nephrotoxicity. The nominee of the Distinguished Service Award Lecture gave an account of his career achievements particularly on the domain of chronically instrumented animals for assessing cardiovascular safety. The value of Safety Pharmacology resides in the benefits delivered to Pharma organizations, regulators, payers and patients. Meticulous due diligence concerning compliance of Safety Pharmacology studies to best practices is an effective means to ensure that equally stringent safety criteria are applied to both in-licensed and in-house compounds. Innovative technologies of great potential for Safety Pharmacology presented at the meeting are organs on chips (lung, heart, intestine) displaying mechanical and biochemical features of native organs, electrical field potential (MEA) or impedance (xCELLigence Cardio) measurements in human induced pluripotent stem cell-derived cardiomyocytes for unveiling cardiac electrophysiological and mechanical liabilities, functional human airway epithelium (MucilAir™) preparations with unique 1-year shelf-life for acute and chronic in vitro evaluation of drug efficacy and toxicity. Custom-designed in silico and in vitro assay platforms defining the receptorome space occupied by chemical entities facilitate, throughout the drug discovery phase, the selection of candidates with optimized safety profile on organ function. These approaches can now be complemented by advanced computational analysis allowing the identification of compounds with receptorome, or clinically adverse effect profiles, similar to those of the drug candidate under scrutiny for extending the safety assessment to potential liability targets not captured by classical approaches. Nonclinical data supporting safety can be quite reassuring for drugs with a discovered signal of risk. However, for marketing authorization

Plasma metabolic profiling of dairy cows affected with clinical ketosis using LC/MS technology.

PubMed

Li, Y; Xu, C; Xia, C; Zhang, Hy; Sun, Lw; Gao, Y

2014-01-01

Ketosis in dairy cattle is an important metabolic disorder. Currently, the plasma metabolic profile of ketosis as determined using liquid chromatography-mass spectrometry (LC/MS) has not been reported. To investigate plasma metabolic profiles from cows with clinical ketosis in comparison to control cows. Twenty Holstein dairy cows were divided into two groups based on clinical signs and plasma β-hydroxybutyric acid and glucose concentrations 7-21 days postpartum: clinical ketosis and control cows. Plasma metabolic profiles were analyzed using LC/MS. Data were processed using principal component analysis and orthogonal partial least-squares discriminant analysis. Compared to control cows, the levels of valine, glycine, glycocholic, tetradecenoic acid, and palmitoleic acid increased significantly in clinical ketosis. On the other hand, the levels of arginine, aminobutyric acid, leucine/isoleucine, tryptophan, creatinine, lysine, norcotinine, and undecanoic acid decreased markedly. Our results showed that the metabolic changes in cows with clinical ketosis involve complex metabolic networks and signal transduction. These results are important for future studies elucidating the pathogenesis, diagnosis, and prevention of clinical ketosis in dairy cows.

Ragweed sublingual tablet immunotherapy: part I - evidence-based clinical efficacy and safety.

PubMed

Creticos, Peter Socrates; Pfaar, Oliver

2018-06-01

Sublingual tablet immunotherapy provides an attractive alternative approach to allergen immunotherapy, as the allergen is administered as a rapidly dissolving sublingual tablet. Part I of this two-part series on the ragweed sublingual tablet describes the dose-ranging clinical work, the safety studies and the clinical outcomes from the pivotal trials which provide clear evidence for statistically significant and clinically meaningful benefit in the treatment of patients suffering from ragweed-induced seasonal allergic rhinitis-conjunctivitis with or without milder asthma. The robust results observed in the clinical trials performed with the ragweed sublingual tablet are defined by the quality of their study design, their use of a standardized allergen extract, their consistent reproducibility in demonstrating therapeutic efficacy and their properly quantified and graded safety data.

SHORT-TERM SAFETY PROFILE OF INTRAVITREAL ZIV-AFLIBERCEPT.

PubMed

Chhablani, Jay; Narayanan, Raja; Mathai, Annie; Yogi, Rohit; Stewart, Michael

2016-06-01

To evaluate the safety of intravitreal ziv-aflibercept (Zaltrap) in the treatment choroidal neovascularization secondary to age-related macular degeneration. Eligible eyes with choroidal neovascularization secondary to age-related macular degeneration each received a single intravitreal injection of ziv-aflibercept. Comprehensive ophthalmic examinations and detailed systemic evaluations were performed at baseline and Days 1, 7, and 30 after injection, and International Society for Clinical Electrophysiology of Vision standard electroretinography was performed at baseline and Day 30. Primary outcome measures were safety parameters that included signs of clinical and electroretinographic toxicity. Secondary outcome measures included changes in best-corrected visual acuity and central subfield thickness. Twelve eyes of 12 patients were treated. None of the patients complained of blurred vision, ocular pain, or bulbar injection at any of the follow-up visits, nor was intraocular inflammation noted. There were no significant differences in implicit times, "a" and "b" wave amplitudes, or b/a ratios at 1 month when compared with baseline (P = 0.4). None of the patients experienced serious ocular or systemic adverse events. Mean best-corrected visual acuity improved only slightly at 30 days (LogMAR 0.45 ± 0.31 [Snellen equivalent: 20/60]) compared with baseline (LogMAR 0.37 ± 0.24 [Snellen equivalent: 20/50]; P = 0.51). Single intravitreal injections of ziv-aflibercept into eyes with neovascular age-related macular degeneration appear to be safe through 1 month. Ziv-aflibercept could become a safe, low-cost therapy for macular diseases in developing countries and in those where intravitreal aflibercept (Eylea) is not available.

Chemotherapy safety in clinical veterinary oncology.

PubMed

Klahn, Shawna

2014-09-01

Exposure to chemotherapy is a health hazard for all personnel in facilities that store, prepare, or administer antineoplastic agents. Contamination levels have been measured as much as 15 times higher in the veterinary medicine sector than in human facilities. Recent publications in human and veterinary medicine indicate that exposure extends beyond the clinic walls to affect the patient's home and family. This article provides an update on the advances in chemotherapy safety, the current issues, and the impact on cancer management in veterinary medicine. Copyright © 2014 Elsevier Inc. All rights reserved.

The safety and effectiveness profile of eldecalcitol in a prospective, post-marketing observational study in Japanese patients with osteoporosis: interim report.

PubMed

Saito, Hitoshi; Kakihata, Hiroyuki; Nishida, Yosuke; Yatomi, Sawako; Nihojima, Shigeru; Kobayashi, Yumiko; Tabata, Hidehiro; Nomura, Makoto

2017-07-01

This large-scale post-marketing surveillance study was conducted to assess the safety and effectiveness of eldecalcitol treatment in patients with osteoporosis in a Japanese clinical setting. A total of 3567 patients with osteoporosis were enrolled and received eldecalcitol 0.75 μg/day for 12 months. For this interim report, 3285 patients were eligible for analysis. Mean age was 74.9 ± 8.7 years; 86.8 % (2854/3285) were women. There were 142 reported adverse drug reactions (ADRs) in 129 patients (3.92 % of the total 3285 patients): the most common were hypercalcemia and increased blood calcium (0.88 %), renal impairment (0.27 %), abdominal discomfort (0.24 %), constipation (0.24 %), and pruritus (0.24 %). The incidence of ADRs was 5.10 % in men and 3.74 % in women. Although 10 serious ADRs were reported in 9 patients (0.27 %), no clinically significant safety issues were identified. Incidence of hypercalcemia or increased blood calcium was 8.47 % in patients with renal impairment and only 0.74 % in patients without renal impairment. At last observation, the incidence of new vertebral and nonvertebral fractures was 2.44 % and 1.70 %, respectively. There was a significant increase in bone mineral density at the lumbar spine and distal radius. The bone turnover markers BAP, serum NTX, urinary NTX, and TRACP-5b were suppressed by eldecalcitol treatment in both sexes. In conclusion, consistent with the findings of the phase III pivotal clinical trial, eldecalcitol was shown to have a favorable safety profile and effectiveness in Japanese patients with osteoporosis. However, periodic measurements of serum calcium were required to prevent occurrence of hypercalcemia during eldecalcitol treatment, especially in patients with renal impairment.

Clinical pharmacology profile of care in Hepatology clinic.

PubMed

Passos, Talita Rocha; Santos, Fabiana Silva; Martins, Maria Cleusa; Pinto, Vanusa Barbosa; Carrilho, Flair José; Ono, Suzane Kioko

2017-05-01

Since 2010, the Clinical Gastroenterology and Hepatology Division of the Central Institute of Hospital das Clínicas of the University of São Paulo Medical School (HC-FMUSP, in the Portuguese acronym) has been developing specialized electives assistance activities in the Outpatient Specialty Clinic, Secondary Level, in São Paulo NGA-63 Várzea do Carmo. The objective of this study was to analyze the pharmacotherapeutic profile of patients. This is a cross-sectional and retrospective study in which patients were seen at the Hepatology sector and the results were submitted to descriptive statistics. During the study period, 492 patients were treated at the clinic, with a mean age of 58.9 years and frequency of 61.2% female and 74.8% living in São Paulo. This population was served by various other medical specialties (cardiology and endocrine among others) and the major liver diagnoses were: chronic hepatitis B and C and fatty liver. Comorbidities were also identified, such as diabetes, hypertension and dyslipidemia. Most patients took their medication in the Basic Health Units. We found that 30% of patients use of more than five medications and the most prescribed were omeprazole 208 (42.3%), metformin 132 (26.8%) and losartan 80 (16.3%). Because it is an adult/elderly population, with several comorbidities and polymedication, it is important to be aware of the rational use of medication. The multidisciplinary team is important in applying correct conducts for the safe use of medicines, to reduce the burden on health spending and improving the quality of life of patients.

Nursing Diagnosis Risk for falls: prevalence and clinical profile of hospitalized patients1

PubMed Central

Luzia, Melissa de Freitas; Victor, Marco Antonio de Goes; Lucena, Amália de Fátima

2014-01-01

Objectives to identify the prevalence of the Nursing Diagnosis (ND) Risk for falls in the hospitalizations of adult patients in clinical and surgical units, to characterize the clinical profile and to identify the risk factors of the patients with this ND. Method a cross-sectional study with 174 patients. The data was collected from the computerized nursing care prescriptions system and on-line hospital records, and analyzed statistically. Results the prevalence of the ND Risk for falls was 4%. The patients' profile indicated older adults, males (57%), those hospitalized in the clinical units (63.2%), with a median length of hospitalization of 20 (10-24) days, with neurological illnesses (26%), cardio-vascular illnesses (74.1%) and various co-morbidities (3±1.8). The prevalent risk factors were neurological alterations (43.1%), impaired mobility (35.6%) and extremes of age (10.3%). Conclusion the findings contributed to evidencing the profile of the patients with a risk of falling hospitalized in clinical and surgical wards, which favors the planning of interventions for preventing this adverse event. PMID:26107834

Safety of Gadobutrol

PubMed Central

Endrikat, Jan; Vogtlaender, Kai; Dohanish, Susan; Balzer, Thomas; Breuer, Josy

2016-01-01

Objective The aim of this study was to provide a systematic safety analysis of gadobutrol after more than 29 million applications in clinical routine. Materials and Methods Forty-two clinical development phase II to IV studies on gadobutrol or comparator and the postmarketing safety surveillance database for gadobutrol (1998–2015) were analyzed. Adverse events (AEs) and drug-related AEs were evaluated in the clinical development database and spontaneous adverse drug reactions (ADRs) in the postmarketing database. Subgroup analyses were run on patients with special medical history and on patients of different age groups. Results In the clinical development studies, 6809 and 2184 patients received gadobutrol or comparators, respectively. The incidence of drug-related AEs was 3.5% for both groups. With the exception of nausea (0.7% related cases in both groups), all other drug-related AEs were 0.3% or less in both groups. Hypersensitivity reactions were sporadic (<0.1%). Patients with history of allergies to contrast agents experienced slightly more drug-related AEs. No differences were seen between age groups. The overall reporting rate of ADRs from postmarketing surveillance was 0.05%. The most frequent ADRs were anaphylactoid/hypersensitivity reactions, nausea, vomiting, and dyspnea. For 3 single-agent reports of nephrogenic systemic fibrosis, using a conservative approach, association with gadobutrol could not be excluded. Conclusions Gadobutrol is well tolerated and has a favorable safety profile for patients of all age groups. PMID:26964075

Translating Patient Safety Research Into Clinical Practice

DTIC Science & Technology

2005-01-01

AIM approach is being used to evaluate a pharmacy alert intervention designed to detect and correct medication prescribing errors for all patients ...Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 Advances in Patient Safety: Vol. 2 164 patients .6, 9 Medication use in the ambulatory care...subjects and patients with chronic illnesses) and settings (e.g., schools, worksites, and medical clinics).32 We illustrate each of the RE-AIM dimensions

Clinical profile of subdural hematomas: dangerousness of subdural subacute hematoma.

PubMed

Kpelao, E; Beketi, K A; Moumouni, A K; Doleagbenou, A; Ntimon, B; Egbohou, P; Mouzou, T; Tomta, K; Sama, D H; Abalo, A; Walla, A; Dossim, A

2016-04-01

Subacute subdural hematomas are a poorly individualized nosological entity, often equated clinically to chronic subdural hematomas. Yet, their neurological deterioration which is usually rapid seems to distinguish them from chronic subdural hematomas. We wanted to show this dangerousness by establishing the clinically evolving profile of the three types of subdural hematomas. This was a prospective and retrospective study of 63 subdural hematoma (18 acute, 13 subacute, and 32 chronic) patients admitted between 2012 and 2014 in the neurosurgery unit of Lomé University Hospital. Hematomas were classified according to the elapsed time after head injury and blood density on CT. The main parameter studied was the evolution of the Glasgow Coma Score (GCS) in the 3 months following the trauma, enabling to establish an evolving profile of each type of hematoma. The average age of patients was 58.1 years for chronic subdural hematomas and 47.6 years for subacute subdural hematomas. Disease duration before admission was 13.1 days for chronic against 36.6 h for subacute hematoma. The clinical profile shows acute worsening within hours during the second week for patients with subacute hematoma, while it is progressive for patients with chronic hematoma. We noted two deaths, all victims of a subacute hematoma (one operated, one patient waiting for surgery). Iso-density hematoma on CT, especially in a young person, must be considered as a predictive factor of rapid neurological aggravation suggesting an urgent care or increased monitoring by paramedics.

Safety evaluation of trelagliptin in the treatment of Japanese type 2 diabetes mellitus patients.

PubMed

Kaku, Kohei

2017-11-01

Trelagliptin is a novel, long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM) in japan. The safety and efficacy of trelagliptin has been evaluated in three published clinical trials to date: one phase II and two phase III studies. As trelagliptin only requires dosing once per week, this new agent has the potential to improve compliance and subsequently, glycaemic control, in patients with T2DM. Areas covered: This article reviews the available safety data for trelagliptin from published clinical trials, and evaluates the published safety profile relative to competitor once-daily and once-weekly DPP-4 inhibitors. Expert opinion: Clinical trial data to date suggest that trelagliptin is a safe and efficacious medication with a similar safety profile to once-daily DPP-4 inhibitors, and to the once-weekly DPP-4 inhibitor, omarigliptin. Trelagliptin is well tolerated when given alone, and in combination with other anti-diabetic medications. An advantage of trelagliptin over existing once-daily DPP-4 inhibitors is the decrease of dosing frequency, rather than once-daily. No specific, serious adverse events have been reported for trelagliptin in published clinical trials, making it an attractive alternative to other DPP-4 inhibitors.

Physicians' Perceptions of Volunteer Service at Safety-Net Clinics.

PubMed

Mcgeehan, Laura; Takehara, Michael A; Daroszewski, Ellen

2017-01-01

Volunteer physicians are crucial for the operation of safety-net clinics, which provide medical care for uninsured and underinsured populations. Thus, identifying ways to maximize the number of physicians volunteering at such clinics is an important goal. To investigate the perceptions, motivations, functions, and barriers associated with physician volunteering in four safety-net clinics in San Bernardino County, Southern California, a location of great medical need with many barriers to care. The study participants are physicians belonging to the Southern California Permanente Medical Group who use a combination of discretionary time (during regular work hours) and personal time in evening and weekend hours to volunteer their services. The experimental design incorporates a mixed methodology: an online survey of 31 physicians and follow-up interviews with 8 of them. Physicians conveyed uniformly positive perceptions of their volunteer service, and most were motivated by humanitarian or prosocial desires. Volunteering also provided a protective "escape hatch" from the pressures of the physicians' regular jobs. Physicians cited few challenges to volunteering. The most common personal barrier was a lack of time. The most common professional barriers were organizational and supply issues at the clinic, along with the patients' social, transportation, and financial challenges. The results suggest that appealing to physicians' values and faith, and highlighting the burnout-prevention qualities of volunteering, may be key to recruitment and retention of volunteer physicians who serve underserved and underinsured populations in community clinics.

Physicians’ Perceptions of Volunteer Service at Safety-Net Clinics

PubMed Central

McGeehan, Laura; Takehara, Michael A; Daroszewski, Ellen

2017-01-01

Background: Volunteer physicians are crucial for the operation of safety-net clinics, which provide medical care for uninsured and underinsured populations. Thus, identifying ways to maximize the number of physicians volunteering at such clinics is an important goal. Objective: To investigate the perceptions, motivations, functions, and barriers associated with physician volunteering in four safety-net clinics in San Bernardino County, Southern California, a location of great medical need with many barriers to care. Methods: The study participants are physicians belonging to the Southern California Permanente Medical Group who use a combination of discretionary time (during regular work hours) and personal time in evening and weekend hours to volunteer their services. The experimental design incorporates a mixed methodology: an online survey of 31 physicians and follow-up interviews with 8 of them. Results: Physicians conveyed uniformly positive perceptions of their volunteer service, and most were motivated by humanitarian or prosocial desires. Volunteering also provided a protective “escape hatch” from the pressures of the physicians’ regular jobs. Physicians cited few challenges to volunteering. The most common personal barrier was a lack of time. The most common professional barriers were organizational and supply issues at the clinic, along with the patients’ social, transportation, and financial challenges. Conclusion: The results suggest that appealing to physicians’ values and faith, and highlighting the burnout-prevention qualities of volunteering, may be key to recruitment and retention of volunteer physicians who serve underserved and underinsured populations in community clinics. PMID:28241907

Safety of 13-valent pneumococcal conjugate vaccine in infants and children: meta-analysis of 13 clinical trials in 9 countries.

PubMed

Thompson, Allison; Gurtman, Alejandra; Patterson, Scott; Juergens, Christine; Laudat, France; Emini, Emilio A; Gruber, William C; Scott, Daniel A

2013-10-25

Meta-analyses enable summarization and interpretation of data across clinical trials. When applied to safety data they allow for detection of rare events. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) was approved in multiple countries worldwide for routine immunization of infants and young children. This meta-analysis was conducted to identify potentially clinically important rare safety events associated with PCV13. To summarize the safety of PCV13 compared with 7-valent pneumococcal conjugate vaccine (PCV7) administered to infants and toddlers. A meta-analysis was performed of integrated safety data from 13 infant studies (PCV13 n=4729 and PCV7 n=2760) conducted in 9 North American, European, and Asian countries. Local reactions at the vaccine injection site and systemic events were collected for 4-7 days after each dose into electronic diaries. Adverse events (AEs) were collected after each vaccination. Overall, rates of local reactions after any dose of the infant series were similar between PCV13 and PCV7 groups: tenderness (46.7% vs 44.8%, respectively); swelling (28.5% vs 26.9%); and redness (36.4% vs 33.9%). After the toddler dose, tenderness was significantly higher among PCV7 subjects than PCV13 subjects (54.4% vs 48.8%; P=0.005). Frequencies of fever (≥38°C) were similar in both groups and mostly mild (≤39°C); incidence of moderate fever (>39°C to ≤40°C) with PCV13 was ≤2.8% after any infant dose and 5.0% after the toddler dose, compared with ≤2.6% and 7.3%, respectively, with PCV7. Fever >40°C was uncommon in both groups. Frequencies of decreased appetite, irritability, and sleep disturbances were similar in both groups. AEs were the types of conditions and symptoms expected in infants and children, and clinically significant differences between vaccine groups were not observed. PCV13 has a favorable safety profile similar to that of PCV7, a vaccine for which there is >10 years clinical experience. Copyright © 2013

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

PubMed

Bates, Katherine E; Vetter, Victoria L; Li, Jennifer S; Cummins, Susan; Aguel, Fernando; Almond, Christopher; Dubin, Anne M; Elia, Josephine; Finkle, John; Hausner, Elizabeth A; Joseph, Francesca; Karkowsky, Abraham M; Killeen, Matthew; Lemacks, Jodi; Mathis, Lisa; McMahon, Ann W; Pinnow, Ellen; Rodriguez, Ignacio; Stockbridge, Norman L; Stockwell, Margaret; Tassinari, Melissa; Krucoff, Mitchell W

2012-10-01

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive

Review of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic.

PubMed

Stollenwerk, Ariane; Sohns, Melanie; Heisig, Fabian; Elling, Christian; von Zabern, Detlef

2018-01-01

Tapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009. This is the first integrated descriptive analysis of post-marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials. The first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses. More than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population. Grünenthal GmbH.

Clinical studies of the effectiveness and safety of antivenoms.

PubMed

Williams, David J; Habib, Abdulrazaq G; Warrell, David A

2018-05-07

In the 1890s, hyperimmune sera proved effective in animals against challenge by the snake venom against which they had been raised. They were first used, apparently successfully, in a human patient in about 1895. Since then, antivenoms have become accepted as the only reliable specific treatment for snake-bite envenoming. Despite decades of accumulated clinical experience and a number of published randomized comparative and observational studies, the clinical effectiveness and safety of some antivenoms remain open to question, due to a lack of robust randomized controlled trial data. Antivenoms in some poorly regulated markets may have high rates of potentially fatal adverse effects and their use must be balanced by demonstrable effectiveness. Even those manufactured to strict regulatory requirements may pose a rare risk of severe adverse reactions. Most antivenoms currently marketed around the world were registered without first being studied clinically. There is increasing pressure to subject antivenoms, even those that are long-established, to the same protocols of rigorous pre-clinical and clinical assessment that are standard regulatory requirements for other drugs. Conventional clinical testing progresses through Phases I, II, III to IV. Most authorities consider antivenoms too dangerous to be used in Phase I studies in healthy volunteers. An alternative method for preliminary estimation of safety, dose-finding and effectiveness, is proposed - the "3 + 3" dose escalation or de-escalation design, in volunteer patients, as used in oncology to test cytotoxic drugs. Antivenoms are so widely used and well trusted, that there are few ethical justifications for placebo controls. However, placebo might be ethically justified if there were no proven effective treatment and or if withholding or delaying treatment posed acceptably negligible risks to the participants. Antivenom trials are most urgently needed in low-to middle-income countries where there are many

Safety of vedolizumab in the treatment of Crohn's disease and ulcerative colitis.

PubMed

Hagan, Matilda; Cross, Raymond K

2015-01-01

Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials. This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug. Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile.

Patient safety culture in Norwegian primary care: a study in out-of-hours casualty clinics and GP practices.

PubMed

Bondevik, Gunnar Tschudi; Hofoss, Dag; Hansen, Elisabeth Holm; Deilkås, Ellen Catharina Tveter

2014-09-01

This study aimed to investigate patient safety attitudes amongst health care providers in Norwegian primary care by using the Safety Attitudes Questionnaire, in both out-of-hours (OOH) casualty clinics and GP practices. The questionnaire identifies five major patient safety factors: Teamwork climate, Safety climate, Job satisfaction, Perceptions of management, and Working conditions. Cross-sectional study. Statistical analysis included multiple linear regression and independent samples t-tests. Seven OOH casualty clinics and 17 GP practices in Norway. In October and November 2012, 510 primary health care providers working in OOH casualty clinics and GP practices (316 doctors and 194 nurses) were invited to participate anonymously. To study whether patterns in patient safety attitudes were related to professional background, gender, age, and clinical setting. The overall response rate was 52%; 72% of the nurses and 39% of the doctors answered the questionnaire. In the OOH clinics, nurses scored significantly higher than doctors on Safety climate and Job satisfaction. Older health care providers scored significantly higher than younger on Safety climate and Working conditions. In GP practices, male health professionals scored significantly higher than female on Teamwork climate, Safety climate, Perceptions of management and Working conditions. Health care providers in GP practices had significant higher mean scores on the factors Safety climate and Working conditions, compared with those working in the OOH clinics. Our study showed that nurses scored higher than doctors, older health professionals scored higher than younger, male GPs scored higher than female GPs, and health professionals in GP practices scored higher than those in OOH clinics - on several patient safety factors.

Safety and efficacy of gadoteric acid in pediatric magnetic resonance imaging: overview of clinical trials and post-marketing studies.

PubMed

Balassy, Csilla; Roberts, Donna; Miller, Stephen F

2015-11-01

Gadoteric acid is a paramagnetic gadolinium macrocyclic contrast agent approved for use in MRI of cerebral and spinal lesions and for body imaging. To investigate the safety and efficacy of gadoteric acid in children by extensively reviewing clinical and post-marketing observational studies. Data were collected from 3,810 children (ages 3 days to 17 years) investigated in seven clinical trials of central nervous system (CNS) imaging (n = 141) and six post-marketing observational studies of CNS, musculoskeletal and whole-body MR imaging (n = 3,669). Of these, 3,569 children were 2-17 years of age and 241 were younger than 2 years. Gadoteric acid was generally administered at a dose of 0.1 mmol/kg. We evaluated image quality, lesion detection and border delineation, and the safety of gadoteric acid. We also reviewed post-marketing pharmacovigilance experience. Consistent with findings in adults, gadoteric acid was effective in children for improving image quality compared with T1-W unenhanced sequences, providing diagnostic improvement, and often influencing the therapeutic approach, resulting in treatment modifications. In studies assessing neurological tumors, gadoteric acid improved border delineation, internal morphology and contrast enhancement compared to unenhanced MR imaging. Gadoteric acid has a well-established safety profile. Among all studies, a total of 10 children experienced 20 adverse events, 7 of which were thought to be related to gadoteric acid. No serious adverse events were reported in any study. Post-marketing pharmacovigilance experience did not find any specific safety concern. Gadoteric acid was associated with improved lesion detection and delineation and is an effective and well-tolerated contrast agent for use in children.

Understanding the positive benefit:risk profile of alemtuzumab in relapsing multiple sclerosis: perspectives from the Alemtuzumab Clinical Development Program.

PubMed

Havrdova, Eva; Cohen, Jeffrey A; Horakova, Dana; Kovarova, Ivana; Meluzinova, Eva

2017-01-01

The introduction of high-efficacy therapies for relapsing-remitting multiple sclerosis has driven re-evaluation of treatment goals and benefit:risk considerations in treatment choice. In the alemtuzumab Phase II and III clinical trials, patients treated with alemtuzumab 12 mg versus subcutaneous interferon beta-1a demonstrated significantly reduced annualized relapse rates and improved magnetic resonance imaging outcomes, and were significantly more likely to achieve no evidence of disease activity and reduction in brain volume loss. In two of the studies, alemtuzumab-treated patients had a significantly reduced risk of 6-month confirmed disease worsening, compared with subcutaneous interferon beta-1a. Benefits were maintained throughout 5 years, with a majority of patients receiving no alemtuzumab retreatment or other disease-modifying therapy. Trial results support alemtuzumab's manageable, consistent safety profile in relapsing-remitting multiple sclerosis. Infusion-associated reactions, the most frequent adverse events (AEs), can be minimized by corticosteroid pretreatment, monitoring, and symptomatic management. Other AEs include infections and autoimmune events. Oral anti-herpes prophylaxis should be initiated on the first day of each alemtuzumab treatment course and continued according to local guidelines. Overall cancer risk was lower in the alemtuzumab clinical trials than in a reference population; however, continuing surveillance will determine if alemtuzumab may be associated with certain malignancies such as thyroid papillary carcinoma and melanoma, which are currently identified as potential risks. The post-approval risk management strategy includes a safety monitoring program. Autoimmune AEs (thyroid events, immune thrombocytopenia, nephropathies) can be detected in a timely manner with the monitoring program, which includes physician and patient education about the signs and symptoms, monthly renal and hematologic monitoring, and quarterly thyroid

Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

PubMed

Rubin, David T; Sandborn, William J; Bosworth, Brian; Zakko, Salam; Gordon, Glenn L; Sale, Mark E; Rolleri, Robert L; Golden, Pamela L; Barrett, Andrew C; Bortey, Enoch; Forbes, William P

2015-11-01

Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis. The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam. Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam. A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration. This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis.

Safety measurement and monitoring in healthcare: a framework to guide clinical teams and healthcare organisations in maintaining safety

PubMed Central

Vincent, Charles; Burnett, Susan; Carthey, Jane

2014-01-01

Patients, clinicians and managers all want to be reassured that their healthcare organisation is safe. But there is no consensus about what we mean when we ask whether a healthcare organisation is safe or how this is achieved. In the UK, the measurement of harm, so important in the evolution of patient safety, has been neglected in favour of incident reporting. The use of softer intelligence for monitoring and anticipation of problems receives little mention in official policy. The Francis Inquiry report into patient treatment at the Mid Staffordshire NHS Foundation Trust set out 29 recommendations on measurement, more than on any other topic, and set the measurement of safety an absolute priority for healthcare organisations. The Berwick review found that most healthcare organisations at present have very little capacity to analyse, monitor or learn from safety and quality information. This paper summarises the findings of a more extensive report and proposes a framework which can guide clinical teams and healthcare organisations in the measurement and monitoring of safety and in reviewing progress against safety objectives. The framework has been used so far to promote self-reflection at both board and clinical team level, to stimulate an organisational check or analysis in the gaps of information and to promote discussion of ‘what could we do differently’. PMID:24764136

Prediction of Driving Safety in Individuals with Homonymous Hemianopia and Quadrantanopia from Clinical Neuroimaging

PubMed Central

Vaphiades, Michael S.; Kline, Lanning B.; McGwin, Gerald; Owsley, Cynthia; Shah, Ritu; Wood, Joanne M.

2014-01-01

Background. This study aimed to determine whether it is possible to predict driving safety of individuals with homonymous hemianopia or quadrantanopia based upon a clinical review of neuroimages that are routinely available in clinical practice. Methods. Two experienced neuroophthalmologists viewed a summary report of the CT/MRI scans of 16 participants with homonymous hemianopic or quadrantanopic field defects which indicated the site and extent of the lesion and they made predictions regarding whether participants would be safe/unsafe to drive. Driving safety was independently defined at the time of the study using state-recorded motor vehicle crashes (all crashes and at-fault) for the previous 5 years and ratings of driving safety determined through a standardized on-road driving assessment by a certified driving rehabilitation specialist. Results. The ability to predict driving safety was highly variable regardless of the driving safety measure, ranging from 31% to 63% (kappa levels ranged from −0.29 to 0.04). The level of agreement between the neuroophthalmologists was only fair (kappa = 0.28). Conclusions. Clinical evaluation of summary reports of currently available neuroimages by neuroophthalmologists is not predictive of driving safety. Future research should be directed at identifying and/or developing alternative tests or strategies to better enable clinicians to make these predictions. PMID:24683493

Prediction of driving safety in individuals with homonymous hemianopia and quadrantanopia from clinical neuroimaging.

PubMed

Vaphiades, Michael S; Kline, Lanning B; McGwin, Gerald; Owsley, Cynthia; Shah, Ritu; Wood, Joanne M

2014-01-01

Background. This study aimed to determine whether it is possible to predict driving safety of individuals with homonymous hemianopia or quadrantanopia based upon a clinical review of neuroimages that are routinely available in clinical practice. Methods. Two experienced neuroophthalmologists viewed a summary report of the CT/MRI scans of 16 participants with homonymous hemianopic or quadrantanopic field defects which indicated the site and extent of the lesion and they made predictions regarding whether participants would be safe/unsafe to drive. Driving safety was independently defined at the time of the study using state-recorded motor vehicle crashes (all crashes and at-fault) for the previous 5 years and ratings of driving safety determined through a standardized on-road driving assessment by a certified driving rehabilitation specialist. Results. The ability to predict driving safety was highly variable regardless of the driving safety measure, ranging from 31% to 63% (kappa levels ranged from -0.29 to 0.04). The level of agreement between the neuroophthalmologists was only fair (kappa = 0.28). Conclusions. Clinical evaluation of summary reports of currently available neuroimages by neuroophthalmologists is not predictive of driving safety. Future research should be directed at identifying and/or developing alternative tests or strategies to better enable clinicians to make these predictions.

Evaluating the Clinical Learning Environment: Resident and Fellow Perceptions of Patient Safety Culture.

PubMed

Bump, Gregory M; Calabria, Jaclyn; Gosman, Gabriella; Eckart, Catherine; Metro, David G; Jasti, Harish; McCausland, Julie B; Itri, Jason N; Patel, Rita M; Buchert, Andrew

2015-03-01

The Accreditation Council for Graduate Medical Education has begun to evaluate teaching institutions' learning environments with Clinical Learning Environment Review visits, including trainee involvement in institutions' patient safety and quality improvement efforts. We sought to address the dearth of metrics that assess trainee patient safety perceptions of the clinical environment. Using the Hospital Survey on Patient Safety Culture (HSOPSC), we measured resident and fellow perceptions of patient safety culture in 50 graduate medical education programs at 10 hospitals within an integrated health system. As institution-specific physician scores were not available, resident and fellow scores on the HSOPSC were compared with national data from 29 162 practicing providers at 543 hospitals. Of the 1337 residents and fellows surveyed, 955 (71.4%) responded. Compared with national practicing providers, trainees had lower perceptions of patient safety culture in 6 of 12 domains, including teamwork within units, organizational learning, management support for patient safety, overall perceptions of patient safety, feedback and communication about error, and communication openness. Higher perceptions were observed for manager/supervisor actions promoting patient safety and for staffing. Perceptions equaled national norms in 4 domains. Perceptions of patient safety culture did not improve with advancing postgraduate year. Trainees in a large integrated health system have variable perceptions of patient safety culture, as compared with national norms for some practicing providers. Administration of the HSOPSC was feasible and acceptable to trainees, and may be used to track perceptions over time.

Evaluating the Clinical Learning Environment: Resident and Fellow Perceptions of Patient Safety Culture

PubMed Central

Bump, Gregory M.; Calabria, Jaclyn; Gosman, Gabriella; Eckart, Catherine; Metro, David G.; Jasti, Harish; McCausland, Julie B.; Itri, Jason N.; Patel, Rita M.; Buchert, Andrew

2015-01-01

Background The Accreditation Council for Graduate Medical Education has begun to evaluate teaching institutions' learning environments with Clinical Learning Environment Review visits, including trainee involvement in institutions' patient safety and quality improvement efforts. Objective We sought to address the dearth of metrics that assess trainee patient safety perceptions of the clinical environment. Methods Using the Hospital Survey on Patient Safety Culture (HSOPSC), we measured resident and fellow perceptions of patient safety culture in 50 graduate medical education programs at 10 hospitals within an integrated health system. As institution-specific physician scores were not available, resident and fellow scores on the HSOPSC were compared with national data from 29 162 practicing providers at 543 hospitals. Results Of the 1337 residents and fellows surveyed, 955 (71.4%) responded. Compared with national practicing providers, trainees had lower perceptions of patient safety culture in 6 of 12 domains, including teamwork within units, organizational learning, management support for patient safety, overall perceptions of patient safety, feedback and communication about error, and communication openness. Higher perceptions were observed for manager/supervisor actions promoting patient safety and for staffing. Perceptions equaled national norms in 4 domains. Perceptions of patient safety culture did not improve with advancing postgraduate year. Conclusions Trainees in a large integrated health system have variable perceptions of patient safety culture, as compared with national norms for some practicing providers. Administration of the HSOPSC was feasible and acceptable to trainees, and may be used to track perceptions over time. PMID:26217435

Integrating patient safety into the clinical microsystem

PubMed Central

Mohr, J; Batalden, P; Barach, P

2004-01-01

Healthcare institutions continue to face challenges in providing safe patient care in increasingly complex organisational and regulatory environments while striving to maintain financial viability. The clinical microsystem provides a conceptual and practical framework for approaching organisational learning and delivery of care. Tensions exist between the conceptual theory and the daily practical applications of providing safe and effective care within healthcare systems. Healthcare organisations are often complex, disorganised, and opaque systems to their users and their patients. This disorganisation may lead to patient discomfort and harm as well as much waste. Healthcare organisations are in some sense conglomerates of smaller systems, not coherent monolithic organisations. The microsystem unit allows organisational leaders to embed quality and safety into a microsystem's developmental journey. Leaders can set the stage for making safety a priority for the organisation while allowing individual microsystems to create innovative strategies for improvement. PMID:15576690

Safety profile of biologic drugs in the therapy of Crohn disease: A systematic review and network meta-analysis.

PubMed

Moćko, Paweł; Kawalec, Paweł; Pilc, Andrzej

2016-12-01

Crohn disease (CD) is an inflammatory bowel disease which occurs especially in developed countries of Western Europe and North America. The aim of the study was to compare the safety profile of biologic drugs in patients with CD. A systematic literature search was performed using PubMed, Embase, and CENTRAL databases, until April 27, 2016. We included randomized controlled trials (RCTs) that compared the safety of biologic drugs (infliximab, adalimumab, vedolizumab, certolizumab pegol, and ustekinumab) with one another or with placebo in patients with CD. The network meta-analysis (NMA) was conducted for an induction phase (6-10 weeks) and maintenance phase (52-56 weeks) with a Bayesian hierarchical random effects model in the ADDIS ® software. The PROSPERO registration number was CRD42016032606. Ten RCTs were included in the systematic review with NMA. In the case of the induction phase, the NMA could be conducted for the assessment of the relative safety profile of adalimumab, vedolizumab, certolizumab pegol, and ustekinumab, and in the case of the maintenance phase-of infliximab, adalimumab, and vedolizumab. There were no significant differences in the rate of adverse events in patients treated with biologics. Statistical analysis revealed that vedolizumab had the greatest probability of being the safest treatment in most endpoints in the induction phase and adalimumab-in the maintenance phase. No significant differences between the biologics in the relative safety profile analysis were observed. Further studies are needed to confirm our findings, including head-to-head comparisons between the analyzed biologics. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

[Comparison of perinatal clinical profiles in newborns of adolescent and non-adolescent mothers].

PubMed

Barrera-de León, Juan Carlos; Higareda-Almaraz, Martha Alicia; Barajas-Serrano, Tanya Lizbeth; Villalvazo-Alfaro, Mónica; González-Bernal, Cesáreo

2014-12-01

Objective. To compare the clinical profiles in newborns of adolescent and non-adolescent mothers. Materials and Methods. Comparative cross-sectional study. Newborns selected by cluster sampling registered in the hospital. Two groups were formed according to the mother's age: adolescent and non-adolescent. The clinical profile was evaluated with: weight, length, Apgar score, gestational age, and presence of neonatal pathology. For the comparison between proportions, we used chi-squared test and student´s t-test between the mean. Results. Of the 2,155 clinical profiles of newborns analyzed, 819 (38%) were newborns of adolescent mothers and 1,336 (62%) of non-adolescent mothers. Differences between birth weight groups 2,859 ± 459 vs. 3,265 ± 486 grams (p = 0.000), male gender 518 (63%) vs. 725 (54%) female (p = 0.000); intrauterine growth restriction in full-term newborns 62 (7.5%) vs. 66 (4.9%) (p = 0.012); prematurity 171 (21%) vs. 213 (16%) (p = 0.003). Factors that favor the alteration of clinical profiles in newborns: adolescent mother OR: 1.58 (1.99-2.99), male gender OR: 1.80 (1.50-2.17), neonatal pathology OR: 3.73 (2.50-5.30), association of low birth weight in newborns of adolescent mothers OR: 2.4 (1.72-3.42). Conclusion. We found a high frequency of observing in newborns of adolescent mothers greater risk of prematurity, intrauterine growth restriction, and neonatal pathology. No differences were seen in length and Apgar score.

From the school of nursing quality and safety officer: nursing students' use of safety reporting tools and their perception of safety issues in clinical settings.

