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Sample records for feasibility drug safety

  1. Drug Safety

    ... 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 ...

  2. What can nanosafety learn from drug development? The feasibility of “safety by design”

    Hjorth, Rune; van Hove, Lilian; Wickson, Fern

    2017-01-01

    Safety by design” (SbD) is an intuitively appealing concept that is on the rise within nanotoxicology and nanosafety research, as well as within nanotechnology research policy. It leans on principles established within drug discovery and development (DDD) and seeks to address safety early, as well...... as throughout product development. However, it remains unclear what the concept of SbD exactly entails for engineered nanomaterials (ENMs) or how it is envisioned to be implemented. Here, we review the concept as it is emerging in European research and compare its resemblance with the safety testing...

  3. Intra-Target Microdosing - A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans.

    Burt, T; MacLeod, D; Lee, K; Santoro, A; DeMasi, D K; Hawk, T; Feinglos, M; Rowland, M; Noveck, R J

    2017-09-01

    Intra-Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18 F-fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well-tolerated. Results are consistent with ITM proof-of-concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  4. Intra‐Target Microdosing – A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans

    MacLeod, D; Lee, K; Santoro, A; DeMasi, DK; Hawk, T; Feinglos, M; Rowland, M; Noveck, RJ

    2017-01-01

    Abstract Intra‐Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first‐in‐human (FIH) testing of new molecular entities (NMEs). ITM combines intra‐target drug delivery and “microdosing,” the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic‐level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18F‐fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well‐tolerated. Results are consistent with ITM proof‐of‐concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach. PMID:28689370

  5. Prospective drug safety monitoring using the UK primary-care General Practice Research Database: theoretical framework, feasibility analysis and extrapolation to future scenarios.

    Johansson, Saga; Wallander, Mari-Ann; de Abajo, Francisco J; García Rodríguez, Luis Alberto

    2010-03-01

    Post-launch drug safety monitoring is essential for the detection of adverse drug signals that may be missed during preclinical trials. Traditional methods of postmarketing surveillance such as spontaneous reporting have intrinsic limitations, many of which can be overcome by the additional application of structured pharmacoepidemiological approaches. However, further improvement in drug safety monitoring requires a shift towards more proactive pharmacoepidemiological methods that can detect adverse drug signals as they occur in the population. To assess the feasibility of using proactive monitoring of an electronic medical record system, in combination with an independent endpoint adjudication committee, to detect adverse events among users of selected drugs. UK General Practice Research Database (GPRD) information was used to detect acute liver disorder associated with the use of amoxicillin/clavulanic acid (hepatotoxic) or low-dose aspirin (acetylsalicylic acid [non-hepatotoxic]). Individuals newly prescribed these drugs between 1 October 2005 and 31 March 2006 were identified. Acute liver disorder cases were assessed using GPRD computer records in combination with case validation by an independent endpoint adjudication committee. Signal generation thresholds were based on the background rate of acute liver disorder in the general population. Over a 6-month period, 8148 patients newly prescribed amoxicillin/clavulanic acid and 5577 patients newly prescribed low-dose aspirin were identified. Within this cohort, searches identified 11 potential liver disorder cases from computerized records: six for amoxicillin/clavulanic acid and five for low-dose aspirin. The independent endpoint adjudication committee refined this to four potential acute liver disorder cases for whom paper-based information was requested for final case assessment. Final case assessments confirmed no cases of acute liver disorder. The time taken for this study was 18 months (6 months for

  6. Intra?Target Microdosing ? A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans

    Burt, T; MacLeod, D; Lee, K; Santoro, A; DeMasi, DK; Hawk, T; Feinglos, M; Rowland, M; Noveck, RJ

    2017-01-01

    Intra-target microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers receive...

  7. Drug Safety: Managing Multiple Drugs

    ... This series is produced by Consumers Union and Consumer Reports Best Buy Drugs , a public information project sup- ported by grants from the Engelberg Foundation and the National Library of Medicine of ... Consumer and Prescriber Education Grant Program which is funded ...

  8. COLD-SAT feasibility study safety analysis

    Mchenry, Steven T.; Yost, James M.

    1991-01-01

    The Cryogenic On-orbit Liquid Depot-Storage, Acquisition, and Transfer (COLD-SAT) satellite presents some unique safety issues. The feasibility study conducted at NASA-Lewis desired a systems safety program that would be involved from the initial design in order to eliminate and/or control the inherent hazards. Because of this, a hazards analysis method was needed that: (1) identified issues that needed to be addressed for a feasibility assessment; and (2) identified all potential hazards that would need to be controlled and/or eliminated during the detailed design phases. The developed analysis method is presented as well as the results generated for the COLD-SAT system.

  9. Safety and feasibility audit of a home-based drug-transitioning approach for patients with pulmonary arterial hypertension: an observational study.

    Dawson, A; Reddecliffe, S; Coghlan, C; Schreiber, B E; Coghlan, J G

    2018-04-01

    Newer endothelin receptor antagonists (ERAs) used to treat patients with pulmonary arterial hypertension (PAH) are associated with fewer drug-drug interactions than bosentan and require less monitoring. This, combined with a pharmacokinetic basis for improved efficacy, means there may be a clinical rationale for changing therapies. However, this can be challenging and few data on its safety in patients with PAH are available. At the Royal Free Hospital in London, UK, home-based medication transitioning has been standard practice since 2009 to avoid unnecessary hospital visits for patients, unless there is a clinical imperative. In this audit of standard practice we evaluated the consequences of adopting such a strategy when transitioning PAH patients between ERA therapies. Using a Clinical Nurse Specialist-led, home-based transitioning strategy, 92 patients with PAH were transitioned from bosentan to macitentan or ambrisentan. Observational data were analysed retrospectively. The majority of patients were female with PAH associated with connective tissue disease and their ERA was changed in the hope of improving efficacy. The process was well tolerated with no adverse events associated with the process. Seventeen patients died during the study (macitentan, n = 5; ambrisentan, n = 12). None of the deaths was considered related to ERA treatment. The majority of patients remained clinically stable, based on WHO functional class and exercise capacity. An established home-based transitioning strategy can be adopted safely for patients with PAH changing ERA therapies. Most patients remained stable and the therapy change was well tolerated.

  10. Diabetes Drugs and Cardiovascular Safety

    Ji Cheol Bae

    2016-06-01

    Full Text Available Diabetes is a well-known risk factor of cardiovascular morbidity and mortality, and the beneficial effect of improved glycemic control on cardiovascular complications has been well established. However, the rosiglitazone experience aroused awareness of potential cardiovascular risk associated with diabetes drugs and prompted the U.S. Food and Drug Administration to issue new guidelines about cardiovascular risk. Through postmarketing cardiovascular safety trials, some drugs demonstrated cardiovascular benefits, while some antidiabetic drugs raised concern about a possible increased cardiovascular risk associated with drug use. With the development of new classes of drugs, treatment options became wider and the complexity of glycemic management in type 2 diabetes has increased. When choosing the appropriate treatment strategy for patients with type 2 diabetes at high cardiovascular risk, not only the glucose-lowering effects, but also overall benefits and risks for cardiovascular disease should be taken into consideration.

  11. ISSUES OF FETUS DRUG SAFETY

    A.V. Ostrovskaya

    2010-01-01

    Full Text Available The article is focused on the issue of fetus drug safety. Development of a child’s health depends both on hereditary information and environment factors. The reason for deviation from the process of normal prenatal development could be any xenobiotics, physical factors and some medications having a pathogenic effect during pregnancy on the embryo and fetus. Due to that, the physician’s preventive work based on the knowledge of embryogenesis processes and critical development periods. Key words: teratogenic action, medications, prenatal development, congenital malformation, newborns, children.(Pediatric Pharmacology. – 2010; 7(1:25-28

  12. Drug safety and the impact of drug warnings

    Hostenkamp, G.; Fischer, K. E.; Borch-Johnsen, K.

    2016-01-01

    Objective To analyse the impact of drug safety warnings from the European Medicines Agency (EMA) on drug utilisation and their interaction with information released through national reimbursement bodies. Methods Insurance claims data on anti-diabetic drug prescriptions in primary care in Germany...

  13. Predictive toxicology in drug safety

    Xu, Jinghai J; Urban, Laszlo

    2011-01-01

    .... It provides information on the present knowledge of drug side effects and their mitigation strategy during drug discovery, gives guidance for risk assessment, and promotes evidence-based toxicology...

  14. Feasibility and safety of outpatient breast cancer surgery

    Duriaud, Helle Molter; Kroman, Niels; Kehlet, Henrik

    2018-01-01

    INTRODUCTION: Improvement in perioperative care programmes has facilitated post-operative recovery and use of short-term or outpatient procedures. The aim of this study was to assess the feasibility and safety of an outpatient breast cancer programme in patients referred to a large breast cancer...

  15. Nuclear power safety reporting system feasibility analysis and concept description

    Finlayson, F.C.; Ims, J.R.; Hussman, T.A.

    1984-01-01

    The Aerospace Corporation is assisting the US Nuclear Regulatory Commission (NRC) in the evaluation of the potential attributes of a voluntary, nonpunitive data gathering system for identifying and quantifying the factors that contribute to the occurrence of significant safety problems involving humans in nuclear power plants. The objectives of the Aerospace Administration (FAA)/National Aeronautics and Space Administration (NASA) Aviation Safety Reporting System (ASRS) in order to determine whether it would be feasible to apply part (or all) of the ASRS concepts for collecting data on human factor related incidents to the nuclear industry; and (2) to identify and define the basic elements and requirements of a Nuclear Power Safety Reporting System (NPSRS), assuming the feasibility of implementing such a system was established

  16. Drug Safety Crises Management in Pharmacovigilance

    Gloria Shalviri

    2018-05-01

    Full Text Available Background: Adverse drug events can cause serious consequences including death. A published report by Lazarou et al in 1998 showed that adverse drug events were the 4th to 6th leading cause of death in the United States. These events may lead to drug safety crises in some issues, which need to take crises management process for solving the problem and/or preventing similar events.Objectives: To evaluate nature of drug safety crises based on adverse events reported to Iranian Pharmacovigilance Center from 1999 through 2012. To mention success and failure outcomes of crises management process taken against detected crises.Methods: All adverse drug events received by Iranian Pharmacovigilance Center from 1999 through 2012 were evaluated for reports with fatal outcome. All alerting letters and manuscripts published by the Center during the same period were reviewed for detailed information on detected crises. World Health Organization definition was used for detecting drug safety crises.Results: Among 42036 registered cases in our database, 463 deaths were recorded. The most frequent suspected drug for adverse events with fatal outcome was ceftriaxone (100 cases. Ten different drug safety crises issues were detected during the study period and their successful or failure outcomes were evaluated. There were 112 issued alerting letters and 17 published manuscript during the same period which was monitored for detailed information.  Conclusion: It is necessary for national pharmacovigilance centers to have prepared programs for crises management. This could be useful for reducing drug related mortality.

  17. Drug safety evaluation of defibrotide.

    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.

  18. Safety and efficacy of drugs in pregnancy.

    Knoppert, David

    2011-01-01

    Although most drugs are used to treat chronic or pregnancy-induced conditions during pregnancy and lactation, very few are studied in pregnant or breastfeeding women. The information we have on drugs taken during pregnancy and lactation is usually obtained after market approval through published case reports or case series and from pregnancy exposure or retrospective birth defect registries. Furthermore, generic drugs approved for use in this vulnerable population may be approved based on results from a male trial population. This disregards the changes that can occur during pregnancy which can affect the pharmacokinetics of drugs. In an effort to improve the information provided to prescribers, in 2008 the United States Food and Drug Administration proposed a change in product labelling where information from pregnancy exposure registries would be required. As of 2009, European Medicines Agency requires additional statements on use during pregnancy within drug labelling information. In Canada, it is anticipated that the efficacy and safety of drugs in pregnancy will be included under the Drug Safety and Effectiveness Network initiative, and that this will offer a unified approach for such assessments. Pregmedic, a non-profit organization for the advancement of safe and effective use of drugs in pregnancy, has presented a number of proposals and draft guidelines to Health Canada on the inclusion of pregnant women in pharmacokinetic studies and the establishment of registries for women who take drugs during pregnancy. Pregmedic advocates for ensuring that drugs indicated for women are studied in women.

  19. Safety and feasibility research of CIPT-Ⅱ irradiation device

    Zhang Zhihua; Mi Xiangmiao; Li Rundong

    2014-01-01

    CITP-Ⅱ irradiation device, which is specially designed for fusion tritium breeder research, works in a thermal neutron reactor. With lithium orthosilicate as the breeder, the safety analysis was done to work out the device's influence on physical parameters of the reactor and get the breeder's temperature distribution and thermo-technical features in the n-γ field. The stiffness and strength were checked, and also the safety characters of the device were assessed. The feasibility of gap gas regulating the temperature and gas refueling the breeder was demonstrated. The calculation and analysis results provide data for comprehensive performance assessment. (authors)

  20. Toxicophores: Investigations in drug safety

    Williams, Dominic P.

    2006-01-01

    Adverse drug reactions, such as hepatotoxicity, blood dyscrasias and hypersensitivity are a major obstacle for the use and the development of new medicines. Many forms of organ-directed toxicity can arise from the bioactivation of drugs to the so-called chemically reactive metabolites, which can modify tissue macromolecules. It is well established that the toxicities of model hepatotoxins, such as acetaminophen, furosemide, bromobenzene and methapyrilene can be correlated with the generation of chemically reactive metabolites, which can be detected by measurement of the irreversible binding of radiolabelled material to hepatic protein and/or the detection of stable phase II metabolites such as glutathione conjugates. The basic chemistry of the reaction of such metabolites with model nucleophiles is relatively well understood. A major challenge is to define how certain reactive intermediates may chemically modify critical proteins and how modification of specific amino acids may alter protein function which in turn may affect cell signalling, regulation, defence, function and viability. This in turn will determine whether or not bioactivation will result in a particular form of drug-induced injury. It is now clear that even relatively simple reactive intermediates can react in a discriminative manner with particular cellular proteins and even with specific amino acids within those proteins. Therefore, both non-covalent, as well as covalent bonds will be important determinants of the target protein for a particular reactive metabolite. Mammalian cells have evolved numerous defence systems against reactive intermediates. Sensitive redox proteins such as Nrf-2 recognise oxidative stress and electrophilic agents, through oxidation or covalent modification of thiol groups. Defence genes, such as epoxide hydrolase and glutamate cysteine ligase then become up-regulated in an attempt to reduce the oxidising environment. However, whether the liver receives mild or severe

  1. Nuclear-power-safety reporting system: feasibility analysis

    Finlayson, F.C.; Ims, J.

    1983-04-01

    The US Nuclear Regulatory Commission (NRC) is evaluating the possibility of instituting a data gathering system for identifying and quantifying the factors that contribute to the occurrence of significant safety problems involving humans in nuclear power plants. This report presents the results of a brief (6 months) study of the feasibility of developing a voluntary, nonpunitive Nuclear Power Safety Reporting System (NPSRS). Reports collected by the system would be used to create a data base for documenting, analyzing and assessing the significance of the incidents. Results of The Aerospace Corporation study are presented in two volumes. This document, Volume I, contains a summary of an assessment of the Aviation Safety Reporting System (ASRS). The FAA-sponsored, NASA-managed ASRS was found to be successful, relatively low in cost, generally acceptable to all facets of the aviation community, and the source of much useful data and valuable reports on human factor problems in the nation's airways. Several significant ASRS features were found to be pertinent and applicable for adoption into a NPSRS

  2. Pharmacogenetics of drug-induced arrhythmias : a feasibility study using spontaneous adverse drug reactions reporting data

    De Bruin, Marie L; van Puijenbroek, Eugene P; Bracke, Madelon; Hoes, Arno W; Leufkens, Hubert G M

    PURPOSE: The bottleneck in pharmacogenetic research on rare adverse drug reactions (ADR) is retrieval of patients. Spontaneous reports of ADRs may form a useful source of patients. We investigated the feasibility of a pharmacogenetic study, in which cases were selected from the database of a

  3. Using Nonexperts for Annotating Pharmacokinetic Drug-Drug Interaction Mentions in Product Labeling: A Feasibility Study.