PubMed

Cooper, Elizabeth

2013-01-01

Improved patient safety and quality are priority goals for nurses and schools of nursing. This article describes the innovative new role of quality and safety officer (QSO) developed by one university in response to the Quality and Safety Education for Nurses challenge to increase quality and safety education for prelicensure nursing students. The article also describes the results of a study conducted by the QSO, obtaining information from prelicensure nursing students about the use of safety tools and identifying the students' perceptions of safety issues, communication, and safety reporting in the clinical setting. Responses of 145 prelicensure nursing students suggest that it is difficult to get all errors and near-miss events reported. Barriers for nursing students are similar to the barriers nurses and physicians identify in reporting errors and near-miss events. The survey reveals that safety for the patient is the primary concern of the student nurse. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluation of features to support safety and quality in general practice clinical software

PubMed Central

2011-01-01

Background Electronic prescribing is now the norm in many countries. We wished to find out if clinical software systems used by general practitioners in Australia include features (functional capabilities and other characteristics) that facilitate improved patient safety and care, with a focus on quality use of medicines. Methods Seven clinical software systems used in general practice were evaluated. Fifty software features that were previously rated as likely to have a high impact on safety and/or quality of care in general practice were tested and are reported here. Results The range of results for the implementation of 50 features across the 7 clinical software systems was as follows: 17-31 features (34-62%) were fully implemented, 9-13 (18-26%) partially implemented, and 9-20 (18-40%) not implemented. Key findings included: Access to evidence based drug and therapeutic information was limited. Decision support for prescribing was available but varied markedly between systems. During prescribing there was potential for medicine mis-selection in some systems, and linking a medicine with its indication was optional. The definition of 'current medicines' versus 'past medicines' was not always clear. There were limited resources for patients, and some medicines lists for patients were suboptimal. Results were provided to the software vendors, who were keen to improve their systems. Conclusions The clinical systems tested lack some of the features expected to support patient safety and quality of care. Standards and certification for clinical software would ensure that safety features are present and that there is a minimum level of clinical functionality that clinicians could expect to find in any system.

Monitoring product safety in the postmarketing environment.

PubMed

Sharrar, Robert G; Dieck, Gretchen S

2013-10-01

The safety profile of a medicinal product may change in the postmarketing environment. Safety issues not identified in clinical development may be seen and need to be evaluated. Methods of evaluating spontaneous adverse experience reports and identifying new safety risks include a review of individual reports, a review of a frequency distribution of a list of the adverse experiences, the development and analysis of a case series, and various ways of examining the database for signals of disproportionality, which may suggest a possible association. Regulatory agencies monitor product safety through a variety of mechanisms including signal detection of the adverse experience safety reports in databases and by requiring and monitoring risk management plans, periodic safety update reports and postauthorization safety studies. The United States Food and Drug Administration is working with public, academic and private entities to develop methods for using large electronic databases to actively monitor product safety. Important identified risks will have to be evaluated through observational studies and registries.

Safety profile comparison between extemporaneous and a licensed preparation of caffeine citrate in preterm infants with apnea of prematurity.

PubMed

Vatlach, Scarlet; Arand, Joerg; Engel, Corinna; Poets, Christian F

2014-01-01

Given the lack of a licensed product (LP), extemporaneous caffeine citrate (ECC) has been used by many hospital pharmacies. Since July 2011, an LP has been available in Germany. We prospectively compared the safety profile of ECC and LP in preterm infants with apnea of prematurity. Between April 2010 and April 2013, selected side effects occurring with ECC or LP were documented in 6 German NICUs for infants ≤34 weeks' gestation using a longitudinal study design. The software developed for daily prescriptions in NICU residents requires entries if any of the following symptoms occurred during the last 24 h: tachycardia (resting heart rate >200/min), clinical or encephalographic seizures, gastric residuals, vomiting, or necrotizing enterocolitis (NEC). ECC and LP were administered at identical doses (20 mg/kg/day loading, 5-10 mg/kg/day maintenance) and in similar formulations either orally or intravenously. 562 infants with 14,590 treatment days on ECC and 538 infants with 12,813 treatment days on LP were evaluated. The mean gestational age was similar (29.20 weeks for ECC vs. 29.14 weeks for LP). No relevant differences were seen concerning tachycardia, gastric residuals, or vomiting, but ECC was associated with a higher risk of NEC (risk ratio: 2.68, 95% CI: 1.01-7.23, p = 0.047) and, albeit not significantly so, seizures (risk ratio: 1.91, 95% CI: 0.53-6.96, p = 0.35). This survey demonstrates a similar safety profile for both forms of caffeine citrate. The lower NEC and seizure rate seen with the LP is intriguing, but requires confirmation in a controlled study design. © 2013 S. Karger AG, Basel.

[Validation of a questionnaire to evaluate patient safety in clinical laboratories].

PubMed

Giménez Marín, Ángeles; Rivas-Ruiz, Francisco

2012-01-01

The aim of this study was to prepare, pilot and validate a questionnaire to evaluate patient safety in the specific context of clinical laboratories. A specific questionnaire on patient safety in the laboratory, with 62 items grouped into six areas, was developed, taking into consideration the diverse human and laboratory contextual factors which may contribute to producing errors. A pilot study of 30 interviews was carried out, including validity and reliability analyses using principal components factor analysis and Cronbach's alpha. Subsequently, 240 questionnaires were sent to 21 hospitals, followed by a test-retest of 41 questionnaires with the definitive version. The sample analyzed was composed of 225 questionnaires (an overall response rate of 80%). Of the 62 items initially assessed, 17 were eliminated due to non-compliance with the criteria established before the principal components factor analysis was performed. For the 45 remaining items, 12 components were identified, with an cumulative variance of 69.5%. In seven of the 10 components with two or more items, Cronbach's alpha was higher than 0.7. The questionnaire items assessed in the test-retest were found to be stable. We present the first questionnaire with sufficiently proven validity and reliability for evaluating patient safety in the specific context of clinical laboratories. This questionnaire provides a useful instrument to perform a subsequent macrostudy of hospital clinical laboratories in Spain. The questionnaire can also be used to monitor and promote commitment to patient safety within the search for continuous quality improvement. Copyright © 2011 SESPAS. Published by Elsevier Espana. All rights reserved.

Evaluating predictive modeling's potential to improve teleretinal screening participation in urban safety net clinics.

PubMed

Ogunyemi, Omolola; Teklehaimanot, Senait; Patty, Lauren; Moran, Erin; George, Sheba

2013-01-01

Screening guidelines for diabetic patients recommend yearly eye examinations to detect diabetic retinopathy and other forms of diabetic eye disease. However, annual screening rates for retinopathy in US urban safety net settings remain low. Using data gathered from a study of teleretinal screening in six urban safety net clinics, we assessed whether predictive modeling could be of value in identifying patients at risk of developing retinopathy. We developed and examined the accuracy of two predictive modeling approaches for diabetic retinopathy in a sample of 513 diabetic individuals, using routinely available clinical variables from retrospective medical record reviews. Bayesian networks and radial basis function (neural) networks were learned using ten-fold cross-validation. The predictive models were modestly predictive with the best model having an AUC of 0.71. Using routinely available clinical variables to predict patients at risk of developing retinopathy and to target them for annual eye screenings may be of some usefulness to safety net clinics.

Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

PubMed

Stasyshyn, O; Djambas Khayat, C; Iosava, G; Ong, J; Abdul Karim, F; Fischer, K; Veldman, A; Blackman, N; St Ledger, K; Pabinger, I

2017-04-01

Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on-demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic

Do clinical safety charts improve paramedic key performance indicator results? (A clinical improvement programme evaluation).

PubMed

Ebbs, Phillip; Middleton, Paul M; Bonner, Ann; Loudfoot, Allan; Elliott, Peter

2012-07-01

Is the Clinical Safety Chart clinical improvement programme (CIP) effective at improving paramedic key performance indicator (KPI) results within the Ambulance Service of New South Wales? The CIP intervention area was compared with the non-intervention area in order to determine whether there was a statistically significant improvement in KPI results. The CIP was associated with a statistically significant improvement in paramedic KPI results within the intervention area. The strategies used within this CIP are recommended for further consideration.

Atorvastatin in clinically-significant macular edema in diabetics with a normal lipid profile.

PubMed

Narang, S; Sood, S; Kaur, B; Singh, R; Mallik, A; Kaur, J

2012-01-01

Lipid-lowering drugs preserve vision and reduce the risk of hard exudates in clinically-significant macular edema(CSME) in diabetics with an abnormal lipid profile. But their role in reducing CSME in diabetics with a normal lipid profile is not yet known. To evaluate the role of atorvastatin in CSME in diabetics with a normal lipid profile. A prospective, randomized clinical trial was carried out. Thirty CSME patients with a normal lipid profile were randomly divided into Group A and B. Atorvastatin had been started in Group A four weeks prior to laser treatment. The main outcome measures were any improvement or deterioration in visual acuity and macular edema and hard exudates at six months follow-up. Both the groups were compared using unpaired t test for quantitative parameters and chi-square test for qualitative parameters. A p value of less than 0.05 was taken as significant. Visual acuity, macular edema and hard exudates resolution was not significantly different in the two groups (P = 0.14, 0.62, 0.39 respectively). Atorvastatin does not affect treatment outcome in CSME with a normal lipid profile over a short term follow-up. © NEPjOPH.

Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia.

PubMed

Botzenhardt, Sebastian; Sing, Chor W; Wong, Ian C K; Chan, Godfrey Chi-Fung; Wong, Lisa Y L; Felisi, Mariagrazia; Rascher, Wolfgang; Ceci, Adriana; Neubert, Antje

2016-01-01

There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. • Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.

A systematic review of evidence on the links between patient experience and clinical safety and effectiveness

PubMed Central

Doyle, Cathal; Lennox, Laura; Bell, Derek

2013-01-01

Objective To explore evidence on the links between patient experience and clinical safety and effectiveness outcomes. Design Systematic review. Setting A wide range of settings within primary and secondary care including hospitals and primary care centres. Participants A wide range of demographic groups and age groups. Primary and secondary outcome measures A broad range of patient safety and clinical effectiveness outcomes including mortality, physical symptoms, length of stay and adherence to treatment. Results This study, summarising evidence from 55 studies, indicates consistent positive associations between patient experience, patient safety and clinical effectiveness for a wide range of disease areas, settings, outcome measures and study designs. It demonstrates positive associations between patient experience and self-rated and objectively measured health outcomes; adherence to recommended clinical practice and medication; preventive care (such as health-promoting behaviour, use of screening services and immunisation); and resource use (such as hospitalisation, length of stay and primary-care visits). There is some evidence of positive associations between patient experience and measures of the technical quality of care and adverse events. Overall, it was more common to find positive associations between patient experience and patient safety and clinical effectiveness than no associations. Conclusions The data presented display that patient experience is positively associated with clinical effectiveness and patient safety, and support the case for the inclusion of patient experience as one of the central pillars of quality in healthcare. It supports the argument that the three dimensions of quality should be looked at as a group and not in isolation. Clinicians should resist sidelining patient experience as too subjective or mood-oriented, divorced from the ‘real’ clinical work of measuring safety and effectiveness. PMID:23293244

Understanding of safety monitoring in clinical trials by individuals with CF or their parents: A qualitative analysis.

PubMed

Kern-Goldberger, Andrew S; Hessels, Amanda J; Saiman, Lisa; Quittell, Lynne M

2018-03-14

Recruiting both pediatric and adult participants for clinical trials in CF is currently of paramount importance as numerous new therapies are being developed. However, recruitment is challenging as parents of children with CF and adults with CF cite safety concerns as a principal barrier to enrollment. In conjunction with the CF Foundation (CFF) Data Safety Monitoring Board (DSMB), a pilot brochure was developed to inform patients and parents of the multiple levels of safety monitoring; the CFF simultaneously created an infographic representing the safety monitoring process. This study explores the attitudes and beliefs of CF patients and families regarding safety monitoring and clinical trial participation, and elicits feedback regarding the educational materials. Semi-structured interviews were conducted using a pre-tested interview guide and audio-recorded during routine CF clinic visits. Participants included 5 parents of children with CF <16years old; 5 adolescents and young adults with CF 16-21years old; and 5 adults with CF ≥22years old from pediatric and adult CF centers. The study team performed systematic text condensation analysis of the recorded interviews using an iterative process. Four major thematic categories with subthemes emerged as supported by exemplar quotations: attitudes toward clinical trials, safety values, conceptualizing the safety monitoring process, and priorities for delivery of patient education. Participant feedback was used to revise the pilot brochure; text was shortened, unfamiliar words clarified (e.g., "pipeline"), abbreviations eliminated, and redundancy avoided. Qualitative analysis of CF patient and family interviews provided insights into barriers to participation in clinical trials, safety concerns, perspectives on safety monitoring and educational priorities. We plan a multicenter study to determine if the revised brochure reduces knowledge, attitude and practice barriers regarding participation in CF clinical trials

Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials.

PubMed

Takeuchi, Tsutomu; Miyasaka, Nobuyuki; Kawai, Shinichi; Sugiyama, Naonobu; Yuasa, Hirotoshi; Yamashita, Noriaki; Sugiyama, Noriko; Wagerle, Lorin Craig; Vlahos, Bonnie; Wajdula, Joseph

2015-03-01

Abstract Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.

Associations of Streptococcus suis Serotype 2 Ribotype Profiles with Clinical Disease and Antimicrobial Resistance

PubMed Central

Rasmussen, S. R.; Aarestrup, F. M.; Jensen, N. E.; Jorsal, S. E.

1999-01-01

A total of 122 Streptococcus suis serotype 2 strains were characterized thoroughly by comparing clinical and pathological observations, ribotype profiles, and antimicrobial resistance. Twenty-one different ribotype profiles were found and compared by cluster analysis, resulting in the identification of three ribotype clusters. A total of 58% of all strains investigated were of two ribotypes belonging to different ribotype clusters. A remarkable relationship existed between the observed ribotype profiles and the clinical-pathological observations because strains of one of the two dominant ribotypes were almost exclusively isolated from pigs with meningitis, while strains of the other dominant ribotype were never associated with meningitis. This second ribotype was isolated only from pigs with pneumonia, endocarditis, pericarditis, or septicemia. Cluster analysis revealed that strains belonging to the same ribotype cluster as one of the dominant ribotypes came from pigs that showed clinical signs similar to those of pigs infected with strains with the respective dominant ribotype profiles. Furthermore, strains belonging to different ribotype clusters had totally different patterns of resistance to antibiotics because strains isolated from pigs with meningitis were resistant to sulfamethazoxazole and strains isolated from pigs with pneumonia, endocarditis, pericarditis, or septicemia were resistant to tetracycline. PMID:9889228

Annotation analysis for testing drug safety signals using unstructured clinical notes

PubMed Central

2012-01-01

Background The electronic surveillance for adverse drug events is largely based upon the analysis of coded data from reporting systems. Yet, the vast majority of electronic health data lies embedded within the free text of clinical notes and is not gathered into centralized repositories. With the increasing access to large volumes of electronic medical data—in particular the clinical notes—it may be possible to computationally encode and to test drug safety signals in an active manner. Results We describe the application of simple annotation tools on clinical text and the mining of the resulting annotations to compute the risk of getting a myocardial infarction for patients with rheumatoid arthritis that take Vioxx. Our analysis clearly reveals elevated risks for myocardial infarction in rheumatoid arthritis patients taking Vioxx (odds ratio 2.06) before 2005. Conclusions Our results show that it is possible to apply annotation analysis methods for testing hypotheses about drug safety using electronic medical records. PMID:22541596

Safety of intranasal corticosteroids in acute rhinosinusitis.

PubMed

Demoly, Pascal

2008-01-01

Treatment guidelines for acute rhinosinusitis (RS) recommend the use of intranasal corticosteroids (INSs) as monotherapy or adjunctive therapy. However, the adverse event (AE) profiles of oral glucocorticoids, which result largely from the systemic absorption of those agents, have engendered concerns about the safety of INSs. These concerns persist for INSs despite significant or marked clinical differences between them and systemic corticosteroids in systemic absorption and among the INSs in bioavailability, mechanism of action, and lipophilicity, which may contribute to differences in AEs. For example, the systemic bioavailability of the INSs as a percentage of the administered drug is less than 0.1% for mometasone furoate, less than 1% for fluticasone propionate, 46% for triamcinolone acetonide, and 44% for beclomethasone dipropionate. A review of the safety profiles of INSs, as reported in clinical trials in acute and chronic RS and allergic rhinitis, shows primarily local AEs (eg, epistaxis and headache) that are generally classified as mild to moderate, with occurrence rates that are similar to those with placebo. Studies of the safety of mometasone furoate, fluticasone propionate, budesonide, and triamcinolone acetonide did not identify any evidence of systemic AEs, such as growth retardation in children due to suppression of the hypothalamic-pituitary-adrenal axis, bone mineral density loss, or cataracts, which suggests that INSs can be safely administered in patients with acute RS without concern for systemic AEs.

Integrating quality and safety education into clinical nursing education through a dedicated education unit.

PubMed

Masters, Kelli

2016-03-01

The Institute of Medicine and American Association of Colleges of Nursing are calling for curriculum redesign that prepares nursing students with the requisite knowledge and skills to provide safe, high quality care. The purpose of this project was to improve nursing students' knowledge of quality and safety by integrating Quality and Safety Education for Nurses into clinical nursing education through development of a dedicated education unit. This model, which pairs nursing students with front-line nursing staff for clinical experiences, was implemented on a medical floor in an acute care hospital. Prior to implementation, nurses and students were educated about the dedicated education unit and quality and safety competencies. During each clinical rotation, students collaborated with their nurses on projects related to these competencies. Students' knowledge was assessed using questions related to quality and safety. Students who participated in the dedicated education unit had higher scores than those with traditional clinical rotations. Focus groups were held mid-semester to assess nurses' perceptions of the experience. Five themes emerged from the qualitative data including thirsting for knowledge, building teamwork and collaboration, establishing trust and decreasing anxiety, mirroring organization and time management skills, and evolving confidence in the nursing role. Copyright © 2015 Elsevier Ltd. All rights reserved.

Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beyerle, Andrea, E-mail: andrea.beyerle@cslbehring.com; Nolte, Marc W.; Solomon, Cristina

Fibrinogen, a soluble 340 kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.5–2.0 g/l. Plasma-derived human fibrinogen concentrate has been available for therapeutic use since 1956. The overall aim of the comprehensive series of non-clinical investigations presented was to evaluate i) the pharmacodynamic and pharmacokinetic characteristics and ii)more » the safety and tolerability profile of human fibrinogen concentrate Haemocomplettan P® (RiaSTAP®). Pharmacodynamic characteristics were assessed in rabbits, pharmacokinetic parameters were determined in rabbits and rats and a safety pharmacology study was performed in beagle dogs. Additional toxicology tests included: single-dose toxicity tests in mice and rats; local tolerance tests in rabbits; and neoantigenicity tests in rabbits and guinea pigs following the introduction of pasteurization in the manufacturing process. Human fibrinogen concentrate was shown to be pharmacodynamically active in rabbits and dogs and well tolerated, with no adverse events and no influence on circulation, respiration or hematological parameters in rabbits, mice, rats and dogs. In these non-clinical investigations, human fibrinogen concentrate showed a good safety profile. This data adds to the safety information available to date, strengthening the current body of knowledge regarding this hemostatic agent. - Highlights: • A comprehensive series of pre-clinical investigations of human fibrinogen concentrate. • Human fibrinogen concentrate was shown to be pharmacodynamically active. • Human fibrinogen concentrate was well

Clinical profile of patients with type 2 diabetes mellitus treated with sodium- glucose cotransporter-2 inhibitors and experience in real-world clinical practice in Spain.

PubMed

Cuatrecasas, Gabriel; Goñi-Goicoechea, Fernando

2016-11-01

The main aim of the treatment of type 2 diabetes is overall control of cardiovascular risk factors. Almost 50% of patients with type 2 diabetes do not achieve glycaemic targets, and a much higher percentage do not achieve weight and blood pressure targets, despite the therapeutic arsenal that has appeared in the last decade for the treatment of this disease. In addition, antidiabetic secretatogues and insulin are associated with weight gain and an increased risk of hyperglycaemic episodes. Clinical practice guidelines recommend sodium-glucose cotransporter-2 inhibitors (SGLT2i) as an alternative in the same therapeutic step as the other options after initiation of metformin therapy. The present study reviews the most appropriate patient profile for SGLT2i therapy, based on their safety and efficacy demonstrated in controlled clinical trials. The article discusses which patients are at risk of experiencing the possible secondary effects due to the mechanism of action of this new therapeutic class, in whom SGLT2i should be used with caution. These considerations on the profile of patients suitable for SGLT2i therapy are contrasted with the results obtained in daily clinical practice, both in retrospective studies from other countries and from real-world experiences in Spain. This article presents a selection of studies performed in distinct centres with a minimum follow-up of 6 months and compares their results with those from clinical trials. SGLT2i are used in clinical practice in any therapeutic step and the efficacy results are very similar to those reported by controlled clinical trials, with a slightly higher proportion of genitourinary infections and a low dropout rate. Half the reported patients are diabetics receiving insulin therapy plus a gliflozin, showing the wide uptake of this therapeutic strategy by clinicians. SGLT2i are especially attractive due to their additional effectiveness in weight and blood pressure control and the possibility of using them

Transarterial Chemoembolization for Hepatocellular Carcinoma with a New Generation of Beads: Clinical–Radiological Outcomes and Safety Profile

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spreafico, Carlo, E-mail: carlo.spreafico@istitutotumori.mi.it; Cascella, Tommaso, E-mail: tommaso.cascella@istitutotumori.mi.it; Facciorusso, Antonio, E-mail: antonio.facciorusso@istitutotumori.mi.it

PurposeTo evaluate the short-term safety and efficacy of the new generation of 70–150 µm drug-eluting beads (M1 DEB) in patients with hepatocellular carcinoma undergoing transarterial chemoembolization (TACE) as a primary therapy or as a bridge to liver transplantation (LT).MethodsForty-five consecutive patients underwent TACE with M1 DEB loaded with doxorubicin (DEBDOX/M1). Clinical data were recorded at 12, 24, and 48 h, 7 and 30 days after treatment. Response was assessed by computed tomographic scan according to the modified response evaluation criteria in solid tumors criteria, and a second DEBDOX/M1 TACE was scheduled within 6 weeks in case of a noncomplete response.ResultsAll patients had well-compensated cirrhosismore » (97.7 % Child A, 44.4 % hepatitis C virus, median age 61 years). Twenty patients (44.4 %) had Barcelona Clinic for Liver Cancer class B disease; the median number of nodules and their sum of diameters were 2 (range 1–6) and 43 mm (range 10–190), respectively. The mean number of TACE procedures per patient was 1.4. Objective response rate (complete + partial response) was 77.7 % with a median time to best response of 3 months (95 % confidence interval 2–4). In 13 patients, DEBDOX/M1 TACE served as a bridge/downstaging to LT/surgery. Pathology showed that more than 90 % necrosis was achieved in 10 of 28 nodules. DEBDOX/M1 TACE was well tolerated, and the grade 3/4 adverse event rate was low (1 of 65 procedures).ConclusionDEBDOX/M1 TACE is an effective procedure with a favorable safety profile and promising results in terms of objective response rate, tumor downstaging, and necrosis.« less

Clinical Profile of Children and Adolescents Attending the Behavioural Paediatrics Unit OPD in a Tertiary Care Set up

ERIC Educational Resources Information Center

Jayaprakash, R.

2012-01-01

Background: There are limited studies on the clinical profile of children attending child guidance clinic under Paediatric background. Aims: To study clinical profile of Children & adolescents attending the Behavioural Paediatrics Unit (BPU) OPD under department of Paediatrics in a tertiary care set up. Methods: Monthly average turnover in the…

Potential cost savings of medication therapy management in safety-net clinics.

PubMed

Truong, Hoai-An; Groves, C Nicole; Congdon, Heather B; Dang, Diem-Thanh Tanya; Botchway, Rosemary; Thomas, Jennifer

2015-01-01

To evaluate potential cost savings based on estimated cost avoidance from medication therapy management (MTM) services delivered in safety-net clinics over 4 years. High-risk patients taking multiple medications and with chronic conditions were referred for MTM services in primary care safety-net clinics in Maryland from October 1, 2009, to September 30, 2013. Medication-related problems (MRPs) were identified and pharmacists' costs determined to evaluate the estimated cost savings and return on investment (ROI). A range of potential economic outcomes for each MRP identified was assigned to a cost avoidance for outpatient visit, urgent care visit, emergency department visit, and/or hospitalization. Over 4 years, 246 patients received MTM, nearly 2,100 medications were reviewed, and 814 MRPs were identified. The most common MRPs identified were subtherapeutic doses, nonadherence, and untreated indications, with respective prevalences of 38%, 19%, and 16%. The corresponding costs of medical services were estimated at $115,220-$614,570 for all MRPs identified, yielding a mean of $141.55-$755.00 per identified MRP. Pharmacists' expenses for encounters were calculated at a total expenditure of $57,307.50 for 16,965 minutes. ROI based on the time spent during billable face-to-face encounters ranged from 1:5 to 1:25. Pharmacist-provided MTM in safety-net clinics yielded potential economic benefits to the organization. The Primary Care Coalition of Montgomery County plans to expand MTM services to additional clinics to improve patient care and increase cost savings through preventable medical services.

Clinical safety and effectiveness of transversus abdominis plane (TAP) block in post-operative analgesia: a systematic review and meta-analysis.

PubMed

Ma, Ning; Duncan, Joanna K; Scarfe, Anje J; Schuhmann, Susanne; Cameron, Alun L

2017-06-01

Transversus abdominis plane (TAP) blocks can provide analgesia postoperatively for a range of surgeries. Abundant clinical trials have assessed TAP block showing positive analgesic effects. This systematic review assesses safety and effectiveness outcomes of TAP block in all clinical settings, comparing with both active (standard care) and inactive (placebo) comparators. PubMed, EMBASE, The Cochrane Library and the University of York CRD databases were searched. RCTs were screened for their eligibility and assessed for risk of bias. Meta-analyses were performed on available data. TAP block showed an equivalent safety profile to all comparators in the incidence of nausea (OR = 1.07) and vomiting (OR = 0.81). TAP block was more effective in reducing morphine consumption [MD = 13.05, 95% CI (8.33, 51.23)] and in delaying time to first analgesic request [MD = 123.49, 95% CI (48.59, 198.39)]. Postoperative pain within 24 h was reduced or at least equivalent in TAP block compared to its comparators. Therefore, TAP block is a safe and effective procedure compared to standard care, placebo and other analgesic techniques. Further research is warranted to investigate whether the TAP block technique can be improved by optimizing dose and technique-related factors.

Fusion of nonclinical and clinical data to predict human drug safety.

PubMed

Johnson, Dale E

2013-03-01

Adverse drug reactions continue to be a major cause of morbidity in both patients receiving therapeutics and in drug R&D programs. Predicting and possibly eliminating these adverse events remains a high priority in industry, government agencies and healthcare systems. With small molecule candidates, the fusion of nonclinical and clinical data is essential in establishing an overall system that creates a true translational science approach. Several new advances are taking place that attempt to create a 'patient context' mechanism early in drug research and development and ultimately into the marketplace. This 'life-cycle' approach has as its core the development of human-oriented, nonclinical end points and the incorporation of clinical knowledge at the drug design stage. The next 5 years should witness an explosion of what the author views as druggable and safe chemical space, pharmacosafety molecular targets and the most important aspect, an understanding of unique susceptibilities in patients developing adverse drug reactions. Our current knowledge of clinical safety relies completely on pharmacovigilance data from approved and marketed drugs, with a few exceptions of drugs failing in clinical trials. Massive data repositories now and soon to be available via cloud computing should stimulate a major effort in expanding our view of clinical drug safety and its incorporation into early drug research and development.

Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method] demonstrates efficacy, safety and low-risk for immunogenicity in routine clinical practice.

PubMed

Oldenburg, J; Goudemand, J; Valentino, L; Richards, M; Luu, H; Kriukov, A; Gajek, H; Spotts, G; Ewenstein, B

2010-11-01

  Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method, (rAHF-PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. Among 408 evaluable subjects, 386 (95%) received excellent/good efficacy ratings for all on-demand assessments; the corresponding number for subjects with previous FVIII inhibitors was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII≤2%, three (0.75%) developed low-titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01-1.59%). A PTP with moderate haemophilia developed a low-titre inhibitor. High-titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The favourable benefit/risk profile of rAHF-PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies. © 2010 Blackwell Publishing Ltd.

A multidisciplinary three-phase approach to improve the clinical utility of patient safety indicators.

PubMed

Najjar, Peter; Kachalia, Allen; Sutherland, Tori; Beloff, Jennifer; David-Kasdan, Jo Ann; Bates, David W; Urman, Richard D

2015-01-01

The AHRQ Patient Safety Indicators (PSIs) are used for calculation of risk-adjusted postoperative rates for adverse events. The payers and quality consortiums are increasingly requiring public reporting of hospital performance on these metrics. We discuss processes designed to improve the accuracy and clinical utility of PSI reporting in practice. The study was conducted at a 793-bed tertiary care academic medical center where PSI processes have been aggressively implemented to track patient safety events at discharge. A three-phased approach to improving administrative data quality was implemented. The initiative consisted of clinical review of all PSIs, documentation improvement, and provider outreach including active querying for patient safety events. This multidisciplinary effort to develop a streamlined process for PSI calculation reduced the reporting of miscoded PSIs and increased the clinical utility of PSI monitoring. Over 4 quarters, 4 of 41 (10%) PSI-11 and 9 of 138 (7%) PSI-15 errors were identified on review of clinical documentation and appropriate adjustments were made. A multidisciplinary, phased approach leveraging existing billing infrastructure for robust metric coding, ongoing clinical review, and frontline provider outreach is a novel and effective way to reduce the reporting of false-positive outcomes and improve the clinical utility of PSIs.

Creatine Metabolism and Safety Profiles after Six-Week Oral Guanidinoacetic Acid Administration in Healthy Humans

PubMed Central

Ostojic, Sergej M.; Niess, Barbara; Stojanovic, Marko; Obrenovic, Milos

2013-01-01

Objectives; Guanidinoacetic acid (GAA) is a natural precursor of creatine, yet the potential use of GAA as a nutritional additive for restoring creatine availability in humans has been limited by unclear efficacy and safety after exogenous GAA administration. The present study evaluated the effects of orally administered GAA on serum and urinary GAA, creatine and creatinine concentration, and on the occurrence of adverse events in healthy humans. Methods and Results; Twenty-four healthy volunteers were randomized in a double-blind design to receive either GAA (2.4 grams daily) or placebo (PLA) by oral administration for 6 weeks. Clinical trial registration: www.clinicaltrials.gov, identification number NCT01133899. Serum creatine and creatinine increased significantly from before to after administration in GAA-supplemented participants (P < 0.05). The proportion of participants who reported minor side effects was 58.3% in the GAA group and 45.5% in the placebo group (P = 0.68). A few participants experienced serum creatine levels above 70 µmol/L. Conclusion; Exogenous GAA is metabolized to creatine, resulting in a significant increase of fasting serum creatine after intervention. GAA had an acceptable side-effects profile with a low incidence of biochemical abnormalities. PMID:23329885

Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: Results from a Spanish real-world cohort.

PubMed

Calleja, Jose Luis; Crespo, Javier; Rincón, Diego; Ruiz-Antorán, Belén; Fernandez, Inmaculada; Perelló, Christie; Gea, Francisco; Lens, Sabela; García-Samaniego, Javier; Sacristán, Begoña; García-Eliz, María; Llerena, Susana; Pascasio, Juan Manuel; Turnes, Juan; Torras, Xavier; Morillas, Rosa Maria; Llaneras, Jordi; Serra, Miguel A; Diago, Moises; Rodriguez, Conrado Fernández; Ampuero, Javier; Jorquera, Francisco; Simon, Miguel A; Arenas, Juan; Navascues, Carmen Alvarez; Bañares, Rafael; Muñoz, Raquel; Albillos, Agustin; Mariño, Zoe

2017-06-01

Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of

Assessment of patient safety culture in clinical laboratories in the Spanish National Health System.

PubMed

Giménez-Marín, Angeles; Rivas-Ruiz, Francisco; García-Raja, Ana M; Venta-Obaya, Rafael; Fusté-Ventosa, Margarita; Caballé-Martín, Inmaculada; Benítez-Estevez, Alfonso; Quinteiro-García, Ana I; Bedini, José Luis; León-Justel, Antonio; Torra-Puig, Montserrat

2015-01-01

There is increasing awareness of the importance of transforming organisational culture in order to raise safety standards. This paper describes the results obtained from an evaluation of patient safety culture in a sample of clinical laboratories in public hospitals in the Spanish National Health System. A descriptive cross-sectional study was conducted among health workers employed in the clinical laboratories of 27 public hospitals in 2012. The participants were recruited by the heads of service at each of the participating centers. Stratified analyses were performed to assess the mean score, standardized to a base of 100, of the six survey factors, together with the overall patient safety score. 740 completed questionnaires were received (88% of the 840 issued). The highest standardized scores were obtained in Area 1 (individual, social and cultural) with a mean value of 77 (95%CI: 76-78), and the lowest ones, in Area 3 (equipment and resources), with a mean value of 58 (95%CI: 57-59). In all areas, a greater perception of patient safety was reported by the heads of service than by other staff. We present the first multicentre study to evaluate the culture of clinical safety in public hospital laboratories in Spain. The results obtained evidence a culture in which high regard is paid to safety, probably due to the pattern of continuous quality improvement. Nevertheless, much remains to be done, as reflected by the weaknesses detected, which identify areas and strategies for improvement.

Clinical safety assessment of oral higenamine supplementation in healthy, young men.

PubMed

Bloomer, R J; Schriefer, J M; Gunnels, T A

2015-10-01

Higenamine, an herbal agent also known as norcoclaurine, is thought to stimulate β-androgenic receptors and possess lipolytic activity. It is currently making its way into the dietary supplement market. To our knowledge, no studies have been conducted to determine the safety profile of oral higenamine when used alone and in conjunction with other commonly used lipolytic agents. Forty-eight men were assigned to ingest either a placebo, higenamine, caffeine, or higenamine + caffeine + yohimbe bark extract daily for a period of 8 weeks. Before and after 4 and 8 weeks of supplementation, the following variables were measured: resting respiratory rate, heart rate, blood pressure, urinalysis, complete blood count, metabolic panel, liver enzyme activity, and lipid panel. No interaction effects were noted for any variable (p > 0.05), with no changes of statistical significance occurring across time for any of the four conditions (p > 0.05). This is the first study to determine the safety profile of oral higenamine intake in human subjects. Our data indicate that 8 weeks of daily higenamine supplementation, either alone or in conjunction with caffeine and yohimbe bark extract, does not result in a statistically significant change in any of the measured outcome variables. Additional studies, inclusive of a larger sample size, are needed to extend these initial findings. © The Author(s) 2015.

Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice.

PubMed

Drakatos, Panagis; Lykouras, Dimosthenis; D'Ancona, Grainne; Higgins, Sean; Gildeh, Nadia; Macavei, Raluca; Rosenzweig, Ivana; Steier, Joerg; Williams, Adrian J; Muza, Rexford; Kent, Brian D; Leschziner, Guy

2017-07-01

Sodium oxybate is licensed in Europe for the treatment of narcolepsy with cataplexy in adults. The aim of this study was to assess the efficacy and safety of sodium oxybate in clinical practice in patients with narcolepsy and cataplexy refractory to other treatments. This was a retrospective single centre study including patients with severe narcolepsy with cataplexy refractory to other treatments, who were initiated on sodium oxybate between 2009 and 2015. Patients were allowed to be on other stimulants or/and anti-cataplectic agents. Epworth sleepiness scale (ESS) and weekly cataplexy events were recorded. Side effects (SEs) were recorded at every follow-up visit. 90 patients were prescribed sodium oxybate, with a total of 3116 patient-months of drug exposure. ESS and weekly cataplexy events were significantly reduced by sodium oxybate for all patients (ΔESS = 4.3 ± 4.4 and Δcataplexy = 21.8 ± 18.5 events/week; p < 0.0001, respectively). The required maintenance dose could not be predicted based upon gender, body mass index, or clinical factors. 60% of patients were able to reduce or come off other medications. Half of the patients experienced at least one SE, and 26.6% had to stop treatment due to limiting SEs. Nausea, mood swings and enuresis were the most commonly reported SEs. SEs that led to drug discontinuation, particularly psychosis, were associated with increasing age and were observed early after the initiation of the drug. Sodium oxybate provides a good clinical efficacy and acceptable safety profile in routine clinical practice for the treatment of patients suffering from narcolepsy with cataplexy. A quarter of patients experience SEs requiring withdrawal of the drug with older patients being more vulnerable to the more serious SEs. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans. Final rule.

PubMed

2010-09-29

The Food and Drug Administration (FDA) is amending its regulations governing safety reporting requirements for human drug and biological products subject to an investigational new drug application (IND). The final rule codifies the agency's expectations for timely review, evaluation, and submission of relevant and useful safety information and implements internationally harmonized definitions and reporting standards. The revisions will improve the utility of IND safety reports, reduce the number of reports that do not contribute in a meaningful way to the developing safety profile of the drug, expedite FDA's review of critical safety information, better protect human subjects enrolled in clinical trials, subject bioavailability and bioequivalence studies to safety reporting requirements, promote a consistent approach to safety reporting internationally, and enable the agency to better protect and promote public health.

Cardiac safety of lacosamide: the non-clinical perspective.

PubMed

Delaunois, A; Colomar, A; Depelchin, B O; Cornet, M

2015-11-01

Lacosamide is indicated for the adjunctive treatment of partial-onset seizures in adult patients. Unlike other sodium channel-blocking antiepileptic drugs, lacosamide selectively enhances sodium channel slow inactivation. Potential effects of lacosamide on cardiac sodium channels and their cardiovascular consequences were comprehensively assessed. This manuscript presents the non-clinical cardiac safety profile of lacosamide. Lacosamide was tested in vitro on sodium and L-type calcium currents from isolated human atrial myocytes and on hERG-mediated potassium currents from stably transfected HEK293 cells. Cardiac action potentials were recorded in guinea pig ventricular myocytes. In vivo, hemodynamic and ECG parameters were evaluated in anesthetized dogs and monkeys receiving acute cumulative intravenous doses of lacosamide. Following intravenous dosing with lacosamide, dose-dependent PR and QRS prolongation and ECG abnormalities (loss of P waves, atrioventricular and intraventricular blocks, junctional premature contractions) were observed in anesthetized dogs and monkeys. In vitro, lacosamide reduced human cardiac sodium currents in a concentration-, voltage- and state-dependent manner. Lacosamide reductions in Vmax in guinea pig myocytes were similar to lamotrigine and carbamazepine. Lacosamide showed no relevant inhibitory effects on hERG and L-type calcium channels and did not prolong QTc in vivo. ECG findings in anesthetized animals correlate well with in vitro sodium channel-related effects and are also consistent with those (PR prolongation, first-degree atrioventricular block) reported in healthy volunteers and patients with epilepsy. Both in vivo and in vitro effects were detected from exposure levels 1.5- to 2-fold above those achieved with the maximum-recommended human lacosamide dose (400 mg/day). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pattern of Altered Lipid Profile in Patients with Subclinical and Clinical Hypothyroidism and its Correlation with Body Mass Index.

PubMed

Humerah, Sobia; Siddiqui, Arif; Khan, Humaira Fayyaz

2016-06-01

To compare the lipid profile of the subclinical and clinical hypothyroid patients and to evaluate the correlation between body mass index (BMI) and lipid profile in hypothyroidism. Cross-sectional study. Islamic International Medical College, Riphah International University, Islamabad, and Citi Laboratory, Rawalpindi, from January to December 2013. The subjects were selected through non-probability, purposive sampling. On the basis of thyroid profile, the subjects were divided into 3 groups: euthyroids (n=20), subclinical hypothyroids (n=50), and clinical hypothyroids (n=30). The blood of these subjects was then analyzed for lipid profile. Data was analyzed using SPSS version 18 statistical software. Both hypothyroid groups showed altered lipid profile which was observed to be significantly raised when compared with the euthyroid subjects. Comparison of lipid profile in euthyroid, subclinical, and clinical hypothyroid groups showed significant differences by non-parametric tests (p < 0.05). An assessment of correlation of lipid profile with the BMI was found to be significant (p < 0.01). Hypothyroidism causes alteration of lipid profile. Clinical and subclinical hypothyroid patients have altered lipid profile as compared to euthyroids. Thyroid status monitoring is very important, since it can induce changes in lipid profile. Such dyslipidemic status is significant not only for the management of thyroid disorders but also for common diseases like obesity and coronary atherosclerosis in the population.

Health profiles of foreigners attending primary care clinics in Malaysia.

PubMed

Ab Rahman, Norazida; Sivasampu, Sheamini; Mohamad Noh, Kamaliah; Khoo, Ee Ming

2016-06-14

The world population has become more globalised with increasing number of people residing in another country for work or other reasons. Little is known about the health profiles of foreign population in Malaysia. The aim of this study was to provide a detailed description of the health problems presented by foreigners attending primary care clinics in Malaysia. Data were derived from the 2012 National Medical Care Survey (NMCS), a cross sectional survey of primary care encounters from public and private primary care clinics sampled from five regions in Malaysia. Patients with foreign nationality were identified and analysed for demographic profiles, reasons for encounter (RFEs), diagnosis, and provision of care. Foreigners accounted for 7.7 % (10,830) of all patient encounters from NMCS. Most encounters were from private clinics (90.2 %). Median age was 28 years (IQR: 24.0, 34.8) and 69.9 % were male. Most visits to the primary care clinics were for symptom-based complaints (69.5 %), followed by procedures (23.0 %) and follow-up visit (7.4 %). The commonest diagnosis in public clinics was antenatal care (21.8 %), followed by high risk pregnancies (7.5 %) and upper respiratory tract infection (URTI) (6.8 %). Private clinics had more cases for general medical examination (13.5 %), URTI (13.1 %) and fever (3.9 %). Medications were prescribed to 76.5 % of these encounters. More foreigners were seeking primary medical care from private clinics and the encounters were for general medical examinations and acute minor ailments. Those who sought care from public clinics were for obstetric problems and chronic diseases. Medications were prescribed to two-thirds of the encounters while other interventions: laboratory investigations, medical procedures and follow-up appointment had lower rates in private clinics. Foreigners are generally of young working group and are expected to have mandatory medical checks. The preponderance of obstetrics seen in public

Repurposing historical control clinical trial data to provide safety context.

PubMed

Bhuyan, Prakash; Desai, Jigar; Louis, Matthew St; Carlsson, Martin; Bowen, Edward; Danielson, Mark; Cantor, Michael N

2016-02-01

Billions of dollars spent, millions of subject-hours of clinical trial experience and an abundance of archived study-level data, yet why are historical data underutilized? We propose that historical data can be aggregated to provide safety, background incidence rate and context to improve the evaluation of new medicinal products. Here, we describe the development and application of the eControls database, which is derived from the control arms of studies of licensed products, and discuss the challenges and potential solutions to the proper application of historical data to help interpret product safety. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluation of the in-service safety performance of safety-shape and vertical concrete barriers.

DOT National Transportation Integrated Search

2011-12-16

Roadside concrete barriers have been widely used to protect errant motorists from hitting : roadside hazards or obstacles. Two concrete barrier profiles, vertical and safety-shape, have been used : for this purpose. The safety-shape profile has been ...

An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants.

PubMed

Fox, Christopher B; Haensler, Jean

2013-07-01

With the exception of alum, emulsion-based vaccine adjuvants have been administered to far more people than any other adjuvant, especially since the 2009 H1N1 influenza pandemic. The number of clinical safety and immunogenicity evaluations of vaccines containing emulsion adjuvants has correspondingly mushroomed. In this review, the authors introduce emulsion adjuvant composition and history before detailing the most recent findings from clinical and postmarketing data regarding the effects of emulsion adjuvants on vaccine immunogenicity and safety, with emphasis on the most widely distributed emulsion adjuvants, MF59® and AS03. The authors also present a summary of other emulsion adjuvants in clinical development and indicate promising avenues for future emulsion-based adjuvant development. Overall, emulsion adjuvants have demonstrated potent adjuvant activity across a number of disease indications along with acceptable safety profiles.

Pharmacokinetic properties and safety profile of histamine dihydrochloride injection in Chinese healthy volunteers: a phase I, single-center, open-label, randomized study.

PubMed

Li, Jiapeng; Huang, Xiaojun; Wang, Qian; Jing, Shan; Jiang, Hao; Wei, Zhongna; Zang, Yannan; Liu, Yang; Zhao, Libo; Fang, Yi; Feng, Wanyu

2015-10-01

Histamine dihydrochloride (HDC) injection has been approved in Europe for the treatment of adults with acute myeloid leukemia, used in combination therapy with the T-cell-derived cytokine interleukin-2. Despite years of clinical applications of HDC in Europe, no data are available on its tolerability and pharmacokinetic properties in Chinese patients. The objective of this study was to determine the safety profile and pharmacokinetic properties of HDC in Chinese healthy volunteers (HVs). In this Phase I, single-center, open-label, randomized study, 20 Chinese HVs were randomized to receive a single dose of 0.5 or 1.0 mg HDC via a 10-minute subcutaneous injection. Whole-blood and urine samples were collected at designated time points after dosing. Plasma and urine concentrations of histamine and metabolite N-methyl histamine were measured using a validated HPLC-MS/MS method. Pharmacokinetic parameters were estimated through noncompartmental procedures based on concentration-time data. Adverse events and evaluation of clinical laboratory tests were used to assess the safety profile. The pharmacokinetic profile for a single-dose of 1.0 mg HDC in Chinese HVs was compared with that in Western HVs. No severe adverse events occurred in this study, and the severity of all adverse events was grade I according to the Common Terminology Criteria for Adverse Events, version 4.0. For the pharmacokinetic parameters of histamine at the 0.5-mg and 1.0-mg dose levels, t½ was 0.50 and 1.02 hours; Tmax was 0.15 and 0.14 hours; mean Cmax was 26.59 and 71.01 nmol/L; AUC0-t was 8.35 and 20.43 nmol/h/L; AUC0-∞ was 9.61 and 22.69 nmol/h/L; accumulated amount excreted in urine within 24 hours was 125.93 and 145.52 nmol; and maximum urine excretion rates were 21.85 and 38.94 nmol/h, respectively. For N-methyl histamine at the 0.5-mg and 1.0-mg dose levels, t½ was 0.58 and 0.66 hours; Tmax was 0.28 and 0.26 hours; mean Cmax was 17.01 and 23.54 nmol/L; AUC0-t was 7.72 and 17.08 nmol

Evaluating predictive modeling’s potential to improve teleretinal screening participation in urban safety net clinics

PubMed Central

Ogunyemi, Omolola; Teklehaimanot, Senait; Patty, Lauren; Moran, Erin; George, Sheba

2013-01-01

Introduction Screening guidelines for diabetic patients recommend yearly eye examinations to detect diabetic retinopathy and other forms of diabetic eye disease. However, annual screening rates for retinopathy in US urban safety net settings remain low. Methods Using data gathered from a study of teleretinal screening in six urban safety net clinics, we assessed whether predictive modeling could be of value in identifying patients at risk of developing retinopathy. We developed and examined the accuracy of two predictive modeling approaches for diabetic retinopathy in a sample of 513 diabetic individuals, using routinely available clinical variables from retrospective medical record reviews. Bayesian networks and radial basis function (neural) networks were learned using ten-fold cross-validation. Results The predictive models were modestly predictive with the best model having an AUC of 0.71. Discussion Using routinely available clinical variables to predict patients at risk of developing retinopathy and to target them for annual eye screenings may be of some usefulness to safety net clinics. PMID:23920536

Efficacy and safety of novel antipsychotics: a critical review.

PubMed

Balestrieri, Matteo; Vampini, Claudio; Bellantuono, Cesario

2000-10-01

Efficacy and safety of novel antipsychotic (AP) drugs (amisulpride, olanzapine, quetiapine, ziprasidone and zotepine) have been reviewed. Data on their antipsychotic efficacy and side effects profile have been evaluated only on the basis of controlled trials so far published. Overall, all these drugs have shown an antipsychotic efficacy on positive symptoms of schizophrenia similar to that of the conventional AP drugs. On negative symptoms, all novel AP drugs, except quetiapine and ziprasidone, demonstrated a better efficacy than haloperidol. Long-term efficacy of these AP drugs in the maintenance treatment of schizophrenia needs to be explored by further, better-designed, epidemiological studies. The safety profile shows that the novel AP drugs are generally well-tolerated and induce significantly less acute extrapyramidal side effects in comparison with haloperidol. Some methodological flaws in the experimental design of the clinical trials analysed are discussed. Although these novel AP drugs have potential clinical advantages, a number of relevant questions still remain to be addressed, in order to establish the impact of these drugs in the overall treatment of schizophrenia. Copyright 2000 John Wiley & Sons, Ltd.

Characteristics, resource utilization and safety profile of patients prescribed with neuropathic pain treatments: a real-world evidence study on general practices in Europe - the role of the lidocaine 5% medicated plaster.

PubMed

Katz, Pablo; Pegoraro, Valeria; Liedgens, Hiltrud

2017-08-01

To identify characteristics, resource utilization, and safety profile of patients prescribed with lidocaine 5% medicated plaster, pregabalin, gabapentin, amitriptyline and duloxetine when experiencing pain in the real-world setting of general practitioners (GPs) in Europe. Retrospective analysis on real world data from IMS Health Longitudinal Patient Database. Patients with at least one prescription of the drugs of interest during 2014 were selected and those with a non-neuropathic pain-related diagnosis were excluded. Patients' demographic and clinical characteristics, resource utilization data and adverse drug reactions (ADRs) as described in the leaflet were extracted. The association between treatments and ADR occurrence was evaluated applying multivariate logistic models. A total of 70,515 patients were selected from Italy, Germany, the UK, Spain and Belgium. Lidocaine 5% medicated plaster patients were the oldest in Italy, the UK and Spain and the most health impaired in Italy, Spain and Belgium. No relevant differences in the number of co-prescriptions, specialist visits, examinations and hospitalizations were found. Significantly less lidocaine 5% plasters patients experienced ADRs, with odds ratios in favor of lidocaine 5% medicated plasters ranging from 3.41 (p = .036) to 52.33 (p < .001). Evidence from daily clinical practice in GP settings agrees with the findings from more controlled clinical-trial settings, with lidocaine 5% medicated plaster patients showing a better safety profile, but also a comparable level of resource utilization. A possible re-evaluation of the scientific value coming from this retrospective study in building up a diagnostic as well as a therapeutic algorithm is suggested.

Cardiovascular safety of prokinetic agents: A focus on drug-induced arrhythmias.

PubMed

Giudicessi, J R; Ackerman, M J; Camilleri, M

2018-02-14

Gastrointestinal sensorimotor dysfunction underlies a wide range of esophageal, gastric, and intestinal motility and functional disorders that collectively constitute nearly half of all referrals to gastroenterologists. As a result, substantial effort has been dedicated toward the development of prokinetic agents intended to augment or restore normal gastrointestinal motility. However, the use of several clinically efficacious gastroprokinetic agents, such as cisapride, domperidone, erythromycin, and tegaserod, is associated with unfavorable cardiovascular safety profiles, leading to restrictions in their use. The purpose of this review is to detail the cellular and molecular mechanisms that lead commonly to drug-induced cardiac arrhythmias, specifically drug-induced long QT syndrome, torsades de pointes, and ventricular fibrillation, to examine the cardiovascular safety profiles of several classes of prokinetic agents currently in clinical use, and to explore potential strategies by which the risk of drug-induced cardiac arrhythmia associated with prokinetic agents and other QT interval prolonging medications can be mitigated successfully. © 2018 John Wiley & Sons Ltd.

Safety profile of solid lipid nanoparticles loaded with rosmarinic acid for oral use: in vitro and animal approaches.

PubMed

Madureira, Ana Raquel; Nunes, Sara; Campos, Débora A; Fernandes, João C; Marques, Cláudia; Zuzarte, Monica; Gullón, Beatriz; Rodríguez-Alcalá, Luís M; Calhau, Conceição; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Maria Manuela; Reis, Flávio

2016-01-01

Rosmarinic acid (RA) possesses several protective bioactivities that have attracted increasing interest by nutraceutical/pharmaceutical industries. Considering the reduced bioavailability after oral use, effective (and safe) delivery systems are crucial to protect RA from gastrointestinal degradation. This study aims to characterize the safety profile of solid lipid nanoparticles produced with Witepsol and Carnauba waxes and loaded with RA, using in vitro and in vivo approaches, focused on genotoxicity and cytotoxicity assays, redox status markers, hematological and biochemical profile, liver and kidney function, gut bacterial microbiota, and fecal fatty acids composition. Free RA and sage extract, empty nanoparticles, or nanoparticles loaded with RA or sage extract (0.15 and 1.5 mg/mL) were evaluated for cell (lymphocytes) viability, necrosis and apoptosis, and antioxidant/prooxidant effects upon DNA. Wistar rats were orally treated for 14 days with vehicle (control) and with Witepsol or Carnauba nanoparticles loaded with RA at 1 and 10 mg/kg body weight/d. Blood, urine, feces, and several tissues were collected for analysis. Free and loaded RA, at 0.15 mg/mL, presented a safe profile, while genotoxic potential was found for the higher dose (1.5 mg/mL), mainly by necrosis. Our data suggest that both types of nanoparticles are safe when loaded with moderate concentrations of RA, without in vitro genotoxicity and cytotoxicity and with an in vivo safety profile in rats orally treated, thus opening new avenues for use in nutraceutical applications.

Safety profile of solid lipid nanoparticles loaded with rosmarinic acid for oral use: in vitro and animal approaches

PubMed Central

Madureira, Ana Raquel; Nunes, Sara; Campos, Débora A; Fernandes, João C; Marques, Cláudia; Zuzarte, Monica; Gullón, Beatriz; Rodríguez-Alcalá, Luís M; Calhau, Conceição; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Maria Manuela; Reis, Flávio

2016-01-01

Rosmarinic acid (RA) possesses several protective bioactivities that have attracted increasing interest by nutraceutical/pharmaceutical industries. Considering the reduced bioavailability after oral use, effective (and safe) delivery systems are crucial to protect RA from gastrointestinal degradation. This study aims to characterize the safety profile of solid lipid nanoparticles produced with Witepsol and Carnauba waxes and loaded with RA, using in vitro and in vivo approaches, focused on genotoxicity and cytotoxicity assays, redox status markers, hematological and biochemical profile, liver and kidney function, gut bacterial microbiota, and fecal fatty acids composition. Free RA and sage extract, empty nanoparticles, or nanoparticles loaded with RA or sage extract (0.15 and 1.5 mg/mL) were evaluated for cell (lymphocytes) viability, necrosis and apoptosis, and antioxidant/prooxidant effects upon DNA. Wistar rats were orally treated for 14 days with vehicle (control) and with Witepsol or Carnauba nanoparticles loaded with RA at 1 and 10 mg/kg body weight/d. Blood, urine, feces, and several tissues were collected for analysis. Free and loaded RA, at 0.15 mg/mL, presented a safe profile, while genotoxic potential was found for the higher dose (1.5 mg/mL), mainly by necrosis. Our data suggest that both types of nanoparticles are safe when loaded with moderate concentrations of RA, without in vitro genotoxicity and cytotoxicity and with an in vivo safety profile in rats orally treated, thus opening new avenues for use in nutraceutical applications. PMID:27536103

Assessment of patient safety culture in clinical laboratories in the Spanish National Health System

PubMed Central

Giménez-Marín, Angeles; Rivas-Ruiz, Francisco; García-Raja, Ana M.; Venta-Obaya, Rafael; Fusté-Ventosa, Margarita; Caballé-Martín, Inmaculada; Benítez-Estevez, Alfonso; Quinteiro-García, Ana I.; Bedini, José Luis; León-Justel, Antonio; Torra-Puig, Montserrat

2015-01-01

Introduction There is increasing awareness of the importance of transforming organisational culture in order to raise safety standards. This paper describes the results obtained from an evaluation of patient safety culture in a sample of clinical laboratories in public hospitals in the Spanish National Health System. Material and methods A descriptive cross-sectional study was conducted among health workers employed in the clinical laboratories of 27 public hospitals in 2012. The participants were recruited by the heads of service at each of the participating centers. Stratified analyses were performed to assess the mean score, standardized to a base of 100, of the six survey factors, together with the overall patient safety score. Results 740 completed questionnaires were received (88% of the 840 issued). The highest standardized scores were obtained in Area 1 (individual, social and cultural) with a mean value of 77 (95%CI: 76-78), and the lowest ones, in Area 3 (equipment and resources), with a mean value of 58 (95%CI: 57-59). In all areas, a greater perception of patient safety was reported by the heads of service than by other staff. Conclusions We present the first multicentre study to evaluate the culture of clinical safety in public hospital laboratories in Spain. The results obtained evidence a culture in which high regard is paid to safety, probably due to the pattern of continuous quality improvement. Nevertheless, much remains to be done, as reflected by the weaknesses detected, which identify areas and strategies for improvement. PMID:26525595

Do differences in profiling criteria bias performance measurements? Economic profiling of medical clinics under the Korea National Health Insurance program: an observational study using claims data.

PubMed

Kang, Hee-Chung; Hong, Jae-Seok

2011-08-16

With a greater emphasis on cost containment in many health care systems, it has become common to evaluate each physician's relative resource use. This study explored the major factors that influence the economic performance rankings of medical clinics in the Korea National Health Insurance (NHI) program by assessing the consistency between cost-efficiency indices constructed using different profiling criteria. Data on medical care benefit costs for outpatient care at medical clinics nationwide were collected from the NHI claims database. We calculated eight types of cost-efficiency index with different profiling criteria for each medical clinic and investigated the agreement between the decile rankings of each index pair using the weighted kappa statistic. The exclusion of pharmacy cost lowered agreement between rankings to the lowest level, and differences in case-mix classification also lowered agreement considerably. A medical clinic may be identified as either cost-efficient or cost-inefficient, even when using the same index, depending on the profiling criteria applied. Whether a country has a single insurance or a multiple-insurer system, it is very important to have standardized profiling criteria for the consolidated management of health care costs.

Safety assessment of genetically modified rice expressing human serum albumin from urine metabonomics and fecal bacterial profile.

PubMed

Qi, Xiaozhe; Chen, Siyuan; Sheng, Yao; Guo, Mingzhang; Liu, Yifei; He, Xiaoyun; Huang, Kunlun; Xu, Wentao

2015-02-01

The genetically modified (GM) rice expressing human serum albumin (HSA) is used for non-food purposes; however, its food safety assessment should be conducted due to the probability of accidental mixture with conventional food. In this research, Sprague Dawley rats were fed diets containing 50% (wt/wt) GM rice expressing HSA or non-GM rice for 90 days. Urine metabolites were detected by (1)H NMR to examine the changes of the metabolites in the dynamic process of metabolism. Fecal bacterial profiles were detected by denaturing gradient gel electrophoresis to reflect intestinal health. Additionally, short chain fatty acids and fecal enzymes were investigated. The results showed that compared with rats fed the non-GM rice, some significant differences were observed in rats fed with the GM rice; however, these changes were not significantly different from the control diet group. Additionally, the gut microbiota was associated with blood indexes and urine metabolites. In conclusion, the GM rice diet is as safe as the traditional daily diet. Furthermore, urine metabonomics and fecal bacterial profiles provide a non-invasive food safety assessment rat model for genetically modified crops that are used for non-food/feed purposes. Fecal bacterial profiles have the potential for predicting the change of blood indexes in future. Copyright © 2014 Elsevier Ltd. All rights reserved.

Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa

PubMed Central

Nel, Annalene; Bekker, Linda-Gail; Bukusi, Elizabeth; Hellstrӧm, Elizabeth; Kotze, Philip; Louw, Cheryl; Martinson, Francis; Masenga, Gileard; Montgomery, Elizabeth; Ndaba, Nelisiwe; van der Straten, Ariane; van Niekerk, Neliëtte; Woodsong, Cynthia

2016-01-01

Background This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. Objectives The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. Methods 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. Results No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. Conclusions The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of

Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa.

PubMed

Nel, Annalene; Bekker, Linda-Gail; Bukusi, Elizabeth; Hellstrӧm, Elizabeth; Kotze, Philip; Louw, Cheryl; Martinson, Francis; Masenga, Gileard; Montgomery, Elizabeth; Ndaba, Nelisiwe; van der Straten, Ariane; van Niekerk, Neliëtte; Woodsong, Cynthia

2016-01-01

This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women

Clinical safety and efficacy of "filgrastim biosimilar 2" in Japanese patients in a post-marketing surveillance study.

PubMed

Tamura, Kazuo; Hashimoto, Kazue; Nishikawa, Kiyohiro

2018-05-01

We conducted a post-marketing surveillance to evaluate the safety and efficacy of TKN732, approved as "filgrastim biosimilar 2", in Japanese patients who developed neutropenia in the course of cancer chemotherapy or hematopoietic stem cell transplantation. A total of 653 patients were registered during the 2-year enrollment period starting from May 2013, and 627 and 614 patients were eligible for safety and efficacy analyses of the G-CSF biosimilar, respectively. Forty-three adverse drug reactions were reported in 33 patients (5.26%). Back pain was most frequently observed and reported in 20 patients (3.19%), followed by pyrexia (1.28%) and bone pain (0.96%). Risk factors for adverse reactions identified by logistic regression analyses were younger age, presence of past medical history, and lower total dose at the onset of adverse reactions. Among the 576 cancer patients who developed Grade 2-4 neutropenia after chemotherapy, recovery to Grade 1/0 was reported in 553 patients (96%) following filgrastim biosimilar 2 treatment. The median duration of neutrophil counts below 1500/μL was 5 days. In addition, all 11 patients who underwent hematopoietic stem cell transplantation had good responses to filgrastim biosimilar 2. In conclusion, this study showed that filgrastim biosimilar 2 has a similar safety profile and comparable effects to the original G-CSF product in the real world clinical setting. Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Profiles of Personal Resiliency for Normative and Clinical Samples of Youth Assessed by the Resiliency Scales for Children and Adolescents[TM

ERIC Educational Resources Information Center

Prince-Embury, Sandra; Steer, Robert A.

2010-01-01

Cluster analyses with the three global scores of the Resiliency Scales for Children and Adolescents[TM] (RSCA) were used to determine personal resiliency profiles within normative (641) and outpatient clinical (285) samples of youth aged 9 to 18 years. Normative and clinical profiles were compared with each other and the clinical profiles were…

Clinical Pharmacology and Cardiovascular Safety of Naproxen.

PubMed

Angiolillo, Dominick J; Weisman, Steven M

2017-04-01

The voluntary withdrawal of Vioxx (rofecoxib) from the market in 2004, as well as the 2005 and 2014 US FDA Advisory Committee meetings about non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, have raised questions surrounding the use of NSAIDs in at-risk populations. This paper discusses the cardiovascular safety profile of naproxen in the context of the NSAID class. The balance of evidence suggests that cardiovascular risk correlates with cyclooxygenase (COX)-2 selectivity, and the low COX-2 selectivity of naproxen results in a lower cardiovascular risk than that of other NSAIDs. The over-the-counter (OTC) use of naproxen is expected to pose minimal cardiovascular risk; however, the benefit-risk ratio and appropriate use should be considered at an individual patient level, particularly to assess underlying conditions that may increase the risk of events. Likewise, regulatory authorities should revisit label information periodically to ensure labeling reflects the current understanding of benefits and risks.

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

PubMed

Andrade, E L; Bento, A F; Cavalli, J; Oliveira, S K; Schwanke, R C; Siqueira, J M; Freitas, C S; Marcon, R; Calixto, J B

2016-12-12

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

Direct measurements of safety factor profiles with motional Stark effect for KSTAR tokamak discharges with internal transport barriers

NASA Astrophysics Data System (ADS)

Ko, J.; Chung, J.

2017-06-01

The safety factor profile evolutions have been measured from the plasma discharges with the external current drive mechanism such as the multi-ion-source neutral beam injection for the Korea Superconducting Tokamak Advanced Research (KSTAR) for the first time. This measurement has been possible by the newly installed motional Stark effect (MSE) diagnostic system that utilizes the polarized Balmer-alpha emission from the energetic neutral deuterium atoms induced by the Stark effect under the Lorentz electric field. The 25-channel KSTAR MSE diagnostic is based on the conventional photoelastic modulator approach with the spatial and temporal resolutions less than 2 cm (for the most of the channels except 2 to 3 channels inside the magnetic axis) and about 10 ms, respectively. The strong Faraday rotation imposed on the optical elements in the diagnostic system is calibrated out from a separate and well-designed polarization measurement procedure using an in-vessel reference polarizer during the toroidal-field ramp-up phase before the plasma experiment starts. The combination of the non-inductive current drive during the ramp-up and shape control enables the formation of the internal transport barrier where the pitch angle profiles indicate flat or slightly hollow profiles in the safety factor.

Pre-clinical efficacy and safety of experimental vaccines based on non-replicating vaccinia vectors against yellow fever.

PubMed

Schäfer, Birgit; Holzer, Georg W; Joachimsthaler, Alexandra; Coulibaly, Sogue; Schwendinger, Michael; Crowe, Brian A; Kreil, Thomas R; Barrett, P Noel; Falkner, Falko G

2011-01-01

Currently existing yellow fever (YF) vaccines are based on the live attenuated yellow fever virus 17D strain (YFV-17D). Although, a good safety profile was historically attributed to the 17D vaccine, serious adverse events have been reported, making the development of a safer, more modern vaccine desirable. A gene encoding the precursor of the membrane and envelope (prME) protein of the YFV-17D strain was inserted into the non-replicating modified vaccinia virus Ankara and into the D4R-defective vaccinia virus. Candidate vaccines based on the recombinant vaccinia viruses were assessed for immunogenicity and protection in a mouse model and compared to the commercial YFV-17D vaccine. The recombinant live vaccines induced γ-interferon-secreting CD4- and functionally active CD8-T cells, and conferred full protection against lethal challenge already after a single low immunization dose of 10(5) TCID(50). Surprisingly, pre-existing immunity against wild-type vaccinia virus did not negatively influence protection. Unlike the classical 17D vaccine, the vaccinia virus-based vaccines did not cause mortality following intracerebral administration in mice, demonstrating better safety profiles. The non-replicating recombinant YF candidate live vaccines induced a broad immune response after single dose administration, were effective even in the presence of a pre-existing immunity against vaccinia virus and demonstrated an excellent safety profile in mice.

Drug safety assurance through clinical genotyping: near-term considerations for a system-wide implementation of personalized medicine.

PubMed

Kane, Michael D; Springer, John A; Sprague, Jon E

2008-07-01

The rationale and overall system-wide behavior of a clinical genotyping information system (both DNA analysis and data management) requires a near-term, scalable approach, which is emerging in the focused implementation of pharmacogenomics and drug safety assurance. The challenges to implementing a successful clinical genotyping system are described, as are how the benefits of a focused, near-term system for drug safety assessment and assurance overcome the logistical and operational challenges that perpetually hinder the development of a societal-scale clinical genotyping system. This rationale is based on the premise that a focused application domain for clinical genotyping, specifically drug safety assurance, provides a transition paradigm for both professionals and consumers of healthcare, thereby facilitating the movement of genotyping from bench to bedside and paving the way for the adoption of prognostic and diagnostic applications in clinical genomics.

75 FR 47602 - Clinical Studies of Safety and Effectiveness of Orphan Products Research Project Grant (R01)

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-06

...] Clinical Studies of Safety and Effectiveness of Orphan Products Research Project Grant (R01) AGENCY: Food... product will be superior to the existing therapy. FDA provides grants for clinical studies on safety and... vaccine annually) and an explanation of how the proposed study will either help support product approval...

Highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulator demonstrates improved safety profile compared to GW501516.

PubMed

Lagu, Bharat; Kluge, Arthur F; Goddeeris, Matthew M; Tozzo, Effie; Fredenburg, Ross A; Chellur, Shekar; Senaiar, Ramesh S; Jaleel, Mahaboobi; Babu, D Ravi Krishna; Tiwari, Nirbhay K; Takahashi, Taisuke; Patane, Michael A

2017-11-04

Compound 1 regulates significantly fewer genes than the PPARδ modulator, GW501516. Both compounds are efficacious in a thermal injury model of muscle regeneration. The restricted gene profile of 1 relative to GW501516 suggests that 1 may be pharmacoequivalent to GW501516 with fewer PPAR-related safety concerns. Copyright © 2017 Elsevier Ltd. All rights reserved.

SAFETY: an integrated clinical reasoning and reflection framework for undergraduate nursing students.

PubMed

Hicks Russell, Bedelia; Geist, Melissa J; House Maffett, Jenny

2013-01-01

Nurse educators can no longer focus on imparting to students knowledge that is merely factual and content specific. Activities that provide students with opportunities to apply concepts in real-world scenarios can be powerful tools. Nurse educators should take advantage of student-patient interactions to model clinical reasoning and allow students to practice complex decision making throughout the entire curriculum. In response to this change in nursing education, faculty in a pediatric course designed a reflective clinical reasoning activity based on the SAFETY template, which is derived from the National Council of State Boards of Nursing RN practice analysis. Students were able to prioritize key components of nursing care, as well as integrate practice issues such as delegation, Health Insurance Portability and Accountability Act violations, and questioning the accuracy of orders. SAFETY is proposed as a framework for integration of content knowledge, clinical reasoning, and reflection on authentic professional nursing concerns. Copyright 2012, SLACK Incorporated.

Safety and tolerability of new-generation anti-obesity medications: a narrative review.

PubMed

Patel, Dhiren K; Stanford, Fatima Cody

2018-03-01

The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk-benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk-benefit for anti-obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk-benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk-benefit.

Biotherapeutics in non-clinical development: Strengthening the interface between safety, pharmacokinetics-pharmacodynamics and manufacturing.

PubMed

Ulrich, Peter; Blaich, Guenter; Baumann, Andreas; Fagg, Rajni; Hey, Adam; Kiessling, Andrea; Kronenberg, Sven; Lindecrona, Rikke Hvid; Mohl, Silke; Richter, Wolfgang F; Tibbitts, Jay; Crameri, Flavio; Weir, Lucinda

2018-04-01

Biological drugs comprise a wide field of different modalities with respect to structure, pharmacokinetics and pharmacological function. Considerable non-clinical experience in the development of proteins (e.g. insulin) and antibodies has been accumulated over the past thirty years. In order to improve the efficacy and the safety of these biotherapeutics, Fc modifications (e.g. Fc silent antibody versions), combinations (antibody-drug conjugates, protein-nanoparticle combinations), and new constructs (darpins, fynomers) have been introduced. In the last decade, advanced therapy medicinal products (ATMPs) in research and development have become a considerable and strongly growing part of the biotherapeutic portfolio. ATMPs consisting of gene and cell therapy modalities or even combinations of them, further expand the level of complexity, which already exists in non-clinical development strategies for biological drugs and has thereby led to a further diversification of expertise in safety and PKPD assessment of biological drugs. It is the fundamental rationale of the BioSafe meetings, held yearly in the EU and in the US, to convene experts on a regular basis and foster knowledge exchange and mutual understanding in this fast growing area. In order to reflect at least partially the variety of the biotherapeutics field, the 2016 EU BioSafe meeting addressed the following topics in six sessions: (i) In vitro Meets in vivo to Leverage Biologics Development (ii) New developments and regulatory considerations in the cell and gene therapy field (iii) CMC Challenges with Biologics development (iv) Minipigs in non-clinical safety assessment (v) Opportunities of PKPD Assessment in Less Common Administration Routes In the breakout sessions the following questions were discussed: (i) Cynomolgus monkey as a reprotoxicology Species: Impact of Immunomodulators on Early Pregnancy Maintenance (ii) Safety Risk of Inflammation and Autoimmunity Induced by Immunomodulators (iii

Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent.

PubMed

Parrish-Novak, Julia; Byrnes-Blake, Kelly; Lalayeva, Narine; Burleson, Stefanie; Fidel, Janean; Gilmore, Rhonda; Gayheart-Walsten, Pamela; Bricker, Gregory A; Crumb, William J; Tarlo, K S; Hansen, Stacey; Wiss, Valorie; Malta, Errol; Dernell, William S; Olson, James M; Miller, Dennis M

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.

Patient safety climate profiles across time: Strength and level of safety climate associated with a quality improvement program in Switzerland-A cross-sectional survey study.

PubMed

Mascherek, Anna C; Schwappach, David L B

2017-01-01

Safety Climate has been acknowledged as an unspecific factor influencing patient safety. However, studies rarely provide in-depth analysis of climate data. As a helpful approach, the concept of "climate strength" has been proposed. In the present study we tested the hypotheses that even if safety climate remains stable on mean-level across time, differences might be evident in strength or shape. The data of two hospitals participating in a large national quality improvement program were analysed for differences in climate profiles at two measurement occasions. We analysed differences on mean-level, differences in percent problematic response, agreement within groups, and frequency histograms in two large hospitals in Switzerland at two measurement occasions (2013 and 2015) applying the Safety Climate Survey. In total, survey responses of 1193 individuals were included in the analyses. Overall, small but significant differences on mean-level of safety climate emerged for some subgroups. Also, although agreement was strong at both time-points within groups, tendencies of divergence or consensus were present in both hospitals. Depending on subgroup and analyses chosen, differences were more or less pronounced. The present study illustrated that taking several measures into account and describing safety climate from different perspectives is necessary in order to fully understand differences and trends within groups and to develop interventions addressing the needs of different groups more precisely.

Patient safety climate profiles across time: Strength and level of safety climate associated with a quality improvement program in Switzerland—A cross-sectional survey study

PubMed Central

Mascherek, Anna C.

2017-01-01

Safety Climate has been acknowledged as an unspecific factor influencing patient safety. However, studies rarely provide in-depth analysis of climate data. As a helpful approach, the concept of “climate strength” has been proposed. In the present study we tested the hypotheses that even if safety climate remains stable on mean-level across time, differences might be evident in strength or shape. The data of two hospitals participating in a large national quality improvement program were analysed for differences in climate profiles at two measurement occasions. We analysed differences on mean-level, differences in percent problematic response, agreement within groups, and frequency histograms in two large hospitals in Switzerland at two measurement occasions (2013 and 2015) applying the Safety Climate Survey. In total, survey responses of 1193 individuals were included in the analyses. Overall, small but significant differences on mean-level of safety climate emerged for some subgroups. Also, although agreement was strong at both time-points within groups, tendencies of divergence or consensus were present in both hospitals. Depending on subgroup and analyses chosen, differences were more or less pronounced. The present study illustrated that taking several measures into account and describing safety climate from different perspectives is necessary in order to fully understand differences and trends within groups and to develop interventions addressing the needs of different groups more precisely. PMID:28753633

Safety and efficacy of elbasvir and grazoprevir for treatment of hepatitis C.

PubMed

Carrion, Andres F; Martin, Paul

2016-06-01

The combination of elbasvir and grazoprevir in a single co-formulated tablet is highly effective for treatment of hepatitis C virus (HCV) infection. This regimen affords profound inhibition of NS3/4A protease and NS5A activity, resulting in potent activity against HCV genotypes 1, 4, and 6 with high rates of sustained virological response. This review covers the mechanism of action, pharmacokinetics, clinical applications, efficacy and safety profile of elbasvir/grazoprevir including special populations such as individuals with compensated and decompensated cirrhosis, HCV/HIV co-infection, advanced chronic kidney disease, and those that previously failed antiviral therapy. Elbasvir/grazoprevir is an effective antiviral regimen for treatment of genotypes 1 and 4 and has a very favorable safety profile based on extensive data from several pre-licensure clinical trials that included patient subgroups at increased risk of toxicity. This regimen is currently the only one licensed for use in individuals with advanced chronic kidney disease requiring hemodialysis.

Conversational assessment in memory clinic encounters: interactional profiling for differentiating dementia from functional memory disorders.

PubMed

Jones, Danielle; Drew, Paul; Elsey, Christopher; Blackburn, Daniel; Wakefield, Sarah; Harkness, Kirsty; Reuber, Markus

2016-01-01

In the UK dementia is under-diagnosed, there is limited access to specialist memory clinics, and many of the patients referred to such clinics are ultimately found to have functional (non-progressive) memory disorders (FMD), rather than a neurodegenerative disorder. Government initiatives on 'timely diagnosis' aim to improve the rate and quality of diagnosis for those with dementia. This study seeks to improve the screening and diagnostic process by analysing communication between clinicians and patients during initial specialist clinic visits. Establishing differential conversational profiles could help the timely differential diagnosis of memory complaints. This study is based on video- and audio recordings of 25 initial consultations between neurologists and patients referred to a UK memory clinic. Conversation analysis was used to explore recurrent communicative practices associated with each diagnostic group. Two discrete conversational profiles began to emerge, to help differentiate between patients with dementia and functional memory complaints, based on (1) whether the patient is able to answer questions about personal information; (2) whether they can display working memory in interaction; (3) whether they are able to respond to compound questions; (4) the time taken to respond to questions; and (5) the level of detail they offer when providing an account of their memory failure experiences. The distinctive conversational profiles observed in patients with functional memory complaints on the one hand and neurodegenerative memory conditions on the other suggest that conversational profiling can support the differential diagnosis of functional and neurodegenerative memory disorders.

Electrical safety Q&A. A reference guide for the clinical engineer.

PubMed

2005-02-01

This guide, which ECRI developed to answer the electrical safety questions most frequently asked by member hospitals, features practical advice for addressing electrical safety concerns in the healthcare environment. Questions addressed include: STANDARDS AND APPROVALS: What electrical safety standards apply? How do NFPA 99 and IEC 60601-1 differ? What organizations approve medical devices? LEAKAGE CURRENT LIMITS AND TESTING: How are leakage current limits established? What limits apply to equipment used in the hospital? And how should the limits be applied in special cases, such as the use of PCs in the patient care area or equipment used in the clinical laboratory? ISOLATED POWER: What are its advantages and disadvantages, and is isolated power needed in the operating room? Other topics addressed include double insulation, ground-fault circuit interrupters (GFCIs), and requirements for medical devices used in the home. Supplementary articles discuss acceptable alternatives to UL listing, the use of Hospital Grade plugs, the limitations of leakage current testing of devices connected to isolated power systems, and the debate about whether to designate ORs as wet locations. Experienced clinical engineers should find this guide to be a handy reference, while those new to the field should find it to be a helpful educational resource.

Safety and clinical performance of acoustic reflex tests.

PubMed

Hunter, L L; Ries, D T; Schlauch, R S; Levine, S C; Ward, W D

1999-12-01

Safety and effectiveness of acoustic reflex tests are important issues because these tests are widely applied to screen for retrocochlear pathology. Previous studies have reported moderately high sensitivity and specificity for detection of acoustic neuroma. However, there have been reports of possible iatrogenic hearing loss resulting from acoustic reflex threshold (ART) and decay (ARD) tests. This study assessed safety and clinical performance of ART tests for detection of acoustic neuroma. We report a case in which ARD testing resulted in a significant bilateral permanent threshold shift. This case was the impetus for us to investigate the clinical utility of ART and ARD tests. We analyzed sensitivity and specificity of ART, as well as asymmetry in pure-tone thresholds (PTT) for detection of acoustic neuroma in 56 tumor and 108 non-tumor ears. Sensitivity and specificity were higher for PTT asymmetry than for ART. Ipsilateral ART at 1000 Hz had poor sensitivity and specificity for detection of acoustic neuroma, and involves some potential risk to residual hearing for presentation levels higher than 115 dB SPL. Approximately half of the acoustic neuroma group had ipsilateral ARTs that would require administration of ARD tests at levels exceeding 115 dB SPL. Therefore, we conclude that PTT asymmetry is a more effective test for detection of acoustic neuroma, and involves no risk to residual hearing. Future studies of contralateral reflex threshold and ARD in combination with PTT asymmetry are recommended.

[Clinical safety data management in company non-sponsored trials].