    Hochheiser, Harry; Ning, Yifan; Hernandez, Andres; Horn, John R; Jacobson, Rebecca; Boyce, Richard D

    2016-04-11

    Because vital details of potential pharmacokinetic drug-drug interactions are often described in free-text structured product labels, manual curation is a necessary but expensive step in the development of electronic drug-drug interaction information resources. The use of nonexperts to annotate potential drug-drug interaction (PDDI) mentions in drug product label annotation may be a means of lessening the burden of manual curation. Our goal was to explore the practicality of using nonexpert participants to annotate drug-drug interaction descriptions from structured product labels. By presenting annotation tasks to both pharmacy experts and relatively naïve participants, we hoped to demonstrate the feasibility of using nonexpert annotators for drug-drug information annotation. We were also interested in exploring whether and to what extent natural language processing (NLP) preannotation helped improve task completion time, accuracy, and subjective satisfaction. Two experts and 4 nonexperts were asked to annotate 208 structured product label sections under 4 conditions completed sequentially: (1) no NLP assistance, (2) preannotation of drug mentions, (3) preannotation of drug mentions and PDDIs, and (4) a repeat of the no-annotation condition. Results were evaluated within the 2 groups and relative to an existing gold standard. Participants were asked to provide reports on the time required to complete tasks and their perceptions of task difficulty. One of the experts and 3 of the nonexperts completed all tasks. Annotation results from the nonexpert group were relatively strong in every scenario and better than the performance of the NLP pipeline. The expert and 2 of the nonexperts were able to complete most tasks in less than 3 hours. Usability perceptions were generally positive (3.67 for expert, mean of 3.33 for nonexperts). The results suggest that nonexpert annotation might be a feasible option for comprehensive labeling of annotated PDDIs across a broader

  4. Drug safety: Pregnancy rating classifications and controversies.

    Wilmer, Erin; Chai, Sandy; Kroumpouzos, George

    2016-01-01

    This contribution consolidates data on international pregnancy rating classifications, including the former US Food and Drug Administration (FDA), Swedish, and Australian classification systems, as well as the evidence-based medicine system, and discusses discrepancies among them. It reviews the new Pregnancy and Lactation Labeling Rule (PLLR) that replaced the former FDA labeling system with narrative-based labeling requirements. PLLR emphasizes on human data and highlights pregnancy exposure registry information. In this context, the review discusses important data on the safety of most medications used in the management of skin disease in pregnancy. There are also discussions of controversies relevant to the safety of certain dermatologic medications during gestation. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Tolerability and safety of antifungal drugs

    Francesco Scaglione

    2013-08-01

    Full Text Available When treating critically ill patients, as those with fungal infections, attention should be focused on the appropriate use of drugs, especially in terms of dose, safety, and tolerability. The fungal infection itself and the concomitant physiological disorders concur to increase the risk of mortality in these patients, therefore the use of any antifungal agent should be carefully evaluated, considering both the direct action on the target fungus and the adverse effects eventually caused. Among antifungal drugs, echinocandins have the greatest tolerability. In fact, unlike amphotericin B, showing nephrotoxicity, and azoles, which are hepatotoxic, the use of echinocandins doesn’t result in major adverse events.http://dx.doi.org/10.7175/rhc.v4i2s.873

  6. MR cholangiopancreatography in children: feasibility, safety, and initial experience

    Delaney, Lisa; Karmazyn, Boaz; Akisik, M.F.; Jennings, S.G.; Applegate, Kimberly E.

    2008-01-01

    The indications for MR cholangiopancreatography (MRCP) in children, and its safety and findings, might differ from those in adults and are not well described. To investigate the safety, feasibility, and accuracy of MRCP in children. We reviewed all prospective MRCP reports, noting the indication, the use of secretin, endoscopic retrograde cholangiopancreatography (ERCP) findings, and patient outcomes. Two readers reviewed each MRCP study by consensus to rate duct visualization and compare pancreatic duct sizes before and after secretin administration (paired t-test). The likelihood of a normal versus an abnormal MRCP study was compared by gender, pancreatitis as the primary indication, secretin use, and whether ERCP was performed (Fisher's exact test), as well as age (t-test). A total of 85 MRCP studies were performed in children (mean age 10.3 years), most commonly for evaluation of pancreatitis (n=47, 55%); 41 (48%) used secretin and 39 (46%) used a negative oral contrast agent. Of the 85 studies, 72 (85%) had excellent image quality and 43 were normal. ERCP was performed after 16 of the 85 MRCP studies (19%); the diagnoses were concordant with those of MRCP in 13 (81%). There were 42 abnormal MRCP studies, and these were more likely to be in girls (P=0.03) and in children who had undergone ERCP (P<0.01). Secretin and the negative oral contrast agent were well-tolerated. Secretin improved duct visualization (P<0.001). MRCP safely and accurately depicted pancreaticobiliary anatomy in children. The use of secretin improved visualization of the pancreatic duct. (orig.)

  7. Feasibility, safety and tolerability of accelerated dobutamine stress echocardiography

    Pavaci Herribert

    2007-11-01

    Full Text Available Abstract A continuous infusion of a single high dose of dobutamine has been, recently, suggested as a simple and effective protocol of stress echocardiography. The present study assesses the feasibility, safety, and tolerability of an accelerated dobutamine stress protocol performed in patients with suspected or known coronary artery disease. Two hundred sixty five consecutive patients underwent accelerated dobutamine stress echocardiography: the dobutamine was administered at a constant dose of 50 μg/kg/min for up to 10 minutes. The mean weight-adjusted cumulative dose of dobutamine used was 330 ± 105.24 μg/kg. Total duration of dobutamine infusion was 6.6 ± 2.1 min. Heart rate rose from 69.9 ± 12.1 to 123.1 ± 22.1 beats/min at peak with a concomitant change in systolic blood pressure (127.6 ± 18.1 vs. 167.6 ± 45.0 mmHg. Dobutamine administration produced a rapid increase in heart rate (9.4 ± 5.9 beats/min2. The side effects were similar to those described with the standard protocol; the most common were frequent premature ventricular complexes (21.5%, frequent premature atrial complexes (1.5% and non sustained ventricular tachycardia (1.5%; among non cardiac symptoms the most frequent were nausea (3.4%, headache (1.1% and symptomatic hypotension (1.1%. No major side effects were observed during the test. Our data demonstrate that a continous infusion of a single high dose of dobutamine is a safe and well tolerated method of performing stress echocardiography in patients with suspected or known coronary artery disease. This new protocol requires the administration of lower cumulative dobutamine dose than standard protocol and results in a significant reduction in test time.

  8. Feasibility of AmbulanCe-Based Telemedicine (FACT) Study : Safety, Feasibility and Reliability of Third Generation Ambulance Telemedicine

    Yperzeele, Laetitia; Van Hooff, Robbert-Jan; De Smedt, Ann; Espinoza, Alexis Valenzuela; Van Dyck, Rita; Van de Casseye, Rohny; Convents, Andre; Hubloue, Ives; Lauwaert, Door; De Keyser, Jacques; Brouns, Raf

    2014-01-01

    Background: Telemedicine is currently mainly applied as an in-hospital service, but this technology also holds potential to improve emergency care in the prehospital arena. We report on the safety, feasibility and reliability of in-ambulance teleconsultation using a telemedicine system of the third

  9. 76 FR 59142 - Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and...

    2011-09-23

    ...] Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk... Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee. General Function of the...., [[Page 59143

  10. A Study on Drug Safety Monitoring Program in India

    Ahmad, A.; Patel, Isha; Sanyal, Sudeepa; Balkrishnan, R.; Mohanta, G. P.

    2014-01-01

    Pharmacovigilance is useful in assuring the safety of medicines and protecting the consumers from their harmful effects. A number of single drugs as well as fixed dose combinations have been banned from manufacturing, marketing and distribution in India. An important issue about the availability of banned drugs over the counter in India is that sufficient adverse drug reactions data about these drugs have not been reported. The most common categories of drugs withdrawn in the last decade were nonsteroidal antiinflammatory drugs (28%), antidiabetics (14.28%), antiobesity (14.28%), antihistamines (14.28%), gastroprokinetic drugs (7.14%), breast cancer and infertility drugs (7.14%), irritable bowel syndrome and constipation drugs (7.14%) and antibiotics (7.14%). Drug withdrawals from market were made mainly due to safety issues involving cardiovascular events (57.14%) and liver damage (14.28%). Majority of drugs have been banned since 3-5 years in other countries but are still available for sale in India. The present study compares the drug safety monitoring systems in the developed countries such as the USA and UK and provides implications for developing a system that can ensure the safety and efficacy of drugs in India. Absence of a gold standard for a drug safety surveillance system, variations in culture and clinical practice across countries makes it difficult for India to completely adopt another country's practices. There should be a multidisciplinary approach towards drug safety that should be implemented throughout the entire duration spanning from drug discovery to usage by consumers. PMID:25425751

  11. NIR spectrometry for counterfeit drug detection - A feasibility study

    Rodionova, O.Y.; Houmøller, Lars P.; Pomerantsev, A.L.

    2005-01-01

    for mathematical data processing for false drugs detection is demonstrated. Also, multivariate hyperspectral image analysis is applied providing additional diagnostic information. Hyperspectral imaging is becoming a useful diagnostic tool for identifying non-homogeneous spatial regions of drug formulation. Two...... types of drugs are used to demonstrate the applicability of these approaches....

  12. Safety, feasibility and efficacy of a rapid ART initiation in pregnancy ...

    Safety, feasibility and efficacy of a rapid ART initiation in pregnancy pilot programme in Cape Town, South Africa. S Black, R Zulliger, L Myer, R Marcus, S Jeneker, R Taliep, D Pienaar, R Wood, L-G Bekker ...

  13. Impact of biomarker development on drug safety assessment

    Marrer, Estelle; Dieterle, Frank

    2010-01-01

    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 and '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.

  14. Advancing Drug Safety Through Prospective Pharmacovigilance.

    Pitts, Peter J; Le Louet, Hervé

    2018-01-01

    Much has changed in a relatively short period of time. There is a raging debate over the level of evidence expected to first introduce a treatment to patients based on smaller, more adaptive data sets. Some argue for less data followed by postapproval follow-up, others for more adaptive clinical trial designs and end-point modification driven by patient-focused drug development and use of real-world evidence. The transition in both the review and postmarketing regulatory framework is happening in front of our eyes in real time. To improve the ability of patients to receive high-quality, safe, effective, and timely care, better information via pharmacovigilance must be a priority as the world's many regulatory systems build the capacity to harness electronic health information to improve health, care quality, and safety. Globally, the widely variable ability of nations to build reliable regulatory systems (from precise review to robust pharmacovigilance) is a dangerous source of health care inequality. Developing validated tools and techniques for "predictive pharmacovigilance" will assist all health systems in better understanding the risks and benefits of the medicines they regulate by understanding what should be happening once a new medicine moves from risk-benefit regulatory efficacy to real-world risk-effectiveness. This will be of particular utility for smaller regulatory agencies with fewer resources. By comparing preapproval predictive pharmacovigilance data, developing regulatory authorities will be able to better understand the potential gap between what was predicted and what was actually measured (via more traditional pharmacovigilance methodologies). Predictive pharmacovigilance recognizes the value of understanding the imperfect reporting of real-world clinical use and that the absence of reporting is, in itself, an important postmarketing signal.

  15. Drug safety: withdrawn medications are only part of the picture.

    Rawson, Nigel S B

    2016-02-13

    In a research article published in BMC Medicine, Onakpoya and colleagues provide a historical review of withdrawals of medications for safety reasons. However, withdrawn medications are only one part of the picture about how regulatory agencies manage drug risks. Moreover, medications introduced before the increased pre-marketing regulations and post-marketing monitoring systems instituted after the thalidomide tragedy have little relevance when considering the present drug safety picture because the circumstances under which they were introduced were completely different. To more fully understand drug safety management and regulatory agency actions, withdrawals should be evaluated within the setting and timeframe in which the medications are approved, which requires information about approvals and safety warnings. Studies are needed that provide a more comprehensive current picture of the identification and evaluation of drug safety risks as well as how regulatory agencies deal with them. Please see related research article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0553-2.

  16. Alcohol and prescription drug safety in older adults

    Zanjani F

    2013-02-01

    Full Text Available Faika Zanjani,1,2 Aasha I Hoogland,1 Brian G Downer11Department of Gerontology, 2Building Interdisciplinary Research Careers in Women's Health University of Kentucky, Lexington, KY, USABackground: The objectives of this study were to investigate older adults' knowledge of prescription drug safety and interactions with alcohol, and to identify pharmacists' willingness to disseminate prescription drug safety information to older adults.Methods: The convenience sample consisted of 48 older adults aged 54–89 years who were recruited from a local pharmacy and who completed surveys addressing their alcohol consumption, understanding of alcohol and prescription drug interactions, and willingness to change habits regarding alcohol consumption and prescription drugs. To address pharmacist willingness, 90 pharmacists from local pharmacies volunteered and answered questions regarding their willingness to convey prescription drug safety information to older adults.Results: Older adults reported low knowledge of alcohol and prescription drug safety, with women tending to be slightly more knowledgeable. More importantly, those who drank in the previous few months were less willing to talk to family and friends about how alcohol can have harmful interactions with prescription drugs, or to be an advocate for safe alcohol and prescription drug use than those who had not had a drink recently. Pharmacists reported that they were willing to convey prescription drug safety information to older adults via a variety of formats, including displaying or distributing a flyer, and directly administering a brief intervention.Conclusion: In this study, older adults were found to have inadequate knowledge of prescription drug safety and interactions with alcohol, but pharmacists who regularly come in contact with older adults indicated that they were ready and willing to talk to older adults about prescription drug safety. Future research should focus on interventions

  17. Differentiating drugs by harm potential: the rational versus the feasible.

    Kalant, H

    1999-01-01

    In an ideal harm reduction model, drugs would be ranked according to their potential to cause harm, with varying implications for control policies and interventions. In such a public health oriented approach, the maximum protection of the public from harm would be balanced with the least possible restriction of freedom. In reality, however, the accuracy and completeness of the necessary information for such a ranking is highly limited. Many other factors not readily incorporated in a rational model, such as values, beliefs, and traditions, also affect drug policy decisions. Thus, rather than relying on acquisition of the necessary knowledge, it may be preferable to focus efforts on developing effective nonlegal measures to reduce drug use and harm. [Translations are provided in the International Abstracts Section of this issue.

  18. 77 FR 2606 - Pipeline Safety: Random Drug Testing Rate

    2012-01-18

    ... DEPARTMENT OF TRANSPORTATION Pipeline and Hazardous Materials Safety Administration [Docket ID PHMSA-2012-0004] Pipeline Safety: Random Drug Testing Rate AGENCY: Pipeline and Hazardous Materials... pipelines and operators of liquefied natural gas facilities must select and test a percentage of covered...

  19. 75 FR 9018 - Pipeline Safety: Random Drug Testing Rate

    2010-02-26

    ... DEPARTMENT OF TRANSPORTATION Pipeline and Hazardous Materials Safety Administration [Docket ID PHMSA-2010-0034] Pipeline Safety: Random Drug Testing Rate AGENCY: Pipeline and Hazardous Materials... pipelines and operators of liquefied natural gas facilities must select and test a percentage of covered...

  20. Determining animal drug combinations based on efficacy and safety.

    Kratzer, D D; Geng, S

    1986-08-01

    A procedure for deriving drug combinations for animal health is used to derive an optimal combination of 200 mg of novobiocin and 650,000 IU of penicillin for nonlactating cow mastitis treatment. The procedure starts with an estimated second order polynomial response surface equation. That surface is translated into a probability surface with contours called isoprobs. The isoprobs show drug amounts that have equal probability to produce maximal efficacy. Safety factors are incorporated into the probability surface via a noncentrality parameter that causes the isoprobs to expand as safety decreases, resulting in lower amounts of drug being used.

  1. WP-Cave - assessment of feasibility, safety and development potential

    1989-09-01

    According to SKB R and D-programme 1986, alternative disposal methods will be investigated to provide a basis for selecting a site and a repository system for the Swedish spent nuclear fuel. The present report is a comparison between the WP-Cave and the reference concept KBS-3. The comparison has resulted in the following conclusions: - Both concepts are judged to be able to provide adequate safety. - A utilization of the potential of the WP-Cave requires, however, extensive development in areas where the current state of knowledge and available data are incomplete. - The higher temperatures in the WP-Cave lead to greater uncertainty as to long-term performance. Reducing this uncertainty would require many yaers of research and substantial resources. - Both repositories, including the barriers they incorporate, could be built with a normal adaption of available technology. -It is not possible to say today whether it would be simpler to find suitable sites for one design or the other. - The WP-Cave is considerably more expensive. A future research direction based on a concentrated emplacement of spent fuel along the lines of the WP-Cave is therefore judged to entail greater uncertainty as regards the possibilities of achieving acceptable safety and to require greater resources for research and development, at the same time as the costs of building the repository would be higher. The studies of the WP-Cave as an integral system should therfore be discontinued. Certain barrier designs in the WP-Cave could also be utulized in repository designs with lower temperature, for example the reduction potential of the steel canisters and the hydraulic cage's diversion of groundwater. Studies within these areas are being conducted within SKB and should continue

  2. Adverse drug reaction and concepts of drug safety in Ayurveda: An overview

    Ajanal, Manjunath; Nayak, Shradda; Prasad, Buduru Sreenivasa; Kadam, Avinash

    2013-01-01

    Drug safety is a very basic and fundamental concept in medical practice. ADRs play an important role in assessing patient safety in any system of medicine. Pharmacovigilance study is thus significant to understand treatment outcomes. Current raised issue with respect to complementary and alternative system medicine (CAM) like Ayurveda is increased in number of safety reports along with report misinterpretation; this generates the negative impact on system. Although, Ayurveda which is holistic system of medicine from India has elaborated the causes and methods of drug-induced consequences along with preventive measures the available data in classical texts is scattered. The compilation and analysis along with modern concept drug safety is need of the hour. Present literature review was conducted from various compendium of Ayurveda and electronic data base with search terms of ‘Vyapad’, ‘Viruddha’, ‘Ahita’, ‘herb–herb interaction’, ‘idiosyncrasy’, ‘Prakritiviruddha’ etc. The reported information was analysed for the possible correlation on concept of ADR and Pharmacovigilance of current science. Overall review demonstrated that drug interaction, iatrogenic, over dose, administration of unsuitable drugs, reprehensive drug administration with respect to disease, complication from five procedural therapies (Panchakarma) and reprehensible preparation of mineral drug are nearer to the modern causes of ADR. Thus, concept of drug safety and ADR is not new to the Ayurveda. The concept “Drug which is not appropriate to be used as medicine”(Abheshaja) of Ayurveda sounds similar as that of modern pharmacovigilance. PMID:24563588

  3. Drug safety in pregnancy - monitoring congenital anomalies

    Morgan, Margery; De Jong-Van Den Berg, Lolkje T. W.; Jordan, Sue

    Aim This paper outlines research into the causes of congenital anomalies, and introduces a pan-European study. The potential roles of nurses and midwives in this area are illustrated by a case report. Background Since the thalidomide disaster, use of drugs in pregnancy has been carefully monitored

  4. Krypton-85 hydrofracture engineering feasibility and safety evaluation

    Peretz, F.J.; Muller, M.E.; Pan, P.Y.

    1981-07-01

    Engineering studies have been made to determine the hazards associated with the disposal of /sup 85/Kr using the hydrofracture process. To assess the hazards, an effort has been made to identify the equipment required to entrain and dissolve the noble gas into the grout stream at hydrofracture pressure (up to 350 bar). Off-the-shelf or slightly modified equipment has been identified for safe and effective compression and gas-grout mixing. Each monthly injection disposes of 1.6 x 10/sup 6/ Ci of /sup 85/Kr. By connecting only one gas cylinder to the injection system at a time, the maximum amount of krypton likely to be released as a result of equipment failure is limited to 128,000 Ci. An evaluation by Los Alamos Technical Associates shows that releasing this amount of gas in less than one hour under worst-case meteorological conditions through a 30-m stack would result in a whole-body dose of 170 millirem at a distance of 1 km from the facility. A krypton collection and recovery system can further reduce this dose to 17 millirem; increasing the distance to the site boundary to 3 km can also reduce the dose by a factor of ten. Lung and skin dose estimates are 1.6 and 120 times the whole-body dose, respectively. These are all worst-case values; releases under more typical conditions would result in a significantly lower dose. No insurmountable safety or engineering problems have been identified.

  5. Krypton-85 hydrofracture engineering feasibility and safety evaluation

    Peretz, F.J.; Muller, M.E.; Pan, P.Y.

    1981-07-01

    Engineering studies have been made to determine the hazards associated with the disposal of 85 Kr using the hydrofracture process. To assess the hazards, an effort has been made to identify the equipment required to entrain and dissolve the noble gas into the grout stream at hydrofracture pressure (up to 350 bar). Off-the-shelf or slightly modified equipment has been identified for safe and effective compression and gas-grout mixing. Each monthly injection disposes of 1.6 x 10 6 Ci of 85 Kr. By connecting only one gas cylinder to the injection system at a time, the maximum amount of krypton likely to be released as a result of equipment failure is limited to 128,000 Ci. An evaluation by Los Alamos Technical Associates shows that releasing this amount of gas in less than one hour under worst-case meteorological conditions through a 30-m stack would result in a whole-body dose of 170 millirem at a distance of 1 km from the facility. A krypton collection and recovery system can further reduce this dose to 17 millirem; increasing the distance to the site boundary to 3 km can also reduce the dose by a factor of ten. Lung and skin dose estimates are 1.6 and 120 times the whole-body dose, respectively. These are all worst-case values; releases under more typical conditions would result in a significantly lower dose. No insurmountable safety or engineering problems have been identified

  6. 78 FR 20327 - Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and...

    2013-04-04

    ... Management Advisory Committee; Amendment of Notice AGENCY: Food and Drug Administration, HHS. ACTION: Notice... of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management... Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee...

  7. Virtual reality and persecutory delusions: safety and feasibility.

    Fornells-Ambrojo, Miriam; Barker, Chris; Swapp, David; Slater, Mel; Antley, Angus; Freeman, Daniel

    2008-09-01

    Virtual reality (VR) has begun to be used to research the key psychotic symptom of paranoia. The initial studies have been with non-clinical individuals and individuals at high risk of psychosis. The next step is to develop the technology for the understanding and treatment of clinical delusions. Therefore the present study investigated the acceptability and safety of using VR with individuals with current persecutory delusions. Further, it set out to determine whether patients feel immersed in a VR social environment and, consequently, experience paranoid thoughts. Twenty individuals with persecutory delusions and twenty non-clinical individuals spent 4 min in a VR underground train containing neutral characters. Levels of simulator sickness, distress, sense of presence, and persecutory ideation about the computer characters were measured. A one-week follow-up was conducted to check longer-term side effects. The VR experience did not raise levels of anxiety or symptoms of simulator sickness. No side effects were reported at the follow-up. There was a considerable degree of presence in the VR scenario for all participants. A high proportion of the persecutory delusions group (65%) had persecutory thinking about the computer characters, although this rate was not significantly higher than the non-clinical group. The study indicates that brief experiences in VR are safe and acceptable to people with psychosis. Further, patients with paranoia can feel engaged in VR scenes and experience persecutory thoughts. Exposure to social situations using VR has the potential to be incorporated into cognitive behavioural interventions for paranoia.

  8. Feasibility and safety of rehabilitation after venous thromboembolism

    Noack F

    2015-07-01

    one. Four patients (0.9% had to be transferred to a primary care hospital for non-PE-associated reasons (acute coronary syndrome, pharyngeal abscess, and acute abdominal problems. No influence of any of the physical activity interventions on the incidence of any AE was found. Conclusion: Since PE is a life-threatening disease, it seems reasonable to recommend rehabilitation at least in PE patients with an intermediate or high risk. It is shown for the first time in this study that a standard rehabilitation program after PE is safe. However, efficacy and safety in the long term need to be studied prospectively. Keywords: venous thromboembolism, pulmonary embolism, rehabilitation

  9. Occupational Therapy and Sensory Integration for Children with Autism: A Feasibility, Safety, Acceptability and Fidelity Study

    Schaaf, Roseann C.; Benevides, Teal W.; Kelly, Donna; Mailloux-Maggio, Zoe

    2012-01-01

    Objective: To examine the feasibility, safety, and acceptability of a manualized protocol of occupational therapy using sensory integration principles for children with autism. Methods: Ten children diagnosed with autism spectrum disorder ages 4-8 years received intensive occupational therapy intervention using sensory integration principles…

  10. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling

    Kammersgaard, L P; Rasmussen, B H; Jørgensen, Henrik Stig

    2000-01-01

    Hypothermia reduces neuronal damage in animal stroke models. Whether hypothermia is neuroprotective in patients with acute stroke remains to be clarified. In this case-control study, we evaluated the feasibility and safety of inducing modest hypothermia by a surface cooling method in awake patients...

  11. Combined leadless pacemaker and subcutaneous implantable defibrillator therapy: feasibility, safety, and performance

    Tjong, F. V. Y.; Brouwer, T. F.; Smeding, L.; Kooiman, K. M.; de Groot, J. R.; Ligon, D.; Sanghera, R.; Schalij, M. J.; Wilde, A. A. M.; Knops, R. E.

    2016-01-01

    The subcutaneous implantable cardioverter-defibrillator (S-ICD) and leadless pacemaker (LP) are evolving technologies that do not require intracardiac leads. However, interactions between these two devices are unexplored. We investigated the feasibility, safety, and performance of combined LP and

  12. Safety learning from drugs of the same class

    Stefansdottir, G; Knol, M J; Arnardottir, A H

    2012-01-01

    This study was aimed at assessing the extent of safety learning from data pertaining to other drugs of the same class. We studied drug classes for which the first and second drugs were centrally registered in the European Union from 1995 to 2008. We assessed whether adverse drug reactions (ADRs......) associated with one of the drugs also appeared in the Summary of Product Characteristics (SPC) of the other drug, either initially or during the postmarketing phase. We identified 977 ADRs from 19 drug pairs, of which 393 ADRs (40.2%) were listed in the SPCs of both drugs of a pair. Of these 393 that were...... present in both SPCs of a drug pair, 241 (61.3%) were present when the drug entered the market and 152 (30.7%) appeared in the postmarketing phase. The mention of ADRs in the SPCs of both same-class drugs in the postmarketing phase was associated with type A ADRs, marketing in the same regulator country...

  13. Feasibility, Safety, and Compliance in a Randomized Controlled Trial of Physical Therapy for Parkinson's Disease

    Jennifer L. McGinley

    2012-01-01

    Full Text Available Both efficacy and clinical feasibility deserve consideration in translation of research outcomes. This study evaluated the feasibility of rehabilitation programs within the context of a large randomized controlled trial of physical therapy. Ambulant participants with Parkinson's disease (PD (n=210 were randomized into three groups: (1 progressive strength training (PST; (2 movement strategy training (MST; or (3 control (“life skills”. PST and MST included fall prevention education. Feasibility was evaluated in terms of safety, retention, adherence, and compliance measures. Time to first fall during the intervention phase did not differ across groups, and adverse effects were minimal. Retention was high; only eight participants withdrew during or after the intervention phase. Strong adherence (attendance >80% did not differ between groups (P=.435. Compliance in the therapy groups was high. All three programs proved feasible, suggesting they may be safely implemented for people with PD in community-based clinical practice.

  14. Trust in the pharmaceutical sector : Analysis of drug safety controversies by means of drug life cycles

    Hernández, J.F.

    2015-01-01

    Before obtaining a marketing approval, the efficacy and safety profile of drugs is studied in specific populations and under well-controlled circumstances. After marketing approval, the drug is made available and used in ‘real world conditions’, which are known to deviate from the trial setting.

  15. Drug research methodology. Volume 2, The identification of drugs of interest in highway safety

    1980-03-01

    This report presents findings of a workshop on the identification of drugs that should be the focus of near-term highway safety research. Drugs of interest are those that have a potential to increase the likelihood of traffic crashes and their attend...

  16. Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study

    Wit, D. de; Erp, N. van; Hartigh, J. den; Wolterbeek, R..; Hollander-van Deursen, M. den; Labots, M.; Guchelaar (LUMC), H.J.; Verheul, H.M.; Gelderblom, H.

    2015-01-01

    BACKGROUND: Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided

  17. Feasibility of AmbulanCe-Based Telemedicine (FACT study: safety, feasibility and reliability of third generation in-ambulance telemedicine.

    Laetitia Yperzeele

    Full Text Available Telemedicine is currently mainly applied as an in-hospital service, but this technology also holds potential to improve emergency care in the prehospital arena. We report on the safety, feasibility and reliability of in-ambulance teleconsultation using a telemedicine system of the third generation.A routine ambulance was equipped with a system for real-time bidirectional audio-video communication, automated transmission of vital parameters, glycemia and electronic patient identification. All patients ( ≥ 18 years transported during emergency missions by a Prehospital Intervention Team of the Universitair Ziekenhuis Brussel were eligible for inclusion. To guarantee mobility and to facilitate 24/7 availability, the teleconsultants used lightweight laptop computers to access a dedicated telemedicine platform, which also provided functionalities for neurological assessment, electronic reporting and prehospital notification of the in-hospital team. Key registrations included any safety issue, mobile connectivity, communication of patient information, audiovisual quality, user-friendliness and accuracy of the prehospital diagnosis.Prehospital teleconsultation was obtained in 41 out of 43 cases (95.3%. The success rates for communication of blood pressure, heart rate, blood oxygen saturation, glycemia, and electronic patient identification were 78.7%, 84.8%, 80.6%, 64.0%, and 84.2%. A preliminary prehospital diagnosis was formulated in 90.2%, with satisfactory agreement with final in-hospital diagnoses. Communication of a prehospital report to the in-hospital team was successful in 94.7% and prenotification of the in-hospital team via SMS in 90.2%. Failures resulted mainly from limited mobile connectivity and to a lesser extent from software, hardware or human error. The user acceptance was high.Ambulance-based telemedicine of the third generation is safe, feasible and reliable but further research and development, especially with regard to high

  18. Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

    Swedberg, Michael D B

    2016-01-01

    Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

  19. 78 FR 16271 - Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and...

    2013-03-14

    ...] Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk... Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee. General Function of the... presentation may be limited. If the number of registrants requesting to speak is greater than can be reasonably...

  20. 76 FR 40735 - Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and...

    2011-07-11

    ...] Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk... Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee. General Function of the... East, Adelphi, MD. The conference center telephone number is: 301 985-7300. Contact Person: Kalyani...

  1. 78 FR 2677 - Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and...

    2013-01-14

    ...] Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk... Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee. General Function of the... before February 7, 2013. Time allotted for each presentation may be limited. If the number of registrants...

  2. 76 FR 59143 - Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and...

    2011-09-23

    ...] Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk... Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee. General Function of the..., Adelphi, MD. The conference center telephone number is 301-985-7300. Contact Person: Kalyani Bhatt, Center...

  3. 75 FR 10490 - Joint Meeting of the Arthritis Drugs Advisory Committee and the Drug Safety and Risk Management...

    2010-03-08

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0001] Joint Meeting of the Arthritis Drugs Advisory Committee and the Drug Safety and Risk Management Advisory... Drug Safety and Risk Management Advisory Committee. General Function of the Committees: To provide...

  4. Exploring Machine Learning Techniques Using Patient Interactions in Online Health Forums to Classify Drug Safety

    Chee, Brant Wah Kwong

    2011-01-01

    This dissertation explores the use of personal health messages collected from online message forums to predict drug safety using natural language processing and machine learning techniques. Drug safety is defined as any drug with an active safety alert from the US Food and Drug Administration (FDA). It is believed that this is the first…

  5. 77 FR 65000 - Drug Safety and Risk Management Advisory Committee; Notice of Meeting

    2012-10-24

    ...] Drug Safety and Risk Management Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Drug Safety and Risk Management Advisory Committee. General Function of the Committee: To provide... Use (ETASU) before CDER's Drug Safety and Risk Management Advisory Committee (DSaRM). The Agency plans...