PubMed

Saito, Akiko; Sakai, Junko; Kurihara, Masaaki; Kami, Masahiro; Kanda, Yoshinobu; Mori, Shin-ichiro; Takaue, Yoichi; Ohashi, Yasuo

2003-09-01

There is currently no harmonized way in Japan to manage safety data which are obtained during clinical trials supported by Government funds. There are two types of clinical trials, 'sponsored trials(sponsored by industrial companies)' and 'non-sponsored trials(funded by the Government, etc.)'. The Japanese Ministry of Health and Welfare has issued many of pharmaceutical laws(GCP, GPMSP etc.) for the regulation of sponsored trials, while none has ever established for non-sponsored trials, thus leaving the most important quality control/assurance unregulated. In this manuscript we discuss that the simple application of pharmaceutical laws to government-sponsored trials can not be a proper answer because of the different nature of the two types of trials.

The effects of the non-contingent presentation of safety signals on the elimination of safety behaviors: An experimental comparison between individuals with low and high obsessive-compulsive profiles.

PubMed

Angelakis, Ioannis; Austin, Jennifer L

2018-06-01

Safety behaviors, defined as engagement in avoidance within safe environments, are a key symptom of obsessive-compulsive and related disorders. They may interfere with daily functioning and as such their emission should be reduced. The purpose of the current study is to investigate the effects of the non-contingent presentation of safety signals (cues produced by safety behaviors) on reducing safety behaviors in participants self-reporting low and high OCD profiles. In total, 32 participants were asked to play a game to gain points and avoid their loss. After having developed avoidance behavior, evidenced by maintaining all of their earned points, they were exposed to safe environments where no point loss was programmed. In Test 1, safety cues (blue bar) were produced contingent on performing safety behaviors. In Test 2, safety cues were presented continuously without any response requirement. Findings demonstrated that high OCD group displayed higher rates of safety behaviors than low OCD group. However, exposure to the non-contingent presentation of safety signals eliminated their emission in both groups. Future studies need to evaluate the effects of different non-contingent schedules on the suppression of safety behaviors. These findings contribute to the literature by demonstrating that non-contingent introduction of safety signals eliminated safety behaviors completely, even in high OCD participants, who performed safety behavior at higher rates. Such a treatment protocol may ameliorate exposure therapy in which response prevention constitutes a key element and is generally associated with increased drop-out rates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies.

PubMed

Ponce, Rafael; Abad, Leslie; Amaravadi, Lakshmi; Gelzleichter, Thomas; Gore, Elizabeth; Green, James; Gupta, Shalini; Herzyk, Danuta; Hurst, Christopher; Ivens, Inge A; Kawabata, Thomas; Maier, Curtis; Mounho, Barbara; Rup, Bonita; Shankar, Gopi; Smith, Holly; Thomas, Peter; Wierda, Dan

2009-07-01

An evaluation of potential antibody formation to biologic therapeutics during the course of nonclinical safety studies and its impact on the toxicity profile is expected under current regulatory guidance and is accepted standard practice. However, approaches for incorporating this information in the interpretation of nonclinical safety studies are not clearly established. Described here are the immunological basis of anti-drug antibody formation to biopharmaceuticals (immunogenicity) in laboratory animals, and approaches for generating and interpreting immunogenicity data from nonclinical safety studies of biotechnology-derived therapeutics to support their progression to clinical evaluation. We subscribe that immunogenicity testing strategies should be adapted to the specific needs of each therapeutic development program, and data generated from such analyses should be integrated with available clinical and anatomic pathology, pharmacokinetic, and pharmacodynamic data to properly interpret nonclinical studies.

The Evaluation Of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model

PubMed Central

Zhang, Yijia; Jia, Zhenshan; Yuan, Hongjiang; Dusad, Anand; Ren, Ke; Wei, Xin; Fehringer, Edward V.; Purdue, P. Edward; Daluiski, Aaron; Goldring, Steven R.; Wang, Dong

2016-01-01

Purpose To evaluate the therapeutic efficiency of a micellar prodrug formulation of simvastatin (SIM/SIM-mPEG) and explore its safety in a closed femoral fracture mouse model. Methods The amphiphilic macromolecular prodrug of simvastatin (SIM-mPEG) was synthesized and formulated together with free simvastatin into micelles. It was also labeled with a near infrared dye for in vivo imaging purpose. A closed femoral fracture mouse model was established using a three-point bending device. The mice with established closed femoral fracture were treated with SIM/SIM-mPEG micelle, using free simvastatin and saline as controls. The therapeutic efficacy of the micelles was evaluated using a high-resolution micro-CT. Serum biochemistry and histology analyses were performed to explore the potential toxicity of the micelle formulation. Results Near Infrared Fluorescence (NIRF) imaging confirmed the passive targeting of SIM/SIM-mPEG micelles to the bone lesion of the mice with closed femoral fracture. The micelle was found to promote fracture healing with an excellent safety profile. In addition, the accelerated healing of the femoral fracture also helped to prevent disuse-associated same-side tibia bone loss accompanying the femur fracture. Conclusion SIM/SIM-mPEG micelle was found to be an effective and safe treatment for closed femoral fracture repair in mice. The evidence obtained in this study suggests that it may have the potential to be translated into a novel therapy for clinical management of skeletal fractures and non-union. PMID:27164897

Pre-Clinical Efficacy and Safety of Experimental Vaccines Based on Non-Replicating Vaccinia Vectors against Yellow Fever

PubMed Central

Schäfer, Birgit; Holzer, Georg W.; Joachimsthaler, Alexandra; Coulibaly, Sogue; Schwendinger, Michael; Crowe, Brian A.; Kreil, Thomas R.; Barrett, P. Noel; Falkner, Falko G.

2011-01-01

Background Currently existing yellow fever (YF) vaccines are based on the live attenuated yellow fever virus 17D strain (YFV-17D). Although, a good safety profile was historically attributed to the 17D vaccine, serious adverse events have been reported, making the development of a safer, more modern vaccine desirable. Methodology/Principal Findings A gene encoding the precursor of the membrane and envelope (prME) protein of the YFV-17D strain was inserted into the non-replicating modified vaccinia virus Ankara and into the D4R-defective vaccinia virus. Candidate vaccines based on the recombinant vaccinia viruses were assessed for immunogenicity and protection in a mouse model and compared to the commercial YFV-17D vaccine. The recombinant live vaccines induced γ-interferon-secreting CD4- and functionally active CD8-T cells, and conferred full protection against lethal challenge already after a single low immunization dose of 105 TCID50. Surprisingly, pre-existing immunity against wild-type vaccinia virus did not negatively influence protection. Unlike the classical 17D vaccine, the vaccinia virus-based vaccines did not cause mortality following intracerebral administration in mice, demonstrating better safety profiles. Conclusions/Significance The non-replicating recombinant YF candidate live vaccines induced a broad immune response after single dose administration, were effective even in the presence of a pre-existing immunity against vaccinia virus and demonstrated an excellent safety profile in mice. PMID:21931732

Drug safety evaluation of defibrotide.

PubMed

Richardson, Paul G; Corbacioglu, Selim; Ho, Vincent Trien-Vinh; Kernan, Nancy A; Lehmann, Leslie; Maguire, Craig; Maglio, Michelle; Hoyle, Margaret; Sardella, Marco; Giralt, Sergio; Holler, Ernst; Carreras, Enric; Niederwieser, Dietger; Soiffer, Robert

2013-01-01

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of chemotherapeutic conditioning used in preparation for hematopoietic stem-cell transplantation (SCT). Defibrotide (DF) has been shown in Phase II and III trials to improve complete response in patients with severe VOD (sVOD). None of the articles, to date, provide a comprehensive review of the safety of DF in VOD and/or a range of other conditions. This article reviews current clinical findings on DF, primarily in terms of safety for use in treatment and prophylaxis of VOD, and relevant safety data for its use in other diseases. The literature review was conducted using a PubMed search with the fixed term 'defibrotide' in combination with ≥ 1 of 'safety', 'veno-occlusive disease' (with and without 'treatment', 'prevention'), 'oncology', 'myeloma', 'microangiopathy', 'anti-thrombotic' and 'peripheral vascular disorder'. Related articles from the EBMT and ASH conference websites were also included. DF was well tolerated in majority of the studies. The safety profile of DF is largely favourable with toxicities comparable to control populations in the setting of SCT complicated by sVOD.

Long-term Safety and Efficacy of Low-dose Azathioprine and Allopurinol Cotherapy in Inflammatory Bowel Disease: A Large Observational Study.

PubMed

Pavlidis, Polychronis; Stamoulos, Panagiotis; Abdulrehman, Answar; Kerr, Patrick; Bull, Claire; Duley, John; Ansari, Azhar

2016-07-01

Low-dose azathioprine with allopurinol (LDAA) has been proposed as a potent therapy in inflammatory bowel disease (IBD) with the benefit of overcoming side effects regularly associated with thiopurine monotherapy and poor responses. Concerns regarding safety remain, while a layer of complexity has been added by the trend toward treatment directed by red cell thioguanine nucleotide (TGN) profiling. We report on the clinical efficacy and safety of LDAA use in IBD undirected by metabolite profiling. Observational study of clinical practice from a single IBD center. Patient outcomes were defined clinically based on established activity scores and corticosteroid withdrawal. Red cell TGN was monitored only for suspected nonadherence. Overall, 113/164 (69%) patients with Crohn's disease and 83/136 (61%) patients with ulcerative/unclassified colitis had a clinical response by the end of follow-up (median 19 months), while 85 (52%) patients with Crohn's disease and 74 (54%) patients with ulcerative/unclassified colitis were in clinical remission. Clinical response was seen in 45/57 (79%) patients with Crohn's disease and 34/53 (64%) patients with ulcerative/unclassified colitis who were thiopurine naive, had active IBD, and received LDAA as the first line immunomodulator, while in 35 (61%) and 28 (53%), respectively, remission was achieved. LDAA was stopped in 20/300 (7%) patients because of side effects, all of which resolved on drug cessation. This is the largest cohort supporting the favorable safety profile and high efficacy of LDAA in IBD. It presents 2 advances in therapy: prescribing LDAA for thiopurine-naive patients, and bypassing TGN monitoring in favor of clinical monitoring (blood counts, etc.), which will make it more accessible for clinics without access to TGN assays.

Nanodrugs: pharmacokinetics and safety

PubMed Central

Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

2014-01-01

To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

The clinical safety of high-dose piracetam--its use in the treatment of acute stroke.

PubMed

De Reuck, J; Van Vleymen, B

1999-03-01

Recent post-marketing surveillance reports have confirmed the benign safety profile and lack of organ toxicity shown by piracetam during its 25 years of clinical usage. Tolerance has proved equally good with the more recent use of larger doses (up to 24 g/day) for the long-term control of cortical myoclonus and when given intravenously to patients with acute stroke. This paper provides a brief review of these findings and records the safety of piracetam as found in the Piracetam in Acute Stroke Study (PASS), a randomized multicenter placebo-controlled study in 927 patients with acute ischemic stroke. Patients receive one intravenous bolus injection of placebo or 12 g piracetam, piracetam 12 g daily for 4 weeks and maintenance treatment for 8 weeks. The major results have been reported (De Deyn et al., Stroke 28 [1997] 2347-2352). Safety was assessed taking into account adverse events including abnormal laboratory test results and mortality. Death within 12 weeks occurred more frequently in the piracetam group but the difference from placebo was not significant. Of many potential risk, prognostic and treatment-related factors examined by logistic regression, 6 contributed significantly to death of which the most important were initial severity of stroke and age. Neither treatment nor any treatment-related factor contributed significantly to death. Adverse events were similar in frequency, type and severity in piracetam and placebo groups. Events of cerebral, non-cerebral and uncertain origin likewise occurred with similar frequency. Few patients discontinued because of adverse events. There was no difference between treatments in the frequency of events associated with bleeding, including hemorrhagic transformation of infarction. An important finding was that, of 31 patients with primary hemorrhagic stroke enrolled, 3 piracetam-treated patients died compared with 6 on placebo. The results suggest that piracetam in high dosage may be given to patients with acute

The Hampstead Clinic at work. Discussions in the Diagnostic Profile Research Group.

PubMed

Koch, Ehud

2012-01-01

Minutes of the Hampstead Clinic's Diagnostic Profile Research Group during a fifteen-month period (1964-1965) are reviewed and discussed. A wide range of topics were considered and discussed, with a special focus on the affective life, object relations, and ego function of atypical children in comparison to the early ego functions and differentiation of normal and neurotic children. These lively clinical and theoretical discussions and their implications for therapeutic work with a wide range of children, demonstrate the multifaceted leadership and contributions of Anna Freud as teacher, clinician, and thinker, and of the Hampstead Clinic as a major center for psychoanalytic studies.

Efficacy and safety of adapalene gel 0.1% and 0.3% and tretinoin gel 0.05% for acne vulgaris: results of a single-center, randomized, double-blinded, placebo-controlled clinical trial on Mexican patients (skin type III-IV).

PubMed

Tirado-Sánchez, Andrés; Espíndola, Yareni Salas; Ponce-Olivera, Rosa María; Bonifaz, Alexandro

2013-06-01

The efficacy of topical retinoids is well known according to several clinical studies conducted predominantly among Caucasian patients. This study aimed to evaluate the efficacy and safety profile of adapalene and tretinoin among Mexican patients. To compare adapalene 0.1 and 0.3% and tretinoin 0.05% in Mexican subjects with acne vulgaris. We enrolled 171 patients in this single-center, randomized, double-blinded, placebo-controlled clinical trial. The patients applied on the face either adapalene 0.1%, adapalene 0.3%, tretinoin 0.05%, or placebo for 90 days and were evaluated for the reduction in total lesion counts and for the level of irritation. Tretinoin 0.05% and adapalene 0.3% were more effective than adapalene 0.1% and placebo in the reduction of both inflammatory and noninflammatory lesions. Most of adverse events to adapalene and many on tretinoin group were related to skin irritation, dry skin, scaling, pruritus, burning, and postinflammatory hyperpigmentation. Adapalene 0.3% and tretinoin 0.05% are comparable in efficacy, and adapalene 0.1% offers a better safety profile in Mexican patients. © 2013 Wiley Periodicals, Inc.

[Clinical and psychopathological profile of women victims of psychological partner violence].

PubMed

Lamy, C; Dubois, F; Jaafari, N; Carl, T; Gaillard, P; Camus, V; El Hage, W

2009-08-01

Partner violence is a serious public health problem, due to their potential short-, medium- or long-term physical and psychological consequences. Violence is unbearable when it occurs between family members, and often remains unrevealed, invisible, hidden and repeated. The woman possibly feels trapped in a relationship of imprisonment. International studies have well-explored the psychopathological aspects of physical and sexual abuse within couples, but few explored the clinical profile of women victims of psychological violence or moral harassment. This study aims to define the clinical and psychopathological profile of women who are victims of psychological intimate partner violence. We contacted 628 women who consulted consecutively at the emergency ward of a university hospital covering a 300,000 catchment area. The telephone screening of psychological violence was therefore carried out using the Women's Experience with Battering (WEB) questionnaire (N=226). An optional clinical interview was given to the women declaring themselves as victims of psychological intimate partner violence (N=56) to evaluate the life events and the psychiatric disorders according to the DSM-IV. Finally, 43 participants (77%) gave their opinion on the qualitative aspects of the WEB questionnaire and their level of ease with this report. In 63% (N=35) of the cases, the victims and their partners had a rather high socioprofessional level. Women refer to emergency ward mostly for complaint of vague idiopathic pain (49%) or for psychiatric disorders (52%) with predominance of anxiety (28%) or addictive disorders (19%). The prevalence of potentially traumatic life events was found to be high in this group (83%). The traumatic psychological intimate partner violence was associated with a heightened prevalence of psychiatric comorbidities, like anxiety (72%), depression (100%), posttraumatic stress disorder (100%), and addiction to alcohol (100%) or another psychoactive substance (50

Motor carrier safety performance profile.

DOT National Transportation Integrated Search

2004-02-01

This report provides a summary of the safety performance of carriers across all the individual segments in the industry. It includes summaries for both for-hire and private carriers in each segment and is drawn from measures that are collected as par...

The objective impact of clinical peer review on hospital quality and safety.

PubMed

Edwards, Marc T

2011-01-01

Despite its importance, the objective impact of clinical peer review on the quality and safety of care has not been studied. Data from 296 acute care hospitals show that peer review program and related organizational factors can explain up to 18% of the variation in standardized measures of quality and patient safety. The majority of programs rely on an outmoded and dysfunctional process model. Adoption of best practices informed by the continuing study of peer review program effectiveness has the potential to significantly improve patient outcomes.

ABC gene expression profiles have clinical importance and possibly form a new hallmark of cancer.

PubMed

Dvorak, Pavel; Pesta, Martin; Soucek, Pavel

2017-05-01

Adenosine triphosphate-binding cassette proteins constitute a large family of active transporters through extracellular and intracellular membranes. Increased drug efflux based on adenosine triphosphate-binding cassette protein activity is related to the development of cancer cell chemoresistance. Several articles have focused on adenosine triphosphate-binding cassette gene expression profiles (signatures), based on the expression of all 49 human adenosine triphosphate-binding cassette genes, in individual tumor types and reported connections to established clinicopathological features. The aim of this study was to test our theory about the existence of adenosine triphosphate-binding cassette gene expression profiles common to multiple types of tumors, which may modify tumor progression and provide clinically relevant information. Such general adenosine triphosphate-binding cassette profiles could constitute a new attribute of carcinogenesis. Our combined cohort consisted of tissues from 151 cancer patients-breast, colorectal, and pancreatic carcinomas. Standard protocols for RNA isolation and quantitative real-time polymerase chain reaction were followed. Gene expression data from individual tumor types as well as a merged tumor dataset were analyzed by bioinformatics tools. Several general adenosine triphosphate-binding cassette profiles, with differences in gene functions, were established and shown to have significant relations to clinicopathological features such as tumor size, histological grade, or clinical stage. Genes ABCC7, A3, A8, A12, and C8 prevailed among the most upregulated or downregulated ones. In conclusion, the results supported our theory about general adenosine triphosphate-binding cassette gene expression profiles and their importance for cancer on clinical as well as research levels. The presence of ABCC7 (official symbol CFTR) among the genes with key roles in the profiles supports the emerging evidence about its crucial role in various

A Review of the Efficacy, Safety, and Clinical Implications of Naturally Derived Dietary Supplements for Dyslipidemia.

PubMed

Thaipitakwong, Thanchanit; Aramwit, Pornanong

2017-02-01

Dyslipidemia is recognized as a major cause of cardiovascular disease. A number of evidence-based guidelines recommend conventional synthetic drugs as standard therapy for dyslipidemia in clinical practice. However, antihyperlipidemic drugs have some serious side effects. Naturally derived dietary supplements are becoming attractive as an alternative strategy because of their high efficacy and safety, as supported by numerous data. Moreover, they could be considered an initial treatment for dyslipidemia. The aims of this literature review were to demonstrate the efficacy, safety, and clinical implications of dietary supplements for treating dyslipidemia. We reviewed the literature, including data from in vitro, in vivo, and human studies, and clinical guideline recommendations. We classified dietary supplements by their proposed mechanisms of action on lipid metabolism and also collected daily dosage recommendations, interactions with concurrent drugs and/or foods, dosage forms, and examples of commercially available products. Various types of naturally derived dietary supplements exhibit lipid-improving properties. Efficacy and safety are acceptable; however, their use in clinical practice will require further well-designed investigations and the support of scientific data.

Integration Profile and Safety of an Adenovirus Hybrid-Vector Utilizing Hyperactive Sleeping Beauty Transposase for Somatic Integration

PubMed Central

Zhang, Wenli; Muck-Hausl, Martin; Wang, Jichang; Sun, Chuanbo; Gebbing, Maren; Miskey, Csaba; Ivics, Zoltan; Izsvak, Zsuzsanna; Ehrhardt, Anja

2013-01-01

We recently developed adenovirus/transposase hybrid-vectors utilizing the previously described hyperactive Sleeping Beauty (SB) transposase HSB5 for somatic integration and we could show stabilized transgene expression in mice and a canine model for hemophilia B. However, the safety profile of these hybrid-vectors with respect to vector dose and genotoxicity remains to be investigated. Herein, we evaluated this hybrid-vector system in C57Bl/6 mice with escalating vector dose settings. We found that in all mice which received the hyperactive SB transposase, transgene expression levels were stabilized in a dose-dependent manner and that the highest vector dose was accompanied by fatalities in mice. To analyze potential genotoxic side-effects due to somatic integration into host chromosomes, we performed a genome-wide integration site analysis using linker-mediated PCR (LM-PCR) and linear amplification-mediated PCR (LAM-PCR). Analysis of genomic DNA samples obtained from HSB5 treated female and male mice revealed a total of 1327 unique transposition events. Overall the chromosomal distribution pattern was close-to-random and we observed a random integration profile with respect to integration into gene and non-gene areas. Notably, when using the LM-PCR protocol, 27 extra-chromosomal integration events were identified, most likely caused by transposon excision and subsequent transposition into the delivered adenoviral vector genome. In total, this study provides a careful evaluation of the safety profile of adenovirus/Sleeping Beauty transposase hybrid-vectors. The obtained information will be useful when designing future preclinical studies utilizing hybrid-vectors in small and large animal models. PMID:24124483

Pooled analysis of large and long-term safety data from the human papillomavirus-16/18-AS04-adjuvanted vaccine clinical trial programme

PubMed Central

Angelo, Maria-Genalin; David, Marie-Pierre; Zima, Julia; Baril, Laurence; Dubin, Gary; Arellano, Felix; Struyf, Frank

2014-01-01

Purpose The purpose of this study is to further evaluate the safety of the human papillomavirus (HPV)-16/18-AS04-adjuvanted vaccine (HPV-16/18-vaccine Cervarix®, GlaxoSmithKline, Belgium) through a pooled analysis of data from 42 completed/ongoing clinical studies. Methods Unsolicited adverse events (AEs) were reported for 30 days after each dose. Medically significant conditions, serious AEs (SAEs), potential immune-mediated diseases (pIMDs) and pregnancy outcomes were captured until study completion. Events leading to subject withdrawal were reviewed. Relative risks compared incidences of spontaneous abortion and pIMDs in controlled studies. Results Thirty one thousand one hundred seventy-three adolescent girls/women received HPV-16/18-vaccine alone (HPV group), 2166 received HPV-16/18-vaccine coadministered with another vaccine and 24 241 were controls. Mean follow-up was 39 months (range 0–113.3). Incidences of unsolicited AEs reported within 30 days after any dose were similar between HPV and Control groups (30.8%/29.7%). During the entire study period, reports of medically significant conditions (25.0%/28.3%) and SAEs (7.9%/9.3%) were also similarly distributed between groups. Deaths were rare: HPV (alone/coadministered) n = 25, controls n = 20 (n = 18 in blinded groups). pIMDs within 1 year were reported by 0.2% of HPV-16/18 vaccinees and controls. For each pIMD event category, no increased relative risks were reported for HPV-16/18 vaccinees versus controls. Coadministration did not change the overall safety profile. Pregnancy outcomes and withdrawal rates were similar between groups. Conclusions Analysis of safety data arising from 57 580 subjects and 96 704 HPV-16/18-vaccine doses shows that the incidences and distribution of AEs were similar among HPV-16/18-vaccine recipients and controls. No new safety signals were identified. The data confirm previous findings that HPV-16/18-vaccine has an acceptable benefit-risk profile in adolescent girls and

Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture

PubMed Central

Malik, Deepika; Tarek, Mohamed; Caceres del Carpio, Javier; Ramirez, Claudio; Boyer, David; Kenney, M Cristina; Kuppermann, Baruch D

2014-01-01

Purpose To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture. Methods Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death. Results Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p<0.0001), but not at lower concentrations. However, no changes were seen in cell viability in ranibizumab-treated cells at all concentrations including 10×. Mitochondrial membrane potential was slightly decreased in 10× ranibizumab-treated cells (89.61%, p=0.0006) and 2× and 10× aflibercept-treated cells (88.76%, 81.46%; p<0.01, respectively). A larger reduction in mitochondrial membrane potential was seen at 1×, 2× and 10× concentrations of bevacizumab (86.53%, 74.38%, 66.67%; p<0.01) and ziv-aflibercept (73.50%, 64.83% and 49.65% p<0.01) suggestive of early apoptosis at lower doses, including the clinical doses. Conclusions At clinical doses, neither ranibizumab nor aflibercept produced evidence of mitochondrial toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses. PMID:24836865

Safety profile and protocol prevention of adverse reactions to uroangiographic contrast media in diagnostic imaging.

PubMed

Rossi, C; Reginelli, A; D'Amora, M; Di Grezia, G; Mandato, Y; D'Andrea, A; Brunese, L; Grassi, R; Rotondi, A

2014-01-01

The purpose of the study is to examine the incidence of adverse reactions caused by non-ionic contrast media in selected patients after desensitization treatment and to evaluate the safety profile of organ iodine contrast media (i.c.m.) in a multistep prevention protocol. In a population of 2000 patients that had received a CT scan, 100 patients with moderate/high risk for adverse reactions against iodinated contrast agents followed a premedication protocol and all adverse reactions are reported and classified as mild, moderate or severe. 1.7 percent of the pre-treated patients reported a mild, immediate type reaction to iodine contrast; of these five patients with allergy 0.71 percent had received iomeprol, 0.35 percent received ioversol and 0.71 percent received iopromide. The incidence of adverse reactions was reported to be higher (4 out of 5 patients) among those that referred a history of hypersensitivity against iodinated i.c.m. Although intravenous contrast materials have greatly improved, especially in terms of their safety profile, they should not be administered if there isn't a clear or justified indication. In conclusion, even if we know that the majority of these reactions are idiosyncratic and unpredictable we propose, with the aim of improving our knowledge on this subject, a multicenter study, based on skin allergy tests (prick test, patch test, intradermal reaction) in selected patients that have had previous experiences of hypersensitivity against parenteral organ iodine contrast media.

The safety profile of Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine (HibMenCY).

PubMed

Rinderknecht, Stephen; Bryant, Kristina; Nolan, Terry; Pavia-Ruz, Noris; Doniz, Carlos Aranza; Weber, Miguel Angel Rodriguez; Cohen, Christopher; Aris, Emmanuel; Mesaros, Narcisa; Miller, Jacqueline M

2012-03-01

The safety profile of HibMenCY was compared with licensed Hib conjugate vaccines in a pooled analysis that included more than 8,500 subjects who were administered a four-dose series of HibMenCY or commercially available Hib vaccines at 2, 4, 6 and 12-15 mo of age in two primary vaccination and two fourth dose phase 3 studies. In all studies, HibMenCY or Hib vaccine was co-administered with age-appropriate, routinely recommended vaccines. In one primary and one fourth dose study (n = 4180), local and general symptoms were solicited using diary cards for 4 d after each dose. Serious adverse events (SAEs) and the occurrence of adverse events (AEs) indicating new onset of chronic disease (NOCD), rash, and conditions prompting Emergency Room (ER) visits were reported from dose 1 until 6 mo after dose 4. The incidences of solicited local and general symptoms were similar following HibMenCY and commercially available Hib vaccines. For some solicited symptoms (pain at the injection site and irritability), rates were lower in the HibMenCY group compared with the Hib control group (p value < 0.05). There were no statistically significant differences between groups in the incidences of SAEs, NOCDs, rash, or AEs leading to ER visits, with the exceptions of anemia and viral gastroenteritis, which occurred significantly less frequently in those receiving HibMenCY than those receiving commercially available Hib vaccines. In this pooled safety analysis, the safety profile of HibMenCY was similar to the safety profile of licensed monovalent Hib vaccines, despite the addition of meningococcal antigens. These studies are registered at www.clinicaltrials.gov NCT00345579 (primary vaccination study), NCT00345683 (fourth dose vaccination study) and NCT00289783 (primary and fourth dose vaccination studies).

A multi-institution evaluation of clinical profile anonymization

PubMed Central

Heatherly, Raymond; Rasmussen, Luke V; Peissig, Peggy L; Pacheco, Jennifer A; Harris, Paul; Denny, Joshua C

2016-01-01

Background and objective: There is an increasing desire to share de-identified electronic health records (EHRs) for secondary uses, but there are concerns that clinical terms can be exploited to compromise patient identities. Anonymization algorithms mitigate such threats while enabling novel discoveries, but their evaluation has been limited to single institutions. Here, we study how an existing clinical profile anonymization fares at multiple medical centers. Methods: We apply a state-of-the-art k-anonymization algorithm, with k set to the standard value 5, to the International Classification of Disease, ninth edition codes for patients in a hypothyroidism association study at three medical centers: Marshfield Clinic, Northwestern University, and Vanderbilt University. We assess utility when anonymizing at three population levels: all patients in 1) the EHR system; 2) the biorepository; and 3) a hypothyroidism study. We evaluate utility using 1) changes to the number included in the dataset, 2) number of codes included, and 3) regions generalization and suppression were required. Results: Our findings yield several notable results. First, we show that anonymizing in the context of the entire EHR yields a significantly greater quantity of data by reducing the amount of generalized regions from ∼15% to ∼0.5%. Second, ∼70% of codes that needed generalization only generalized two or three codes in the largest anonymization. Conclusions: Sharing large volumes of clinical data in support of phenome-wide association studies is possible while safeguarding privacy to the underlying individuals. PMID:26567325

Clinical profile of STD clinic patients seropositive for HIV antibodies.

PubMed

Krishnaiah, Y R; Babu, V S; Lakshmi, N; Kumar, A G

1989-01-01

This article provides clinical profiles for HIV seropositive patients discovered at an STD clinic in Tirupati, India. Considering that sexual contact is the most common mode of transmission of HIV, researchers from the SV Medical College at Tirupati conducted a surveillance for HIV infection among patients attending an STD clinic. From January 1988 to April 1989, the researchers collected serum samples from 2320 patients. 11 people were found to be infected with HIV, 1 of whom exhibited the AIDS Related Complex (ARC). 9 out the HIV-infected patients were 20-30 year-old males categorized as heterosexually promiscuous; the remaining 2 seropositive patients were female prostitutes. The seropositivity rate among heterosexually promiscuous males was 0.58%, and 6.7% among female prostitutes (the total seropositivity rate was 0.47%). Among the HIV-infected patients, the most commonly associated STD was syphilis. 5 of the patients had syphilis alone, and 2 others had syphilis and another STD. One of the HIV-infected patients, a 50 year-old heterosexual male with a history of multiple partners, suffered from a nonhealing genital ulcer and inguinal buboes of 1 month duration. A biopsy of the genital ulcer revealed a pattern consistent with that of granuloma venereum. He also developed angular stomatitis which did not respond to B complex therapy. Furthermore, suffering from persistent lymphadenopathy, weight loss, slight thrombo-cytopenia, an opportunistic infection in the form of oral candidosis and persistent seropositivity for HIV antibodies, the patient was deemed to have the AIDS Related Complex. Tirupati's seropositivity rate of .47% was higher that noticed in other parts of the country, leading the authors call for a plan to investigate the problems of HIV-infected people.

PIGE - Resonance profiling applied to a clinical test of flouride varnishes

NASA Astrophysics Data System (ADS)

Zschau, H. E.; Plier, F.; Otto, G.; Wyrwich, C.; Treide, A.

1992-03-01

A clinical in-vivo experiment had been carried out to compare two caries preventing fluorine varnishes. The fluorine depth profiles in the near surface region of tooth enamel were measured using the 935 keV resonance of the nuclear reaction 19F( p, p' γ) 19F. The results can be understood by studying the flourine anamnese of the patients.

Hypertensive crisis: clinical-epidemiological profile.

PubMed

Vilela-Martin, José Fernando; Vaz-de-Melo, Renan Oliveira; Kuniyoshi, Cristina Hiromi; Abdo, André Neder Ramires; Yugar-Toledo, Juan Carlos

2011-03-01

Hypertensive crisis (HC) stands out as one type of acute elevation in blood pressure (BP) and can manifest as hypertensive emergency (HE-with target-organ damage (TOD)) or hypertensive urgency (HU-without TOD), usually accompanied by levels of diastolic BP ≥120 mmHg. The aim of this study was to characterize the clinical-epidemiological profile of HC over the course of 1 year in a university reference hospital and perform a review of the literature. The study was a cross-sectional study, conducted over a period of 1 year (2006) in 362 patients who presented for treatment at the emergency hospital with HC, as described above. Among all patients examined, 231 individuals met the criteria for HE and 131 met the criteria for HU. Patients with HE were older (P<0.001) and more sedentary (P=0.026) than those with HU. Furthermore, fewer HE patients than HU patients had previously undergone antihypertensive treatment (P=0.006). The groups did not differ regarding BP levels, gender, smoking or body mass index. Dyspnea (41.1%), thoracic pain (37.2%) and neurological deficit (27.2%) were common signs/symptoms in those with HE. Meanwhile, in the group with HU, we most frequently found headache (42.0%), thoracic pain (41.2%) and dyspnea (34.3%). Among the forms of HE, we most frequently observed acute lung edema (30.7%), myocardial infarction/unstable angina (25.1%), and ischemic (22.9%) and hemorrhagic (14.8%) stroke. HC is a clinical entity associated with high morbidity in the emergency room. Individuals with HE are older and sedentary and have lower rates of antihypertensive treatment. Adequate control of BP should be pursued as a way to avoid this severe complication of hypertension. © 2011 The Japanese Society of Hypertension All rights reserved

Postmarketing Safety Surveillance and Reevaluation of Danhong Injection: Clinical Study of 30888 Cases

PubMed Central

Li, Xue-Lin; Tang, Jin-Fa; Li, Wei-Xia; Li, Chun-Xiao; Zhao, Tao; Zhao, Bu-Chang; Wang, Yong; Zhang, Hui; Chen, Xiao-Fei; Xu, Tao; Zhu, Ming-Jun

2015-01-01

Traditional Chinese medicine injections (TCMIs) have played an irreplaceable role for treating some clinical emergency, severe illness, and infectious diseases in China. In recent years, the incidence rates of adverse drug reactions (ADRs) of TCMIs have increased year by year. Danhong injection (DHI) is one representative TCMI comprised of Danshen and Honghua for treating cardiovascular and cerebrovascular diseases in clinic. In present study, the postmarketing safety surveillance and reevaluation of DHI were reported. Total 30888 patients in 37 hospitals from 6 provinces participated in the study. The results showed that the ADR incidence rate of DHI was 3.50‰. Seventeen kinds of new adverse reactions of DHI were found. The main type of ADRs of DHI was type A (including sweating, dizziness, headache, flushing, vasodilation, eye hemorrhage, faintness, chest pain, palpitations, breathlessness, anxious, nausea, flatulence, vomiting, hypotension, hypertension, local numbness, dyspnea, joint disease, and tinnitus) accounting for 57.75%. The severities of most ADRs of DHI were mild and moderate reactions accounting for 25.93% and 66.67%, respectively. The main disposition of ADRs of DHI was drug withdrawal and without any treatments. The results can provide basis for amendment and improvement of the instructions of DHI, as well as demonstration and reference for the postmarketing safety surveillance and reevaluation of other TCMIs. And the rationality, scientificity, and safety of clinical applications of TCMIs could be improved. PMID:26508981

Using quality and safety education for nurses to guide clinical teaching on a new dedicated education unit.

PubMed

McKown, Terri; McKeon, Leslie; McKown, Leslie; Webb, Sherry

2011-12-01

Gaps exist in health professional education versus the demands of current practice. Leveraging front-line nurses to teach students exemplary practice in a Dedicated Education Unit (DEU) may narrow this gap. The DEU is an innovative model for experiential learning, capitalizing on the expertise of staff nurses as clinical teachers. This study evaluated the effectiveness of a new academic-practice DEU in facilitating quality and safety competency achievement among students. Six clinical teachers received education in clinical teaching and use of Quality and Safety Education for Nurses (QSEN) competencies to guide acquisition of essential knowledge, skills, and attitudes for continuous health care improvement. Twelve students assigned to the six teachers completed daily logs for the 10-week practicum. Findings suggest that DEU students achieved QSEN competencies through clinical teacher mentoring in interdisciplinary collaboration, using electronic information for best practice and patient teaching, patient/family decision making, quality improvement, and resolution of safety issues.

Safety Profile during Initiation of Propranolol for Treatment of Infantile Hemangiomas in an Ambulatory Day-Care Hospitalization Setting.

PubMed

Fogel, Itay; Ollech, Ayelet; Zvulunov, Alex; Valdman-Greenshpon, Yulia; Atar-Sagie, Vered; Friedland, Rivka; Lapidoth, Moshe; Ben-Amitai, Dan

2018-03-24

Propranolol is the mainstay of treatment for infantile hemangioma. Despite its good safety profile, it is not risk-free. Guidelines for propranolol initiation and monitoring have been suggested, but protocols vary among practitioners. This study sought to assess the prevalence of adverse events and clinically significant fluctuations in hemodynamic parameters in children with infantile hemangioma during initiation of treatment with propranolol in a day-hospitalization setting. Children with infantile hemangioma treated with propranolol in a day-hospitalization department of a tertiary pediatric medical center in 2008-2014 were identified retrospectively. The pretreatment evaluation included clinical examination by a pediatric dermatologist and electrocardiography, echocardiography, and clinical examination by a pediatric cardiologist. The propranolol dosage was escalated from 0.5mg/kg/day to 2mg/kg/day, divided into 3 doses/day, over 3 days. Heart rate, blood pressure, and blood glucose level were measured before treatment onset and 60 min after the first two doses each day. The third dose was given at home. The cohort included 220 children aged 1 month to 5 years. No severe treatment-related adverse events were documented; 27 patients had minor side effects. There was a significant decrease in heart rate each day after the first two doses (p<0.001), and in systolic blood pressure, on day 2 (1mg/kg/day) after the first dose (p=0.01). Blood glucose level remained stable. The hemodynamic changes were clinically asymptomatic and did not require intervention. Propranolol treatment (2mg/kg/day in three doses) for infantile hemangioma is well tolerated and safe and may be administered and monitored in an ambulatory setting. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Advancing interprofessional patient safety education for medical, nursing, and pharmacy learners during clinical rotations.

PubMed

Thom, Kerri A; Heil, Emily L; Croft, Lindsay D; Duffy, Alison; Morgan, Daniel J; Johantgen, Mary

2016-11-01

Clinical errors are common and can lead to adverse events and patient death. Health professionals must work within interprofessional teams to provide safe and effective care to patients, yet current curricula is lacking with regards to interprofessional education and patient safety. We describe the development and implementation of an interprofessional course aimed at medical, nursing, and pharmacy learners during their clinical training at a large academic medical centre. The course objectives were based on core competencies for interprofessional education and patient safety. The course was offered as recurring three 1-hour sessions, including case-based discussions and a mock root cause analysis. Forty-three students attended at least one session over a 7-month period. We performed a cross-sectional survey of participants to assess readiness for interprofessional learning and a before and after comparison of patient safety knowledge. All students reported a high level of readiness for interprofessional learning, indicating an interest in interprofessional opportunities. In general, understanding and knowledge of the four competency domains in patient safety was low before the course and 100% of students reported an increase in knowledge in these domains after participating in the course.

A Quality Model to Select Patients in Cupping Therapy Clinics: A New Tool for Ensuring Safety in Clinical Practice.

PubMed

Aboushanab, Tamer; AlSanad, Saud

2018-06-08

Cupping therapy is a popular treatment in various countries and regions, including Saudi Arabia. Cupping therapy is regulated in Saudi Arabia by the National Center for Complementary and Alternative Medicine (NCCAM), Ministry of Health. The authors recommend that this quality model for selecting patients in cupping clinics - first version (QMSPCC-1) - be used routinely as part of clinical practice and quality management in cupping clinics. The aim of the quality model is to ensure the safety of patients and to introduce and facilitate quality and auditing processes in cupping therapy clinics. Clinical evaluation of this tool is recommended. Continued development, re-evaluation and reassessment of this tool are important. Copyright © 2018. Published by Elsevier B.V.