  6. 78 FR 30929 - Drug Safety and Risk Management Advisory Committee; Notice of Meeting

    2013-05-23

    ...] Drug Safety and Risk Management Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Drug Safety and Risk Management Advisory Committee. General Function of the Committee: To provide... (REMS) with elements to assure safe use (ETASU) before its Drug Safety and Risk Management Advisory...

  7. 77 FR 75176 - Drug Safety and Risk Management Advisory Committee; Notice of Meeting

    2012-12-19

    ...] Drug Safety and Risk Management Advisory Committee; Notice of Meeting AGENCY: Food and Drug... being rescheduled due to the postponement of the October 29-30, 2012, Drug Safety and Risk Management... Committee: Drug Safety and Risk Management Advisory Committee. General Function of the Committee: To provide...

  8. Feasibility studies of safety assessment methods for programmable automation systems. Final report of the AVV project

    Haapanen, P.; Maskuniitty, M.; Pulkkinen, U.; Heikkinen, J.; Korhonen, J.; Tuulari, E.

    1995-10-01

    Feasibility studies of two different groups of methodologies for safety assessment of programmable automation systems has been executed at the Technical Research Centre of Finland (VTT). The studies concerned the dynamic testing methods and the fault tree (FT) and failure mode and effects analysis (FMEA) methods. In order to get real experience in the application of these methods, an experimental testing of two realistic pilot systems were executed and a FT/FMEA analysis of a programmable safety function accomplished. The purpose of the studies was not to assess the object systems, but to get experience in the application of methods and assess their potentials and development needs. (46 refs., 21 figs.)

  9. Pooling, meta-analysis, and the evaluation of drug safety

    Leizorovicz Alain

    2002-03-01

    Full Text Available Abstract Background The "integrated safety report" of the drug registration files submitted to health authorities usually summarizes the rates of adverse events observed for a new drug, placebo or active control drugs by pooling the safety data across the trials. Pooling consists of adding the numbers of events observed in a given treatment group across the trials and dividing the results by the total number of patients included in this group. Because it considers treatment groups rather than studies, pooling ignores validity of the comparisons and is subject to a particular kind of bias, termed "Simpson's paradox." In contrast, meta-analysis and other stratified analyses are less susceptible to bias. Methods We use a hypothetical, but not atypical, application to demonstrate that the results of a meta-analysis can differ greatly from those obtained by pooling the same data. In our hypothetical model, a new drug is compared to 1 a placebo in 4 relatively small trials in patients at high risk for a certain adverse event and 2 an active reference drug in 2 larger trials of patients at low risk for this event. Results Using meta-analysis, the relative risk of experiencing the adverse event with the new drug was 1.78 (95% confidence interval [1.02; 3.12] compared to placebo and 2.20 [0.76; 6.32] compared to active control. By pooling the data, the results were, respectively, 1.00 [0.59; 1.70] and 5.20 [2.07; 13.08]. Conclusions Because these findings could mislead health authorities and doctors, regulatory agencies should require meta-analyses or stratified analyses of safety data in drug registration files.

  10. Feasibility and safety of augmented reality-assisted urological surgery using smartglass.

    Borgmann, H; Rodríguez Socarrás, M; Salem, J; Tsaur, I; Gomez Rivas, J; Barret, E; Tortolero, L

    2017-06-01

    To assess the feasibility, safety and usefulness of augmented reality-assisted urological surgery using smartglass (SG). Seven urological surgeons (3 board urologists and 4 urology residents) performed augmented reality-assisted urological surgery using SG for 10 different types of operations and a total of 31 urological operations. Feasibility was assessed using technical metadata (number of photographs taken/number of videos recorded/video time recorded) and structured interviews with the urologists on their use of SG. Safety was evaluated by recording complications and grading according to the Clavien-Dindo classification. Usefulness of SG for urological surgery was queried in structured interviews and in a survey. The implementation of SG use during urological surgery was feasible with no intrinsic (technical defect) or extrinsic (inability to control the SG function) obstacles being observed. SG use was safe as no grade 3-5 complications occurred for the series of 31 urological surgeries of different complexities. Technical applications of SG included taking photographs/recording videos for teaching and documentation, hands-free teleconsultation, reviewing patients' medical records and images and searching the internet for health information. Overall usefulness of SG for urological surgery was rated as very high by 43 % and high by 29 % of surgeons. Augmented reality-assisted urological surgery using SG is both feasible and safe and also provides several useful functions for urological surgeons. Further developments and investigations are required in the near future to harvest the great potential of this exciting technology for urological surgery.

  11. Safety Improvements on Wood Chippers Currently in Use: A Study on Feasibility in the Italian Context

    Giorgia Bagagiolo

    2017-12-01

    Full Text Available Following formal opposition by France, the harmonized safety standards regarding manually-loaded wood chippers (EN 13525:2005+A2:2009 which presumed compliance with the Essential Health and Safety Requirements (EHSR required by the Machine Directive (Directive 2006/42/EC, have recently been withdrawn, and a new draft of the standard is currently under revision. In order to assess the potential impact of the expected future harmonized standards within the Italian context, this study has examined the main issues in implementing EHSRs on wood chippers already being used. Safety issues regarding wood chippers already in use were identified in an analysis of the draft standard, through the observation of a number of case studies, and qualitative analysis of the essential technical interventions. A number of agricultural and forestry operators and companies participated in the study, pointing out the technical and economic obstacle facing the safety features requested by the pending new standard. It emerged that the main safety issues concerned the implementation of the reverse function, the stop bar, and the protective devices, the infeed chute dimension, the emergency stop function, and the designated feeding area. The possibility of adopting such solutions mainly depends on technical feasibility and costs, but an important role is also played by the attitude towards safety and a lack of adequate information regarding safety obligations and procedures among users.

  12. Development and feasibility of the misuse, abuse, and diversion drug event reporting system (MADDERS®).

    Treister, Roi; Trudeau, Jeremiah J; Van Inwegen, Richard; Jones, Judith K; Katz, Nathaniel P

    2016-12-01

    Inappropriate use of analgesic drugs has become increasingly pervasive over the past decade. Currently, drug abuse potential is primarily assessed post-marketing; no validated tools are available to assess this potential in phase II and III clinical trials. This paper describes the development and feasibility testing of a Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS), which aims to identify potentially abuse-related events and classify them according to a recently developed classification scheme, allowing the quantification of these events in clinical trials. The system was initially conceived and designed with input from experts and patients, followed by field-testing to assess its feasibility and content validity in both completed and ongoing clinical trials. The results suggest that MADDERS is a feasible system with initial validity. It showed higher rates of the triggering events in subjects taking medications with known abuse potential than in patients taking medications without abuse potential. Additionally, experts agreed on the classification of most abuse-related events in MADDERS. MADDERS is a new systematic approach to collect information on potentially abuse-related events in clinical trials and classify them. The system has demonstrated feasibility for implementation. Additional research is ongoing to further evaluate its validity. Currently, there are no validated tools to assess drug abuse potential during clinical trials. Because of its ease of implementation, its systematic approach, and its preliminary validation results, MADDERS could provide such a tool for clinical trials. (Am J Addict 2016;25:641-651). © 2016 American Academy of Addiction Psychiatry.

  13. 78 FR 36711 - Food and Drug Administration Safety and Innovation Act Title VII-Drug Supply Chain; Standards for...

    2013-06-19

    ... inspections, and drive safety and quality throughout the supply chain. Implementation of these authorities... authorities granted to FDA under Title VII and their importance in ensuring drug safety, effectiveness, and.... FDA-2013-N-0683, FDA-2013-N-0684, and FDA-2013-N-0685] Food and Drug Administration Safety and...

  14. Global patient safety and antiretroviral drug-drug interactions in the resource-limited setting.

    Seden, Kay; Khoo, Saye H; Back, David; Byakika-Kibwika, Pauline; Lamorde, Mohammed; Ryan, Mairin; Merry, Concepta

    2013-01-01

    Scale-up of HIV treatment services may have contributed to an increase in functional health facilities available in resource-limited settings and an increase in patient use of facilities and retention in care. As more patients are reached with medicines, monitoring patient safety is increasingly important. Limited data from resource-limited settings suggest that medication error and antiretroviral drug-drug interactions may pose a significant risk to patient safety. Commonly cited causes of medication error in the developed world include the speed and complexity of the medication use cycle combined with inadequate systems and processes. In resource-limited settings, specific factors may contribute, such as inadequate human resources and high disease burden. Management of drug-drug interactions may be complicated by limited access to alternative medicines or laboratory monitoring. Improving patient safety by addressing the issue of antiretroviral drug-drug interactions has the potential not just to improve healthcare for individuals, but also to strengthen health systems and improve vital communication among healthcare providers and with regulatory agencies.

  15. The SHIELD (Safety & Health Improvement: Enhancing Law Enforcement Departments Study: Feasibility and Findings

    Kerry Stephen Kuehl

    2014-05-01

    Full Text Available This randomized prospective trial aimed to assess the feasibility and efficacy of a team-based worksite health and safety intervention for law enforcement personnel. Four-hundred and eight subjects were enrolled and half were randomized to meet participants met for weekly, peer-led sessions delivered from a scripted team-based health and safety curriculum. Curriculum addressed: exercise, nutrition, stress, sleep, body weight, injury, and other unhealthy lifestyle behaviours such as smoking and heavy alcohol use. Health and safety questionnaires administered before and after the intervention found significant improvements for increased fruit and vegetable consumption, overall healthy eating, increased sleep quantity and sleep quality, and reduced personal stress.

  16. Echocardiography-based hemodynamic management of left ventricular diastolic dysfunction: a feasibility and safety study.

    Shillcutt, Sasha K; Montzingo, Candice R; Agrawal, Ankit; Khaleel, Maseeha S; Therrien, Stacey L; Thomas, Walker R; Porter, Thomas R; Brakke, Tara R

    2014-11-01

    Patients with left ventricular diastolic dysfunction (LVDD) are at increased risk of postoperative adverse events. The primary aim of this study was to evaluate the safety and feasibility of using echocardiography-guided hemodynamic management (EGHEM) during surgery in subjects with LVDD compared to conventional management. The feasibility of using echocardiography to direct a treatment algorithm and clinical outcomes were compared for safety between groups. Subjects were screened for LVDD by preoperative transthoracic echocardiography (TTE) and randomized to the conventional or EGHEM group. Subjects in EGHEM received hemodynamic management based on left ventricular filling patterns on transesophageal echocardiography (TEE). Primary outcomes measured were the feasibility to obtain TEE images and follow a TEE-based treatment algorithm. Safety outcomes also compared the following clinical differences between groups: length of hospitalization, incidence of atrial fibrillation, congestive heart failure (CHF), myocardial infarction, cerebrovascular accident, transient ischemic attack and renal failure measured 30 days postoperatively. Population consisted of 28 surgical subjects (14 in conventional group and 14 in EGHEM group). Mean subject age was 73.4 ± 6.7 years (36% male) in conventional group and 65.9 ± 14.4 years (36% male) in EGHEM group. Procedures included orthopedic (conventional = 29%, EGHEM 36%), general (conventional = 50%, EGHEM = 36%), vascular (conventional = 7%, EGHEM = 21%), and thoracic (conventional = 14%, EGHEM = 7%). There was no statistically significant difference in adverse clinical events between the 2 groups. The EGHEM group had less CHF, atrial fibrillation, and shorter length of stay. Echocardiography-guided hemodynamic management of patients with LVDD during surgery is feasible and may be a safe alternative to conventional management. © 2014, Wiley Periodicals, Inc.

  17. Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy

    Jinsoo Lee

    2016-01-01

    Full Text Available Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p=0.0284, Fisher’s exact test. Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children.

  18. Practices, patients and (imperfect data - feasibility of a randomised controlled clinical drug trial in German general practices

    Hummers-Pradier Eva

    2011-04-01

    Full Text Available Abstract Background Randomised controlled clinical (drug trials supply high quality evidence for therapeutic strategies in primary care. Until now, experience with drug trials in German general practice has been sparse. In 2007/2008, the authors conducted an investigator-initiated, non-commercial, double-blind, randomised controlled pilot trial (HWI-01 to assess the clinical equivalence of ibuprofen and ciprofloxacin in the treatment of uncomplicated urinary tract infection (UTI. Here, we report the feasibility of this trial in German general practices and the implementation of Good Clinical Practice (GCP standards as defined by the International Conference on Harmonisation (ICH in mainly inexperienced general practices. Methods This report is based on the experience of the HWI-01 study conducted in 29 German general practices. Feasibility was defined by 1 successful practice recruitment, 2 sufficient patient recruitment, 3 complete and accurate data collection and 4 appropriate protection of patient safety. Results The final practice recruitment rate was 18%. In these practices, 79 of 195 screened UTI patients were enrolled. Recruitment differed strongly between practices (range 0-12, mean 2.8 patients per practice and was below the recruitment goal of approximately 100 patients. As anticipated, practice nurses became the key figures in the screening und recruitment of patients. Clinical trial demands, in particular for completing symptom questionnaires, documentation of source data and reporting of adverse events, did not agree well with GPs' documentation habits and required support from study nurses. In many cases, GPs and practice staff seemed to be overwhelmed by the amount of information and regulations. No sudden unexpected serious adverse reactions (SUSARs were observed during the trial. Conclusions To enable drug trials in general practice, it is necessary to adapt the setup of clinical research infrastructure to the needs of GPs and

  19. Feasibility and safety of general anesthesia for bronchial thermoplasty: a description of early 10 treatments.

    Aizawa, Mariko; Ishihara, Satoshi; Yokoyama, Takeshi; Katayama, Katsuyuki

    2018-03-20

    Bronchial thermoplasty (BT) is a recently introduced bronchoscopic treatment for patients with asthma refractory to pharmacotherapy. Intraprocedural sedation management is important for successful performance of BT. However, the results of general anesthesia in patients undergoing BT have not been well described. The aim of this study was to evaluate the feasibility and safety of general anesthesia in patients undergoing BT. We retrospectively reviewed the records of 10 consecutive BT treatments performed under general anesthesia in 4 patients. The feasibility outcomes were coughing and body movement during the procedure, procedure abandonment, and the relative frequency of thermal activation failure. The safety outcomes were bronchospasm and hypoxemia during the procedure, respiratory symptoms, and the need for oxygen after the procedure. Coughing occurred in two treatments. Neither body movement nor procedure abandonment occurred in any treatments. Neither intraprocedural bronchospasm nor hypoxemia occurred in any treatments. Respiratory symptoms occurred in 7 of 10 treatments within 1 day after the procedure and resolved within 4 days, which is comparable with a previous report. These results indicate that general anesthesia is feasible and safe for patients undergoing BT.

  20. A feasibility study for Arizona's roadway safety management process using the Highway Safety Manual and SafetyAnalyst : final report.

    2016-07-01

    To enable implementation of the American Association of State Highway Transportation (AASHTO) Highway Safety Manual using : SaftetyAnalyst (an AASHTOWare software product), the Arizona Department of Transportation (ADOT) studied the data assessment :...

  1. Feasibility and Safety of Pressurized Intraperitoneal Aerosol Chemotherapy for Peritoneal Carcinomatosis: A Retrospective Cohort Study

    Martin Hübner

    2017-01-01

    Full Text Available Background. Pressurized intraperitoneal aerosol chemotherapy (PIPAC has been introduced as a novel repeatable treatment for peritoneal carcinomatosis. The available evidence from the pioneer center suggests good tolerance and high response rates, but independent confirmation is needed. A single-center cohort was analyzed one year after implementation for feasibility and safety. Methods. PIPAC was started in January 2015, and every patient was entered into a prospective database. This retrospective analysis included all consecutive patients operated until April 2016 with emphasis on surgical feasibility and early postoperative outcomes. Results. Forty-two patients (M : F = 8 : 34, median age 66 (59–73 years with 91 PIPAC procedures in total (4×: 1,  3×: 17,  2×: 12, and  1×: 12 were analyzed. Abdominal accessibility rate was 95% (42/44; laparoscopic access was not feasible in 2 patients with previous HIPEC. Median initial peritoneal carcinomatosis index (PCI was 10 (IQR 5–17. Median operation time was 94 min (89–108 with no learning curve observed. One PIPAC application was postponed due to intraoperative intestinal lesion. Overall morbidity was 9% with 7 minor complications (Clavien I-II and one PIPAC-unrelated postoperative mortality. Median postoperative hospital stay was 3 days (2-3. Conclusion. Repetitive PIPAC is feasible in most patients with refractory carcinomatosis of various origins. Intraoperative complications and postoperative morbidity rates were low. This encourages prospective studies assessing oncological efficacy.

  2. Observational Pharmacoepidemiology in the Drug Safety and Effectiveness Evaluation

    José Cabrita

    2017-04-01

    Full Text Available Observational epidemiological studies have been used in the medicines context for more than 40 years, contributing to characterize drug use patterns and safety, efficacy and effectiveness profiles. Its use has been increased in recognition of the clinical trials limitations to assess the therapeutic and iatrogenic potential of the medicines after its commercialization. The evolution of the regulatory framework for pharmacovigilance, requiring post-marketing studies, post-authorization safety studies (PASS and the post-authorization efficacy studies (PAES to approve certain drugs, reinforced the importance of observational pharmacoepidemiology for the characterization of the medicines safety and effectiveness profiles. Pharmacoepidemiological research can be carried out from field studies designed to obtain the necessary information or in databases with health records of population samples that already contain the information. This 2nd option is more efficient and more and more frequent. Although, observational research from field studies continues to have its space, the increasing availability of databases allowed a new development to observational pharmacoepidemiology. Indeed, access to automated records databases with up-to-date information on medical prescriptions and global health care to representative population samples with long follow-up periods is a valuable tool for the study of drug use patterns and therapeutic and iatrogenic potential in routine clinical practice. In this context, observational pharmacoepidemiology reinforces its role as a scientific area particularly suitable for evaluating the safety and the effectiveness of the medicines in the “real world”, making a relevant contribution to overcome the gap in translating the evidence from the clinical trials for clinical practice.

  3. Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast.

    Miller, Jessica A; Thompson, Patricia A; Hakim, Iman A; Lopez, Ana Maria; Thomson, Cynthia A; Chew, Wade; Hsu, Chiu-Hsieh; Chow, H-H Sherry

    2012-10-01

    Limonene, a major component in citrus oil, has demonstrated anti-cancer effects in preclinical mammary cancer models. However, the effective oral dose translates to a human dose that may not be feasible for chronic dosing. We proposed to evaluate topical application of limonene to the breast as an alternative dosing strategy. We conducted a mouse disposition study to determine whether limonene would be bio available in the mammary tissue after topical application. SKH-1 mice received topical or oral administration of limonene in the form of orange oil every day for 4 weeks. Plasma and mammary pads were collected 4 hrs after the final dosing. We also conducted an exploratory clinical study to evaluate the safety and feasibility of topically applied limonene in the form of orange oil to the breast. Healthy women were recruited to apply orange oil containing massage oil to their breasts daily for four weeks. Safety and feasibility were assessed by reported adverse events, clinical labs, and usage compliance. Pre and post-intervention nipple aspirate fluid (NAF) and plasma were collected for limonene concentration determination. The mouse disposition study showed that topical and oral orange oil administration resulted in similar mammary tissue disposition of limonene with no clinical signs of toxicity. In the clinical study, the topical application of limonene containing massage oil to the breast was found to be safe with high levels of usage compliance for daily application, although NAF and plasma limonene concentrations were not significantly changed after the massage oil application. Our studies showed that limonene is bio available in mammary tissue after topical orange oil application in mice and this novel route of administration to the breast is safe and feasible in healthy women.

  4. 75 FR 23782 - Drug Safety and Risk Management Advisory Committee; Notice of Meeting

    2010-05-04

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0001] Drug Safety and Risk Management Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Drug Safety and Risk Management Advisory Committee. General Function of the Committee: To provide...

  5. Analyzing research trends on drug safety using topic modeling.

    Zou, Chen

    2018-04-06

    Published drug safety data has evolved in the past decade due to scientific and technological advances in the relevant research fields. Considering that a vast amount of scientific literature has been published in this area, it is not easy to identify the key information. Topic modeling has emerged as a powerful tool to extract meaningful information from a large volume of unstructured texts. Areas covered: We analyzed the titles and abstracts of 4347 articles in four journals dedicated to drug safety from 2007 to 2016. We applied Latent Dirichlet allocation (LDA) model to extract 50 main topics, and conducted trend analysis to explore the temporal popularity of these topics over years. Expert Opinion/Commentary: We found that 'benefit-risk assessment and communication', 'diabetes' and 'biologic therapy for autoimmune diseases' are the top 3 most published topics. The topics relevant to the use of electronic health records/observational data for safety surveillance are becoming increasingly popular over time. Meanwhile, there is a slight decrease in research on signal detection based on spontaneous reporting, although spontaneous reporting still plays an important role in benefit-risk assessment. The topics related to medical conditions and treatment showed highly dynamic patterns over time.

  6. 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.

    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.

  7. The Feasibility of Interventions to Reduce HIV Risk and Drug Use among Heterosexual Methamphetamine Users.

    Corsi, Karen F; Lehman, Wayne E; Min, Sung-Joon; Lance, Shannon P; Speer, Nicole; Booth, Robert E; Shoptaw, Steve

    2012-06-04

    This paper reports on a feasibility study that examined contingency management among out-of-treatment, heterosexual methamphetamine users and the reduction of drug use and HIV risk. Fifty-eight meth users were recruited through street outreach in Denver from November 2006 through March 2007. The low sample size reflects that this was a pilot study to see if CM is feasible in an out-of-treatment, street-recruited population of meth users. Secondary aims were to examine if reductions and drug use and risk behavior could be found. Subjects were randomly assigned to contingency management (CM) or CM plus strengths-based case management (CM/SBCM), with follow-up at 4 and 8 months. Participants were primarily White (90%), 52% male and averaged 38 years old. Eighty-three percent attended at least one CM session, with 29% attending at least fifteen. All participants reduced meth use significantly at follow-up. Those who attended more sessions submitted more stimulant-free urines than those who attended fewer sessions. Participants assigned to CM/SBCM attended more sessions and earned more vouchers than clients in CM. Similarly, participants reported reduced needle-sharing and sex risk. Findings demonstrate that CM and SBCM may help meth users reduce drug use and HIV risk.

  8. Incorporation of in silico biodegradability screening in early drug development--a feasible approach?

    Steger-Hartmann, Thomas; Länge, Reinhard; Heuck, Klaus

    2011-05-01

    The concentration of a pharmaceutical found in the environment is determined by the amount used by the patient, the excretion and metabolism pattern, and eventually by its persistence. Biological degradation or persistence of a pharmaceutical is experimentally tested rather late in the development of a pharmaceutical, often shortly before submission of the dossier to regulatory authorities. To investigate whether the aspect of persistence of a compound could be assessed early during drug development, we investigated whether biodegradation of pharmaceuticals could be predicted with the help of in silico tools. To assess the value of in silico prediction, we collected results for the OECD 301 degradation test ("ready biodegradability") of 42 drugs or drug synthesis intermediates and compared them to the prediction of the in silico tool BIOWIN. Of these compounds, 38 were predictable with BIOWIN, which is a module of the Estimation Programs Interface (EPI) Suite™ provided by the US EPA. The program failed to predict the two drugs which proved to be readily biodegradable in the degradation tests. On the other hand, BIOWIN predicted two compounds to be readily biodegradable which, however, proved to be persistent in the test setting. The comparison of experimental data with the predicted one resulted in a specificity of 94% and a sensitivity of 0%. The results of this study do not indicate that application of the biodegradation prediction tool BIOWIN is a feasible approach to assess the ready biodegradability during early drug development.

  9. Safety of diabetes drugs in patients with heart failure.

    Carrasco-Sánchez, F J; Ostos-Ruiz, A I; Soto-Martín, M

    2018-03-01

    Heart failure (HF) and diabetes mellitus are 2 clinical conditions that often coexist, particularly in patients older than 65 years. Diabetes mellitus promotes the development of HF and confers a poorer prognosis. Hypoglycaemic agents (either by their mechanism of action, hypoglycaemic action or adverse effects) can be potentially dangerous for patients with HF. In this study, we performed a review of the available evidence on the safety of diabetes drugs in HF, focused on the main observational and experimental studies. Recent studies on cardiovascular safety have evaluated, although as a secondary objective, the impact of new hypoglycaemic agents on HF, helping us understand the neutrality, risks and potential benefits of these agents. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  10. Feasibility study of applying the passive safety system concept to fusion–fission hybrid reactor

    Yu, Zhang-cheng; Xie, Heng

    2014-01-01

    The fusion–fission hybrid reactor can produce energy, breed nuclear fuel, and handle the nuclear waste, etc., with the fusion neutron source striking the subcritical blanket. The passive safety system consists of passive residual heat removal system, passive safety injection system and automatic depressurization system was adopted into the fusion–fission hybrid reactor in this paper. Modeling and nodalization of primary loop, partial secondary loop and passive core cooling system for the fusion–fission hybrid reactor using relap5 were conducted and small break LOCA on cold leg was analyzed. The results of key transient parameters indicated that the actuation of passive safety system could mitigate the accidental consequence of the 4-inch cold leg small break LOCA on cold leg in the early time effectively. It is feasible to apply the passive safety system concept to fusion–fission hybrid reactor. The minimum collapsed liquid level had great increase if doubling the volume of CMTs to increase its coolant injection and had no increase if doubling the volume of ACCs

  11. Technical feasibility and reliability of passive safety systems of AC600

    Niu, W.; Zeng, X.

    1996-01-01

    The first step conceptual design of the 600 MWe advanced PWR (AC-600) has been finished by the Nuclear Power Institute of China. Experiments on the passive system of AC-600 are being carried out, and are expected to be completed next year. The main research emphases of AC-600 conceptual design include the advanced core, the passive safety system and simplification. The design objective of AC-600 is that the safety, reliability, maintainability, operation cost and construction period are all improved upon compared to those of PWR plant. One of important means to achieve the objective is using a passive system, which has the following functions whenever its operation is required: providing the reactor core with enough coolant when others fail to make up the lost coolant; reactor residual heat removal; cooling and reducing pressure in the containment and preventing radioactive substances from being released into the environment after occurrence of accident (e.g. LOCA). The system should meet the single failure criterion, and keep operating when a single active component or passive component breaks down during the first 72 hour period after occurrence of accident, or in the long period following the 72 hour period. The passive safety system of AC-600 is composed of the primary safety injection system, the secondary emergency core residual heat removal system and the containment cooling system. The design of the system follows some relevant rules and criteria used by current PWR plant. The system has the ability to bear single failure, two complete separate subsystems are considered, each designed for 100% working capacity. Normal operation is separate from safety operation and avoids cross coupling and interference between systems, improves the reliability of components, and makes it easy to maintain, inspect and test the system. The paper discusses the technical feasibility and reliability of the passive safety system of AC-600, and some issues and test plans are also

  12. Technical feasibility and reliability of passive safety systems of AC600

    Niu, W; Zeng, X [Nuclear Power Inst. of China, Chendu (China)

    1996-12-01

    The first step conceptual design of the 600 MWe advanced PWR (AC-600) has been finished. Experiments on the passive system of AC-600 are being carried out, and are expected to be completed next year. The main research emphases of AC-600 conceptual design include the advanced core, the passive safety system and simplification. The design objective of AC-600 is that the safety, reliability, maintainability, operation cost and construction period are all improved upon compared to those of PWR plant. One of important means to achieve the objective is using a passive system, which has the following functions whenever its operation is required: providing the reactor core with enough coolant when others fail to make up the lost coolant; reactor residual heat removal; cooling and reducing pressure in the containment and preventing radioactive substances from being released into the environment after occurrence of accident (e.g. LOCA). The system should meet the single failure criterion, and keep operating when a single active component or passive component breaks down during the first 72 hour period after occurrence of accident, or in the long period following the 72 hour period. The passive safety system of AC-600 is composed of the primary safety injection system, the secondary emergency core residual heat removal system and the containment cooling system. The design of the system follows some relevant rules and criteria used by current PWR plant. The system has the ability to bear single failure, two complete separate subsystems are considered, each designed for 100% working capacity. Normal operation is separate from safety operation and avoids cross coupling and interference between systems, improves the reliability of components, and makes it easy to maintain, inspect and test the system. The paper discusses the technical feasibility and reliability of the passive safety system of AC-600, and some issues and test plans are also involved. (author). 3 figs, 1 tab.

  13. Feasibility study for the adoption of POSRV for KNGR safety depressurization system

    Kwon, Young Min; Lim, Hong Sik; Song, Jin Ho; Sim, Suk Ku; Park, Jong Kyun

    1999-03-01

    The Korean Next Generation Reactor (KNGR) adopted an advanced design feature of safety depressurization system(SDS) to rapidly de pressurize the reactor coolant system(RCS) in case of beyond design basis events of severe accidents, or a highly unlikely event of a total loss of feedwater (TLOFW) to both steam generators. Two design approaches were considered for the KNGR SDS design. The use of bleed valves similar to those of ABB-CE's system 80+ is design option 1, while in design option 2, the Power Operated Safety Relief valve (POSRV) is considered to provide the combined function of overpressure protection and rapid depressurization. The purpose of this report is to investigate the feasibility of adoption of French SebimPOSRVs for KNGR SDS (design option 2). This report provides the methodology to analyze the TLOFW event with Sebim valves and presents the results of thermal hydraulic analyses using a best-estimate version CEFLASH-4AS/REM for the TLOFW event with feed and bleed. The analyses were performed using a preliminary KNGR design data. For design option 2, if the operator opens two out of the three Sebim valves in conjunction with the four HPSI pumps before a hot leg saturation condition, the decay heat removal and core inventory make-up function can be successfully accomplished. The results of the present investigation demonstrate that the two design options are both feasible to mitigate the consequences of the TLOFW event with a sufficient margin. (Author). 22 refs., 3 tabs., 19 figs

  14. Patient Drug Safety Reporting: Diabetes Patients' Perceptions of Drug Safety and How to Improve Reporting of Adverse Events and Product Complaints.

    Patel, Puja; Spears, David; Eriksen, Betina Østergaard; Lollike, Karsten; Sacco, Michael

    2018-03-01

    Global health care manufacturer Novo Nordisk commissioned research regarding awareness of drug safety department activities and potential to increase patient feedback. Objectives were to examine patients' knowledge of pharmaceutical manufacturers' responsibilities and efforts regarding drug safety, their perceptions and experiences related to these efforts, and how these factors influence their thoughts and behaviors. Data were collected before and after respondents read a description of a drug safety department and its practices. We conducted quantitative survey research across 608 health care consumers receiving treatment for diabetes in the United States, Germany, United Kingdom, and Italy. This research validated initial, exploratory qualitative research (across 40 comparable consumers from the same countries) which served to guide design of the larger study. Before reading a drug safety department description, 55% of respondents were unaware these departments collect safety information on products and patients. After reading the description, 34% reported the department does more than they expected to ensure drug safety, and 56% reported "more confidence" in the industry as a whole. Further, 66% reported themselves more likely to report an adverse event or product complaint, and 60% reported that they were more likely to contact a drug safety department with questions. The most preferred communication methods were websites/online forums (39%), email (27%), and telephone (25%). Learning about drug safety departments elevates consumers' confidence in manufacturers' safety efforts and establishes potential for patients to engage in increased self-monitoring and reporting. Study results reveal potentially actionable insights for the industry across patient and physician programs and communications.