Comparison on the Effects and Safety of Tualang Honey and Tribestan in Sperm Parameters, Erectile Function, and Hormonal Profiles among Oligospermic Males

PubMed Central

Ismail, Shaiful Bahari; Bakar, Mohd. Bustamanizan; Nik Hussain, Nik Hazlina; Sulaiman, Siti Amrah; Jaafar, Hasnan; Draman, Samsul; Ramli, Roszaman; Wan Yusoff, Wan Zahanim

2014-01-01

Introduction. This study aims to evaluate the effectiveness of Tualang honey on sperm parameters, erectile function, and hormonal and safety profiles. Methodology. A randomized control trial was done using Tualang honey (20 grams) and Tribestan (750 mg) over a period of 12 weeks. Sperm parameters including sperm concentration, motility, and morphology were analyzed and erectile function was assessed using IIEF-5 questionnaire. Hormonal profiles of testosterone, FSH, and LH were studied. The volunteers were randomized into two groups and the outcomes were analyzed using SPSS version 18. Results. A total of 66 participants were involved. A significant increment of mean sperm concentration (P < 0.001), motility (P = 0.015) and morphology (P = 0.008) was seen in Tualang honey group. In Tribestan group, a significant increment of mean sperm concentration (P = 0.007), and morphology (P = 0.009) was seen. No significant differences of sperm concentration, motility, and morphology were seen between Tualang honey and Tribestan group and similar results were also seen in erectile function and hormonal profile. All safety profiles were normal and no adverse event was reported. Conclusion. Tualang honey effect among oligospermic males was comparable with Tribestan in improving sperm concentration, motility, and morphology. The usage of Tualang honey was also safe with no reported adverse event. PMID:25505918

Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer

PubMed Central

Blackhall, Fiona; Ross Camidge, D; Shaw, Alice T; Soria, Jean-Charles; Solomon, Benjamin J; Mok, Tony; Hirsh, Vera; Jänne, Pasi A; Shi, Yuankai; Yang, Pan-Chyr; Pas, Tommaso De; Hida, Toyoaki; Carpeño, Javier De Castro; Lanzalone, Silvana; Polli, Anna; Iyer, Shrividya; Reisman, Arlene; Wilner, Keith D; Kim, Dong-Wan

2017-01-01

Purpose Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. Patients and methods PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients’ tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13. Results 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life. Conclusion The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066

Safety of clinical and non-clinical decision makers in telephone triage: a narrative review.

PubMed

Wheeler, Sheila Q; Greenberg, Mary E; Mahlmeister, Laura; Wolfe, Nicole

2015-09-01

Patient safety is a persistent problem in telephone triage research; however, studies have not differentiated between clinicians' and non-clinicians' respective safety. Currently, four groups of decision makers perform aspects of telephone triage: clinicians (physicians, nurses), and non-clinicians (emergency medical dispatchers (EMD) and clerical staff). Using studies published between 2002-2012, we applied Donabedian's structure-process-outcome model to examine groups' systems for evidence of system completeness (a minimum measure of structure and quality). We defined system completeness as the presence of a decision maker and four additional components: guidelines, documentation, training, and standards. Defining safety as appropriate referrals (AR) - (right time, right place with the right person), we measured each groups' corresponding AR rate percentages (outcomes). We analyzed each group's respective decision-making process as a safe match to the telephone triage task, based on each group's system structure completeness, process and AR rates (outcome). Studies uniformly noted system component presence: nurses (2-4), physicians (1), EMDs (2), clerical staff (1). Nurses had the highest average appropriate referral (AR) rates (91%), physicians' AR (82% average). Clerical staff had no system and did not perform telephone triage by standard definitions; EMDs may represent the use of the wrong system. Telephone triage appears least safe after hours when decision makers with the least complete systems (physicians, clerical staff) typically manage calls. At minimum, telephone triage decision makers should be clinicians; however, clinicians' safety calls for improvement. With improved training, standards and CDSS quality, the 24/7 clinical call center has potential to represent the national standard. © The Author(s) 2015.

A 2-year study of patient safety competency assessment in 29 clinical laboratories.

PubMed

Reed, Robyn C; Kim, Sara; Farquharson, Kara; Astion, Michael L

2008-06-01

Competency assessment is critical for laboratory operations and is mandated by the Clinical Laboratory Improvement Amendments of 1988. However, no previous reports describe methods for assessing competency in patient safety. We developed and implemented a Web-based tool to assess performance of 875 laboratory staff from 29 laboratories in patient safety. Question categories included workplace culture, categorizing error, prioritization of patient safety interventions, strength of specific interventions, and general patient safety concepts. The mean score was 85.0%, with individual scores ranging from 56% to 100% and scores by category from 81.3% to 88.6%. Of the most difficult questions (<72% correct), 6 were about intervention strength, 3 about categorizing error, 1 about workplace culture, and 1 about prioritization of interventions. Of the 13 questions about intervention strength, 6 (46%) were in the lowest quartile, suggesting that this may be a difficult topic for laboratory technologists. Computer-based competency assessments help laboratories identify topics for continuing education in patient safety.

Safety and efficacy of collagen crosslinking for the treatment of keratoconus.

PubMed

Kolli, Sai; Aslanides, Ioannis M

2010-11-01

Keratoconus is a condition that causes corneal ectasia and reduced vision in young adults. A proportion of these patients have progressive disease requiring corneal transplantation. A revolutionary new treatment that is purported to halt progression of keratoconus, known as collagen crosslinking (CXL), has recently been introduced into clinical practice. CXL involves the treatment of the cornea with riboflavin followed by photoactivation with UVA light leading to corneal strengthening. This article reviews the basic science, clinical protocols, safety aspects and clinical results of CXL. The reader will gain a comprehensive understanding of: i) the basic science of CXL; ii) the optimised protocols for clinical use of CXL; iii) the results of all the main clinical trials in the literature; iv) contraindications to treatment and v) full clinical safety profile of CXL. CXL represents a new treatment that uniquely allows the halt of progression of keratoconus, thus preventing visual loss and the need for surgical intervention. Available data suggest that this treatment has high efficacy and is very safe and may represent the future standard treatment for progressive keratoconus.

A Review of the Clinical Efficacy and Safety of Insulin Degludec and Glargine 300 U/mL in the Treatment of Diabetes Mellitus.

PubMed

Woo, Vincent C

2017-08-01

The treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) using insulin is not ideal at this time. Despite advances made with basal insulin analogues, many individuals achieve less than optimal glycemic control or are at risk for hypoglycemia. Currently available basal insulin analogues do not deliver steady, peakless, continuous insulin for >24 hours and are associated with adverse events, including hypoglycemia. The objective of this paper was to review the clinical efficacy and safety of upcoming long-acting insulin analogues such as insulin degludec and insulin glargine 300 U/mL (Gla-300). A comprehensive literature search of PubMed and Google Scholar was conducted from 1966 to 2015. The search included randomized controlled trials that specifically assessed the efficacy and safety of insulin degludec and Gla-300 in patients with T1DM and T2DM. The efficacy of insulin degludec and Gla-300 in achieving glycemic control has been reported in clinical trials in adults with T1DM and T2DM. Not only did a large number of patients succeed in meeting glycosylated hemoglobin targets, but they also experienced reductions in hypoglycemic events. These 2 therapies are associated with a reduced risk of nocturnal hypoglycemia and are generally well tolerated. The long-acting insulin analogues insulin degludec and Gla-300 are promising therapies in the treatment of T1DM and T2DM. Their improved insulin delivery for >24 hours offers glycemic control with a good safety profile. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection.

PubMed

Nell, Andre S; D'lom, Eva; Bouic, Patrick; Sabaté, Montserrat; Bosser, Ramon; Picas, Jordi; Amat, Mercè; Churchyard, Gavin; Cardona, Pere-Joan

2014-01-01

To evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection. Double-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV-) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/-): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV- status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation. This Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future trials, preceded by an extended safety clinical

Safety, Tolerability, and Immunogenicity of the Novel Antituberculous Vaccine RUTI: Randomized, Placebo-Controlled Phase II Clinical Trial in Patients with Latent Tuberculosis Infection

PubMed Central

Nell, Andre S.; D’lom, Eva; Bouic, Patrick; Sabaté, Montserrat; Bosser, Ramon; Picas, Jordi; Amat, Mercè; Churchyard, Gavin; Cardona, Pere-Joan

2014-01-01

Objectives To evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection. Methods and Findings Double-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV−) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/−): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV− status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation. Conclusion This Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future

Safety Profile of Cough and Cold Medication Use in Pediatrics.

PubMed

Green, Jody L; Wang, George Sam; Reynolds, Kate M; Banner, William; Bond, G Randall; Kauffman, Ralph E; Palmer, Robert B; Paul, Ian M; Dart, Richard C

2017-06-01

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. 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. 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. 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. Copyright © 2017 by the American Academy of Pediatrics.

Template protocol for clinical trials investigating vaccines—Focus on safety elements☆

PubMed Central

Bonhoeffer, Jan; Imoukhuede, Egeruan B.; Aldrovandi, Grace; Bachtiar, Novilia S.; Chan, Eng-Soon; Chang, Soju; Chen, Robert T.; Fernandopulle, Rohini; Goldenthal, Karen L.; Heffelfinger, James D.; Hossain, Shah; Jevaji, Indira; Khamesipour, Ali; Kochhar, Sonali; Makhene, Mamodikoe; Malkin, Elissa; Nalin, David; Prevots, Rebecca; Ramasamy, Ranjan; Sellers, Sarah; Vekemans, Johan; Walker, Kenneth B.; Wilson, Pam; Wong, Virginia; Zaman, Khalequz; Heininger, Ulrich

2015-01-01

This document is intended as a guide to the protocol development for trials of prophylactic vaccines. The template may serve phases I–IV clinical trials protocol development to include safety relevant information as required by the regulatory authorities and as deemed useful by the investigators. This document may also be helpful for future site strengthening efforts. PMID:23499603

Immunogenicity, reactogenicity and safety of human rotavirus vaccine (RIX4414) in Indian infants.

PubMed

Narang, Anil; Bose, Anuradha; Pandit, Anand Nilkanth; Dutta, Phalguni; Kang, Gagandeep; Bhattacharya, Sujit Kumar; Datta, Sanjoy Kumar; Suryakiran, P V; Delem, Andrée; Han, Htay Htay; Bock, Hans Ludwig

2009-06-01

This study was undertaken to assess the immunogenicity, reactogenicity and safety of two doses of an oral live-attenuated human rotavirus vaccine, strain RIX4414 (Rotarix()) in an Indian setting. The seroconversion rate observed one month post-dose 2 in the RIX4414 group 58.3% [95% CI: 48.7; 67.4] was significantly higher when compared to the placebo group 6.3%; [95% CI: 2.5; 12.5]. The reactogenicity and safety profile was similar for both groups. Healthy infants (N = 363), approximately eight weeks of age were enrolled to receive two doses of RIX4414 vaccine (n = 182) or placebo (n = 181) separated by one month. To assess the immune response, blood samples were taken before vaccination and one month post-dose 2 of RIX4414/placebo. Solicited symptoms were collected for eight-days post each dose and safety data was collected throughout the study. Two doses of RIX4414 (Rotarix()) were immunogenic, had a good safety profile and were well-tolerated when administered to healthy Indian infants. ClinicalTrials.gov; NCT00289172; eTrack 103792.

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers.

PubMed

Muñoz, Jose; Ballester, Maria Rosa; Antonijoan, Rosa Maria; Gich, Ignasi; Rodríguez, Montse; Colli, Enrico; Gold, Silvia; Krolewiecki, Alejandro J

2018-01-01

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

PubMed Central

Antonijoan, Rosa Maria; Gich, Ignasi; Rodríguez, Montse; Colli, Enrico; Gold, Silvia

2018-01-01

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI

Safety profile and complications of autologous limbal conjunctival transplantation for primary pterygium

PubMed Central

Prabhakar, Srinivasapuram Krishnachary

2014-01-01

Purpose Primary pterygium is a fibrovascular proliferation over the nasal cornea, probably resulting from the limbal stem cell deficiency. Intraoperative mitomycin-C application seems to associate with reduced recurrences, however produced ocular surface problems and vision threatening complications. The present clinical study investigated the safety profile of autologous limbal conjunctival transplantation in terms of recurrence rate, as the main outcome measure and complications as the secondary outcome. Methods The present study was randomised, interventional and prospective clinical study conducted from a tertiary Hospital. Pterygium excision was performed with limbal conjunctival autograft availed from the affected eye. Secondary pterygia resulting from inflammation, trauma and other diseases were excluded. Patients were followed up for 18 months for recurrence and other complications. Microsoft Office Excel 2007 was used for statistical analysis. Results A total of 71 eyes of sixty-eight patients with primary pterygia included between November 2007 and October 2010. The study recruited 35 (51%) males and 33 (49%) females with mean age of 36.9 with ±12.82 years standard deviation (mean, SD) ranging from 19 to 75 years. Age grouped by range intervals categorised into six groups. Pterygium was diagnosed in 32 (45%) right eyes and 39 (55%) left eyes. There were 65 (91.55%) nasal and 4 (5.63%) temporal pterygium and no case of double head pterygia found. Average horizontal extension of the pterygium measured was 1.67 mm (±4.23) from the apex to the corneal limbus. Graft oedema in 1 (0.71%) patient, graft bleed in 2 (1.42%) cases and 1 (0.72%) case of granuloma observed. No recurrences encountered during 18 months follow up. Conclusions Pterygium occurred predominantly in the younger population group 36.9 mm (±12.82) probably due to the increased outdoor activity with high exposure to sunlight and dusty atmosphere. Absence of recurrences was probably

Clinical features and endocrine profile of Laron syndrome in Indian children.

PubMed

Phanse-Gupte, Supriya R; Khadilkar, Vaman V; Khadilkar, Anuradha V

2014-11-01

Patients with growth hormone (GH) insensitivity (also known as Laron syndome) have been reported from the Mediterranean region and Southern Eucador, with few case reports from India. We present here the clinical and endocrine profile of 9 children with Laron syndrome from India. Nine children diagnosed with Laron syndrome based on clinical features of GH deficiency and biochemical profile suggestive of GH resistance were studied over a period of 5 years from January 2008 to January 2013. Age of presentation was between 2.5-11.5 years. All children were considerably short on contemporary Indian charts with mean (SD) height Z score -5.2 (1.6). However, they were within ± 2 SD on Laron charts. No child was overweight [mean (SD) BMI Z score 0.92 (1.1)]. All children had characteristic facies of GH deficiency with an added feature of prominent eyes. Three boys had micropenis and 1 had unilateral undescended testis. All children had low IGF-1 (<5 percentile) and IGFP-3 (<0.1 percentile) with high basal and stimulated GH [Basal GH mean (SD) = 13.78 (12.75) ng/ml, 1-h stimulated GH mean (SD) = 46.29 (25.68) ng/ml]. All children showed poor response to IGF generation test. Laron syndrome should be suspected in children with clinical features of GH deficiency, high GH levels and low IGF-1/IGFBP-3. These children are in a state of GH resistance and need IGF-1 therapy.

Clinical characteristics and airway inflammation profile of COPD persistent sputum producers.

PubMed

Khurana, S; Ravi, A; Sutula, J; Milone, R; Williamson, R; Plumb, J; Vestbo, J; Singh, D

2014-12-01

COPD patients with chronic bronchitis include a subgroup with persistent sputum production on most or every day. We hypothesized that COPD patients with persistent sputum production have a different profile of airway inflammation, and more severe clinical characteristics. To compare the airway inflammation profile and clinical characteristics of COPD persistent and non-persistent sputum producers. COPD persistent sputum producers (n = 26) and non-persistent sputum producers (n = 26) underwent sputum induction and pulmonary function tests. Exacerbation history was recorded; the St. George's Respiratory Questionnaire, Modified Medical Research Council Dyspnoea scale and COPD Assessment Tool were completed. 33 COPD patients provided sputum for bacteriology. Persistent sputum producers had lower post-bronchodilator FEV1% predicted (p = 0.01), diffusion capacity (p = 0.04), 6 min walk test distance (p = 0.05), and higher closing volume (p = 0.01), BODE index (p = 0.01), rate of bacterial colonization (p = 0.004) and exacerbations (p = 0.03) compared to non-persistent sputum producers. The mean SGRQ and CAT scores were higher in persistent sputum producers (p = 0.01 and 0.03 respectively). Sputum neutrophil and eosinophil total cell counts were higher in persistent sputum producers (p = 0.02 and 0.05 respectively). Sputum levels of eotaxin (p = 0.02), MCP-1 (p = 0.02), TNF-α (p = 0.03) and IL-6 (p = 0.05) were higher in persistent sputum producers. COPD persistent sputum producers have more severe clinical characteristics and increased concentrations of some inflammatory mediators in the airways.

Impact of INTERMACS Profile on Clinical Outcomes for Patients Supported With the Total Artificial Heart.

PubMed

Shah, Keyur B; Thanavaro, Kristin L; Tang, Daniel G; Quader, Mohammed A; Mankad, Anit K; Tchoukina, Inna; Thacker, Leroy R; Smallfield, Melissa C; Katlaps, Gundars; Hess, Michael L; Cooke, Richard H; Kasirajan, Vigneshwar

2016-11-01

Insufficient data delineate outcomes for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 patients with the total artificial heart (TAH). We studied 66 consecutive patients implanted with the TAH at our institution from 2006 through 2012 and compared outcome by INTERMACS profile. INTERMACS profiles were adjudicated retrospectively by a reviewer blinded to clinical outcomes. Survival after TAH implantation at 6 and 12 months was 76% and 71%, respectively. INTERMACS profile 1 patients had decreased 6-month survival on the device compared with those in profiles 2-4 (74% vs 95%, log rank: P = .015). For the 50 patients surviving to heart transplantation, the 1-year posttransplant survival was 82%. There was no difference in 1-year survival when comparing patients in the INTERMACS 1 profile with less severe profiles (79% vs 84%; log rank test P = .7; hazard ratio [confidence interval] 1.3 [0.3-4.8]). Patients implanted with the TAH as INTERMACS profile 1 had reduced survival to transplantation compared with less sick profiles. INTERMACS profile at the time of TAH implantation did not affect 1-year survival after heart transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

Measures to Improve Diagnostic Safety in Clinical Practice.

PubMed

Singh, Hardeep; Graber, Mark L; Hofer, Timothy P

2016-10-20

Timely and accurate diagnosis is foundational to good clinical practice and an essential first step to achieving optimal patient outcomes. However, a recent Institute of Medicine report concluded that most of us will experience at least one diagnostic error in our lifetime. The report argues for efforts to improve the reliability of the diagnostic process through better measurement of diagnostic performance. The diagnostic process is a dynamic team-based activity that involves uncertainty, plays out over time, and requires effective communication and collaboration among multiple clinicians, diagnostic services, and the patient. Thus, it poses special challenges for measurement. In this paper, we discuss how the need to develop measures to improve diagnostic performance could move forward at a time when the scientific foundation needed to inform measurement is still evolving. We highlight challenges and opportunities for developing potential measures of "diagnostic safety" related to clinical diagnostic errors and associated preventable diagnostic harm. In doing so, we propose a starter set of measurement concepts for initial consideration that seem reasonably related to diagnostic safety and call for these to be studied and further refined. This would enable safe diagnosis to become an organizational priority and facilitate quality improvement. Health-care systems should consider measurement and evaluation of diagnostic performance as essential to timely and accurate diagnosis and to the reduction of preventable diagnostic harm.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Single Enantiomer (+)-Mefloquine Compared with Racemic Mefloquine in Healthy Persons

PubMed Central

Tansley, Robert; Lotharius, Julie; Priestley, Anthony; Bull, Fiona; Duparc, Stephan; Möhrle, Jörg

2010-01-01

Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (−) enantiomer. We sought to compare the safety, tolerability and pharmacokinetic profile of (+)-mefloquine with racemic mefloquine in a randomized, ascending-dose, double-blind, active and placebo-controlled, parallel cohort study in healthy male and female adult volunteers. Although differing in its manifestations, both study drugs displayed a substantially worse tolerability profile compared with placebo. The systemic clearance was slower for (−)-mefloquine than (+)-mefloquine. Thus, (+)-mefloquine has a different safety and tolerability profile compared with racemic mefloquine but its global safety profile is not superior and replacement of the currently used antimalarial drug with (+)-mefloquine is not warranted. PMID:21118921

Disintegration/dissolution profiles of copies of Fosamax (alendronate).

PubMed

Epstein, S; Cryer, B; Ragi, S; Zanchetta, J R; Walliser, J; Chow, J; Johnson, M A; Leyes, A E

2003-01-01

Poor quality has been reported for some generics and other copies of original products. We performed a pilot study to compare the disintegration/dissolution profiles of FOSAMAX (alendronate) 70 mg tablets with those of copies of FOSAMAX that were manufactured outside the United States. We used the standard United States Pharmacopeia (USP) disintegration method to evaluate FOSAMAX 70 mg tablets and 13 copies. At least 12 (n = 12) dosage units were tested for each product (except Fosmin, n = 10). The dissolution profiles of FOSAMAX and one representative copy were also compared. Nine copies (Osteomax, Defixal, Fosmin, Endronax, Osteomix, Genalmen, Fixopan, Osteoplus, and Fosval) disintegrated two- to ten-fold faster than FOSAMAX. Three other copies (Neobon, Regenesis, and Ostenan) disintegrated at least five-fold slower than FOSAMAX. Neobon is a softgel capsule, so special consideration was given to this different dosage form. One copy (Arendal) did not fall into either category but exhibited potentially large inter- and intra-lot variability. Dissolution of alendronate from Regenesis lagged behind that from FOSAMAX. Slower disintegration may reduce efficacy because bisphosphonates must be taken in the fasting state and contact with food or even certain beverages severely reduces bioavailability. Faster disintegration (or the use of gel-caps or other alterations to the drug formulation) could increase the risk of esophagitis, an adverse event associated with prolonged contact of the esophagus with bisphosphonates. These disintegration and dissolution results suggest that important differences may exist between FOSAMAX and its copies with regard to bioavailability, pharmacokinetics, and clinical efficacy and safety profiles. Additional testing is warranted to evaluate the pharmacokinetics and clinical safety of these copies.

Assessment of cognitive safety in clinical drug development

PubMed Central

Roiser, Jonathan P.; Nathan, Pradeep J.; Mander, Adrian P.; Adusei, Gabriel; Zavitz, Kenton H.; Blackwell, Andrew D.

2016-01-01

Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements. Here, we review the rationale for cognitive safety assessment, and explain several basic methodological principles for measuring cognition during clinical drug development, including study design and statistical analysis, from Phase I through to postmarketing. The crucial issue of how cognition should be assessed is emphasized, especially the sensitivity of measurement. We also consider how best to interpret the magnitude of any identified effects, including comparison with benchmarks. We conclude by discussing strategies for the effective communication of cognitive risks. PMID:26610416

Safety and clinical effect of i.v. infusion of cyclopropyl-methoxycarbonyl etomidate (ABP-700), a soft analogue of etomidate, in healthy subjects.

PubMed

Valk, B I; Absalom, A R; Meyer, P; Meier, S; den Daas, I; van Amsterdam, K; Campagna, J A; Sweeney, S P; Struys, M M R F

2018-06-01

Cyclopropyl-methoxycarbonyl metomidate, or ABP-700, is a second generation analogue of etomidate, developed to retain etomidate's beneficial haemodynamic and respiratory profile but diminishing its suppression of the adrenocortical axis. The objective of this study was to characterise the safety and efficacy of 30-min continuous infusions of ABP-700, and to assess its effect on haemodynamics and the adrenocortical response in healthy human volunteers. Five cohorts involving 40 subjects received increasing infusion doses of ABP-700, propofol 60 μg kg -1  min -1 or placebo. Safety was evaluated through adverse event (AE) monitoring, safety laboratory tests, and arterial blood gasses. Haemodynamic and respiratory stability were assessed by continuous monitoring. Adrenocortical function was analysed by adrenocorticotropic hormone (ACTH) stimulation tests. Clinical effect was measured using the modified observer's assessment of alertness/sedation (MOAA/S) and continuous bispectral index monitoring. No serious AEs were reported. Haemodynamic and respiratory effects included mild dose-dependent tachycardia, slightly elevated blood pressure, and no centrally mediated apnoea. Upon stimulation with ACTH, no adrenocortical depression was observed in any subject. Involuntary muscle movements (IMM) were reported, which were more extensive with higher dosing regimens. Higher dosages of ABP-700 were associated with deeper sedation and increased likelihood of sedation. Time to onset of clinical effect was variable throughout the cohorts and recovery was swift. Infusions of ABP-700 showed a dose-dependent hypnotic effect, and did not cause severe hypotension, severe respiratory depression, or adrenocortical suppression. The presentation and nature of IMM is a matter of concern. NTR4735. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Active SMS-based influenza vaccine safety surveillance in Australian children.

PubMed

Pillsbury, Alexis; Quinn, Helen; Cashman, Patrick; Leeb, Alan; Macartney, Kristine

2017-12-18

Australia's novel, active surveillance system, AusVaxSafety, monitors the post-market safety of vaccines in near real time. We analysed cumulative surveillance data for children aged 6 months to 4 years who received seasonal influenza vaccine in 2015 and/or 2016 to determine: adverse event following immunisation (AEFI) rates by vaccine brand, age and concomitant vaccine administration. Parent/carer reports of AEFI occurring within 3 days of their child receiving an influenza vaccine in sentinel immunisation clinics were solicited by Short Message Service (SMS) and/or email-based survey. Retrospective data from 2 years were combined to examine specific AEFI rates, particularly fever and medical attendance as a proxy for serious adverse events (SAE), with and without concomitant vaccine administration. As trivalent influenza vaccines (TIV) were funded in Australia's National Immunisation Program (NIP) in 2015 and quadrivalent (QIV) in 2016, respectively, we compared their safety profiles. 7402 children were included. Data were reported weekly through each vaccination season; no safety signals or excess of adverse events were detected. More children who received a concomitant vaccine had fever (7.5% versus 2.8%; p < .001). Meningococcal B vaccine was associated with the highest increase in AEFI rates among children receiving a specified concomitant vaccine: 30.3% reported an AEFI compared with 7.3% who received an influenza vaccine alone (p < .001). Reported fever was strongly associated with medical attendance (OR: 42.6; 95% Confidence Interval (CI): 25.6-71.0). TIV and QIV safety profiles included low and expected AEFI rates (fever: 4.3% for TIV compared with 3.2% for QIV (p = .015); injection site reaction: 1.9% for TIV compared with 3.0% for QIV (p < .001)). There was no difference in safety profile between brands. Active participant-reported data provided timely vaccine brand-specific safety information. Our surveillance system has

A multi-institution evaluation of clinical profile anonymization.

PubMed

Heatherly, Raymond; Rasmussen, Luke V; Peissig, Peggy L; Pacheco, Jennifer A; Harris, Paul; Denny, Joshua C; Malin, Bradley A

2016-04-01

There is an increasing desire to share de-identified electronic health records (EHRs) for secondary uses, but there are concerns that clinical terms can be exploited to compromise patient identities. Anonymization algorithms mitigate such threats while enabling novel discoveries, but their evaluation has been limited to single institutions. Here, we study how an existing clinical profile anonymization fares at multiple medical centers. We apply a state-of-the-artk-anonymization algorithm, withkset to the standard value 5, to the International Classification of Disease, ninth edition codes for patients in a hypothyroidism association study at three medical centers: Marshfield Clinic, Northwestern University, and Vanderbilt University. We assess utility when anonymizing at three population levels: all patients in 1) the EHR system; 2) the biorepository; and 3) a hypothyroidism study. We evaluate utility using 1) changes to the number included in the dataset, 2) number of codes included, and 3) regions generalization and suppression were required. Our findings yield several notable results. First, we show that anonymizing in the context of the entire EHR yields a significantly greater quantity of data by reducing the amount of generalized regions from ∼15% to ∼0.5%. Second, ∼70% of codes that needed generalization only generalized two or three codes in the largest anonymization. Sharing large volumes of clinical data in support of phenome-wide association studies is possible while safeguarding privacy to the underlying individuals. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cyclic fatigue of ProFile rotary instruments after prolonged clinical use.

PubMed

Gambarini, G

2001-07-01

The purpose of the present study was to evaluate resistance to cyclic fatigue of new and used ProFile Ni-Ti rotary instruments. Used instruments were operated in 10 clinical cases using passive instrumentation and a crown-down preparation technique. Cyclic fatigue testing of new and used engine-driven instruments was then performed with a specific device which allowed the instruments to rotate freely inside a stainless steel artificial canal, whilst maintaining conditions close to the clinical situation. Instruments were rotated until fracture occurred and time to fracture was visually recorded with a chronometer. A significant reduction of rotation time to breakage (life span) was noted between new and used instruments. In all sizes new instruments were significantly more resistant than used ones (two-sample t-test, P < 0.01). No instrument underwent intracanal failure during clinical use. Prolonged clinical use of Ni-Ti engine-driven instruments significantly reduced their cyclic fatigue resistance. Nevertheless, each rotary instrument was successfully operated in up to 10 clinical cases without any intracanal failure.

The clinical impact of using complex molecular profiling strategies in routine oncology practice.

PubMed

Laes, Jean-François; Aftimos, Philippe; Barthelemy, Philippe; Bellmunt, Joaquim; Berchem, Guy; Camps, Carlos; Peñas, Ramón de Las; Finzel, Ana; García-Foncillas, Jesús; Hervonen, Petteri; Wahid, Ibrahim; Joensuu, Timo; Kathan, Louis; Kong, Anthony; Mackay, James; Mikropoulos, Christos; Mokbel, Kefah; Mouysset, Jean-Loup; Odarchenko, Sergey; Perren, Timothy J; Pienaar, Rika; Regonesi, Carlos; Alkhayyat, Shadi Salem; El Kinge, Abdul Rahman; Abulkhair, Omalkhair; Galal, Khaled Morsi; Ghanem, Hady; El Karak, Fadi; Garcia, Angel; Ghitti, Gregori; Sadik, Helen

2018-04-17

Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients' treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests. The resulting information was interpreted and personalized treatments for each patient were suggested. Our data showed that NGS alone provided the oncologist with useful information in 10-50% of cases (depending on cancer type), whereas the addition of IHC/other tests increased extensively the usefulness of the information provided. Using internet surveys, we investigated how therapy recommendations influenced treatment choice of the oncologist. For patients who were still alive after the provision of the molecular information (76.8%), 60.4% of their oncologists followed report recommendations. Most treatment decisions (93.4%) were made based on the combination of NGS and IHC/other tests, and an approved drug- rather than clinical trial enrolment- was the main treatment choice. Most common reasons given by physicians to explain the non-adherence to recommendations were drug availability and cost, which remain barriers to personalised precision medicine. Finally, we observed that 27% of patients treated with the suggested therapies had an overall survival > 12 months. Our study demonstrates that the combination of NGS and IHC/other tests provides the most useful information in aiding treatment decisions by oncologists in routine clinical practice.

Analysis of pain behavior profiles and functional disability in outpatient physical therapy clinics.

PubMed

Hankin, H A; Spencer, T; Kegerreis, S; Worrell, T; Rice, J M

2001-02-01

Descriptive, ex post facto. To determine the proportion of physical therapy outpatients with pain who exhibit various pain behavior profiles, and to determine whether there are differences in functional disability across the profiles. Physical therapists treat many patients who have chronic pain. Research suggests that early identification and multidisciplinary treatment are effective and economical for these patients. The Multidimensional Pain Inventory (MPI) and the Pain Disability Index (PDI) are potential screening tools that could be used in physical therapy clinics to determine which patients should be referred for multidisciplinary treatment. MPI and PDI data were gathered on 57 physical therapy outpatients (mean age 44.3 +/- 14.5 years, 22 men and 35 women) with pain of 3 or more months duration. ANOVA was used to analyze differences in mean PDI scores across the MPI profiles. Of all patients, 42.1% fit the Adaptive Coper profile, 29.8% fit the Interpersonally Distressed profile, and 28.1% fit the Dysfunctional profile. There were significant differences in PDI scores among profile groups. Post hoc analysis showed that the PDI scores of the Adaptive Coper and Interpersonally Distressed groups were different from the Dysfunctional group, but that there was no difference between the Adaptive Coper and Interpersonally Distressed groups. Many patients in outpatient physical therapy settings exhibit behavioral, affective, and cognitive characteristics associated with chronic pain. Thirty-three patients (57.9%) had MPI profiles (interpersonally distressed and dysfunctional) that suggest they might benefit from multidisciplinary treatment.

Asperger Syndrome in India: Findings from a Case-Series with Respect to Clinical Profile and Comorbidity

PubMed Central

Sreedaran, Priya; Ashok, M. V.

2015-01-01

Asperger syndrome (AS) is an autism spectrum disorder with a high rate of psychiatric comorbidity. We describe the clinical profile and psychiatric comorbidity in a series of affected individuals referred to an Indian general hospital psychiatry setting. Gilliam Asperger's disorder scale was used to evaluate the clinical characteristics while Mini-International Neuropsychiatric Interview (MINI)-KID and MINI-PLUS were used to assess psychiatric comorbidity. The profile of subjects with AS in our case-series appears similar to that published elsewhere with high rates of psychiatric comorbidity. Mental health professionals should evaluate for psychiatric comorbidity in individuals with autism spectrum disorders. PMID:25969609

Asperger syndrome in India: findings from a case-series with respect to clinical profile and comorbidity.

PubMed

Sreedaran, Priya; Ashok, M V

2015-01-01

Asperger syndrome (AS) is an autism spectrum disorder with a high rate of psychiatric comorbidity. We describe the clinical profile and psychiatric comorbidity in a series of affected individuals referred to an Indian general hospital psychiatry setting. Gilliam Asperger's disorder scale was used to evaluate the clinical characteristics while Mini-International Neuropsychiatric Interview (MINI)-KID and MINI-PLUS were used to assess psychiatric comorbidity. The profile of subjects with AS in our case-series appears similar to that published elsewhere with high rates of psychiatric comorbidity. Mental health professionals should evaluate for psychiatric comorbidity in individuals with autism spectrum disorders.

Safety and pharmacokinetic profile of rufinamide in pediatric patients aged less than 4 years with Lennox-Gastaut syndrome: An interim analysis from a multicenter, randomized, active-controlled, open-label study.

PubMed

Arzimanoglou, Alexis; Ferreira, Jose A; Satlin, Andrew; Mendes, Shannon; Williams, Betsy; Critchley, David; Schuck, Edgar; Hussein, Ziad; Kumar, Dinesh; Dhadda, Shobha; Bibbiani, Francesco

2016-05-01

A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (AEDs) in young pediatric patients is of great importance in clinical practice. This paper presents 6-month interim safety and PK from an ongoing 2-year open-label study (Study 303) of adjunctive rufinamide treatment in pediatric subjects ≥ 1 to < 4 years with inadequately controlled epilepsies of the Lennox-Gastaut syndrome (LGS) spectrum. Subjects (N = 37) were randomized to either rufinamide or any other approved AED chosen by the investigator as adjunctive therapy to the subject's existing regimen of 1-3 AEDs. Interim safety results showed that treatment-emergent adverse events (TEAEs) were similar between the rufinamide (22 [88.0%]) and any-other-AED group (9 [81.8%]), with most events considered mild or moderate. A population PK analysis was conducted including plasma rufinamide concentrations from Study 303 and two other study populations of LGS subjects ≥ 4 years. The rufinamide PK profile was dose independent. The apparent clearance (CL/F) estimated from the PK model was 2.19 L/h; it was found to increase significantly as a function of body weight. Coadministration of valproic acid significantly decreased rufinamide CL/F. CL/F was not significantly affected by other concomitant AEDs, age, gender, race, hepatic function, or renal function. No adjustments to body weight-based rufinamide dosing in subjects ≥ 1 to < 4 years are necessary. Rufinamide was safe and well tolerated in these pediatric subjects. Results from the interim analysis demonstrate that rufinamide's safety and PK profile is comparable in subjects ≥ 1 to < 4 and ≥ 4 years with LGS. Study 303 (clinicaltrials.gov: NCT01405053). Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Video capture of clinical care to enhance patient safety

PubMed Central

Weinger, M; Gonzales, D; Slagle, J; Syeed, M

2004-01-01



 Experience from other domains suggests that videotaping and analyzing actual clinical care can provide valuable insights for enhancing patient safety through improvements in the process of care. Methods are described for the videotaping and analysis of clinical care using a high quality portable multi-angle digital video system that enables simultaneous capture of vital signs and time code synchronization of all data streams. An observer can conduct clinician performance assessment (such as workload measurements or behavioral task analysis) either in real time (during videotaping) or while viewing previously recorded videotapes. Supplemental data are synchronized with the video record and stored electronically in a hierarchical database. The video records are transferred to DVD, resulting in a small, cheap, and accessible archive. A number of technical and logistical issues are discussed, including consent of patients and clinicians, maintaining subject privacy and confidentiality, and data security. Using anesthesiology as a test environment, over 270 clinical cases (872 hours) have been successfully videotaped and processed using the system. PMID:15069222

Drug safety is a barrier to the discovery and development of new androgen receptor antagonists.

PubMed

Foster, William R; Car, Bruce D; Shi, Hong; Levesque, Paul C; Obermeier, Mary T; Gan, Jinping; Arezzo, Joseph C; Powlin, Stephanie S; Dinchuk, Joseph E; Balog, Aaron; Salvati, Mark E; Attar, Ricardo M; Gottardis, Marco M

2011-04-01

Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs. Copyright © 2010 Wiley-Liss, Inc.

Clinical Oversight: Conceptualizing the Relationship Between Supervision and Safety

PubMed Central

Lingard, Lorelei; Baker, G. Ross; Kitchen, Lisa; Regehr, Glenn

2007-01-01

Background Concern about the link between clinical supervision and safe, quality health care has led to widespread increases in the supervision of medical trainees. The effects of increased supervision on patient care and trainee education are not known, primarily because the current multifacted and poorly operationalized concept of clinical supervision limits the potential for evaluation. Objective To develop a conceptual model of clinical supervision to inform and guide policy and research. Design, Setting, and Participants Observational fieldwork and interviews were conducted in the Emergency Department and General Internal Medicine in-patient teaching wards of two academic health sciences centers associated with an urban Canadian medical school. Members of 12 Internal Medicine and Emergency Medicine teaching teams (n = 88) were observed during regular clinical activities (216 hours). Sixty-five participants (12 physicians, 28 residents, 17 medical students, 8 nurses) also completed interviews about supervision. Field notes and interview transcripts were analyzed for emergent themes using grounded theory methodology. Results The term “clinical oversight” was developed to describe patient care activities performed by supervisors to ensure quality of care. “Routine oversight” (preplanned monitoring of trainees’ clinical work) can expose supervisors to concerns that trigger “responsive oversight” (a double-check or elaboration of trainees’ clinical work). Supervisors sometimes engage in “backstage oversight” (oversight of which the trainee is not directly aware). When supervisors encounter a situation that exceeds a trainee’s competence, they move beyond clinical oversight to “direct patient care”. Conclusions This study elaborates a typology of clinical oversight activities including routine, responsive, and backstage oversight. This new typology provides a framework for clinical supervision policy and for research to evaluate the

Preclinical profile of cabazitaxel

PubMed Central

Vrignaud, Patricia; Semiond, Dorothée; Benning, Veronique; Beys, Eric; Bouchard, Hervé; Gupta, Sunil

2014-01-01

First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated

Safety Profile of Stromal Hydration of Clear Corneal Incisions with Cefuroxime in the Mouse Model.

PubMed

Moosajee, Mariya; Tracey-White, Dhani; Harbottle, Richard P; Ferguson, Veronica

2016-09-01

The use of sutureless clear corneal incisions (CCIs) for phacoemulsification is an established surgical technique, but the dynamic morphology of the wound and poor construction can lead to an increased risk of postoperative endophthalmitis. Stromal hydration with balanced salt solution (BSS) can improve the self-sealing status. Intracameral cefuroxime has reduced endophthalmitis rates. This study investigates the safety profile of stromal hydration with cefuroxime, as sequestering antibiotic at the wound may potentially provide added protection against infection. MF-1 mice underwent bilateral CCI, followed by stromal hydration with 5 μL of 10 mg/mL cefuroxime, cefuroxime-texas red conjugate (for detection using confocal microscopy), or BSS. Corneas were harvested from 1 h to 12 weeks postoperatively; gross morphology, histology, and apoptotic cell death levels were investigated to determine the safety profile. Bactericidal activity of cefuroxime was assayed using homogenized whole cornea following stromal hydration at 1 h, 24 h, and day 7 against gram-negative Escherichia coli. Cefuroxime stromal hydration did not alter corneal morphology, with no evidence of corneal scarring or vascularization. Corneal histology and levels of apoptosis were minimal and comparable to the BSS groups up to 12 weeks. Confocal microscopy detected cefuroxime-texas red up to 1 week surrounding the corneal wound. Whole corneal tissue homogenates displayed bactericidal activity up to 24 h postoperatively. Stromal hydration of CCI with cefuroxime is safe in mouse corneas. A reservoir of antibiotic at the wound can potentially act as a barrier of defense against infection following cataract and associated ocular surgery.