  15. Feasibility of Using Soccer and Job Training to Prevent Drug Abuse and HIV.

    Rotheram-Borus, Mary Jane; Tomlinson, Mark; Durkin, Andrew; Baird, Kelly; DeCelles, Jeff; Swendeman, Dallas

    2016-09-01

    Many young, South African men use alcohol and drugs and have multiple partners, but avoid health care settings-the primary site for delivery of HIV intervention activities. To identify the feasibility of engaging men in HIV testing and reducing substance use with soccer and vocational training programs. In two Cape Town neighborhoods, all unemployed men aged 18-25 years were recruited and randomized by neighborhood to: (1) an immediate intervention condition with access to a soccer program, random rapid diagnostic tests (RDT) for alcohol and drug use, and an opportunity to enter a vocational training program (n = 72); or (2) a delayed control condition (n = 70). Young men were assessed at baseline and 6 months later by an independent team. Almost all young men in the two neighborhoods participated (98 %); 85 % attended at least one practice (M = 42.3, SD = 34.4); 71 % typically attended practice. Access to job training was provided to the 35 young men with the most on-time arrivals at practice, drug-free RDT, and no red cards for violence. The percentage of young men agreeing to complete RDT at soccer increased significantly over time; RDTs with evidence of alcohol and drug use decreased over time. At the pre-post assessments, the frequency of substance use decreased; and employment and income increased in the immediate condition compared to the delayed condition. HIV testing rates, health care contacts, sexual behaviors, HIV knowledge, condom use and attitudes towards women were similar over time. Alternative engagement strategies are critical pathways to prevent HIV among young men. This feasibility study shows that soccer and job training offer such an alternative, and suggest that a more robust evaluation of this intervention strategy be pursued.

  16. Safety and feasibility of fasting in combination with platinum-based chemotherapy

    Dorff, Tanya B.; Groshen, Susan; Garcia, Agustin; Shah, Manali; Tsao-Wei, Denice; Pham, Huyen; Cheng, Chia-Wei; Brandhorst, Sebastian; Cohen, Pinchas; Wei, Min; Longo, Valter; Quinn, David I.

    2016-01-01

    Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients. 3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state. The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period. Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An onging randomized trial is studying the effect of 72 h of fasting. Clinicaltrials.gov: NCT00936364, registered propectively on July 9, 2009. The online version of this article (doi:10.1186/s12885-016-2370-6) contains supplementary material, which is available to authorized users

  17. Safety and feasibility of fasting in combination with platinum-based chemotherapy.

    Dorff, Tanya B; Groshen, Susan; Garcia, Agustin; Shah, Manali; Tsao-Wei, Denice; Pham, Huyen; Cheng, Chia-Wei; Brandhorst, Sebastian; Cohen, Pinchas; Wei, Min; Longo, Valter; Quinn, David I

    2016-06-10

    Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients. 3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state. The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period. Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An onging randomized trial is studying the effect of 72 h of fasting. NCT00936364 , registered propectively on July 9, 2009.

  18. Direct transcatheter aortic valve implantation with self-expandable bioprosthesis: Feasibility and safety

    Fiorina, Claudia, E-mail: clafiorina@yahoo.it [Cardiac Catheterization Laboratory, Cardiothoracic Department, Spedali Civili, Brescia (Italy); Maffeo, Diego; Curello, Salvatore [Cardiac Catheterization Laboratory, Cardiothoracic Department, Spedali Civili, Brescia (Italy); Lipartiti, Felicia [Division of Cardiology, Cardiothoracic Department, Spedali Civili, Brescia (Italy); Chizzola, Giuliano [Cardiac Catheterization Laboratory, Cardiothoracic Department, Spedali Civili, Brescia (Italy); D' Aloia, Antonio [Division of Cardiology, Cardiothoracic Department, Spedali Civili, Brescia (Italy); Adamo, Marianna [Cardiac Catheterization Laboratory, Cardiothoracic Department, Spedali Civili, Brescia (Italy); Mastropierro, Rosy [Division of Cardiothoracic Anestesiology, Cardiothoracic Department, Spedali Civili, Brescia (Italy); Gavazzi, Emanuele [Department of Radiology, University of Brescia, Spedali Civili, Brescia (Italy); Ciccarese, Camilla; Chiari, Ermanna [Division of Cardiology, Cardiothoracic Department, Spedali Civili, Brescia (Italy); Ettori, Federica [Cardiac Catheterization Laboratory, Cardiothoracic Department, Spedali Civili, Brescia (Italy)

    2014-06-15

    Background: Balloon valvuloplasty has been considered a mandatory step of the transcatheter aortic valve implantation (TAVI), although it is not without risk. The aim of this work was to evaluate the feasibility and safety of TAVI performed without pre-dilation (direct TAVI) of the stenosed aortic valve. Material and Methods: Between June 2012 and June 2013, 55 consecutive TAVI performed without pre-dilation at our institution using the self-expandable CoreValve prosthesis (Medtronic, Minneapolis, MN) were analyzed and compared with 45 pre-dilated TAVI performed the previous year. Inclusion criteria were a symptomatic and severe aortic stenosis. Exclusion criteria were defined as presence of pure aortic regurgitation, degenerated surgical bioprosthesis or bicuspid aortic valve and prior procedure of balloon aortic valvuloplasty performed as a bridge to TAVI. Results: High-burden calcification in the device landing zone, assessed by CT scan, was found in most of the patients. The valve size implanted was similar in both groups. Device success was higher in direct TAVI (85% vs. 64%, p = 0.014), mostly driven by a significant lower incidence of paravalvular leak (PVL ≥2; 9% vs. 33%, p = 0.02). Safety combined end point at 30 days was similar in both groups. Conclusion: Compared to TAVI with pre-dilation, direct TAVI is feasible regardless of the presence of bulky calcified aortic valve and the valve size implanted. Device success was higher in direct TAVI, mostly driven by a lower incidence of paravalvular leak. Safety at 30 days was similar in two groups.

  19. Safety and feasibility of platelet rich fibrin matrix injections for treatment of common urologic conditions

    Ethan L Matz

    2018-01-01

    Full Text Available Purpose: Autologous platelet rich plasma (PRP is used increasingly in a variety of settings. PRP injections have been used for decades to improve angiogenesis and wound healing. They have also been offered commercially in urology with little to no data on safety or efficacy. PRP could theoretically improve multiple urologic conditions, such as erectile dysfunction (ED, Peyronie's disease (PD, and stress urinary incontinence (SUI. A concern with PRP, however, is early washout, a situation potentially avoided by conversion to platelet rich fibrin matrix (PRFM. Before clinical trials can be performed, safety analysis is desirable. We reviewed an initial series of patients receiving PRFM for urologic pathology to assess safety and feasibility. Materials and Methods: Data were reviewed for patients treated with PRFM at our center from November 2012 to July 2017. Patients were observed immediately post-injection and at follow-up for complications and tolerability. Where applicable, International Index of Erectile Function (IIEF-5 scores were reviewed before and after injections for ED and/or PD. Pad use data was collected pre/post injection for SUI. Results: Seventeen patients were identified, with a mean receipt of 2.1 injections per patient. Post-procedural minor adverse events were seen in 3 men, consisting of mild pain at injection site and mild penile bruising. No patients experienced complications at follow-up. No decline was observed in men completing pre/post IIEF-5 evaluations. Conclusions: PRFM appears to be a safe and feasible treatment modality in patients with urologic disease. Further placebo-controlled trials are warranted.

  20. Feasibility and safety of virtual-reality-based early neurocognitive stimulation in critically ill patients.

    Turon, Marc; Fernandez-Gonzalo, Sol; Jodar, Mercè; Gomà, Gemma; Montanya, Jaume; Hernando, David; Bailón, Raquel; de Haro, Candelaria; Gomez-Simon, Victor; Lopez-Aguilar, Josefina; Magrans, Rudys; Martinez-Perez, Melcior; Oliva, Joan Carles; Blanch, Lluís

    2017-12-01

    Growing evidence suggests that critical illness often results in significant long-term neurocognitive impairments in one-third of survivors. Although these neurocognitive impairments are long-lasting and devastating for survivors, rehabilitation rarely occurs during or after critical illness. Our aim is to describe an early neurocognitive stimulation intervention based on virtual reality for patients who are critically ill and to present the results of a proof-of-concept study testing the feasibility, safety, and suitability of this intervention. Twenty critically ill adult patients undergoing or having undergone mechanical ventilation for ≥24 h received daily 20-min neurocognitive stimulation sessions when awake and alert during their ICU stay. The difficulty of the exercises included in the sessions progressively increased over successive sessions. Physiological data were recorded before, during, and after each session. Safety was assessed through heart rate, peripheral oxygen saturation, and respiratory rate. Heart rate variability analysis, an indirect measure of autonomic activity sensitive to cognitive demands, was used to assess the efficacy of the exercises in stimulating attention and working memory. Patients successfully completed the sessions on most days. No sessions were stopped early for safety concerns, and no adverse events occurred. Heart rate variability analysis showed that the exercises stimulated attention and working memory. Critically ill patients considered the sessions enjoyable and relaxing without being overly fatiguing. The results in this proof-of-concept study suggest that a virtual-reality-based neurocognitive intervention is feasible, safe, and tolerable, stimulating cognitive functions and satisfying critically ill patients. Future studies will evaluate the impact of interventions on neurocognitive outcomes. Trial registration Clinical trials.gov identifier: NCT02078206.

  1. Feasibility of mini-tablets as a flexible drug delivery tool.

    Mitra, Biplob; Chang, Jessica; Wu, Sy-Juen; Wolfe, Chad N; Ternik, Robert L; Gunter, Thomas Z; Victor, Michael C

    2017-06-15

    Mini-tablets have potential applications as a flexible drug delivery tool in addition to their generally perceived use as multi-particulates. That is, mini-tablets could provide flexibility in dose finding studies and/or allow for combination therapies in the clinic. Moreover, mini-tablets with well controlled quality attributes could be a prudent choice for administering solid dosage forms as a single unit or composite of multiple mini-tablets in patient populations with swallowing difficulties (e.g., pediatric and geriatric populations). This work demonstrated drug substance particle size and concentration ranges that achieve acceptable mini-tablet quality attributes for use as a single or composite dosage unit. Immediate release and orally disintegrating mini-tablet formulations with 30μm to 350μm (particle size d 90 ) acetaminophen and Compap™ L (90% acetaminophen) at concentrations equivalent to 6.7% and 26.7% acetaminophen were evaluated. Mini-tablets achieved acceptable weight variability, tensile strength, friability, and disintegration time at a reasonable solid fraction for each formulation. The content uniformity was acceptable for mini-tablets of 6.7% formulations with ≤170μm drug substance, mini-tablets of all 26.7% formulations, and composite dosage units containing five or more mini-tablets of any formulation. Results supported the manufacturing feasibility of quality mini-tablets, and their applicability as a flexible drug delivery tool. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. A Quantitative Feasibility Study on Potential Safety Improvement Effects of Advanced Safety Features in APR-1400 when Applied to OPR-1000

    Ualikhan Zhiyenbayev [KAIST, Daejeon (Korea, Republic of); Chung, Dae Wook [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

    2015-10-15

    This study aims to test the feasibility of the applications using Probabilistic Safety Assessment (PSA). Particularly, three of those advanced safety features are selected as follows: 1. Providing an additional Emergency Diesel Generator (EDG); 2. Increasing the capacity of Class 1E batteries; 3. Placing a Refueling Water Storage Tank (RWST) inside containment, i.e., change from RWST to IRWST. The Advanced Power Reactor 1400 (APR-1400) adopts several advanced safety features compared to its predecessor, the Optimized Power Reactor 1000 (OPR-1000), which includes an additional Emergency Diesel Generator, increase in battery capacity, in-containment refueling water storage tank (IRWST), and so on. Considering the remarkable advantages of these safety features in safety improvement and the design similarities between APR-1400 and OPR-1000, it is feasible to apply key advanced safety features of APR-1400 to OPR-1000 to enhance the safety. The selected safety features are incorporated into OPR-1000 PSA model using the Advanced Information Management System (AIMS) for PSA and CDFs are re-evaluated for each application and combination of three applications. Based on current results, it is concluded that three of key advanced safety features of APR-1400 can be effectively applied to OPR-1000, resulting in considerable safety improvement. In aggregate, three advanced safety features, which are an additional EDG, increased battery capacity and IRWST, can reduce the CDF of OPR-1000 by more than 15% when applied altogether.

  3. A Quantitative Feasibility Study on Potential Safety Improvement Effects of Advanced Safety Features in APR-1400 when Applied to OPR-1000

    Ualikhan Zhiyenbayev; Chung, Dae Wook

    2015-01-01

    This study aims to test the feasibility of the applications using Probabilistic Safety Assessment (PSA). Particularly, three of those advanced safety features are selected as follows: 1. Providing an additional Emergency Diesel Generator (EDG); 2. Increasing the capacity of Class 1E batteries; 3. Placing a Refueling Water Storage Tank (RWST) inside containment, i.e., change from RWST to IRWST. The Advanced Power Reactor 1400 (APR-1400) adopts several advanced safety features compared to its predecessor, the Optimized Power Reactor 1000 (OPR-1000), which includes an additional Emergency Diesel Generator, increase in battery capacity, in-containment refueling water storage tank (IRWST), and so on. Considering the remarkable advantages of these safety features in safety improvement and the design similarities between APR-1400 and OPR-1000, it is feasible to apply key advanced safety features of APR-1400 to OPR-1000 to enhance the safety. The selected safety features are incorporated into OPR-1000 PSA model using the Advanced Information Management System (AIMS) for PSA and CDFs are re-evaluated for each application and combination of three applications. Based on current results, it is concluded that three of key advanced safety features of APR-1400 can be effectively applied to OPR-1000, resulting in considerable safety improvement. In aggregate, three advanced safety features, which are an additional EDG, increased battery capacity and IRWST, can reduce the CDF of OPR-1000 by more than 15% when applied altogether

  4. Drug research methodology. Volume 5, Experimentation in drugs and highway safety : the study of drug effects on skills related to driving

    1980-06-01

    This report presents the findings of a workshop on experimental research in the area of drugs and highway safety. Complementing studies of drug use in different driving populations, experimentation here refers to studies performed under controlled co...

  5. Drug research methodology. Volume 4, Epidemiology in drugs and highway safety : the study of drug use among drivers and its role in traffic crashes

    1980-06-01

    This report presents the findings of a workshop on epidemiology in drugs and highway safety. A cross-disciplinary panel of experts (1) identified methodological issues and constraints present in research to define the nature and magnitude of the drug...

  6. The French underground research laboratory program, contribution to the feasibility and safety studies of geological disposal

    Hoorelbeke, J.M.; Niezborala, J.M.; Ben Slimane, K.

    2001-01-01

    The paper presents the content of the research program to be performed during the construction and the operation of the National Agency for Radioactive Waste Management's (ANDRA) underground laboratory, located in the east of France. The general architecture of the program is presented. Emphasis is put on an iterative process, the purpose of which is mainly to: Prepare site behavior models before starting each phase of the field work (bore hole drilling, shaft sinking, construction of underground galleries, specific experiments); Test and check each model through actual observations and measurements; Adjust the models to take into account the results of the former phase and predict the results expected during the following one. All these models, after validation, will be exploited during the assessment of the safety related performance of the components of the potential repository as well as the whole facility; Obtain necessary data related to the feasibility study of the disposal facility (mechanical design, thermal design, etc.,) and its safety assessment. The relationship between the experimental program, the conceptual design program and the safety evaluation program is explained in order to reach the project objectives which is the final document set to be provided to French authorities in 2006 according to the French law of December 1991. (author)

  7. Assuring consumer safety without animal testing: a feasibility case study for skin sensitisation.

    Maxwell, Gavin; Aleksic, Maja; Aptula, Aynur; Carmichael, Paul; Fentem, Julia; Gilmour, Nicola; Mackay, Cameron; Pease, Camilla; Pendlington, Ruth; Reynolds, Fiona; Scott, Daniel; Warner, Guy; Westmoreland, Carl

    2008-11-01

    Allergic Contact Dermatitis (ACD; chemical-induced skin sensitisation) represents a key consumer safety endpoint for the cosmetics industry. At present, animal tests (predominantly the mouse Local Lymph Node Assay) are used to generate skin sensitisation hazard data for use in consumer safety risk assessments. An animal testing ban on chemicals to be used in cosmetics will come into effect in the European Union (EU) from March 2009. This animal testing ban is also linked to an EU marketing ban on products containing any ingredients that have been subsequently tested in animals, from March 2009 or March 2013, depending on the toxicological endpoint of concern. Consequently, the testing of cosmetic ingredients in animals for their potential to induce skin sensitisation will be subject to an EU marketing ban, from March 2013 onwards. Our conceptual framework and strategy to deliver a non-animal approach to consumer safety risk assessment can be summarised as an evaluation of new technologies (e.g. 'omics', informatics), leading to the development of new non-animal (in silico and in vitro) predictive models for the generation and interpretation of new forms of hazard characterisation data, followed by the development of new risk assessment approaches to integrate these new forms of data and information in the context of human exposure. Following the principles of the conceptual framework, we have been investigating existing and developing new technologies, models and approaches, in order to explore the feasibility of delivering consumer safety risk assessment decisions in the absence of new animal data. We present here our progress in implementing this conceptual framework, with the skin sensitisation endpoint used as a case study. 2008 FRAME.