The Relationship of Financial Pressures and Community Characteristics to Closure of Private Safety Net Clinics.

PubMed

Li, Suhui; Dor, Avi; Pines, Jesse M; Zocchi, Mark S; Hsia, Renee Y

2016-10-01

In order to better understand what threatens vulnerable populations' access to primary care, it is important to understand the factors associated with closing safety net clinics. This article examines how a clinic's financial position, productivity, and community characteristics are associated with its risk of closure. We examine patterns of closures among private-run primary care clinics (PCCs) in California between 2006 and 2012. We use a discrete-time proportional hazard model to assess relative hazard ratios of covariates, and a random-effect hazard model to adjust for unobserved heterogeneity among PCCs. We find that lower net income from patient care, smaller amount of government grants, and lower productivity were associated with significantly higher risk of PCC closure. We also find that federally qualified health centers and nonfederally qualified health centers generally faced the same risk factors of closure. These results underscore the critical role of financial incentives in the long-term viability of safety net clinics. © The Author(s) 2015.

[Profile of adolescents with repeated pregnancies attended at a prenatal clinic].

PubMed

Persona, Lia; Shimo, Antonieta Keiko Kakuda; Tarallo, Maria Celina

2004-01-01

This study identified the biopsychosocial profile of adolescent with repeated pregnancies, who were attended at a prenatal clinic. Data were collected through patient records and interviews and were subject to quantitative analysis. Based on the obtained results and in accordance with literature, factors that are strongly associated with the occurrence of pregnancy repetition were selected in the adolescents' profiles. These are: early menarche; first sexual intercourse shortly after menarche; school repetition; school dropout; non remunerated occupation; low family income; involvement with older partners; living with the partner; consensual union with the partner; one partner; low condom use; family history of adolescent pregnancy; father's absence because of death or abandonment; positive family reaction to previous pregnancy; previous abortion; adolescent's positive concepts about previous delivery; and absence from previous postpartum consultations.

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns.

PubMed

Resetca, Diana; Neschadim, Anton; Medin, Jeffrey A

2016-09-01

Advances in cancer immunotherapies utilizing engineered hematopoietic cells have recently generated significant clinical successes. Of great promise are immunotherapies based on chimeric antigen receptor-engineered T (CAR-T) cells that are targeted toward malignant cells expressing defined tumor-associated antigens. CAR-T cells harness the effector function of the adaptive arm of the immune system and redirect it against cancer cells, overcoming the major challenges of immunotherapy, such as breaking tolerance to self-antigens and beating cancer immune system-evasion mechanisms. In early clinical trials, CAR-T cell-based therapies achieved complete and durable responses in a significant proportion of patients. Despite clinical successes and given the side effect profiles of immunotherapies based on engineered cells, potential concerns with the safety and toxicity of various therapeutic modalities remain. We discuss the concerns associated with the safety and stability of the gene delivery vehicles for cell engineering and with toxicities due to off-target and on-target, off-tumor effector functions of the engineered cells. We then overview the various strategies aimed at improving the safety of and resolving toxicities associated with cell-based immunotherapies. Integrating failsafe switches based on different suicide gene therapy systems into engineered cells engenders promising strategies toward ensuring the safety of cancer immunotherapies in the clinic.

Comparative Studies of Collaborative Team Depression Care Adoption in Safety Net Clinics

ERIC Educational Resources Information Center

Ell, Kathleen; Wu, Shinyi; Guterman, Jeffrey; Schulman, Sandra-Gross; Sklaroff, Laura; Lee, Pey-Jiuan

2018-01-01

Purpose: To evaluate three approaches adopting collaborative depression care model in Los Angeles County safety net clinics with predominantly Latino type 2 diabetes patients. Methods: Pre-post differences in treatment rates and symptom reductions were compared between baseline, 6-month, and 12-month follow-ups for each approach: (a) Multifaceted…

Clinical Profiles of Children with Disruptive Behaviors Based on the Severity of Their Conduct Problems, Callous-Unemotional Traits and Emotional Difficulties.

PubMed

Andrade, Brendan F; Sorge, Geoff B; Na, Jennifer Jiwon; Wharton-Shukster, Erika

2015-08-01

This study identified clinical profiles of referred children based on the severity of callous-unemotional (CU) traits, emotional difficulties, and conduct problems. Parents of 166 children (132 males) aged 6-12 years referred to a hospital clinic because of disruptive behavior completed measures to assess these key indicators, and person-centered analysis was used to identify profiles. Four distinct profiles were identified that include: (1) Children low in severity on the three domains, (2) Children high in severity on the three domains, (3) Children high in severity in conduct problems and CU traits with minimal emotional difficulties, and (4) Children high in severity in conduct problems and emotional difficulties with minimal CU traits. Profiles differed in degree of aggression and behavioral impairment. Findings show that clinic-referred children with disruptive behaviors can be grouped based on these important indicators into profiles that have important implications for assessment and treatment selection.

Clinical profiles and outcomes in idiopathic duct-centric chronic pancreatitis (type 2 autoimmune pancreatitis): the Mayo Clinic experience.

PubMed

Hart, Phil A; Levy, Michael J; Smyrk, Thomas C; Takahashi, Naoki; Abu Dayyeh, Barham K; Clain, Jonathan E; Gleeson, Ferga C; Pearson, Randall K; Petersen, Bret T; Topazian, Mark D; Vege, Santhi S; Zhang, Lizhi; Chari, Suresh T

2016-10-01

Idiopathic duct-centric chronic pancreatitis (IDCP), also known as type 2 autoimmune pancreatitis (AIP), is an uncommon subtype of AIP. International Consensus Diagnostic Criteria for IDCP propose that the diagnosis requires pancreatic histology and/or concurrent IBD. We examined our experience with IDCP (type 2 AIP) to assess the appropriateness of these criteria, and identify unique characteristics in patients presenting with acute pancreatitis. We reviewed the Mayo Clinic AIP database through May 2014 to identify subjects with either definitive (n=31) or probable (n=12) IDCP. We compared demographic and clinical factors based on strength of diagnostic confidence (definitive versus probable), presence of IBD, and acute pancreatitis as the presenting manifestation. Relapse-free survival was determined using the Kaplan-Meier method. The clinical profiles were similar irrespective of the diagnostic criteria fulfilled. Common clinical presentations included acute pancreatitis (n=25, 58.1%, 12 of whom (27.9%) had recurrent pancreatitis) and pancreatic mass/obstructive jaundice (n=15, 34.9%). The cumulative relapse rate was 10.6% at 3 years (median follow-up 2.9 years). Relapse-free survival was similar for the different diagnostic categories, but was decreased in those initially presenting with acute pancreatitis (p=0.047) or treated with steroids (vs surgery, p=0.049). The current diagnostic classification of probable IDCP and the inclusion of IBD as a supportive criterion appear valid, because patients have similar clinical profiles and disease-related outcomes to those with definitive IDCP. Concurrent IBD, especially in young patients, may suggest when IDCP is the underlying cause of recurrent acute pancreatitis, but additional studies are needed for validation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Association of Immunological Cell Profiles with Specific Clinical Phenotypes of Scleroderma Disease

PubMed Central

Calzada, David; Mayayo, Teodoro; González-Rodríguez, María Luisa; Rabasco, Antonio María; Lahoz, Carlos

2014-01-01

This study aimed to search the correlation among immunological profiles and clinical phenotypes of scleroderma in well-characterized groups of scleroderma patients, comparing forty-nine scleroderma patients stratified according to specific clinical phenotypes with forty-nine healthy controls. Five immunological cell subpopulations (B, CD4+ and CD8+ T-cells, NK, and monocytes) and their respective stages of apoptosis and activation were analyzed by flow cytometry, in samples of peripheral blood mononuclear cells (PBMCs). Analyses of results were stratified according to disease stage, time since the diagnosis, and visceral damage (pulmonary fibrosis, pulmonary hypertension, and cardiac affliction) and by time of treatment with corticosteroids. An increase in the percentages of monocytes and a decrease in the B cells were mainly related to the disease progression. A general apoptosis decrease was found in all phenotypes studied, except in localized scleroderma. An increase of B and NK cells activation was found in patients diagnosed more than 10 years ago. Specific cell populations like monocytes, NK, and B cells were associated with the type of affected organ. This study shows how, in a heterogeneous disease, proper patient's stratification according to clinical phenotypes allows finding specific cellular profiles. Our data may lead to improvements in the knowledge of prognosis factors and to aid in the analysis of future specific therapies. PMID:24818126

The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial.

PubMed

Rodríguez, P C; Prada, D M; Moreno, E; Aira, L E; Molinero, C; López, A M; Gómez, J A; Hernández, I M; Martínez, J P; Reyes, Y; Milera, J M; Hernández, M V; Torres, R; Avila, Y; Barrese, Y; Viada, C; Montero, E; Hernández, P

2018-02-01

Itolizumab is a humanized anti-CD6 monoclonal antibody (mAb) that has previously shown encouraging results, in terms of safety and positive clinical effects, in a 6-week monotherapy clinical trial conducted in rheumatoid arthritis (RA) patients. The current Phase I study evaluated the safety and clinical response for a longer treatment of 12 itolizumab intravenous doses in subjects with active RA despite previous disease-modifying anti-rheumatic drug (DMARD) therapy. Twenty-one subjects were enrolled into four dosage groups (0·1, 0·2, 0·4 and 0·8 mg/kg). Efficacy end-points including American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates and disease activity score in 28 joints (DAS28) were monitored at baseline and at specific time-points during a 10-week follow-up period. Itolizumab was well tolerated up to the highest tested dose. No related serious adverse events were reported and most adverse events were mild. Remarkably, itolizumab treatment did not produce lymphopenia and, therefore, was not associated with infections. All patients achieved a clinical response (ACR20) at least once during the study. Eleven subjects (55%) achieved at least a 20% improvement in ACR just 1 week after the first itolizumab administration. The clinical response was observed from the beginning of the treatment and was sustained during 24 weeks. The efficacy profile of this 12-week treatment was similar to that of the previous study (6-week treatment). These results reinforce the safety profile of itolizumab and provide further evidence on the clinical benefit from the use of this anti-CD6 mAb in RA patients. © 2017 British Society for Immunology.

How 3 rural safety net clinics integrate care for patients: a qualitative case study.

PubMed

Derrett, Sarah; Gunter, Kathryn E; Nocon, Robert S; Quinn, Michael T; Coleman, Katie; Daniel, Donna M; Wagner, Edward H; Chin, Marshall H

2014-11-01

Integrated care focuses on care coordination and patient centeredness. Integrated care supports continuity of care over time, with care that is coordinated within and between settings and is responsive to patients' needs. Currently, little is known about care integration for rural patients. To examine challenges to care integration in rural safety net clinics and strategies to address these challenges. Qualitative case study. Thirty-six providers and staff from 3 rural clinics in the Safety Net Medical Home Initiative. Interviews were analyzed using the framework method with themes organized within 3 constructs: Team Coordination and Empanelment, External Coordination and Partnerships, and Patient-centered and Community-centered Care. Participants described challenges common to safety net clinics, including limited access to specialists for Medicaid and uninsured patients, difficulty communicating with external providers, and payment models with limited support for care integration activities. Rurality compounded these challenges. Respondents reported benefits of empanelment and team-based care, and leveraged local resources to support care for patients. Rural clinics diversified roles within teams, shared responsibility for patient care, and colocated providers, as strategies to support care integration. Care integration was supported by 2 fundamental changes to organize and deliver care to patients-(1) empanelment with a designated group of patients being cared for by a provider; and (2) a multidisciplinary team able to address rural issues. New funding and organizational initiatives of the Affordable Care Act may help to further improve care integration, although additional solutions may be necessary to address particular needs of rural communities.

Clinical features and endocrine profile of Laron syndrome in Indian children

PubMed Central

Phanse-Gupte, Supriya R.; Khadilkar, Vaman V.; Khadilkar, Anuradha V.

2014-01-01

Introduction: Patients with growth hormone (GH) insensitivity (also known as Laron syndome) have been reported from the Mediterranean region and Southern Eucador, with few case reports from India. We present here the clinical and endocrine profile of 9 children with Laron syndrome from India. Material and Methods: Nine children diagnosed with Laron syndrome based on clinical features of GH deficiency and biochemical profile suggestive of GH resistance were studied over a period of 5 years from January 2008 to January 2013. Results and Discussion: Age of presentation was between 2.5-11.5 years. All children were considerably short on contemporary Indian charts with mean (SD) height Z score -5.2 (1.6). However, they were within ± 2 SD on Laron charts. No child was overweight [mean (SD) BMI Z score 0.92 (1.1)]. All children had characteristic facies of GH deficiency with an added feature of prominent eyes. Three boys had micropenis and 1 had unilateral undescended testis. All children had low IGF-1 (<5 percentile) and IGFP-3 (<0.1 percentile) with high basal and stimulated GH [Basal GH mean (SD) = 13.78 (12.75) ng/ml, 1-h stimulated GH mean (SD) = 46.29 (25.68) ng/ml]. All children showed poor response to IGF generation test. Conclusion: Laron syndrome should be suspected in children with clinical features of GH deficiency, high GH levels and low IGF-1/IGFBP-3. These children are in a state of GH resistance and need IGF-1 therapy. PMID:25364685

Recommendations for Clinical Pathology Data Generation, Interpretation, and Reporting in Target Animal Safety Studies for Veterinary Drug Development.

PubMed

Siska, William; Gupta, Aradhana; Tomlinson, Lindsay; Tripathi, Niraj; von Beust, Barbara

Clinical pathology testing is routinely performed in target animal safety studies in order to identify potential toxicity associated with administration of an investigational veterinary pharmaceutical product. Regulatory and other testing guidelines that address such studies provide recommendations for clinical pathology testing but occasionally contain outdated analytes and do not take into account interspecies physiologic differences that affect the practical selection of appropriate clinical pathology tests. Additionally, strong emphasis is often placed on statistical analysis and use of reference intervals for interpretation of test article-related clinical pathology changes, with limited attention given to the critical scientific review of clinically, toxicologically, or biologically relevant changes. The purpose of this communication from the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology is to provide current recommendations for clinical pathology testing and data interpretation in target animal safety studies and thereby enhance the value of clinical pathology testing in these studies.

The challenge of compiling data profiles to stimulate local preventive health action: a European case study from child safety.

PubMed

Alexander, Denise; Rigby, Michael; Gissler, Mika; Köhler, Lennart; MacKay, Morag

2015-05-01

Positive recent experience of presenting comparative child safety data at national level has instigated policy action in Europe. It was hoped a Child Safety Index could quantify how safe a community, region or locality is for its children in comparison with similar areas within Europe, as a focus for local targeted action. Validated indicators proposed by previous European projects identified from areas of child injury prevention, such as road safety, burns or poisoning, were selected to give a balanced profile, and populated from available published data. An index using a sub-score for each specific injury topic was proposed. The indicators' presentation, sensitivity and appropriateness were considered, as well as data availability. Satisfactory indicators were not identified for all areas and very few local area data were available. This forced the researchers to conclude that at present, constructing a reliable Child Safety Index for use at the local level is not feasible. There is a worrying lack of data available at the sub-national level to support injury prevention, evaluate interventions, and enable informed local decision making.

Procedural and short-term safety of bronchial thermoplasty in clinical practice: evidence from a national registry and Hospital Episode Statistics.

PubMed

Burn, Julie; Sims, Andrew J; Keltie, Kim; Patrick, Hannah; Welham, Sally A; Heaney, Liam G; Niven, Robert M

2017-10-01

Bronchial thermoplasty (BT) is a novel treatment for severe asthma. Its mode of action and ideal target patient group remain poorly defined, though clinical trials provided some evidence on efficacy and safety. This study presents procedural and short-term safety evidence from routine UK clinical practice. Patient characteristics and safety outcomes (procedural complications, 30-day readmission and accident and emergency (A&E) attendance, length of stay) were assessed using two independent data sources, the British Thoracic Society UK Difficult Asthma Registry (DAR) and Hospital Episodes Statistics (HES) database. A matched cohort (with records in both) was used to estimate safety outcome event rates and compare them with clinical trials. Between June 2011 and January 2015, 215 procedure records (83 patients; 68 treated in England) were available from DAR and 203 (85 patients) from HES. 152 procedures matched (59 patients; 6 centres), and of these, 11.2% reported a procedural complication, 11.8% resulted in emergency respiratory readmission, 0.7% in respiratory A&E attendance within 30 days (20.4% had at least one event) and 46.1% involved a post-procedure stay. Compared with published clinical trials which found lower hospitalisation rates, BT patients in routine clinical practice were, on average, older, had worse baseline lung function and asthma quality of life. A higher proportion of patients experienced adverse events compared with clinical trials. The greater severity of disease amongst patients treated in clinical practice may explain the observed rate of post-procedural stay and readmission. Study of long-term safety and efficacy requires continuing data collection.

[Safety profile of heterologous serum produced by the Butantan Institute, in São Paulo-SP, Brazil, from 2012 to 2015].

PubMed

Gattás, Vera Lúcia; Braga, Patrícia Emília; Koike, Marcelo Eiji; Lucchesi, Maria Beatriz; Precioso, Alexander Roberto

2017-01-01

to describe the safety profile of the heterologous serum produced by the Butantan Institute (BI) of São Paulo-SP, Brazil. a descriptive study of adverse events (AEs) post-exposure to serum produced by the BI, encoded in the medical terminology of the Medical Dictionary for Regulatory Activities (MedDRA), and spontaneously reported to BI from 2012 to 2015. 52 individuals reported AEs, mainly related to Bothrops antivenom (n=11), diphtheria antitoxin (n=9) and unspecified snakebite serum (n=9); a mean of 3.2 AEs per individual was observed; among the total of 173 AEs, 63.0% were expected considering that they were described in the package insert; most of them were classified as skin and subcutaneous tissue disorders (30.6%); there were six deaths temporally related to the use of serum, but this association was discarded. in the studied period, the serum produced by the BI had no changes in their safety profiles, considering that the AEs were expected, according to the information previously described in the package insert.

Template protocol for clinical trials investigating vaccines--focus on safety elements.

PubMed

Bonhoeffer, Jan; Imoukhuede, Egeruan B; Aldrovandi, Grace; Bachtiar, Novilia S; Chan, Eng-Soon; Chang, Soju; Chen, Robert T; Fernandopulle, Rohini; Goldenthal, Karen L; Heffelfinger, James D; Hossain, Shah; Jevaji, Indira; Khamesipour, Ali; Kochhar, Sonali; Makhene, Mamodikoe; Malkin, Elissa; Nalin, David; Prevots, Rebecca; Ramasamy, Ranjan; Sellers, Sarah; Vekemans, Johan; Walker, Kenneth B; Wilson, Pam; Wong, Virginia; Zaman, Khalequz; Heininger, Ulrich

2013-11-12

This document is intended as a guide to the protocol development for trials of prophylactic vaccines. The template may serve phases I-IV clinical trials protocol development to include safety relevant information as required by the regulatory authorities and as deemed useful by the investigators. This document may also be helpful for future site strengthening efforts. Copyright © 2013 Elsevier Ltd. All rights reserved.

Safety and efficacy of canagliflozin in elderly patients with type 2 diabetes mellitus: a 1-year post-marketing surveillance in Japan.

PubMed

Goda, Maki; Yamakura, Tomoko; Sasaki, Kazuyo; Tajima, Takumi; Ueno, Makoto

2018-02-01

To evaluate the safety and efficacy of canagliflozin in elderly patients with type 2 diabetes mellitus (T2DM) in clinical settings. The authors conducted a 1-year post-marketing surveillance (PMS) of canagliflozin in almost all the elderly patients (≥65 years old) with T2DM who began taking canagliflozin during the first 3 months after its launch in Japan. The main outcomes included the incidences of adverse drug reactions (ADRs), serious ADRs, and the changes of laboratory tests as well as efficacy variables. An ADR was reported in 9.09% (125 of 1375 patients) in the safety analysis set. The main ADRs were dehydration, constipation, thirst, pollakiuria, dizziness, cystitis, eczema, pruritus, and rash. The incidence of serious ADRs was 1.02% (14 patients), which included urinary tract infection, dehydration, hypoglycemia, and cerebral infarction (two patients each). ADRs of special interest that had been reported in clinical trials of SGLT2 inhibitors, such as hypoglycemia, volume depletion-related events, genital/urinary tract infection, polyuria/pollakiuria, and ketone body increased were also observed in this PMS. The safety profiles were similar to the results of a previous clinical study of canagliflozin, and new safety concerns were not identified in this survey. The mean change in HbA1c was -0.77% after 12 months of treatment in the efficacy analysis set. In this PMS, the safety and efficacy profiles of canagliflozin in elderly patients with T2DM were obtained in the clinical settings in Japan and the drug was well tolerated and effective in improving glycemic control.

[Analysis of patient complaints in Primary Care: An opportunity to improve clinical safety].

PubMed

Añel-Rodríguez, R M; Cambero-Serrano, M I; Irurzun-Zuazabal, E

2015-01-01

To determine the prevalence and type of the clinical safety problems contained in the complaints made by patients and users in Primary Care. An observational, descriptive, cross-sectional study was conducted by analysing both the complaint forms and the responses given to them in the period of one year. At least 4.6% of all claims analysed in this study contained clinical safety problems. The family physician is the professional who received the majority of the complaints (53.6%), and the main reason was the problems related to diagnosis (43%), mainly the delay in diagnosis. Other variables analysed were the severity of adverse events experienced by patients (in 68% of cases the patient suffered some harm), the subsequent impact on patient care, which was affected in 39% of cases (7% of cases even requiring hospital admission), and the level of preventability of adverse events (96% avoidable) described in the claims. Finally the type of response issued to each complaint was analysed, being purely bureaucratic in 64% of all cases. Complaints are a valuable source of information about the deficiencies identified by patients and healthcare users. There is considerable scope for improvement in the analysis and management of claims in general, and those containing clinical safety issues in particular. To date, in our area, there is a lack of appropriate procedures for processing these claims. Likewise, we believe that other pathways or channels should be opened to enable communication by patients and healthcare users. Copyright © 2015 SECA. Published by Elsevier Espana. All rights reserved.

Enhanced clinical outcome with manual massage following cryolipolysis treatment: a 4-month study of safety and efficacy.

PubMed

Boey, Gerald E; Wasilenchuk, Jennifer L

2014-01-01

Cryolipolysis procedures have been shown to safely and effectively reduce the thickness of fat in a treated region. This study was conducted to determine whether the addition of post-treatment manual massage would improve efficacy while maintaining the safety profile of the original cryolipolysis treatment protocol. The study population consisted of an efficacy group (n = 10) and a safety group (n = 7). Study subjects were treated on each side of the lower abdomen with a Cooling Intensity Factor of 42 (-72.9 mW/cm(2) ) for 60 minutes. One side of the abdomen was massaged post-treatment and the other side served as the control. Immediately post-treatment, the massage side was treated for 1 minute using a vigorous kneading motion followed by 1 minute of circular massage using the pads of the fingers. For the efficacy group, photos and ultrasound measurements were taken at baseline, 2 months, and 4 months post-treatment. For the safety group, histological analysis was completed at 0, 3, 8, 14, 30, 60, and 120 days post-treatment to examine the effects of massage on subcutaneous tissue over time. Post-treatment manual massage resulted in a consistent and discernible increase in efficacy over the non-massaged side. At 2 months post-treatment, mean fat layer reduction was 68% greater in the massage side than in the non-massage side as measured by ultrasound. By 4 months, mean fat layer reduction was 44% greater in the massage side. Histological results showed no evidence of necrosis or fibrosis resulting from the massage. Post-treatment manual massage is a safe and effective technique to enhance the clinical outcome from a cryolipolysis procedure. © 2013 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Profiling the clinical presentation of diagnostic characteristics of a sample of symptomatic TMD patients.

PubMed

Pimenta e Silva Machado, Luciana; de Macedo Nery, Marianita Batista; de Góis Nery, Cláudio; Leles, Cláudio Rodrigues

2012-08-02

Temporomandibular disorder (TMD) patients might present a number of concurrent clinical diagnoses that may be clustered according to their similarity. Profiling patients' clinical presentations can be useful for better understanding the behavior of TMD and for providing appropriate treatment planning. The aim of this study was to simultaneously classify symptomatic patients diagnosed with a variety of subtypes of TMD into homogenous groups based on their clinical presentation and occurrence of comorbidities. Clinical records of 357 consecutive TMD patients seeking treatment in a private specialized clinic were included in the study sample. Patients presenting multiple subtypes of TMD diagnosed simultaneously were categorized according to the AAOP criteria. Descriptive statistics and two-step cluster analysis were used to characterize the clinical presentation of these patients based on the primary and secondary clinical diagnoses. The most common diagnoses were localized masticatory muscle pain (n = 125) and disc displacement without reduction (n = 104). Comorbidity was identified in 288 patients. The automatic selection of an optimal number of clusters included 100% of cases, generating an initial 6-cluster solution and a final 4-cluster solution. The interpretation of within-group ranking of the importance of variables in the clustering solutions resulted in the following characterization of clusters: chronic facial pain (n = 36), acute muscle pain (n = 125), acute articular pain (n = 75) and chronic articular impairment (n = 121). Subgroups of acute and chronic TMD patients seeking treatment can be identified using clustering methods to provide a better understanding of the clinical presentation of TMD when multiple diagnosis are present. Classifying patients into identifiable symptomatic profiles would help clinicians to estimate how common a disorder is within a population of TMD patients and understand the probability of certain

Medical Systemic Therapies for Hepatocellular Carcinoma: Clinical Perspectives and Safety Profile.

PubMed

Facciorusso, Antonio; Antonino, Matteo; Del Prete, Valentina; Amoruso, Annabianca; Neve, Viviana; Barone, Michele

2015-01-01

A multidisciplinary approach based on clinical expertise and knowledge of molecular processes involved in hepatocarcinogenesis is needed for the proper management of hepatocellular carcinoma (HCC) patients. Such information must be considered in the context of pathobiology of the underlying liver disease. New drugs targeting specific molecular steps in pathways involved in HCC growth and development bear the promise to radically modify the pharmacological therapies currently in use in hepatooncology. Sorafenib was the first drug approved in the setting of advanced HCC, but although it produces some improvement in survival, the responses are not durable. In addition, there are significant side effects. Other angiogenesis inhibitors are in development to treat HCC both in the first-line setting and after progression following sorafenib failure; among them, tivantinib, an inhibitor of cMET receptor, showed interesting results in a recent phase-II study. Additional agents currently studied for the treatment of HCC patients are briefly examined in this review. Aim of this paper is to discuss the state of the art in the management of advanced HCC patients, with a particular interest for the description of their side effects.

Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic.

PubMed

Citrome, L

2011-02-01

To describe the efficacy and safety of lurasidone for the treatment of schizophrenia. The pivotal registration trials were accessed by querying the literature databases PubMed, EMBASE, ISI Web of Knowledge, as well as http://www.fda.gov and http://www.clinicaltrials.gov for the search term 'lurasidone'. Product labelling provided additional information. All available clinical reports of studies were identified. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports, abstracts and posters. Additional safety outcomes subject to NNH analysis were obtained from product labelling. Lurasidone is a second-generation antipsychotic approved for the treatment of schizophrenia at a recommended starting dose of 40 mg/day administered once daily with food (≥350 calories). The maximum recommended dose is 80 mg/day. Regulatory approval was based primarily on a clinical trial programme that included four 6-week randomised clinical trials demonstrating efficacy vs. placebo in acute patients with schizophrenia. One additional Phase II clinical trial was considered a failed study because neither lurasidone nor the active control, haloperidol, separated from placebo on the primary outcome measure. One additional Phase III study was completed after the new drug application was submitted to the US Food and Drug Administration. Efficacy outcomes appear consistently in favour of lurasidone 80 mg/day vs. placebo on multiple measures of psychopathology, however, at least two studies also demonstrated efficacy for the doses of 40 and 120 mg/day. NNT vs. placebo was 3-6 for response as defined by ≥20% reduction in psychopathological rating scale total scores from baseline, depending on the study and the dose. Response as defined by a ≥30% improvement yielded NNTs ranging from 7 to 13. The most common adverse events in the clinical trials were

Durability, safety, and efficacy of rilpivirine in clinical practice: results from the SCOLTA Project.

PubMed

Bagella, Paola; De Socio, Giuseppe Vl; Ricci, Elena; Menzaghi, Barbara; Martinelli, Canio; Squillace, Nicola; Maggi, Paolo; Orofino, Giancarlo; Calza, Leonardo; Carenzi, Laura; Celesia, Benedetto Maurizio; Penco, Giovanni; Di Biagio, Antonio; Valsecchi, Laura; Vichi, Francesca; Colombo, Valeria; Parruti, Giustino; Dentone, Chiara; Falasca, Katia; Bonfanti, Paolo; Madeddu, Giordano

2018-01-01

Rilpivirine is associated with a good efficacy and safety profile. However, data from real-life settings are scarce. We investigated the durability, safety and efficacy of Rilpivirine-based antiretroviral therapy in a prospective, observational, multicenter study. We enrolled 499 HIV-infected patients, 360 (72.1%) males, mean age 43.4 ± 10.5 years, mean CD4 600 ± 327 cell/μL, mean HIV-RNA 3.80 ± 1.15 log 10 cp/mL. After a median follow up of 16 months, 81 (16.2%) interruptions were reported, 36 (7.2%) of which for adverse events (16 of grade ≥3), most commonly neurological and gastrointestinal. We observed virological failures in only 8 (1.6%) patients. Naive patients showed a significant reduction in eGFR at week 24, 48 and 72 and in total cholesterol (TC)/HDL ratio at week 48 ( p =0.007). In patients switching from PI we found a significant decrease at week 24 and 48 in TC and triglycerides at week 24, 48 and 72. eGFR showed a significant decrease at week 48 and 72. TC/HDL ratio showed a statistically significant decrease at week 24 ( p =0.0008) and 72 ( p =0.04). A significant increase at week 24 and 48 in AST and ALT values was observed. Patients switching from TDF/FTC/EFV showed a reduction in HDL, total cholesterol and triglycerides at week 24 and 48 and in eGFR at all follow up times. TC/HDL ratio showed a significant decrease at week 48 ( p =0.01). CDC stage C and antiretroviral-experience (especially Protease Inhibitors) were associated with RPV discontinuation. In conclusion, our data confirm Rilpivirine efficacy, safety and tolerability with improvement in lipid profile. Although hepatic and renal events rarely caused discontinuation, liver and kidney parameters should be monitored.

Durability, safety, and efficacy of rilpivirine in clinical practice: results from the SCOLTA Project

PubMed Central

Bagella, Paola; De Socio, Giuseppe VL; Ricci, Elena; Menzaghi, Barbara; Martinelli, Canio; Squillace, Nicola; Maggi, Paolo; Orofino, Giancarlo; Calza, Leonardo; Carenzi, Laura; Celesia, Benedetto Maurizio; Penco, Giovanni; Di Biagio, Antonio; Valsecchi, Laura; Vichi, Francesca; Colombo, Valeria; Parruti, Giustino; Dentone, Chiara; Falasca, Katia; Bonfanti, Paolo; Madeddu, Giordano

2018-01-01

Rilpivirine is associated with a good efficacy and safety profile. However, data from real-life settings are scarce. Methods We investigated the durability, safety and efficacy of Rilpivirine-based antiretroviral therapy in a prospective, observational, multicenter study. Results We enrolled 499 HIV-infected patients, 360 (72.1%) males, mean age 43.4 ± 10.5 years, mean CD4 600 ± 327 cell/μL, mean HIV-RNA 3.80 ± 1.15 log10 cp/mL. After a median follow up of 16 months, 81 (16.2%) interruptions were reported, 36 (7.2%) of which for adverse events (16 of grade ≥3), most commonly neurological and gastrointestinal. We observed virological failures in only 8 (1.6%) patients. Naive patients showed a significant reduction in eGFR at week 24, 48 and 72 and in total cholesterol (TC)/HDL ratio at week 48 (p=0.007). In patients switching from PI we found a significant decrease at week 24 and 48 in TC and triglycerides at week 24, 48 and 72. eGFR showed a significant decrease at week 48 and 72. TC/HDL ratio showed a statistically significant decrease at week 24 (p=0.0008) and 72 (p=0.04). A significant increase at week 24 and 48 in AST and ALT values was observed. Patients switching from TDF/FTC/EFV showed a reduction in HDL, total cholesterol and triglycerides at week 24 and 48 and in eGFR at all follow up times. TC/HDL ratio showed a significant decrease at week 48 (p=0.01). CDC stage C and antiretroviral-experience (especially Protease Inhibitors) were associated with RPV discontinuation. Conclusion In conclusion, our data confirm Rilpivirine efficacy, safety and tolerability with improvement in lipid profile. Although hepatic and renal events rarely caused discontinuation, liver and kidney parameters should be monitored. PMID:29731650

Clinical profile, treatment, and visual outcome of ampiginous choroiditis.

PubMed

Jyotirmay, Biswas; Jafferji, Shafiq S; Sudharshan, Sridharan; Kalpana, Badami

2010-01-01

To report the clinical profile and management of patients diagnosed to have ampiginous choroiditis in a tertiary care referral centre in India. Retrospective cohort study. Twenty-six eyes of 16 patients were included in the study, which was diagnosed as choroiditis, serpiginous choroiditis, and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) or ampiginous choroiditis. Those who were initially diagnosed as having other forms of choroiditis were later classified as having ampiginous choroiditis clinically. Systemic steroids and immunosuppressives were the mainstay of therapy. There was a male preponderance (7:3). Age at presentation ranged from 22 years to 57 years with a (median 34 years); 81% had bilateral involvement and 35% had recurrences. Vision improved or maintained in 24 eyes, whereas it deteriorated in 2 eyes due to subretinal fibrosis and macula involvement, respectively. Resolution of lesions and improvement or stability of vision can occur with administration of timely steroids and immunosuppressive therapy. Regular follow-up is necessary to monitor the disease progression, recurrences, and involvement of the other eye. Ampiginous choroiditis is a separate disease entity due to its distinct clinical features. It is a disease with multiple relapses, which can be effectively controlled with a combination of immunosuppressive therapy, and a good visual acuity can be maintained on long-term follow-up.

Leukogram Profile and Clinical Status in vivax and falciparum Malaria Patients from Colombia

PubMed Central

Tobón-Castaño, Alberto; Mesa-Echeverry, Esteban; Miranda-Arboleda, Andrés Felipe

2015-01-01

Introduction. Hematological alterations are frequent in malaria patients; the relationship between alterations in white blood cell counts and clinical status in malaria is not well understood. In Colombia, with low endemicity and unstable transmission for malaria, with malaria vivax predominance, the hematologic profile in malaria patients is not well characterized. The aim of this study was to characterize the leukogram in malaria patients and to analyze its alterations in relation to the clinical status. Methods. 888 leukogram profiles of malaria patients from different Colombian regions were studied: 556 with P. falciparum infection (62.6%), 313 with P. vivax infection (35.2%), and 19 with mixed infection by these species (2.1%). Results. Leukocyte counts at diagnosis were within normal range in 79% of patients and 18% had leucopenia; the most frequent alteration was lymphopenia (54%) followed by monocytosis (11%); the differential granulocyte count in 298 patients revealed eosinophilia (15%) and high basophil counts (8%). Leukocytosis, eosinopenia, and neutrophilia were associated with clinical complications. The utility of changes in leukocyte counts as markers of severity should be explored in depth. A better understanding of these hematological parameters will allow their use in prompt diagnosis of malaria complications and monitoring treatment response. PMID:26664413

Automated validation of patient safety clinical incident classification: macro analysis.

PubMed

Gupta, Jaiprakash; Patrick, Jon

2013-01-01

Patient safety is the buzz word in healthcare. Incident Information Management System (IIMS) is electronic software that stores clinical mishaps narratives in places where patients are treated. It is estimated that in one state alone over one million electronic text documents are available in IIMS. In this paper we investigate the data density available in the fields entered to notify an incident and the validity of the built in classification used by clinician to categories the incidents. Waikato Environment for Knowledge Analysis (WEKA) software was used to test the classes. Four statistical classifier based on J48, Naïve Bayes (NB), Naïve Bayes Multinominal (NBM) and Support Vector Machine using radial basis function (SVM_RBF) algorithms were used to validate the classes. The data pool was 10,000 clinical incidents drawn from 7 hospitals in one state in Australia. In first part of the study 1000 clinical incidents were selected to determine type and number of fields worth investigating and in the second part another 5448 clinical incidents were randomly selected to validate 13 clinical incident types. Result shows 74.6% of the cells were empty and only 23 fields had content over 70% of the time. The percentage correctly classified classes on four algorithms using categorical dataset ranged from 42 to 49%, using free-text datasets from 65% to 77% and using both datasets from 72% to 79%. Kappa statistic ranged from 0.36 to 0.4. for categorical data, from 0.61 to 0.74. for free-text and from 0.67 to 0.77 for both datasets. Similar increases in performance in the 3 experiments was noted on true positive rate, precision, F-measure and area under curve (AUC) of receiver operating characteristics (ROC) scores. The study demonstrates only 14 of 73 fields in IIMS have data that is usable for machine learning experiments. Irrespective of the type of algorithms used when all datasets are used performance was better. Classifier NBM showed best performance. We think the

Study of neurontin: titrate to effect, profile of safety (STEPS) trial: a narrative account of a gabapentin seeding trial.

PubMed

Krumholz, Samuel D; Egilman, David S; Ross, Joseph S

2011-06-27

Seeding trials, clinical studies conducted by pharmaceutical companies for marketing purposes, have rarely been described in detail. We examined all documents relating to the clinical trial Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) produced during the Neurontin marketing, sales practices, and product liability litigation, including company internal and external correspondence, reports, and presentations, as well as depositions elicited in legal proceedings of Harden Manufacturing vs Pfizer and Franklin vs Warner-Lambert, most which were created between 1990 and 2009. Using a systematic search strategy, we identified and reviewed all documents related to the STEPS trial in order to identify key themes related to the trial's conduct and determine the extent of marketing involvement in its planning and implementation. Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company's marketing plans. Documents demonstrated that at least 2 external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in 2 published articles. The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, and marketing was extensively involved in its planning and implementation.

The role of the Data and Safety Monitoring Board in a clinical trial: the CRISIS study.

PubMed

Holubkov, Richard; Casper, T Charles; Dean, J Michael; Anand, K J S; Zimmerman, Jerry; Meert, Kathleen L; Newth, Christopher J L; Berger, John; Harrison, Rick; Willson, Douglas F; Nicholson, Carol

2013-05-01

Randomized clinical trials are commonly overseen by a Data and Safety Monitoring Board comprised of experts in medicine, ethics, and biostatistics. Data and Safety Monitoring Board responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. Data and Safety Monitoring Board decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate Data and Safety Monitoring Board oversight into the design, monitoring, and reporting of randomized trials. Case study, narrative review. The Data and Safety Monitoring Board's role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described. The National Institutes of Health-appointed CRISIS Data and Safety Monitoring Board was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested Data and Safety Monitoring Board interim review before opening CRISIS to children below 1 yr of age. The first interim analysis found higher 28-day mortality in one treatment arm. The Data and Safety Monitoring Board maintained trial closure to younger children and requested a second interim data review 6 months later. At this second meeting, mortality was no longer of concern, whereas a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the Data and Safety Monitoring Board elected to examine conditional power and unmask treatment arm identities. On finding somewhat greater efficacy in the placebo arm, the Data and Safety Monitoring Board recommended stopping CRISIS due to futility. The design and operating procedures of a multicenter randomized trial must consider a pivotal Data and Safety Monitoring Board role. Maximum

Safety of famciclovir in patients with herpes zoster and genital herpes.