  8. Bladder tissue engineering using biocompatible nanofibrous electrospun constructs: feasibility and safety investigation.

    Shakhssalim, Nasser; Dehghan, Mohammad Mehdi; Moghadasali, Reza; Soltani, Mohammad Hossein; Shabani, Iman; Soleimani, Masoud

    2012-01-01

    To investigate the feasibility and safety of using biocompatible, nanofibrous electrospun polycaprolactone (PCL) and combination of polylactic acid (PLLA) and PCL mats in a canine model. Plasma-treated electrospun unseeded mats were implanted in three dogs. The first dog was sacrificed after 3 months and the second and third ones after 4 months, and then, the graft was examined macroscopically with subsequent morphological and histochemical evaluation. Both films showed high levels of cell infiltration and tissue formation, but body response to PLLA/PCL mat in comparison to PCL mat was very low. All three implantation models showed the same light microscopic morphology, immunohistochemistry, and scanning electron microscopy results; nevertheless, only the PCL/PLLA model showed favorable clinical results. Based on these data, nanofibrous PLLA/PCL scaffolding could be a suitable material for the bladder tissue engineering; however, it deserves further investigations.

  9. Novel Percutaneous Radiofrequency Ablation of Portal Vein Tumor Thrombus: Safety and Feasibility

    Mizandari, Malkhaz [High Technology Medical Center, Tbilisi State Medical University (Georgia); Ao, Guokun [The 309 Hospital of People' s Liberation Army, Department on Oncology (China); Zhang Yaojun; Feng Xi [Imperial College London, Department of Surgery and Cancer (United Kingdom); Shen Qiang [The First Minimally Invasive Department of Eastern Hepatobiliary Surgery Hospital (China); Chen Minshan [Cancer Centre of Sun Yat-Sen University, Department of Hepatobiliary Surgery (China); Lau, Wan Yee [Chinese University of Hong Kong, Department of Surgery, Faculty of Medicine (Hong Kong); Nicholls, Joanna; Jiao Long; Habib, Nagy, E-mail: nagy.habib@imperial.ac.uk [Imperial College London, Department of Surgery and Cancer (United Kingdom)

    2013-02-15

    We report our experience of the safety of partial recanalization of the portal vein using a novel endovascular radiofrequency (RF) catheter for portal vein tumor thrombosis. Six patients with liver cancer and tumor thrombus in the portal vein underwent percutaneous intravascular radiofrequency ablation (RFA) using an endovascular bipolar RF device. A 0.035-inch guidewire was introduced into a tributary of the portal vein and through which a 5G guide catheter was introduced into the main portal vein. After manipulation of the guide catheter over the thrombus under digital subtraction angiography, the endovascular RF device was inserted and activated around the thrombus. There were no observed technique specific complications, such as hemorrhage, vessel perforation, or infection. Post-RFA portography showed partial recanalization of portal vein. RFA of portal vein tumor thrombus in patients with hepatocellular carcinoma is technically feasible and warrants further investigation to assess efficacy compared with current recanalization techniques.

  10. Feasibility and safety of fiber optic micro-imaging in canine peripheral airways.

    Yijun Liu

    Full Text Available PURPOSE: To assess the feasibility and safety of imaging canine peripheral airways (0.05. Comparing pre-manipulation and post-manipulation values, SpO2 (F = 13.06, P<0.05 and PaO2 (F = 3.01, P = 0.01 were decreased, whereas RR (F = 3.85, P<0.05 was elevated during the manipulation. (3 Self-limited bleeding was observed in one dog; severe bleeding or other complications did not occur. CONCLUSION: Although the new apparatus had little effect on SpO2, PaO2 and RR, it can probe into small peripheral airways (<1 mm, which may provide a new platform for the early diagnosis of bronchiolar diseases.

  11. Feasibility and safety of prehospital administration of bivalirudin in patients with ST-elevation myocardial infarction

    Sejersten, Maria; Nielsen, Søren Loumann; Engstrøm, Thomas

    2009-01-01

    undergoing angiography with no difference between groups. Bivalirudin was easy to administer in the prehospital setting and did not affect the prehospital run times. In conclusion, the results suggest that prehospital bivalirudin administration is as safe and effective as heparin in the treatment of patients...... of this preliminary study was to describe the feasibility and safety of a switch from prehospital administration of unfractionated heparin to bivalirudin in ST-elevation acute myocardial infarction (STEMI) patients referred for primary percutaneous coronary intervention. Patients with STEMI treated with a 1-mg...... patients (59%) receiving bivalirudin and 72 receiving heparin were followed during hospitalization. The baseline characteristics and prehospital treatment times were comparable between the 2 groups. The thrombolysis in myocardial infarction flow before and after primary percutaneous coronary intervention...

  12. Addressing conflicts of interest in nanotechnology oversight: lessons learned from drug and pesticide safety testing

    Elliott, Kevin C., E-mail: ke@sc.edu [University of South Carolina, Department of Philosophy, USC NanoCenter (United States); Volz, David C. [University of South Carolina, Department of Environmental Health Sciences, Arnold School of Public Health (United States)

    2012-01-15

    Financial conflicts of interest raise significant challenges for those working to develop an effective, transparent, and trustworthy oversight system for assessing and managing the potential human health and ecological hazards of nanotechnology. A recent paper in this journal by Ramachandran et al., J Nanopart Res, 13:1345-1371 (2011) proposed a two-pronged approach for addressing conflicts of interest: (1) developing standardized protocols and procedures to guide safety testing; and (2) vetting safety data under a coordinating agency. Based on past experiences with standardized test guidelines developed by the international Organization for Economic Cooperation and Development (OECD) and implemented by national regulatory agencies such as the U.S. Environmental Protection Agency (EPA) and Food and Drug Administration (FDA), we argue that this approach still runs the risk of allowing conflicts of interest to influence toxicity tests, and it has the potential to commit regulatory agencies to outdated procedures. We suggest an alternative approach that further distances the design and interpretation of safety studies from those funding the research. In case the two-pronged approach is regarded as a more politically feasible solution, we also suggest three lessons for implementing this strategy in a more dynamic and effective manner.

  13. Addressing conflicts of interest in nanotechnology oversight: lessons learned from drug and pesticide safety testing

    Elliott, Kevin C.; Volz, David C.

    2012-01-01

    Financial conflicts of interest raise significant challenges for those working to develop an effective, transparent, and trustworthy oversight system for assessing and managing the potential human health and ecological hazards of nanotechnology. A recent paper in this journal by Ramachandran et al., J Nanopart Res, 13:1345–1371 (2011) proposed a two-pronged approach for addressing conflicts of interest: (1) developing standardized protocols and procedures to guide safety testing; and (2) vetting safety data under a coordinating agency. Based on past experiences with standardized test guidelines developed by the international Organization for Economic Cooperation and Development (OECD) and implemented by national regulatory agencies such as the U.S. Environmental Protection Agency (EPA) and Food and Drug Administration (FDA), we argue that this approach still runs the risk of allowing conflicts of interest to influence toxicity tests, and it has the potential to commit regulatory agencies to outdated procedures. We suggest an alternative approach that further distances the design and interpretation of safety studies from those funding the research. In case the two-pronged approach is regarded as a more politically feasible solution, we also suggest three lessons for implementing this strategy in a more dynamic and effective manner.

  14. Addressing conflicts of interest in nanotechnology oversight: lessons learned from drug and pesticide safety testing

    Elliott, Kevin C.; Volz, David C.

    2012-01-01

    Financial conflicts of interest raise significant challenges for those working to develop an effective, transparent, and trustworthy oversight system for assessing and managing the potential human health and ecological hazards of nanotechnology. A recent paper in this journal by Ramachandran et al., J Nanopart Res, 13:1345-1371 (2011) proposed a two-pronged approach for addressing conflicts of interest: (1) developing standardized protocols and procedures to guide safety testing; and (2) vetting safety data under a coordinating agency. Based on past experiences with standardized test guidelines developed by the international Organization for Economic Cooperation and Development (OECD) and implemented by national regulatory agencies such as the U.S. Environmental Protection Agency (EPA) and Food and Drug Administration (FDA), we argue that this approach still runs the risk of allowing conflicts of interest to influence toxicity tests, and it has the potential to commit regulatory agencies to outdated procedures. We suggest an alternative approach that further distances the design and interpretation of safety studies from those funding the research. In case the two-pronged approach is regarded as a more politically feasible solution, we also suggest three lessons for implementing this strategy in a more dynamic and effective manner.

  15. Safety and feasibility of inpatient exercise training in pediatric heart failure: a preliminary report.

    McBride, Michael G; Binder, Tracy Jo; Paridon, Stephen M

    2007-01-01

    To determine the safety and feasibility of an inpatient exercise training program for a group of pediatric heart transplantation candidates on multiple inotropic support. Children with end-stage heart disease often require heart transplantation. Currently, no data exist on the safety and feasibility of an inpatient exercise training program in pediatric patients awaiting heart transplantation while on inotropic support. Twenty ambulatory patients (11 male; age, 13.6 +/- 3.2 years) were admitted, listed, and subsequently enrolled into an exercise training program while awaiting heart transplantation. Patient diagnoses consisted of dilated cardiomyopathy (n = 15), restrictive cardiomyopathy (n = 1), and failing single-ventricle physiology (n = 4). Inotropic support consisted of a combination of dobutamine, dopamine, or milrinone. Exercise sessions were scheduled three times a week lasting from 30 to 60 minutes and consisted of aerobic and musculoskeletal conditioning. Over 6.2 +/- 4.2 months, 1,251 of a possible 1,508 exercise training sessions were conducted, with a total of 615 hours (26.3 +/- 2.7 min/session) dedicated to low-intensity aerobic exercise. Reasons for noncompliance included a change in medical status, staffing, or patient cooperation. Two adverse episodes (seizures) occurred, neither of which resulted in termination from the program. No adverse episodes of hypotension or significant complex arrhythmias occurred. No complication of medication administration or loss of intravenous access occurred. Data from this study indicate that pediatric patients on inotropic support as a result of systemic ventricular or biventricular heart failure can safely participate in exercise training programs with relatively moderate to high compliance.

  16. Cervical cancer screening: Safety, acceptability, and feasibility of a single-visit approach in Bulawayo, Zimbabwe.

    Fallala, Muriel S; Mash, Robert

    2015-05-05

    Cervical cancer is the commonest cancer amongst African women, and yet preventative services are often inadequate. The purpose of the study was to assess the safety, acceptability and feasibility of visual inspection with acetic acid and cervicography (VIAC) followed by cryotherapy or a loop electrical excision procedure (LEEP) at a single visit for prevention of cancer of the cervix. The United Bulawayo Hospital, Zimbabwe. The study was descriptive, using retrospective data extracted from electronic medical records of women attending the VIAC clinic. Over 24 months 4641 women visited the clinic and were screened for cervical cancer using VIAC. Cryotherapy or LEEP was offered immediately to those that screened positive. Treated women were followed up at three months and one year. The rate of positive results on VIAC testing was 10.8%. Of those who were eligible, 17.0% received immediate cryotherapy, 44.1% received immediate LEEP, 1.9% delayed treatment, and 37.0% were referred to a gynaecologist. No major complications were recorded after cryotherapy or LEEP. Amongst those treated 99.5% expressed satisfaction with their experience. Only 3.2% of those treated at the clinic had a positive result on VIAC one year later. The service was shown to be feasible to sustain over time with the necessary consumables. There were no service-related treatment postponements and the clinic staff and facility were able to meet the demand for the service. A single-visit approach using VIAC, followed by cryotherapy or LEEP, proved to be safe, acceptable and feasible in an urban African setting in Bulawayo, Zimbabwe. Outcomes a year later suggested that treatment had been effective.

  17. Safety and Feasibility of Transradial Access for Visceral Interventions in Patients with Thrombocytopenia.

    Titano, J J; Biederman, D M; Marinelli, B S; Patel, R S; Kim, E; Tabori, N E; Nowakowski, F S; Lookstein, R A; Fischman, A M

    2016-05-01

    Transradial access (TRA) has shown lower morbidity and decreased bleeding complications compared to transfemoral access. This study evaluates the safety and feasibility of TRA in thrombocytopenic patients undergoing visceral interventions. Patients who underwent visceral interventions via the radial artery with platelet count less than or equal to 50,000/µL were included in the study. Outcome variables included technical success, access site, bleeding, transfusion, and neurological complications. From July 1, 2012, to May 31, 2015, a total of 1353 peripheral interventions via TRA were performed, of which 85 procedures were performed in 64 patients (mean age 62.2 years) with a platelet count <50,000/µL (median 39,000/µL). Interventions included chemoembolization (n = 46), selective internal radiation therapy (n = 30), and visceral embolization (n = 9). Technical success was 97.6% with two cases of severe vessel spasm requiring ipsilateral femoral crossover. There was no major access site, bleeding, or neurological adverse events at 30 days. Minor access site hematomas occurred in five cases (5.9%) and were treated conservatively in all cases. Pre-procedural platelet transfusions were administered in 23 (27.1%) cases. There was no statistically significant difference in access site or bleeding complications between the transfused and nontransfused groups. Transradial visceral interventions in patients with thrombocytopenia are both feasible and safe, possibly without the need for platelet transfusions.

  18. Feasibility study of silica sol as the carrier of a hydrophobic drug in aqueous solution using enrofloxacin as the model

    Song Meirong; Song Junling; Ning Aimin; Cui Baoan; Cui Shumin; Zhou Yaobing; An Wankai; Dong Xuesong; Zhang Gege

    2010-01-01

    The aim of this study was to determine the feasibility of using silica sol to carry a hydrophobic drug in aqueous solution. Enrofloxacin, which was selected as the model drug because it is a broad-spectrum antibiotic drug with poor solubility in water, was adsorbed onto silica sol in aqueous solution during cooling from 60 deg. C to room temperature. The drug-loaded silica sol was characterized by transmission electron microscopy, Fourier transform infrared spectrum, thermal gravimetric analysis and ultraviolet-visible light spectroscopy. The results showed that enrofloxacin was adsorbed by silica sol without degradation at a loading of 15.23 wt.%. In contrast to the rapid release from pure enrofloxacin, the drug-loaded silica sol showed a slower release over a longer time. Kinetics analysis suggested the drug release from silica sol was mainly a diffusion-controlled process. Therefore, silica sol can be used to carry a hydrophobic drug in aqueous solution for controlled drug delivery.

  19. Epigenetics and cancer: implications for drug discovery and safety assessment

    Moggs, Jonathan G.; Goodman, Jay I.; Trosko, James E.; Roberts, Ruth A.