PubMed Central

Saltzman, R; Jurewicz, R; Boon, R

1994-01-01

Safety reporting from individual ongoing and completed clinical studies has demonstrated that famciclovir, the well-absorbed oral form of the antiherpesvirus agent penciclovir, has been well tolerated by more than 3,000 individuals worldwide. An integrated safety evaluation has been performed and includes over 1,600 patients from 11 completed, randomized, double-blind clinical trials and 2 open trials. The famciclovir population consisted of 816 herpes zoster patients (four trials), 409 patients with acute genital herpesvirus infections (seven trials), and 382 patients from two genital herpes suppression studies. Overall, the famciclovir-treated patient population was 57.7% female and ranged in age from 15 to 102 years (mean, 42.6 years), with 31.2% aged 50 years or more and 15.7% aged 65 years or more. The mean duration of exposure to famciclovir was 28.8 days (5.8 days excluding suppression studies). The total daily doses ranged from 125 mg to 2.25 g. The most common adverse experiences reported as related to study medication (famciclovir and placebo) were headache, nausea, and diarrhea. The frequencies of adverse experiences and laboratory abnormalities (hematology, clinical chemistry, and urinalysis parameters) were similar in both famciclovir and placebo recipients. Thus, safety data from the analysis of 13 completed clinical studies demonstrate that famciclovir is tolerated well by patients with either herpes zoster or genital and has a safety profile comparable to that of placebo. PMID:7840587

Development and evaluation of a culture-free microbiota profiling platform (MYcrobiota) for clinical diagnostics.

PubMed

Boers, Stefan A; Hiltemann, Saskia D; Stubbs, Andrew P; Jansen, Ruud; Hays, John P

2018-06-01

Microbiota profiling has the potential to greatly impact on routine clinical diagnostics by detecting DNA derived from live, fastidious, and dead bacterial cells present within clinical samples. Such results could potentially be used to benefit patients by influencing antibiotic prescribing practices or to generate new classical-based diagnostic methods, e.g., culture or PCR. However, technical flaws in 16S rRNA gene next-generation sequencing (NGS) protocols, together with the requirement for access to bioinformatics, currently hinder the introduction of microbiota analysis into clinical diagnostics. Here, we report on the development and evaluation of an "end-to-end" microbiota profiling platform (MYcrobiota), which combines our previously validated micelle PCR/NGS (micPCR/NGS) methodology with an easy-to-use, dedicated bioinformatics pipeline. The newly designed bioinformatics pipeline processes micPCR/NGS data automatically and summarizes the results in interactive, but simple web reports. In order to explore the utility of MYcrobiota in clinical diagnostics, 47 clinical samples (40 "damaged skin" samples and 7 synovial fluids) were investigated using routine bacterial culture as comparator. MYcrobiota confirmed the presence of bacterial DNA in 37/37 culture-positive samples and detected bacterial taxa in 2/10 culture-negative samples. Moreover, 36/38 potentially relevant aerobic bacterial taxa and 3/3 mixtures of anaerobic bacteria were identified using culture and MYcrobiota, with the sensitivity and specificity being 95%. Interestingly, the majority of the 448 bacterial taxa identified using MYcrobiota were not identified using culture, which could potentially have an impact on clinical decision-making. Taken together, the development of MYcrobiota is a promising step towards the introduction of microbiota analysis into clinical diagnostic laboratories.

[Cognitive impairment, nutritional status and clinical profile in chronic obstructive pulmonary disease].

PubMed

López Torres, Isabel; Torres-Sánchez, Irene; Martín Salvador, Adelina; Ortiz Rubio, Araceli; Rodríguez Alzueta, Elisabeth; Valenza, Marie Carmen

2014-11-01

Chronic obstructive pulmonary disease (COPD) is a progressive disease with a prevalence that increases with the aging of the subject. It presents a high prevalence of comorbidities, such as cognitive decline, which is gaining great clinical relevance in recent years. Factors such as pulmonary function, hypoxemia, hypercapnia or exacerbations contribute to the decline of cognitive functions. The nutritional status has been added to these factors as contributing to cognitive function decline when presenting in COPD. To evidence the relationship between cognitive decline, nutritional status and the clinical profile of patients admitted because of an acute exacerbation of COPD (AECOPD). 110 subjects hospitalized because of COPD, divided in two groups according to their nutritional status and assessment of cognitive decline at admittance, nutritional status and clinical profile. Significant differences between groups concerning nutritional status in anthropometric variables (sex and IMC), functional ability (Barthel index and Daily Life Activities Scale), quality of life (Euroqol- 5D y SGRQ), sleep quality (Pittsburgh), mood (HAD) and cognitive decline (MoCa attention, MoCa abstraction). (p<0.05). Cognitive function is affected in COPD patients with an altered nutritional status when compared to those with a normal nutritional status. The nutritional decline is a factor contributing to the impairment of cognitive functions in this kind of patients, particularly a decline in attention and abstraction ability. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

[News items about clinical errors and safety perceptions in hospital patients].

PubMed

Mira, José Joaquín; Guilabert, Mercedes; Ortíz, Lidia; Navarro, Isabel María; Pérez-Jover, María Virtudes; Aranaz, Jesús María

2010-01-01

To analyze how news items about clinical errors are treated by the press in Spain and their influence on patients. We performed a quantitative and qualitative study. Firstly, news items published between April and November 2007 in six newspapers were analyzed. Secondly, 829 patients from five hospitals in four autonomous regions were surveyed. We analyzed 90 cases generating 128 news items, representing a mean of 16 items per month. In 91 news items (71.1%) the source was checked. In 78 items (60.9%) the author could be identified. The impact of these news items was -4.86 points (95% confidence interval [95%CI]: -4.15-5.57). In 59 cases (57%) the error was attributed to the system, in 27 (21.3%) to health professionals, and in 41 (32.3%) to both. Neither the number of columns (p=0.702), nor the inclusion of a sub-header (p=0.195), nor a complementary image (p=0.9) were found to be related to the effect of the error on safety perceptions. Of the 829 patients, 515 (62.1%; 95%CI: 58.8-65.4%) claimed to have recently seen or heard news about clinical errors in the press, on the radio or on television. The perception of safety decreased when the same person was worried about being the victim of a clinical error and had seen a recent news item about such adverse events (chi(2)=15.17; p=0.001). Every week news items about clinical errors are published or broadcast. The way in which newspapers report legal claims over alleged medical errors is similar to the way they report judicial sentences for negligence causing irreparable damage or harm. News about errors generates insecurity in patients. It is advisable to create interfaces between journalists and health professionals. Copyright 2009 SESPAS. Published by Elsevier Espana. All rights reserved.

Clinical safety issues of measles, mumps and rubella vaccines.

PubMed Central

Afzal, M. A.; Minor, P. D.; Schild, G. C.

2000-01-01

The clinical safety of measles and measles-mumps-rubella vaccines has been questioned in recent reports that propose a possible link between measles virus or measles vaccines and the occurrence of juvenile Crohn disease and autism. This article reviews the outcomes of several laboratory investigations which were carried out independently to identify the presence or absence of measles virus in the intestinal tissues derived from cases of inflammatory bowel disease. One research group reported the presence of measles virus particles and genomic RNA in inflammatory bowel disease tissues, but this could not be confirmed by other groups, despite use of techniques that are highly specific and sensitive for the detection of measles virus nucleic acid in clinical specimens down to the molecular level. Based on the published data reviewed here, it can be concluded that there is no direct association between measles virus or measles vaccines and the development of Crohn disease, a conclusion which is supported by most epidemiological findings. PMID:10743285

[Malpractice in Urology: lessons of clinical and legal safety.

PubMed

Vargas-Blasco, César; Gómez-Durán, Esperanza L; Martin-Fumadó, Carles; Arimany-Manso, Josep

2018-06-01

Data about urology malpractice claims in our environment are scarce and should be considered a potential opportunity to "learn from errors". We analyzed every claim for alleged malpractice in Urology managed by the Council of Medical Colleges of Catalonia between 1990 and 2012, and specifically evaluated the clinical and medicolegal features of those cases with medical professional responsibility. We identified 182 cases in 22 years, but only the 25,74%showed professional liability. Testicular torsion misdiagnosis, pregnancies after vasectomy and complications of lithiasis should be noted for their frequency of claims and rate of liability. 246 physicians were involved, 89% were males and mean age was 45.6 years. Most cases (n=137, 75.27%) were processed in the courts. Urology has a medium risk of claims, with a moderate rate of medical professional liability and amount of compensation. There are specific actions that would lead to clinical safety improvements, particularly in testicular pathologies, vasectomy and lithiasis. Finally, more attention should be paid to proper patient information.

Clinical Implications of Cluster Analysis-Based Classification of Acute Decompensated Heart Failure and Correlation with Bedside Hemodynamic Profiles.

PubMed

Ahmad, Tariq; Desai, Nihar; Wilson, Francis; Schulte, Phillip; Dunning, Allison; Jacoby, Daniel; Allen, Larry; Fiuzat, Mona; Rogers, Joseph; Felker, G Michael; O'Connor, Christopher; Patel, Chetan B

2016-01-01

Classification of acute decompensated heart failure (ADHF) is based on subjective criteria that crudely capture disease heterogeneity. Improved phenotyping of the syndrome may help improve therapeutic strategies. To derive cluster analysis-based groupings for patients hospitalized with ADHF, and compare their prognostic performance to hemodynamic classifications derived at the bedside. We performed a cluster analysis on baseline clinical variables and PAC measurements of 172 ADHF patients from the ESCAPE trial. Employing regression techniques, we examined associations between clusters and clinically determined hemodynamic profiles (warm/cold/wet/dry). We assessed association with clinical outcomes using Cox proportional hazards models. Likelihood ratio tests were used to compare the prognostic value of cluster data to that of hemodynamic data. We identified four advanced HF clusters: 1) male Caucasians with ischemic cardiomyopathy, multiple comorbidities, lowest B-type natriuretic peptide (BNP) levels; 2) females with non-ischemic cardiomyopathy, few comorbidities, most favorable hemodynamics; 3) young African American males with non-ischemic cardiomyopathy, most adverse hemodynamics, advanced disease; and 4) older Caucasians with ischemic cardiomyopathy, concomitant renal insufficiency, highest BNP levels. There was no association between clusters and bedside-derived hemodynamic profiles (p = 0.70). For all adverse clinical outcomes, Cluster 4 had the highest risk, and Cluster 2, the lowest. Compared to Cluster 4, Clusters 1-3 had 45-70% lower risk of all-cause mortality. Clusters were significantly associated with clinical outcomes, whereas hemodynamic profiles were not. By clustering patients with similar objective variables, we identified four clinically relevant phenotypes of ADHF patients, with no discernable relationship to hemodynamic profiles, but distinct associations with adverse outcomes. Our analysis suggests that ADHF classification using simultaneous

A longitudinal study of clinical peer review's impact on quality and safety in U.S. hospitals.

PubMed

Edwards, Marc T

2013-01-01

Clinical peer review is the dominant method of event analysis in U.S. hospitals. It is pivotal to medical staff efforts to improve quality and safety, yet the quality assurance process model that has prevailed for the past 30 years evokes fear and is fundamentally antithetical to a culture of safety. Two prior national studies characterized a quality improvement model that corrects this dysfunction but failed to demonstrate progress toward its adoption despite a high rate of program change between 2007 and 2009. This study's online survey of 470 organizations participating in either of the prior studies further assessed relationships between clinical peer review program factors, including the degree of conformance to the quality improvement model (the QI model score), and subjectively measured program impact variables. Among the 300 hospitals (64%) that responded, the median QI model score was only 60 on a 100-point scale. Scores increased somewhat for the 2007 cohort (mean pair-wise difference of 5.9 [2-10]), but not for the 2009 cohort. The QI model is expanded as the result of the finding that self-reporting of adverse events, near misses, and hazardous conditions--an essential practice in high-reliability organizations--is no longer rare in hospitals. Self-reporting and the quality of case review are additional multivariate predictors of the perceived ongoing impact of clinical peer review on quality and safety, medical staff perceptions of the program, and medical staff engagement in quality and safety initiatives. Hospital leaders and trustees who seek to improve patient outcomes should facilitate the adoption of this best practice model for clinical peer review.

Biologic and clinical significance of molecular profiling in Chronic Lymphocytic Leukemia.

PubMed

Butler, Tom; Gribben, J G

2010-05-01

CLL is extremely heterogeneous in its clinical course, with some patients living decades with no need for treatment whilst others have a rapidly aggressive clinical course. A major focus of research has been to try to identify those biological factors that influence this heterogeneity. The goal of therapy has been to maintain the best quality of life and treat only when patients become symptomatic from their disease. For the majority of patients this means following a "watch and wait" approach to determine the rate of progression of the disease and assess for development of symptoms. Any alteration to this approach will require identification of criteria that define patients sufficiently "high-risk" that they gain benefit by introduction of early therapy. The use of molecular profiling to suggest particular therapies is currently appropriate only in defining the treatment of the minority of patients with 17p deletions or p53 mutations and in all other circumstances remains a clinical trial question. Copyright 2010 Elsevier Ltd. All rights reserved.

A meta-model for computer executable dynamic clinical safety checklists.

PubMed

Nan, Shan; Van Gorp, Pieter; Lu, Xudong; Kaymak, Uzay; Korsten, Hendrikus; Vdovjak, Richard; Duan, Huilong

2017-12-12

Safety checklist is a type of cognitive tool enforcing short term memory of medical workers with the purpose of reducing medical errors caused by overlook and ignorance. To facilitate the daily use of safety checklists, computerized systems embedded in the clinical workflow and adapted to patient-context are increasingly developed. However, the current hard-coded approach of implementing checklists in these systems increase the cognitive efforts of clinical experts and coding efforts for informaticists. This is due to the lack of a formal representation format that is both understandable by clinical experts and executable by computer programs. We developed a dynamic checklist meta-model with a three-step approach. Dynamic checklist modeling requirements were extracted by performing a domain analysis. Then, existing modeling approaches and tools were investigated with the purpose of reusing these languages. Finally, the meta-model was developed by eliciting domain concepts and their hierarchies. The feasibility of using the meta-model was validated by two case studies. The meta-model was mapped to specific modeling languages according to the requirements of hospitals. Using the proposed meta-model, a comprehensive coronary artery bypass graft peri-operative checklist set and a percutaneous coronary intervention peri-operative checklist set have been developed in a Dutch hospital and a Chinese hospital, respectively. The result shows that it is feasible to use the meta-model to facilitate the modeling and execution of dynamic checklists. We proposed a novel meta-model for the dynamic checklist with the purpose of facilitating creating dynamic checklists. The meta-model is a framework of reusing existing modeling languages and tools to model dynamic checklists. The feasibility of using the meta-model is validated by implementing a use case in the system.

The Clinically Tested Gardos Channel Inhibitor Senicapoc Exhibits Antimalarial Activity

PubMed Central

Tubman, Venée N.; Mejia, Pedro; Shmukler, Boris E.; Bei, Amy K.; Alper, Seth L.; Mitchell, James R.

2015-01-01

Senicapoc, a Gardos channel inhibitor, prevented erythrocyte dehydration in clinical trials of patients with sickle cell disease. We tested the hypothesis that senicapoc-induced blockade of the Gardos channel inhibits Plasmodium growth. Senicapoc inhibited in vitro growth of human and primate plasmodia during the clinical blood stage. Senicapoc treatment suppressed P. yoelii parasitemia in vivo in C57BL/6 mice. The reassuring safety and biochemical profile of senicapoc encourage its use in antimalarial development. PMID:26459896

States Respond to School Safety Concerns with 2013 Legislation. School Safety: 2013 Legislative Session

ERIC Educational Resources Information Center

Wixom, Micah Ann

2014-01-01

School safety policies are constantly evolving, often in response to fatal events. After several high-profile and tragic shootings over the past 15 years, school safety has become a major focus for parents, school officials, policymakers and the public nationwide. ECS [Education Commission of the States] conducted a scan of school safety-related…

CEDRIC: a computerized chronic disease management system for urban, safety net clinics.

PubMed

Ogunyemi, Omolola; Mukherjee, Sukrit; Ani, Chizobam; Hindman, David; George, Sheba; Ilapakurthi, Ramarao; Verma, Mary; Dayrit, Melvin

2010-01-01

To meet the challenge of improving health care quality in urban, medically underserved areas of the US that have a predominance of chronic diseases such as diabetes, we have developed a new information system called CEDRIC for managing chronic diseases. CEDRIC was developed in collaboration with clinicians at an urban safety net clinic, using a community-participatory partnered research approach, with a view to addressing the particular needs of urban clinics with a high physician turnover and large uninsured/underinsured patient population. The pilot implementation focuses on diabetes management. In this paper, we describe the system's architecture and features.

Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib.

PubMed

Curtis, Jeffrey R; Zhang, Richard; Krishnaswami, Sriram; Anisfeld, Andrew; Chen, Yan; Strengholt, Sander; Chen, Connie; Geier, Jamie

2017-03-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs' exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (≥1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ≥1.5×), as well as opportunistic infections and gastrointestinal perforations (≥2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.

Pharmacokinetics of piperaquine and safety profile of dihydroartemisinin-piperaquine co-administered with antiretroviral therapy in malaria-uninfected HIV-positive Malawian adults.

PubMed

Banda, Clifford G; Dzinjalamala, Fraction; Mukaka, Mavuto; Mallewa, Jane; Maiden, Victor; Terlouw, Dianne J; Lalloo, David G; Khoo, Saye H; Mwapasa, Victor

2018-05-21

There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus infected (HIV+) individuals taking antiretroviral therapy (ART). In a two step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared area under the concentration-time curve (AUC 0-28 days ) and safety outcomes of piperaquine among malaria-uninfected HIV+ adults. In step 1, half the adult dose of DHA-PQ was administered for three days as an intitial safety check in four groups (n=6/group) of HIV+ adults (age≥18 years): (i) antiretroviral-naïve, (ii) on nevirapine-based ART, (iii) on efavirenz-based ART, and (iv) on ritonavir-boosted lopinavir-based ART. In step 2, a full adult treatment course of DHA-PQ was administered to a different cohort of participants in three groups: (i) antiretroviral naïve, (ii) on efavirenz-based ART and (iii) on nevirapine-based ART (n=10-15/group). Ritonavir-boosted lopinavir-based ART group was dropped in step 2 due to limited number of participants who were on this second line ART and were eligible for recruitment. Piperaquine's AUC 0-28 days in both steps was 43% lower among participants on efavirenz-based ART compared to ART naïve participants. There were no significant differences in AUC 0-28 days between the other ART groups and the ART naïve group in each of the two steps. Furthermore, no differences in treatment-emergent clinical and laboratory adverse events were observed across the groups in steps 1 and 2. Although well tolerated at half and full standard adult treatment courses, efavirenz based antiretroviral regimen was associated with reduced piperaquine exposure which may compromise dihydroartemisinin-piperaquine's effectiveness in programmatic settings. Copyright © 2018 Banda et al.

Efficacy and Safety of Remifentanil as an Alternative Labor Analgesic

PubMed Central

Devabhakthuni, Sandeep

2013-01-01

The objective of this review was to evaluate the clinical efficacy and safety of remifentanil in the management of labor pain. Although neuraxial analgesia is the best option during labor, alternative analgesic options are needed for patients with contraindications. Using a systematic literature search, clinical outcomes of remifentanil for labor pain have been summarized. Also, comparisons of remifentanil to other options including meperidine, epidural analgesia, fentanyl, and nitrous oxide are provided. Based on the literature review, remifentanil is associated with high overall maternal satisfaction and favorable side-effect profile. However, due to the low reporting of adverse events, large, randomized controlled trials are needed to evaluate maternal and neonatal safety adequately and determine the optimal dosing needed to provide effective analgesia. While remifentanil is a feasible alternative for patients who cannot or do not want to receive epidural analgesia, administration should be monitored closely for potential adverse effects. PMID:24665213

Teleretinal screening for diabetic retinopathy in six Los Angeles urban safety-net clinics: initial findings.

PubMed

Ogunyemi, Omolola; Terrien, Elizabeth; Eccles, Alicia; Patty, Lauren; George, Sheba; Fish, Allison; Teklehaimanot, Senait; Ilapakurthi, Ramarao; Aimiuwu, Otaren; Baker, Richard

2011-01-01

Diabetic retinopathy is a leading cause of blindness in US adults. This paper presents initial results of a teleretinal screening project for diabetic retinopathy involving six Los Angeles safety net clinics. A total of 1,943 patients have been screened for diabetic retinopathy by three ophthalmologist readers, with 416 receiving a recommendation for referral to specialty care. Of the cases recommended for referral, 24 had proliferative diabetic retinopathy, 62 had severe non-proliferative diabetic retinopathy (NPDR), 60 had moderate NPDR, 19 had mild NPDR, 138 had a non-diabetic condition, such as glaucoma, 63 had clinically significant macular edema without retinopathy and 50 had non-gradable images. Between 3% and 12.2% of retinal images taken at the clinics were assessed by readers as inadequate for any interpretation. The study shows the feasibility and challenges of teleretinal screening for diabetic retinopathy in urban areas facing specialist shortages and an overburdened, under-resourced safety net care-delivery system.

Teleretinal Screening for Diabetic Retinopathy in Six Los Angeles Urban Safety-Net Clinics: Initial Findings

PubMed Central

Ogunyemi, Omolola; Terrien, Elizabeth; Eccles, Alicia; Patty, Lauren; George, Sheba; Fish, Allison; Teklehaimanot, Senait; Ilapakurthi, Ramarao; Aimiuwu, Otaren; Baker, Richard

2011-01-01

Diabetic retinopathy is a leading cause of blindness in US adults. This paper presents initial results of a teleretinal screening project for diabetic retinopathy involving six Los Angeles safety net clinics. A total of 1,943 patients have been screened for diabetic retinopathy by three ophthalmologist readers, with 416 receiving a recommendation for referral to specialty care. Of the cases recommended for referral, 24 had proliferative diabetic retinopathy, 62 had severe non-proliferative diabetic retinopathy (NPDR), 60 had moderate NPDR, 19 had mild NPDR, 138 had a non-diabetic condition, such as glaucoma, 63 had clinically significant macular edema without retinopathy and 50 had non-gradable images. Between 3% and 12.2% of retinal images taken at the clinics were assessed by readers as inadequate for any interpretation. The study shows the feasibility and challenges of teleretinal screening for diabetic retinopathy in urban areas facing specialist shortages and an overburdened, under-resourced safety net care-delivery system. PMID:22195163

A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-D-mannuronic acid in rheumatoid arthritis patients.

PubMed

Ahmadi, Hossein; Jamshidi, Ahmad Reza; Gharibdoost, Farhad; Mahmoudi, Mahdi; Rastkari, Noushin; Mostafaei, Shayan; Fattahi, Mohammad Javad; Vojdanian, Mahdi; Cuzzocrea, Salvatore; Rehm, Bernd H A; Matsuo, Hidenori; Hosseini, Mostafa; Aghazadeh, Zahra; Mortazavi-Jahromi, Seyed Shahabeddin; Mirshafiey, Abbas

2018-06-01

Following the potent efficacy of β-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy. The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient's adverse events occurred during this study. Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.

Safety of fenbendazole in Chinese ring-necked pheasants (Phasianus colchicus).

PubMed

Griffith, R; Yaeger, M; Hostetter, S; Tell, L A; Wetzlich, S; Vickroy, T; Lillie, B; MacFarlane, W; Laudenslager, T; Whitley, E; Dzikamunhenga, R; Larson, W

2014-03-01

Ring-necked pheasants raised on propagation farms can be severely parasitized with Syngamus trachea (gapeworm) and other parasitic worms. Fenbendazole is a highly effective benzimidazole-class anthelmintic that is not currently approved for game bird species in the United States. The objective of this work was to provide target animal safety data to support a label claim for fenbendazole in pheasants at 100 parts per million (ppm) in the feed for 7 consecutive days. Demonstration of safety in young pheasants and a separate demonstration of reproductive safety in adult birds were required. In the young bird study, 160 Chinese ring-necked pheasants (Phasianus colchicus, 80 males and 80 females) were fed a commercial game bird starter ration containing no antibiotics, growth promoters, or coccidiostats until day 0 of the study (approximately 21 days of age). On day 0 the birds were placed on their respective study diets containing fenbendazole at 0, 100, 300, and 500 ppm for 21 days (three times the normal treatment duration). Clinical observations were recorded twice daily. Feed consumption, feed conversion rate, and body weights were determined for each pen. Three birds from each pen were randomly selected for necropsy, histopathology, and clinical pathology. Birds were carefully examined for feathering abnormalities immediately following euthanasia. The remaining birds in each pen were submitted for drug concentration analysis so that concentrations (for low vs. high treatment levels) could be correlated with clinical observations, clinical pathology, and histologic findings. There no morbidities or mortalities after study day--1. There were no statistically significant treatment-related differences in feed consumption, feed conversion rates, body weights, serum biochemistry profiles, hematologic profiles, gross necropsy findings, histopathologic examination, and feathering. Allowable liver and muscle concentrations of fenbendazole sulfone in turkeys are 6 and 2

A network meta-analysis of randomized controlled trials for comparing the effectiveness and safety profile of treatments with marketing authorization for relapsing multiple sclerosis.

PubMed

Hadjigeorgiou, G M; Doxani, C; Miligkos, M; Ziakas, P; Bakalos, G; Papadimitriou, D; Mprotsis, T; Grigoriadis, N; Zintzaras, E

2013-12-01

The relative effectiveness and safety profile of the treatments with marketing authorization for relapsing multiple sclerosis (MS) are not well known because randomized controlled trials with head-to-head comparisons between these treatments do not exist. Thus, a network of multiple-treatments meta-analysis was performed using four clinical outcomes: 'patients free of relapse', 'patients without disease progression', 'patients without MRI progression' and 'patients with adverse events'. Randomized controlled trials (RCTs) on MS were systematically searched in PubMed and Cochrane Central Register of Controlled Trial. The network analysis performed pairwise comparisons between the marketed treatments (Betaferon 250mcg, Avonex 30mcg, Rebif 44mcg, Rebif 22mcg, Aubagio 7 mg, Aubagio 14 mg, Copaxone 20 mg, Tysabri 300 mg, Gilenya 0·5 mg and Novantrone 12 mg/m(2)) using direct and indirect analyses. The analysis included 48 articles, involving 20 455 patients with MS. The direct analysis showed better response for more than one outcome for Gilenya compared with Avonex ('patients free of relapse' and 'patients without MRI progression') and for Betaferon compared with Avonex ('patients without disease progression' and 'patients without MRI progression'). The indirect analysis indicated that Tysabri may have better relative effectiveness compared with the other treatments for two outcomes: 'patients free of relapse' and 'patients without MRI progression'. Regarding 'patients with adverse events', no data were available for all comparisons to make fair inferences. This was an attempt, for the first time, to compare the efficacy and safety profile of existing approved treatments for relapsing MS. Although some treatments have shown better response, the results of the network analysis should be interpreted with caution because of the lack of RCTs with head-to-head comparisons between treatments. © 2013 John Wiley & Sons Ltd.

Safety of treatment options for spondyloarthritis: a narrative review.

PubMed

D'Angelo, Salvatore; Carriero, Antonio; Gilio, Michele; Ursini, Francesco; Leccese, Pietro; Palazzi, Carlo

2018-05-01

Spondyloarthritis (SpA) are chronic inflammatory diseases with overlapping pathogenic mechanisms and clinical features. Treatment armamentarium against SpA includes non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs, including sulfasalazine, methotrexate, leflunomide, cyclosporine), targeted synthetic DMARDs (apremilast) and biological DMARDs (TNF inhibitors, anti-IL 12/23 and anti-IL-17 agents). Areas covered: A narrative review of published literature on safety profile of available SpA treatment options was performed. Readers will be provided with a comprehensive overview on frequent and rare adverse events associated with each drug listed in current SpA treatment recommendations. Expert opinion: The overall safety profile of such molecules is good and serious adverse events are rare but need to be promptly recognized and treated. However, the monitoring of adverse events is a major challenge for clinicians because it is not adequately addressed by current treatment recommendations. A tailored treatment is crucial and rheumatologists must accurately select patients in order to identify those more susceptible to develop adverse events.

Efficacy and safety profile evaluation of acarbose alone and in association with other antidiabetic drugs: a systematic review.

PubMed

Derosa, Giuseppe; Maffioli, Pamela

2012-06-01

Epidemiologic studies have revealed that postprandial hyperglycemia significantly contributes to high glycated hemoglobin concentrations and could be linked to the development of chronic diabetic complications. The purpose of our review was to evaluate the clinical efficacy and safety profile of treatment with acarbose alone and combined with other antidiabetic drugs. A systematic search strategy was developed to identify randomized controlled trials included in MEDLINE and the Cochrane Register of Controlled Trials. The terms acarbose, α-glucosidase inhibitors, type 2 diabetes, adverse events, combination therapy, and postprandial glucose were incorporated into an electronic search strategy that included the Dickersin filter for randomized controlled trials. To qualify for inclusion, clinical trials had to be randomized trials comparing treatment with acarbose at any dosage with any other antidiabetic drug in patients with type 2 diabetes mellitus or impaired glucose tolerance. Eligible trials had to present results on glycemic control or adverse events. Trial participants needed to be affected by type 2 diabetes mellitus or have impaired glucose tolerance, and the intervention had to include acarbose at any dosage as monotherapy or combined with other antidiabetic drugs. A validated 3-item scale was used to evaluate the overall reporting quality of the trials selected for inclusion in the present review. Nineteen trials were included. Treatment with acarbose significantly reduced glycated hemoglobin levels when given as monotherapy and as an add-on to other antidiabetic drug treatment (P < 0.0001). Acarbose treatment was effective in patients with uncontrolled type 2 diabetes and in patients with apparently good metabolic control owing to its positive effect on postprandial hyperglycemia (P < 0.0001). Treatment with acarbose seemed to improve the lipid profile (P < 0.05), reduce circulating levels of cell adhesion molecules (P < 0.05), reduce intima

Biologic Therapy in Inflammatory and Immunomediated Arthritis: Safety Profile.

PubMed

Luchetti, Michele Maria; Balloni, Andrea; Gabrielli, Armando

2016-01-01

The increasing insights into the pathogenetic mechanisms of inflammatory autoimmune arthritis and the development of innovative systems of industrial production have led to discover molecules that are able to target/block other molecules that play a critical role in the immune system functioning, and that have been introduced in clinical practice alone and/or in addiction with other "old" disease-modifying anti-rheumatic drugs. For this reason, such drugs are currently known as "biological drugs" and include molecules that induce the immunosuppression acting on several immune pathways. However, though the biological drugs have been employed from more than a decade, there still exist some drawbacks of their use, in particular about the high costs of this therapy and their overall safety, including the route of administration for the intravenous use. In this review we provide an update on the correct use and current therapeutic indications of such drugs, including some of the new biologic therapies that will be soon available for the clinical use, focusing on these biological drugs: • Tumor necrosis factor-alpha (TNF-alpha) inhibitors (adalimumab, certolizumab-pegol, etanercept, golimumab and infliximab); • The T cell co-stimulation inhibitor, abatacept; • The anti-CD20 receptor monoclonal B cell agent, rituximab; • The interlukin-6 (IL-6) receptor-blocking monoclonal antibody, tocilizumab; • The interlukin-1 (IL-1) inhibitor, anakinra; • The interlukin-IL17 (IL-17) pathway inhibitors (ustekinumab, secukinumab, brodalumab).

Teleretinal screening for diabetic retinopathy in six Los Angeles urban safety-net clinics: final study results.

PubMed

Ogunyemi, Omolola; George, Sheba; Patty, Lauren; Teklehaimanot, Senait; Baker, Richard

2013-01-01

In a previous paper, we presented initial findings from a study on the feasibility and challenges of implementing teleretinal screening for diabetic retinopathy in an urban safety net setting facing eyecare specialist shortages. This paper presents some final results from that study, which involved six South Los Angeles safety net clinics. A total of 2,732 unique patients were screened for diabetic retinopathy by three ophthalmologist readers, with 1035 receiving a recommendation for referral to specialty care. Referrals included 48 for proliferative diabetic retinopathy, 115 for severe non-proliferative diabetic retinopathy (NPDR), 247 for moderate NPDR, 246 for mild NPDR, 97 for clinically significant macular edema, and 282 for a non-diabetic condition, such as glaucoma. Image quality was also assessed, with ophthalmologist readers grading 4% to 13% of retinal images taken at the different clinics as being inadequate for any diagnostic interpretation.

Safety, efficacy and clinical generalization of the STAR protocol: a retrospective analysis.

PubMed

Stewart, Kent W; Pretty, Christopher G; Tomlinson, Hamish; Thomas, Felicity L; Homlok, József; Noémi, Szabó Némedi; Illyés, Attila; Shaw, Geoffrey M; Benyó, Balázs; Chase, J Geoffrey

2016-12-01

The changes in metabolic pathways and metabolites due to critical illness result in a highly complex and dynamic metabolic state, making safe, effective management of hyperglycemia and hypoglycemia difficult. In addition, clinical practices can vary significantly, thus making GC protocols difficult to generalize across units.The aim of this study was to provide a retrospective analysis of the safety, performance and workload of the stochastic targeted (STAR) glycemic control (GC) protocol to demonstrate that patient-specific, safe, effective GC is possible with the STAR protocol and that it is also generalizable across/over different units and clinical practices. Retrospective analysis of STAR GC in the Christchurch Hospital Intensive Care Unit (ICU), New Zealand (267 patients), and the Gyula Hospital, Hungary (47 patients), is analyzed (2011-2015). STAR Christchurch (BG target 4.4-8.0 mmol/L) is also compared to the Specialized Relative Insulin and Nutrition Tables (SPRINT) protocol (BG target 4.4-6.1 mmol/L) implemented in the Christchurch Hospital ICU, New Zealand (292 patients, 2005-2007). Cohort mortality, effectiveness and safety of glycemic control and nutrition delivered are compared using nonparametric statistics. Both STAR implementations and SPRINT resulted in over 86 % of time per episode in the blood glucose (BG) band of 4.4-8.0 mmol/L. Patients treated using STAR in Christchurch ICU spent 36.7 % less time on protocol and were fed significantly more than those treated with SPRINT (73 vs. 86 % of caloric target). The results from STAR in both Christchurch and Gyula were very similar, with the BG distributions being almost identical. STAR provided safe GC with very few patients experiencing severe hypoglycemia (BG < 2.2 mmol/L, <5 patients, 1.5 %). STAR outperformed its predecessor, SPRINT, by providing higher nutrition and equally safe, effective control for all the days of patient stay, while lowering the number of measurements and

Non-Clinical Safety Studies of IMT504, a Unique Non-CpG Oligonucleotide

PubMed Central

Franco, Raúl; Rodriguez, Juan M.; Elías, Fernanda; Hernando-Insúa, Andrés; Fló, Juan; López, Ricardo; Nagle, Carlos; Lago, Néstor; Zorzopulos, Jorge; Horn, David L.

2014-01-01

IMT504 is a non-CpG 24-mer oligodeoxynucleotide (ODN) with immunomodulatory as well as tissue repair activity. IMT504 has been previously proven to be effective in animal models of vaccine potency, chronic lymphocytic leukemia, tissue regeneration, and sepsis. Here, we assessed the safety, including pharmacokinetics and toxicity studies in rats and monkeys, of IMT504 in a single- or repeated-dose administration by the subcutaneous (SC) or intravenous (IV) routes. In rats, the maximum tolerated dose was determined to be 50 mg/kg when administered SC. Adverse effects at 50 mg/kg were mild and reversible liver injury, revealed as lobular inflammation, focal necrosis, and small changes in the transaminase profile. Dose-dependent splenomegaly and lymphoid hyperplasia, most probably associated with immune stimulation, were commonly observed. Rats and monkeys were also IV injected with a single dose of 10 or 3.5 mg/kg, and no adverse effects were observed. Rats injected IV with 10 mg/kg showed a transient increase in spleen weight, together with a slight increase in the marginal zone of the white pulp and in leukocyte count 2 days post-administration. In monkeys, this dosage caused slight changes in total serum complement and leukocyte count on day 14. No adverse effects were observed at 3.5 mg/kg IV in rats or monkeys. Therefore, this dose was defined as the “no observed adverse effect level” for this route. Furthermore, repeated-dose toxicity studies were performed in these species using 3.5 or 0.35 mg/kg/day IV for 6 weeks. A transient increase in the spleen and liver weight was observed at 3.5 mg/kg/day only in female rats. No changes in clotting time and activation of the alternative complement pathway were observed. The toxicity profile of IMT504 herein reported suggests a dose range in which IMT504 can be used safely in clinical trials. PMID:24720569

Comparative study of sickle cell anemia and hemoglobin SC disease: clinical characterization, laboratory biomarkers and genetic profiles.

PubMed

Aleluia, Milena Magalhães; Fonseca, Teresa Cristina Cardoso; Souza, Regiana Quinto; Neves, Fábia Idalina; da Guarda, Caroline Conceição; Santiago, Rayra Pereira; Cunha, Bruna Laís Almeida; Figueiredo, Camylla Villas Boas; Santana, Sânzio Silva; da Paz, Silvana Sousa; Ferreira, Júnia Raquel Dutra; Cerqueira, Bruno Antônio Veloso; Gonçalves, Marilda de Souza

2017-01-01

In this study, we evaluate the association of different clinical profiles, laboratory and genetic biomarkers in patients with sickle cell anemia (SCA) and hemoglobin SC disease (HbSC) in attempt to characterize the sickle cell disease (SCD) genotypes. We conducted a cross-sectional study from 2013 to 2014 in 200 SCD individuals (141 with SCA; 59 with HbSC) and analyzed demographic data to characterize the study population. In addition, we determined the association of hematological, biochemical and genetic markers including the β S -globin gene haplotypes and the 3.7 Kb deletion of α-thalassemia (-α 3.7Kb -thal), as well as the occurrence of clinical events in both SCD genotypes. Laboratory parameters showed a hemolytic profile associated with endothelial dysfunction in SCA individuals; however, the HbSC genotype was more associated with increased blood viscosity and inflammatory conditions. The BEN haplotype was the most frequently observed and was associated with elevated fetal hemoglobin (HbF) and low S hemoglobin (HbS). The -α 3.7Kb -thal prevalence was 0.09 (9%), and it was associated with elevated hemoglobin and hematocrit concentrations. Clinical events were more frequent in SCA patients. Our data emphasize the differences between SCA and HbSC patients based on laboratory parameters and the clinical and genetic profile of both genotypes.

Driver behaviour profiles for road safety analysis.

PubMed

Ellison, Adrian B; Greaves, Stephen P; Bliemer, Michiel C J

2015-03-01

Driver behaviour is a contributing factor in over 90 percent of road crashes. As a consequence, there is significant benefit in identifying drivers who engage in unsafe driving practices. Driver behaviour profiles (DBPs) are introduced here as an approach for evaluating driver behaviour as a function of the risk of a casualty crash. They employ data collected using global positioning system (GPS) devices, supplemented with spatiotemporal information. These profiles are comprised of common risk scores that can be used to compare drivers between each other and across time and space. The paper details the development of these DBPs and demonstrates their use as an input into modelling the factors that influence driver behaviour. The results show that even having controlled for the influence of the road environment, these factors remain the strongest predictors of driver behaviour suggesting different spatiotemporal environments elicit a variety of psychological responses in drivers. The approach and outcomes will be of interest to insurance companies in enhancing the risk-profiling of drivers with on-road driving and government through assessing the impacts of behaviour-change interventions. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Maraviroc: clinical trials results].

PubMed

Chidiac, C; Katlama, C; Yeni, P

2008-03-01

Just over a decade after identification of chemokine receptors CCR5 and CXCR4 as coreceptors for HIV, maraviroc (Celsentri), the first CCR5 antagonist, has recently obtained its Marketing Authorization in the United States and Europe, for treatment of treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable. CCR5 antagonists, after fusion inhibitor enfuvirtide available since 2003, also belong to entry inhibitors. These molecules, unlike previous antiretrovirals, do not target the virus but its target cell by blocking viral penetration. Maraviroc has shown its clinical efficacy in patients failing other antiretroviral classes. Its safety profile was similar to placebo in two large phase III trials. However, careful assessment of both hepatic and immunologic safety of this new therapeutic class is needed. Viral tropism testing has to be investigated before using maraviroc in the clinic, because CCR5 antagonists are not active against CXCR4 viruses. For the moment indicated for the treatment-experienced patient population, maraviroc could in the future benefit to other types of patients, depending on ongoing trials results.

Bioactive properties and clinical safety of a novel milk protein peptide

PubMed Central

2011-01-01

Background Milk protein fractions and peptides have been shown to have bioactive properties. This preliminary study examined the potential mechanisms of action and clinical safety of novel milk protein peptide (MP). Findings A novel MP mixture inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and insulin receptor (IR) with IC50 of 9.85 μM, 7.7 μM, and 6.18 μM respectively. In vitro, this multi-kinase inhibitor causes apoptosis in HT-29 colon cancer cells, and in a C. elegans worm study, showed a weak but significant increase in lifespan. A six week double-blind, placebo-controlled study involving 73 healthy volunteers demonstrated that the MP mixture is safe to consume orally. All clinical blood markers remained within normal levels and no clinically significant side effects were reported. There was some evidence of improved insulin sensitivity, neutrophil-to-lymphocyte ratio (NLR), and quality of life assessment of role of physical function. Conclusions These data in combination with the observed in vitro anti-cancer properties warrant further clinical studies to investigate this MP mixture as a potential clinical nutrition intervention for improving the quality of life and clinical outcomes in cancer patients. Trial Registration NCT01412658 PMID:21943352

The changing profile of eating disorders at a tertiary psychiatric clinic in Hong Kong (1987-2007).

PubMed

Lee, Sing; Ng, King Lam; Kwok, Kathleen; Fung, Corina

2010-05-01

To examine the clinical profile of Chinese eating disorder patients at a tertiary psychiatric clinic in Hong Kong from 1987 to 2007. Data on 195 consecutive patients were retrieved from a standardized intake interview by an eating disorder specialist. Patients seen between 1987-1997 (n = 67) and 1998-2007 (n = 128) and fat-phobic (n = 76) and nonfat-phobic (n = 39) anorexic patients were compared. Patients were predominantly single (91.8%), female (99.0%), in their early-20s and suffered from anorexia (n = 115; 59.0%) or bulimia (n = 78; 40.0%) nervosa. The number of patients increased twofold across the two periods. Bulimia nervosa became more common while anorexia nervosa exhibited an increasingly fat-phobic pattern. Nonfat-phobic anorexic patients exhibited significantly lower premorbid body weight, less body dissatisfaction, less weight control behavior, and lower EAT-26 scores than fat-phobic anorexic patients. The clinical profile of eating disorders in Hong Kong has increasingly conformed to that of Western countries. 2009 by Wiley Periodicals, Inc.

Building clinical and organizational resilience to reconcile safety threats, tensions and trade-offs: insights from theory and evidence.

PubMed

Jeffs, Lianne; Tregunno, Deborah; MacMillan, Kathleen; Espin, Sherry

2009-01-01

Healthcare delivery settings are complex adaptive and tightly coupled, interrelated systems. Within the larger healthcare system, a key subsystem is the "clinical microsystem" level. It is at this level that clinicians are faced with high levels of uncertainty in their daily work - uncertainty that impacts the quality and safety of care that patients receive. The first aim of this paper is to enhance healthcare leaders' understanding of what is currently known about safety threats and strategies to manage the inherent tensions and trade-offs that occur in everyday practice. The second aim is to inform strategies that build clinical and organizational resilience through a multi-level framework derived from the collective theoretical and empirical work. Together, this information can strengthen safety practices throughout healthcare organizations.

Impact of biomarker development on drug safety assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marrer, Estelle, E-mail: estelle.marrer@novartis.co; Dieterle, Frank

2010-03-01

Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative andmore » 'door opening' safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the 'know how' acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example.« less

Surveillance on The Safety and Efficacy of Ambrisentan (Volibris Tablet 2.5 mg) in Patients with Pulmonary Arterial Hypertension in Real Clinical Practice: Post-marketing Surveillance (Interim Analysis Report).

PubMed

Takahashi, Tomohiko; Hayata, Satoru; Kobayashi, Akihiro; Onaka, Yuna; Ebihara, Takeshi; Hara, Terufumi

2018-03-01

Pulmonary arterial hypertension (PAH) is an intractable and rare disease and the accumulation of clinical evidence under real-world setting is needed. A post-marketing surveillance for the endothelin receptor antagonist ambrisentan (Volibris tablet) has been conducted by all-case investigation since September 2010. This paper is an interim report on the safety and efficacy of ambrisentan in 702 patients with PAH. PAH patients aged 15 years or older were subjected to the analysis. The safety analysis by overall cases or stratification of patient backgrounds and the efficacy analysis were investigated. Regarding patient characteristics, the 702 patients subjected to safety analysis included 543 (77.4%) women and 546 (77.8%) patients at WHO functional class II/III. The mean observational time was 392.7 days. A total of 324 adverse drug reaction (ADR) occurred in 204 (29.1%) patients. Common ADRs (≥ 2%) included anemia (4.6%), peripheral edema (4.1%), headache (3.6%), edema and face edema (2.6% each), abnormal hepatic function (2.3%), and epistaxis (2.1%). There were 82 serious ADRs occurring in 44 (6.3%) patients (385 serious adverse events in 184 (26.2%) patients). Although 11 (1.6%) interstitial lung disease (ILD) cases were reported, all were observed in patients with disease that may contribute to ILD and therefore it is difficult to assess if ambrisentan was associated with these events. There was no difference in safety in relation to the presence/absence of connective tissue disease-related PAH (CTD-PAH) or combination therapy. Among 677 patients subjected to efficacy analysis, those in whom hemodynamic status was determined before and after treatment showed improvement in the mean pulmonary arterial pressure and pulmonary vascular resistance after treatment. The interim results showed safety consistent with the known profile of ambrisentan in terms of the types and frequencies of ADRs in patients with PAH in real clinical practice, in comparison with

Clinical Evaluation of a Safety-device to Prevent Urinary Catheter Inflation Related Injuries.

PubMed

Davis, Niall F; Cunnane, Eoghan M; Mooney, Rory O'C; Forde, James C; Walsh, Michael T

2018-05-01

To evaluate the feasibility of a novel "safety-valve" device for preventing catheter related urethral trauma during urethral catheterization (UC). To assess the opinions of clinicians on the performance of the safety-valve device. A validated prototype "safety-valve" device for preventing catheter balloon inflation related urethral injuries was prospectively piloted in male patients requiring UC in a tertiary referral teaching hospital (n = 100). The device allows fluid in the catheter system to decant through an activated safety threshold pressure valve if the catheter anchoring balloon is misplaced. Users evaluated the "safety-valve" with an anonymous questionnaire. The primary outcome measurement was prevention of anchoring balloon inflation in the urethra. Secondary outcome measurement was successful inflation of urinary catheter anchoring balloon in the bladder. Patient age was 76 ± 12 years and American Society of Anaesthesiologists grade was 3 ± 1.4. The "safety-valve" was utilized by 34 clinicians and activated in 7% (n = 7/100) patients during attempted UC, indicating that the catheter anchoring balloon was incorrectly positioned in the patient's urethra. In these 7 cases, the catheter was successfully manipulated into the urinary bladder and inflated. 31 of 34 (91%) clinicians completed the questionnaire. Ten percent (n = 3/31) of respondents had previously inflated a urinary catheter anchoring balloon in the urethra and 100% (n = 31) felt that a safety mechanism for preventing balloon inflation in the urethra should be compulsory for all UCs. The safety-valve device piloted in this clinical study offers an effective solution for preventing catheter balloon inflation related urethral injuries. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of Olanzapine on Clinical and Polysomnography Profiles in Patients with Schizophrenia

PubMed Central

Sarkar, Sukanto; Nizamie, S. Haque

2018-01-01

Acute and short-term administration of olanzapine has a favorable effect on sleep in schizophrenia patients. This study aimed to clarify the effect of olanzapine on polysomnographic profiles of schizophrenia patients during the acute phase of illness after controlling for previous drug exposure. Twenty-five drug-naïve or drug-free schizophrenia patients were assessed at baseline and after six weeks of olanzapine treatment on Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), and Udvalg for Kliniske Undersogelser (UKU) side-effect rating scale and a whole-night polysomnography; fifteen patients completed the study. There was a significant reduction in all psychopathological variables with maximum reduction in PANSS total, BPRS total, and PANSS positive scores. A significant increase in total sleep time (TST), sleep efficiency (SE), nonrapid eye movement (NREM) stage 1 duration, stage 3 duration, stage 4 duration, and stage 4 percentage of TST, number of rapid eye movement (REM) periods, REM duration, and REM percentage of TST was observed. REM latency at baseline inversely predicted the reduction in BPRS total and PANSS total and positive scores. In summary, short-term treatment with olanzapine produced significant improvement in clinical and polysomnography profiles of patients with schizophrenia with shorter REM latency predicting a good clinical response. PMID:29675276

The chemical evolution of oligonucleotide therapies of clinical utility

PubMed Central

Khvorova, Anastasia; Watts, Jonathan K.

2017-01-01

After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency properties are derived primarily from the chemical structure of the oligonucleotide, while their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design demonstrate appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized as a whole, using a combination of sugar, backbone, nucleobase and 3′/5′-terminal modifications. A portfolio of chemistries can be used to confer drug like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. Outstanding challenges in oligonucleotide chemical development include optimization of chemical architectures to ensure long-term safety and to enable robust clinical activity beyond the liver. PMID:28244990

Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers

PubMed Central

Hirshfield, Kim M.; Tolkunov, Denis; Zhong, Hua; Ali, Siraj M.; Stein, Mark N.; Murphy, Susan; Vig, Hetal; Vazquez, Alexei; Glod, John; Moss, Rebecca A.; Belyi, Vladimir; Chan, Chang S.; Chen, Suzie; Goodell, Lauri; Foran, David; Yelensky, Roman; Palma, Norma A.; Sun, James X.; Miller, Vincent A.; Stephens, Philip J.; Ross, Jeffrey S.; Kaufman, Howard; Poplin, Elizabeth; Mehnert, Janice; Tan, Antoinette R.; Bertino, Joseph R.; Aisner, Joseph; DiPaola, Robert S.

2016-01-01

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical

Drug Safety

MedlinePlus

... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

The safety profile of parecoxib for the treatment of postoperative pain: a pooled analysis of 28 randomized, double-blind, placebo-controlled clinical trials and a review of over 10 years of postauthorization data

PubMed Central

Schug, Stephan A; Parsons, Bruce; Li, Chunming; Xia, Feng

2017-01-01

Background Nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors are associated with safety issues including cardiovascular, renal, and gastrointestinal (GI) events. Objective To examine the safety of parecoxib, a COX-2 inhibitor, for the management of postoperative pain. Design Pooled analysis of 28 placebo-controlled trials of parecoxib and review of postauthorization safety data. Main outcome measures Prespecified safety events commonly associated with COX-2 inhibitors and/or NSAIDs. In the clinical trial analysis, the frequency of each event was compared between treatment groups using a chi-square test. In the postauthorization review, the number of confirmed cases, along with outcome, was presented for each event. Results In the clinical trial analysis, GI-related events occurred in ~0.2% of patients in the parecoxib and placebo groups. Renal failure and impairment was similar between parecoxib (1.0%) and placebo (0.9%). The occurrence of arterial (parecoxib=0.3%; placebo=0.2%) and venous (parecoxib=0.2%; placebo=0.1%) cardiovascular embolic and thrombotic events was similar between groups. Hypersensitivity reactions including anaphylactic reactions (parecoxib=8.7%; placebo=8.6%), hypotension (parecoxib=2.6%; placebo=2.1%), angioedema (parecoxib=2.5%; placebo=2.8%), and severe cutaneous adverse reactions (0% in both groups) were similar between groups. Incision site or other skin/tissue infections occurred in <0.1% of patients in both groups. The occurrence of these events (total reports/serious reports) in the postauthorization database, based on 69,567,300 units of parecoxib, was as follows: GI ulceration-related events (35/35), renal failure and impairment (77/68), cardiovascular embolic and thrombotic events (66/64), hypersensitivity reactions including hypotension-related events (32/25) and severe cutaneous adverse events (17/17), and masking signs of inflammation (18/18). A majority of reported

The safety profile of parecoxib for the treatment of postoperative pain: a pooled analysis of 28 randomized, double-blind, placebo-controlled clinical trials and a review of over 10 years of postauthorization data.

PubMed

Schug, Stephan A; Parsons, Bruce; Li, Chunming; Xia, Feng

2017-01-01

Nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors are associated with safety issues including cardiovascular, renal, and gastrointestinal (GI) events. To examine the safety of parecoxib, a COX-2 inhibitor, for the management of postoperative pain. Pooled analysis of 28 placebo-controlled trials of parecoxib and review of postauthorization safety data. Prespecified safety events commonly associated with COX-2 inhibitors and/or NSAIDs. In the clinical trial analysis, the frequency of each event was compared between treatment groups using a chi-square test. In the postauthorization review, the number of confirmed cases, along with outcome, was presented for each event. In the clinical trial analysis, GI-related events occurred in ~0.2% of patients in the parecoxib and placebo groups. Renal failure and impairment was similar between parecoxib (1.0%) and placebo (0.9%). The occurrence of arterial (parecoxib=0.3%; placebo=0.2%) and venous (parecoxib=0.2%; placebo=0.1%) cardiovascular embolic and thrombotic events was similar between groups. Hypersensitivity reactions including anaphylactic reactions (parecoxib=8.7%; placebo=8.6%), hypotension (parecoxib=2.6%; placebo=2.1%), angioedema (parecoxib=2.5%; placebo=2.8%), and severe cutaneous adverse reactions (0% in both groups) were similar between groups. Incision site or other skin/tissue infections occurred in <0.1% of patients in both groups. The occurrence of these events (total reports/serious reports) in the postauthorization database, based on 69,567,300 units of parecoxib, was as follows: GI ulceration-related events (35/35), renal failure and impairment (77/68), cardiovascular embolic and thrombotic events (66/64), hypersensitivity reactions including hypotension-related events (32/25) and severe cutaneous adverse events (17/17), and masking signs of inflammation (18/18). A majority of reported outcomes were classified as recovered or recovering

CSF Hypocretin-1 Levels and Clinical Profiles in Narcolepsy and Idiopathic CNS Hypersomnia in Norway

PubMed Central

Heier, Mona Skard; Evsiukova, Tatiana; Vilming, Steinar; Gjerstad, Michaela D.; Schrader, Harald; Gautvik, Kaare

2007-01-01

Objective: To evaluate the relationship between CSF hypocretin-1 levels and clinical profiles in narcolepsy and CNS hypersomnia in Norwegian patients. Method: CSF hypocretin-1 was measured by a sensitive radioimmunoassay in 47 patients with narcolepsy with cataplexy, 7 with narcolepsy without cataplexy, 10 with idiopathic CNS hypersomnia, and a control group. Results: Low hypocretin-1 values were found in 72% of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy. Patients with low CSF hypocretin-1 levels reported more extensive muscular involvement during cataplectic attacks than patients with normal levels. Hypnagogic hallucinations and sleep paralysis occurred more frequently in patients with cataplexy than in the other patient groups, but with no correlation to hypocretin-1 levels. Conclusion: About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity. Narcolepsy without cataplexy could not be distinguished from idiopathic CNS hypersomnia by clinical symptoms or biochemical findings. Citation: Heier MS; Evsiukova T; Vilming S; Gjerstad MD; Schrader H; Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in norway. SLEEP 2007;30(8):969-973. PMID:17702265

Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances

PubMed Central

Segal, Ehud; Pan, Huaizhong; Benayoun, Liat; Kopečková, Pavla; Shaked, Yuval; Kopeček, Jindčrich; Satchi-Fainaro, Ronit

2015-01-01

Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances. PMID:21429572

Clinical profiles of stigma experiences, self-esteem and social relationships among people with schizophrenia, depressive, and bipolar disorders.

PubMed

Oliveira, Sandra E H; Esteves, Francisco; Carvalho, Helena

2015-09-30

Some mental illnesses and certain mental health care environments can be severely stigmatizing, which seems to be related to decreased self-esteem and a deterioration of the quality of social relationships for people with mental illness. This study aims to identify clinical profiles characterized by clinical diagnoses more strongly associated with the treatment settings and related to internalized stigma, self-esteem and satisfaction with social relationships. It also aimed to analyze associations between clinical profiles and socio-demographic indicators. Multiple correspondence analysis and cluster analysis were performed on a sample of 261 individuals with schizophrenia and mood disorders, from hospital-based and community-based facilities. MCA showed four distinct clinical profiles allowing a differentiation among levels of: internalized stigma, social relationship satisfaction and self-esteem. Overall, results revealed that internalized stigma remains a pervasive problem for some people with schizophrenia and mood disorders. Particularly, internalized stigma and social relationships dissatisfaction and associated socio-demographic indicators appear to be a risk factor for social isolation for individuals with schizophrenia, which may worsen the course of the disorder. Our findings highlight the importance to develop structured interventions aimed to reduce internalized stigma, and exclusion of those who suffer the loss of their social roles and networks. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Clinical and Biochemical Profiles according to Homeostasis Model Assessment-insulin Resistance (HOMA-IR) in Korean Women with Polycystic Ovary Syndrome.

PubMed

Lee, Da Eun; Park, Soo Yeon; Park, So Yun; Lee, Sa Ra; Chung, Hye Won; Jeong, Kyungah

2014-12-01

The aim of this study was to investigate the clinical and biochemical profiles according to homeostasis model assessment of insulin resistance (HOMA-IR) in Korean polycystic ovary syndrome (PCOS) patients. In 458 PCOS patients diagnosed by the Rotterdam European Society for Human Reproduction and Embryology (ESHRE) criteria, measurements of somatometry, blood test of hormones, glucose metabolic and lipid profiles, and transvaginal or transrectal ultrasonogram were carried out. HOMA-IR was then calculated and compared with the clinical and biochemical profiles related to PCOS. The patients were divided into 4 groups by quartiles of HOMA-IR. The mean level of HOMA-IR was 2.18 ± 1.73. Among the four groups separated according to HOMA-IR, body weight, body mass index (BMI), waist-to-hip ratio (WHR), triglyceride (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, lipid accumulation product (LAP) index, high-sensitivity C-reactive protein (hs-CRP), Apoprotein B, free testosterone, and sex hormone binding globulin (SHBG) were found to be significantly different. TG, LAP index, glucose metabolic profiles, and hs-CRP were positively correlated with HOMA-IR after adjustment for BMI. Our results suggest that the clinical and biochemical profiles which are applicable as cardiovascular risk factors are highly correlated with HOMA-IR in Korean women with PCOS.

[Clinical heterogeneity of Alzheimer's disease. Different clinical profiles can predict the progression rate].

PubMed

Mangone, C A

Alzheimer's disease (AD) is a degenerative dementia that may disclose different cognitive, behavioral, psychiatric and functional symptoms since onset. These distinct cognitive profiles support the conception of clinical heterogeneity and account for AD's highly variable rate of progression. In spite of strict diagnostic criteria NINCS ADRDA's and DSM IV the clinical certainty is only about 85%. Mayeux define 4 subtypes: a). Benign: mild cognitive and functional impairment without focal signs and late onset behavioral signs, slow progression; b). Myoclonic: usually of presenile onset with severe cognitive deterioration, mutism and early onset myoclonus; c). Extrapyramidal: early onset akineto rigid signs with severe cognitive, behavioral and psychiatric involvement; d). Typical: gradual and progressive cognitive, behavioral and functional impairment. The differentiation of these subtypes will allow us to define discrete patterns of progression, to define prognostic subgroups, and to homogenize them for clinical research and drug trials. We examined 1000 charts of probable AD patients from the Santojanni Center. We found 42% extrapyramidal, 35% typical, 15% benign and 8% myoclonic. The early onset of parkinsonism and myoclonus predict a rapidly evolving cognitive impairment and a more severe rate of progression with psychiatric disorders and dependency in activities of daily living. (DADL) Patients with low level of education, low cognitive performance at entry as well as those with rapid rate of cognitive deterioration had a faster rate of progression to DADL. Delusions, low level of education, extrapyramidal signs and motor hyperactivity but not hallucinations, and anosognosia were the best non cognitive predictors of DADL.

An Assessment of Basic Patient Safety Skills in Residents Entering the First Year of Clinical Training.

PubMed

Comunale, Mark E; Sandoval, Mathew; Broussard, La Toya

2018-06-01

During safety rounds, we observed few residents demonstrating hand hygiene and patient identification as they began their postgraduate clinical training. We assessed baseline performance of these 2 basic safety skills in residents entering the first year of postgraduate clinical training (PGY1). PGY1 residents beginning training on July 1, 2013, and July 1, 2014, at our institution were examined using a simulated scenario testing for hand hygiene and patient identification. Nurse volunteers posed as patients and evaluated each resident using a standardized scoring tool. Residents were observed for the following behaviors when interacting: (1) hand hygiene before or upon entry into the patient's room (HHE); (2) resident introducing himself or herself (INTRO); (3) resident identifying patient (IDNB); (4) resident comparing patient's stated name and date of birth to patient's ID band (IDC); (5) resident explaining procedure to patient (EXP); and (6) resident performing hand hygiene upon exiting patient's room (HHL). A total of 114 residents were examined. Compliance results were as follows: HHE at 66% (75); INTRO at 96% (110); IDNB at 52% (59); IDC at 42% (48); EXP at 90% (103); and HHL at 58% (66). Developing and hardwiring basic patient safety skills is essential for creating an institutional culture of safety. We used a simulated patient scenario to provide a baseline assessment of 2 important safety skills.The results obtained demonstrate poor compliance with hand hygiene and patient identification. Our results suggest that there is a need for additional training and perhaps new methods of training and reinforcement in medical school and beyond, to hardwire these basic patient safety skills.

Teleretinal Screening for Diabetic Retinopathy in Six Los Angeles Urban Safety-Net Clinics: Final Study Results

PubMed Central

Ogunyemi, Omolola; George, Sheba; Patty, Lauren; Teklehaimanot, Senait; Baker, Richard

2013-01-01

In a previous paper, we presented initial findings from a study on the feasibility and challenges of implementing teleretinal screening for diabetic retinopathy in an urban safety net setting facing eyecare specialist shortages. This paper presents some final results from that study, which involved six South Los Angeles safety net clinics. A total of 2,732 unique patients were screened for diabetic retinopathy by three ophthalmologist readers, with 1035 receiving a recommendation for referral to specialty care. Referrals included 48 for proliferative diabetic retinopathy, 115 for severe non-proliferative diabetic retinopathy (NPDR), 247 for moderate NPDR, 246 for mild NPDR, 97 for clinically significant macular edema, and 282 for a non-diabetic condition, such as glaucoma. Image quality was also assessed, with ophthalmologist readers grading 4% to 13% of retinal images taken at the different clinics as being inadequate for any diagnostic interpretation. PMID:24551394

Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example.

PubMed

Wiśniowska, Barbara; Polak, Sebastian

2016-11-01

A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration. ten Tusscher's human ventricular cardiomyocyte model was used to simulate the pseudo-ECG traces and further predict the pharmacodynamic consequences of DDI. Consistent with clinical observations, predicted plasma concentration profiles of terfenadine show considerable intra-subject variability with recorded C max values below 5 ng/mL for most virtual subjects. The pharmacokinetic and pharmacodynamic effects of inhibitors were predicted with reasonable accuracy. In all cases, a combination of the physiologically based pharmacokinetic and physiology-based pharmacodynamic models was able to differentiate between the terfenadine alone and terfenadine + inhibitor scenario. The range of QT prolongation was comparable in the clinical and virtual studies. The results indicate that mechanistic in vitro-in vivo correlation can be applied to predict the clinical effects of DDI even without comprehensive knowledge on all mechanisms contributing to the interaction. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Safety of human papillomavirus vaccines: a review.

PubMed

Macartney, Kristine K; Chiu, Clayton; Georgousakis, Melina; Brotherton, Julia M L

2013-06-01

Vaccination to prevent human papillomavirus (HPV)-related infection leading to cancer, particularly cervical cancer, is a major public health breakthrough. There are currently two licensed HPV vaccines, both of which contain recombinant virus-like particles of HPV types 16 and 18 (which account for approximately 70 % of cervical cancer). One vaccine also protects against HPV types 6 and 11, which cause genital warts. The safety profile of both vaccines was assessed extensively in randomised controlled clinical trials conducted prior to licensure and has been further elucidated following licensure from surveillance and specific studies in large populations. This review aims to examine current evidence regarding the safety of HPV vaccines. In summary, both vaccines are associated with relatively high rates of injection site reactions, particularly pain, but this is usually of short duration and resolves spontaneously. Systemic reactions have generally been mild and self-limited. Post vaccination syncope has occurred, but can be avoided with appropriate care. Serious vaccine-attributable adverse events, such as anaphylaxis, are rare, and although not recommended for use in pregnancy, abnormal pregnancy outcomes following inadvertent administration do not appear to be associated with vaccination. HPV vaccines are used in a three-dose schedule predominantly in adolescent females: as such case reports linking vaccination with a range of new onset chronic conditions, including autoimmune diseases, have been made. However, well-conducted population-based studies show no association between HPV vaccine and a range of such conditions. Whilst this reassuring safety profile affirms the positive risk benefit of vaccination, as HPV vaccine use expands into more diverse populations, including males, ongoing safety assessment using well-conducted studies is appropriate.

The safety of pharmacologic treatment for pediatric obesity.

PubMed

Chao, Ariana M; Wadden, Thomas A; Berkowitz, Robert I

2018-04-01

Pediatric obesity is a serious public health concern. Five medications have been approved by the Food and Drug Administration (FDA) for chronic weight management in adults with obesity, when used as an adjunct to lifestyle modification. Orlistat is the only FDA-approved medication for pediatric patients aged 12 years and above. Areas covered: This paper summarizes safety and efficacy data from clinical trials of weight loss medications conducted among pediatric samples. Relevant studies were identified through searches in PubMed. Expert opinion: Orlistat, as an adjunct to lifestyle modification, results in modest weight losses and may be beneficial for some pediatric patients with obesity. However, gastrointestinal side effects are common and may limit use. In adults taking orlistat, rare but severe adverse events, including liver and renal events, have been reported. Recent pediatric pharmacokinetic studies of liraglutide have demonstrated similar safety and tolerability profiles as found in adults, with gastrointestinal disorders being the most common adverse events. Clinical trials are needed of liraglutide, as well as other medications for obesity, that systematically evaluate their risks and benefits in pediatric patients.

Linagliptin: farmacology, efficacy and safety in type 2 diabetes treatment

PubMed Central

2013-01-01

Type 2 diabetes mellitus (T2DM) has a high prevalence and incidence around the world. The complex pathophysiology mechanism is among the barriers for diabetes treatment. Type 2 diabetes patients have dysfunction in incretin hormones (as glucagon-like peptide-1 or GLP-1, and glucose-dependent insulinotropic polypeptide or GIP). By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, it is possible to slow the inactivation of GLP-1 and GIP, promoting blood glucose level reduction in a glucose-dependent manner. Linagliptin is a highly specific and potent inhibitor of DPP-4 that is currently indicated for the treatment of type 2 diabetes. Clinical studies with linagliptin demonstrated efficacy in reducing glycated hemoglobin (HbA1c) levels in type 2 diabetes patients, while maintaining a placebo-like safety and tolerability profile. Linagliptin has an interesting pharmacokinetic profile in terms of its predominantly non-renal elimination and the main implication of this characteristic is that no dose adjustment is necessary in patients with renal disease. Also, no dose adjustment is required in patients with hepatic insufficiency, as well in elderly or obese patients. This article will review the pharmacokinetic profile, efficacy data and safety aspects of linagliptin in type 2 diabetes patients. PMID:23697612

Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier.

PubMed

Couch, Jessica A; Yu, Y Joy; Zhang, Yin; Tarrant, Jacqueline M; Fuji, Reina N; Meilandt, William J; Solanoy, Hilda; Tong, Raymond K; Hoyte, Kwame; Luk, Wilman; Lu, Yanmei; Gadkar, Kapil; Prabhu, Saileta; Ordonia, Benjamin A; Nguyen, Quyen; Lin, Yuwen; Lin, Zhonghua; Balazs, Mercedesz; Scearce-Levie, Kimberly; Ernst, James A; Dennis, Mark S; Watts, Ryan J

2013-05-01

Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on the therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific antibody variants in mouse and show that reducing TfR binding affinity improves not only brain uptake but also peripheral exposure and the safety profile of these antibodies. We identify and seek to address liabilities of targeting TfR with antibodies, namely, acute clinical signs and decreased circulating reticulocytes observed after dosing. By eliminating Fc effector function, we ameliorated the acute clinical signs and partially rescued a reduction in reticulocytes. Furthermore, we show that complement mediates a residual decrease in reticulocytes observed after Fc effector function is eliminated. These data raise important safety concerns and potential mitigation strategies for the development of TfR-based therapies that are designed to cross the blood-brain barrier.

Clinical Usefulness of Response Profiles to Rapidly Incremental Cardiopulmonary Exercise Testing

PubMed Central

Ramos, Roberta P.; Alencar, Maria Clara N.; Treptow, Erika; Arbex, Flávio; Ferreira, Eloara M. V.; Neder, J. Alberto

2013-01-01

The advent of microprocessed “metabolic carts” and rapidly incremental protocols greatly expanded the clinical applications of cardiopulmonary exercise testing (CPET). The response normalcy to CPET is more commonly appreciated at discrete time points, for example, at the estimated lactate threshold and at peak exercise. Analysis of the response profiles of cardiopulmonary responses at submaximal exercise and recovery, however, might show abnormal physiologic functioning which would not be otherwise unraveled. Although this approach has long been advocated as a key element of the investigational strategy, it remains largely neglected in practice. The purpose of this paper, therefore, is to highlight the usefulness of selected submaximal metabolic, ventilatory, and cardiovascular variables in different clinical scenarios and patient populations. Special care is taken to physiologically justify their use to answer pertinent clinical questions and to the technical aspects that should be observed to improve responses' reproducibility and reliability. The most recent evidence in favor of (and against) these variables for diagnosis, impairment evaluation, and prognosis in systemic diseases is also critically discussed. PMID:23766901

Safety update on the use of recombinant activated factor VII in approved indications.

PubMed

Neufeld, Ellis J; Négrier, Claude; Arkhammar, Per; Benchikh el Fegoun, Soraya; Simonsen, Mette Duelund; Rosholm, Anders; Seremetis, Stephanie

2015-06-01

This updated safety review summarises the large body of safety data available on the use of recombinant activated factor VII (rFVIIa) in approved indications: haemophilia with inhibitors, congenital factor VII (FVII) deficiency, acquired haemophilia and Glanzmann's thrombasthenia. Accumulated data up to 31 December 2013 from clinical trials as well as post-marketing data (registries, literature reports and spontaneous reports) were included. Overall, rFVIIa has shown a consistently favourable safety profile, with no unexpected safety concerns, in all approved indications. No confirmed cases of neutralising antibodies against rFVIIa have been reported in patients with congenital haemophilia, acquired haemophilia or Glanzmann's thrombasthenia. The favourable safety profile of rFVIIa can be attributed to the recombinant nature of rFVIIa and its localised mechanism of action at the site of vascular injury. Recombinant FVIIa activates factor X directly on the surface of activated platelets, which are present only at the site of injury, meaning that systemic activation of coagulation is avoided and the risk of thrombotic events (TEs) thus reduced. Nonetheless, close monitoring for signs and symptoms of TE is warranted in all patients treated with any pro-haemostatic agent, including rFVIIa, especially the elderly and any other patients with concomitant conditions and/or predisposing risk factors to thrombosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Computer use, language, and literacy in safety net clinic communication

PubMed Central

Barton, Jennifer L; Lyles, Courtney R; Wu, Michael; Yelin, Edward H; Martinez, Diana; Schillinger, Dean

2017-01-01

Objective: Patients with limited health literacy (LHL) and limited English proficiency (LEP) experience suboptimal communication and health outcomes. Electronic health record implementation in safety net clinics may affect communication with LHL and LEP patients. We investigated the associations between safety net clinician computer use and patient-provider communication for patients with LEP and LHL. Materials and Methods: We video-recorded encounters at 5 academically affiliated US public hospital clinics between English- and Spanish-speaking patients with chronic conditions and their primary and specialty care clinicians. We analyzed changes in communication behaviors (coded with the Roter Interaction Analysis System) with each additional point on a clinician computer use score, controlling for clinician type and visit length and stratified by English proficiency and health literacy status. Results: Greater clinician computer use was associated with more biomedical statements (+12.4, P = .03) and less positive affect (−0.6, P < .01) from LEP/LHL patients. In visits with patients with adequate English proficiency/health literacy, greater clinician computer use was associated with less positive patient affect (−0.9, P < .01), fewer clinician psychosocial statements (−3.5, P < .05), greater clinician verbal dominance (+0.09, P < .01), and lower ratings on quality of care and communication. Conclusion: Higher clinician computer use was associated with more biomedical focus with LEP/LHL patients, and clinician verbal dominance and lower ratings with patients with adequate English proficiency and health literacy. Discussion: Implementation research should explore interventions to enhance relationship-centered communication for diverse patient populations in the computer era. PMID:27274017

The Affordable Care Act Decreased the Proportion of Uninsured Patients in a Safety Net Orthopaedic Clinic.

PubMed

Gil, Joseph A; Goodman, Avi D; Kleiner, Justin; Kamal, Robin N; Baker, Laurence C; Akelman, Edward

2018-05-01

The Patient Protection and Affordable Care Act (ACA) was approved in 2010, substantially altering the economics of providing and receiving healthcare services in the United States. One of the primary goals of this legislation was to expand insurance coverage for under- and uninsured residents. Our objective was to examine the effect of the ACA on the insurance status of patients at a safety net clinic. Our institution houses a safety net clinic that provides the dominant majority of orthopaedic care for uninsured patients in our state. Therefore, our study allows us to accurately examine the magnitude of the effect on insurance status in safety net orthopaedic clinics. (1) Did the ACA result in a decrease in the number of uninsured patients at a safety net orthopaedic clinic that provides the dominant majority of orthopaedic care for the uninsured in the state? (2) Did the proportion of patients insured after passage of the ACA differ across age or demographic groups in one state? We retrospectively examined our longitudinally maintained adult orthopaedic surgery clinic database from January 2009 to March 2015 and collected visit and demographic data, including zip code income quartile. Based on the data published by the Rhode Island Department of Health, our clinic provides the dominant majority of orthopaedic care for uninsured patients in our state. Therefore, examination of the changes in the proportion of insurance status in our clinic allows us to assess the effect of the ACA on the state level. Univariate and multivariable logistic regression analyses were used to determine the relationship between demographic variables and insurance status. Adjusted odds ratios and 95% CIs were calculated for the proportion of uninsured visits. The proportion of uninsured visits before and after implementation of the ACA was evaluated with an interrupted time-series analysis. The reduction in the proportion of patients without insurance between demographic groups (ie, race

A survey of North Carolina safety-net dental clinics' methods for communicating with patients of limited english proficiency (LEP).

PubMed

Hammersmith, Kimberly J; Lee, Jessica Y

2009-01-01

Dental providers are increasingly challenged in communicating with patients with limited English proficiency (LEP). Accordingly, the purpose of the study was to examine methods of communicating with patients with LEP in North Carolina (NC) safety-net dental clinics as perceived by dental staff. An anonymous, 36-item, cross-sectional survey was distributed to representatives of 68 NC safety-net dental clinics. Question domains included: a) a perceived need for language services; b) methods of language services provided; c) perceptions of dental staff about dental care experiences for patients with LEP; and d) perceived legal and financial roles in providing language services. Of the 68 clinics, 55 responded (81 percent). All clinics reported treating patients with LEP, and 93 percent of clinics reported a need for providing language services. Many clinics used multiple methods to provide language services. Some clinics reported differences in treatment recommendations (13 percent), treatment provided (19 percent), and visit length (61 percent) for patients with LEP. All responded that additional costs are incurred to treat patients with LEP, and only 69 percent of responding clinics recognized legal obligations of treating patients with LEP. There is a reported need for language services in NC safety-net dental clinics. These services often resulted in additional costs to the dental clinic. To maintain the quality of care and to comply with legal requirements related to dental patients with LEP, additional funding sources might be required to recruit multilingual staff, support language services in dental clinics, and provide language skills training for practicing dentists. Additionally, studies are suggested to measure the perception of the effectiveness of communication methods of patients with LEP.

Ethnic variations regarding clinical profiles and symptom representation in prisoners with psychotic disorders.

PubMed

Denzel, A Dorina; Harte, Joke M; van den Bergh, Mattis; Scherder, Erik J A

2018-01-01

Black and minority ethnic (BME) groups are known to have higher prevalences of psychotic disorders and are over-represented in western penitentiaries and forensic psychiatric institutions. Research from regular mental healthcare settings suggests that they could show different and more severe psychotic symptoms. Aims To explore ethnic variations in severity of symptomatology of BME and non-BME detainees with psychotic disorders. In this study, 824 patients with psychotic disorders from seven different ethnic groups, imprisoned in a penitentiary psychiatric centre in the Netherlands, were compared on symptom severity and symptom representation using the BPRS-E clinical interview. Data were analysed by means of a multilevel analysis. BME patients with psychotic disorders are over-represented in forensic psychiatry, and symptom profiles of prisoners with psychotic disorders vary by ethnicity. Additionally, severity levels of overall psychopathology differ between ethnic groups: patients with an ethnic majority status show more severe levels of psychopathology compared with BME patients. There are differences in symptom severity and symptom profiles between BME patients and non-BME patients. Disregarding these differences could have an adverse effect on the outcome of the treatment. Possible explanations and clinical impact are discussed. Declaration of interest None.

Impact of IgG Fc-Oligosaccharides on Recombinant Monoclonal Antibody Structure, Stability, Safety, and Efficacy.

PubMed

Liu, Hongcheng; Nowak, Christine; Andrien, Bruce; Shao, Mei; Ponniah, Gomathinayagam; Neill, Alyssa

2017-09-01

Glycosylation of the conserved asparagine residue in the CH2 domain is the most common posttranslational modification of recombinant monoclonal antibodies. Ideally, a consistent oligosaccharide profile should be maintained from early clinical material to commercial material for the development of recombinant monoclonal therapeutics, though variation in the profile is a typical result of process changes. The risk of oligosaccharide variation posed to further development is required to be thoroughly evaluated based on its impact on antibody structure, stability, efficacy and safety. The variation should be controlled within a range so that there is no detrimental impact on safety and efficacy and thus allowing the use of early phase safety and efficacy data to support project advancement to later phase. This review article focuses on the current scientific understanding of the commonly observed oligosaccharides found in recombinant monoclonal antibodies and their impact on structure, stability and biological functions, which are the basis to evaluate safety and efficacy. It also provides a brief discussion on critical quality attribute (CQA) assessment with regard to oligosaccharides based on the mechanism of action (MOA). © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1173-1181, 2017. © 2017 American Institute of Chemical Engineers.

Antibiotic resistance and molecular characterization of probiotic and clinical Lactobacillus strains in relation to safety aspects of probiotics.

PubMed

Klein, Günter

2011-02-01

The evaluation of the safety of probiotic strains includes the exclusion of antibiotic resistance of clinical importance. Ninety-two strains from the genus Lactobacillus isolated from probiotics, food, and clinical sources were included in the investigation. Species tested were the L. acidophilus group, L. casei group, L. reuteri/fermentum group, and L. sakei/curvatus group. Cell and colony morphology, fermentation patterns, and growth characteristics as well as soluble whole cell proteins were analyzed. Antibiotic resistance against clinically important agents was determined by broth dilution tests. The vanA and tet genes were confirmed. Resistances occurred mainly against gentamicin, ciprofloxacin, clindamycin, sulfonamides, and, in some cases, glycopeptides. The natural glycopeptide resistance within the L. casei group and L. reuteri appears to be not of clinical relevance, as there was no vanA gene present. Therefore, the transfer of this resistance is very unlikely. Tet-(A), -(B), -(C), -(M), or -(O) gene could not be detected. The protein fingerprinting within the L. casei group proved that L. rhamnosus strains of clinical origin clustered together with probiotic strains. For safety evaluations resistance patterns of a broad range of strains are a useful criterion together with the exclusion of known resistance genes (like the vanA gene) and can be used for decision making on the safety of probiotics, both by authorization bodies and manufacturers.