    2004-01-01

    It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can be altered markedly via several diverse epigenetic mechanisms that can lead to permanent or reversible changes in cellular behavior. Key molecular events underlying these mechanisms include the alteration of DNA methylation and chromatin, and changes in the function of cell surface molecules. Thus, for example, DNA methyltransferase enzymes together with chromatin-associated proteins such as histone modifying enzymes and remodelling factors can modify the genetic code and contribute to the establishment and maintenance of altered epigenetic states. This is relevant to many types of toxicity including but not limited to cancer. In this paper, we describe the potential for interplay between genetic alteration and epigenetic changes in cell growth regulation and discuss the implications for drug discovery and safety assessment

  20. Nonsteroidal anti-inflammatory drug gastropathy: new avenues for safety

    Roth SH

    2011-05-01

    Full Text Available Sanford H RothArizona Research and Education, Arthritis Laboratory, Arizona State University, Phoenix, AZ, USAAbstract: Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less frequent. These complications can be life-threatening in at-risk populations such as older adults, who are common users of long-term oral systemic NSAID therapy. Topical NSAID formulations deliver effective doses of analgesics directly to the affected joints, thereby limiting systemic exposure and potentially the risk of systemic adverse events, such as gastropathy and serious cardiovascular events. There are currently two topical NSAIDs approved by the US Food and Drug Administration for osteoarthritis-associated pain, as well as for the signs and symptoms of osteoarthritis. This review discusses the relative safety, and the gastrointestinal, cardiovascular, and renal risks of chronic oral or systemic NSAID therapy and topical NSAID formulations in patients with osteoarthritis.Keywords: NSAIDs, osteoarthritis, topical administration, synovial fluid, peptic ulcer, Helicobacter pylori

  1. Nonsteroidal anti-inflammatory drug gastropathy: new avenues for safety.

    Roth, Sanford H

    2011-01-01

    Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID) therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less frequent. These complications can be life-threatening in at-risk populations such as older adults, who are common users of long-term oral systemic NSAID therapy. Topical NSAID formulations deliver effective doses of analgesics directly to the affected joints, thereby limiting systemic exposure and potentially the risk of systemic adverse events, such as gastropathy and serious cardiovascular events. There are currently two topical NSAIDs approved by the US Food and Drug Administration for osteoarthritis-associated pain, as well as for the signs and symptoms of osteoarthritis. This review discusses the relative safety, and the gastrointestinal, cardiovascular, and renal risks of chronic oral or systemic NSAID therapy and topical NSAID formulations in patients with osteoarthritis.

  2. A primer of drug safety surveillance: an industry perspective. Part I: Information flow, new drug development, and federal regulations.

    Allan, M C

    1992-01-01

    To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part I of this series provides a background for the discussion of drug safety by defining the basic terms and showing the flow of safety information through a pharmaceutical company. The customers for adverse drug event data are identified to provide a basis for providing quality service. The development of a drug product is briefly reviewed to show the evolution of safety data. Drug development and safety are defined by federal regulations. These regulations are developed by the FDA with information from pharmaceutical manufacturers. The intent of the regulations and the accompanying guidelines is described. An illustration from the news media is cited to show an alternative, positive approach to handling an adverse event report. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are presented in an appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction ;of the components

  3. Safety and feasibility of transcranial direct current stimulation in pediatric hemiparesis: randomized controlled preliminary study.

    Gillick, Bernadette T; Feyma, Tim; Menk, Jeremiah; Usset, Michelle; Vaith, Amy; Wood, Teddi Jean; Worthington, Rebecca; Krach, Linda E

    2015-03-01

    Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation that has shown improved adult stroke outcomes. Applying tDCS in children with congenital hemiparesis has not yet been explored. The primary objective of this study was to explore the safety and feasibility of single-session tDCS through an adverse events profile and symptom assessment within a double-blind, randomized placebo-controlled preliminary study in children with congenital hemiparesis. A secondary objective was to assess the stability of hand and cognitive function. A double-blind, randomized placebo-controlled pretest/posttest/follow-up study was conducted. The study was conducted in a university pediatric research laboratory. Thirteen children, ages 7 to 18 years, with congenital hemiparesis participated. Adverse events/safety assessment and hand function were measured. Participants were randomly assigned to either an intervention group or a control group, with safety and functional assessments at pretest, at posttest on the same day, and at a 1-week follow-up session. An intervention of 10 minutes of 0.7 mA tDCS was applied to bilateral primary motor cortices. The tDCS intervention was considered safe if there was no individual decline of 25% or group decline of 2 standard deviations for motor evoked potentials (MEPs) and behavioral data and no report of adverse events. No major adverse events were found, including no seizures. Two participants did not complete the study due to lack of MEP and discomfort. For the 11 participants who completed the study, group differences in MEPs and behavioral data did not exceed 2 standard deviations in those who received the tDCS (n=5) and those in the control group (n=6). The study was completed without the need for stopping per medical monitor and biostatisticial analysis. A limitation of the study was the small sample size, with data available for 11 participants. Based on the results of this study, tDCS appears to be safe

  4. Safety and feasibility of pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic chemotherapy: an innovative approach to treat peritoneal carcinomatosis.

    Robella, Manuela; Vaira, Marco; De Simone, Michele

    2016-04-29

    Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new treatment that applies chemotherapeutic drugs into the peritoneal cavity as an aerosol under pressure. It improves local bioavailability of chemotherapeutic drugs as compared with conventional intraperitoneal chemotherapy. It has been proved to be safe and feasible if performed as an exclusive treatment in patients affected by peritoneal carcinomatosis. The first results in patients treated with PIPAC associated with systemic chemotherapy are presented. Between June 2015 and February 2016, 57 PIPAC applications with oxaliplatin or cisplatin + doxorubicin every 6 weeks at 37 °C and 12 mmHg for 30 min were performed. Forty PIPAC procedures performed in 14 patients were included in this study; thirteen patients were undergoing systemic chemotherapy with a wash-out interval of at least 2 weeks before and 1 week after each PIPAC. Safety, tolerability, and postoperative complications were assessed by collection of adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) 2. Forty PIPAC administrations were performed in 14 patients with no major perioperative complications. CTCAE grades 1 and 2 were observed after six and eight procedures, respectively, for abdominal pain and nausea. Renal and hepatic functions were not impaired; no cumulative renal toxicity was observed after repeated PIPAC procedures in association with systemic chemotherapy. These preliminary data show that the association of PIPAC and systemic chemotherapy does not induce significant hepatic and renal toxicity. It allows inclusion of patients with extraperitoneal disease or at a high risk of developing it. Further studies are needed to assess whether this combination therapy could become part of the standard treatment for peritoneal carcinomatosis.

  5. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay.

    Alley, M C; Scudiero, D A; Monks, A; Hursey, M L; Czerwinski, M J; Fine, D L; Abbott, B J; Mayo, J G; Shoemaker, R H; Boyd, M R

    1988-02-01

    For the past 30 years strategies for the preclinical discovery and development of potential anticancer agents have been based largely upon the testing of agents in mice bearing transplantable leukemias and solid tumors derived from a limited number of murine as well as human sources. The feasibility of implementing an alternate approach, namely combined in vitro/in vivo screening for selective cytotoxicity among panels of human tumor cell lines derived from a broad spectrum of human solid tumors is under investigation. A group of 30 cell lines acquired from a variety of sources and representing 8 lung cancer pathologies as well as 76 cell lines representing 10 other categories of human cancer (carcinomas of colon, breast, kidney, prostate, ovary, head and neck; glioma; leukemia; melanoma; and sarcoma) have exhibited acceptable growth characteristics and suitable colorimetric profiles in a single, standard culture medium. Measurements of in vitro growth in microculture wells by cell-mediated reduction of tetrazolium showed excellent correlation (0.89 less than r2 less than 0.98) with measurements of cellular protein in adherent cell line cultures as well as viable cell count in suspension cell line cultures (0.94 less than r2 less than 0.99). Since the microculture tetrazolium assay provides sensitive and reproducible indices of growth as well as drug sensitivity in individual cell lines over the course of multiple passages and several months' cultivation, it appears suitable for initial-stage in vitro drug screening.

  6. Feasibility evaluation of 3 automated cellular drug screening assays on a robotic workstation.

    Soikkeli, Anne; Sempio, Cristina; Kaukonen, Ann Marie; Urtti, Arto; Hirvonen, Jouni; Yliperttula, Marjo

    2010-01-01

    This study presents the implementation and optimization of 3 cell-based assays on a TECAN Genesis workstation-the Caspase-Glo 3/7 and sulforhodamine B (SRB) screening assays and the mechanistic Caco-2 permeability protocol-and evaluates their feasibility for automation. During implementation, the dispensing speed to add drug solutions and fixative trichloroacetic acid and the aspiration speed to remove the supernatant immediately after fixation were optimized. Decontamination steps for cleaning the tips and pipetting tubing were also added. The automated Caspase-Glo 3/7 screen was successfully optimized with Caco-2 cells (Z' 0.7, signal-to-base ratio [S/B] 1.7) but not with DU-145 cells. In contrast, the automated SRB screen was successfully optimized with the DU-145 cells (Z' 0.8, S/B 2.4) but not with the Caco-2 cells (Z' -0.8, S/B 1.4). The automated bidirectional Caco-2 permeability experiments separated successfully low- and high-permeability compounds (Z' 0.8, S/B 84.2) and passive drug permeation from efflux-mediated transport (Z' 0.5, S/B 8.6). Of the assays, the homogeneous Caspase-Glo 3/7 assay benefits the most from automation, but also the heterogeneous SRB assay and Caco-2 permeability experiments gain advantages from automation.

  7. Regulatory aspects of oncology drug safety evaluation: Past practice, current issues, and the challenge of new drugs

    Rosenfeldt, Hans; Kropp, Timothy; Benson, Kimberly; Ricci, M. Stacey; McGuinn, W. David; Verbois, S. Leigh

    2010-01-01

    The drug development of new anti-cancer agents is streamlined in response to the urgency of bringing effective drugs to market for patients with limited life expectancy. FDA's regulation of oncology drugs has evolved from the practices set forth in Arnold Lehman's seminal work published in the 1950s through the current drafting of a new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) safety guidance for anti-cancer drug nonclinical evaluations. The ICH combines the efforts of the regulatory authorities of Europe, Japan, and the United States and the pharmaceutical industry from these three regions to streamline the scientific and technical aspects of drug development. The recent development of new oncology drug classes with novel mechanisms of action has improved survival rates for some cancers but also brings new challenges for safety evaluation. Here we present the legacy of Lehman and colleagues in the context of past and present oncology drug development practices and focus on some of the current issues at the center of an evolving harmonization process that will generate a new safety guidance for oncology drugs, ICH S9. The purpose of this new guidance will be to facilitate oncology drug development on a global scale by standardizing regional safety requirements.

  8. Surgical procedures performed in the neonatal intensive care unit on critically ill neonates: feasibility and safety

    Mallick, M.S.; Jado, A.M.; Al-Bassam, A.R.

    2008-01-01

    Transferring unstable, ill neonates to and from the operating rooms carries significant risks and can lead to morbidity. We report on our experience in performing certain procedures in critically ill neonates in the neonatal intensive care unit (NICU). We examined the feasibility and safety for such an approach. All surgical procedures performed in the NICU between January 1999 and December 2005 were analyzed in terms of demographic data, diagnosis, preoperative stability of the patient, procedures performed, complications and outcome. Operations were performed at beside in the NICU in critically ill, unstable neonates who needed emergency surgery, in neonates of low birth weight (<1000 gm) and in neonates on special equipments like higher frequency ventilators and nitrous oxide. Thirty-seven surgical procedures were performed including 12 laparotomies, bowel resection and stomies, 7 repairs of congenital diaphragmatic hernias, 4 ligations of patent ductus arteriosus and various others. Birth weights ranged between 850 gm and 3500 gm (mean 2000 gm). Gestational age ranged between 25 to 42 weeks (mean, 33 weeks). Age at surgery was between 1 to 30 days (mean, 30 days). Preoperatively, 19 patients (51.3%) were on inotropic support and all were intubated and mechanically ventilated. There was no mortality related to surgical procedures. Postoperatively, one patient developed wound infection and disruption. Performing major surgical procedures in the NICU is both feasible and safe. It is useful in very low birth weight, critically ill neonates who have definite risk attached to transfer to the operating room. No special area is needed in the NICU to perform complication-free surgery, but designing an operating room within the NICU will be ideal. (author)

  9. TIA triage in emergency department using acute MRI (TIA-TEAM): a feasibility and safety study.

    Vora, Nirali; Tung, Christie E; Mlynash, Michael; Garcia, Madelleine; Kemp, Stephanie; Kleinman, Jonathan; Zaharchuk, Greg; Albers, Gregory; Olivot, Jean-Marc

    2015-04-01

    Positive diffusion weighted imaging (DWI) on MRI is associated with increased recurrent stroke risk in TIA patients. Acute MRI aids in TIA risk stratification and diagnosis. To evaluate the feasibility and safety of TIA triage directly from the emergency department (ED) with acute MRI and neurological consultation. Consecutive ED TIA patients assessed by a neurologist underwent acute MRI/MRA of head/neck per protocol and were hospitalized if positive DWI, symptomatic vessel stenosis, or per clinical judgment. Stroke neurologist adjudicated the final TIA diagnosis as definite, possible, or not a cerebrovascular event. Stroke recurrence rates were calculated at 7, 90, 365 days and compared with predicted stroke rates derived from historical DWI and ABCD(2) score data. One hundred twenty-nine enrolled patients had a mean age of 69 years (± 17) and median ABCD(2) score of 3 (interquartile range [IQR] 3-4). During triage, 112 (87%) patients underwent acute MRI after a median of 16 h (IQR 10-23) from symptom onset. No patients experienced a recurrent event before imaging. Twenty-four (21%) had positive DWI and 8 (7%) had symptomatic vessel stenosis. Of the total cohort, 83 (64%) were discharged and 46 (36%) were hospitalized. By one-year follow-up, one patient in each group had experienced a stroke. Of 92 patients with MRI and index cerebrovascular event, recurrent stroke rates were 1.1% at 7 and 90 days. These were similar to predicted recurrence rates. TIA triage in the ED using a protocol with neurological consultation and acute MRI is feasible and safe. The majority of patients were discharged without hospitalization and rates of recurrent stroke were not higher than predicted. © 2014 World Stroke Organization.

  10. Feasibility and safety of GliaSite brachytherapy in treatment of CNS tumors following neurosurgical resection

    Wernicke A

    2010-01-01

    Full Text Available Purpose: To investigate feasibility and safety of GliaSite brachytherapy for treatment of central nervous system (CNS tumors following neurosurgical resection. We report mature results of long-term follow-up, outcomes and toxicity. Materials and Methods: In the period from 2004 to 2007, 10 consecutive adult patients with recurrent, newly diagnosed, and metastatic brain malignancies underwent GliaSite brachytherapy following maximally safe neurosurgical resection. While 6/10 (60% patients were treated for recurrence, having previously been treated with external beam radiotherapy (EBRT, 4/10 (40% received radiotherapy (RT for the first time. A median dose of 52.0 Gy (range, 45.0 - 60.0 Gy was prescribed to 0.5 cm - 1.0 cm from the balloon surface. Radiation Therapy Oncology Group (RTOG criteria were used to assess toxicities associated with this technique. Follow-up was assessed with MRI scans and was available on all enrolled patients. Results: Median follow-up was 38 months (range, 18 - 57 months. Mean size of GliaSite balloon was 3.4 cm (range, 2.0 - 4.0 cm. Median survival was 14.0 months for the entire cohort after the treatment. The 17.6 and 16.0 months average survival for newly diagnosed and recurrent high grade gliomas (HGG, respectively, translated into a three-month improvement in survival in patients with newly diagnosed HGG compared to historical controls (P = 0.033. There were no RTOG grades 3 or 4 acute or late toxicities. Follow-up magnetic resonance imaging (MRI imaging did not identify radiation necrosis. Conclusions: Our data indicate that treatment with GliaSite brachytherapy is feasible, safe and renders acceptable local control, acute and long-term toxicities. We are embarking on testing larger numbers of patients with this treatment modality.

  11. Feasibility and safety of a novel in vivo model to assess playground falls in children.

    Ehrlich, Peter F; Young, Justin G; Ulin, Sheryl; Wooley, Charles; Armstrong, Thomas J; Buschmann, Bethany; Galecki, Andrzej; Ashton-Miller, James A

    2013-07-01

    Falls are the leading cause of nonfatal unintentional injuries among hospitalized children with playground equipment accounting for more than 50%. National standards for playground rung and rail design exist, but there a lack of in vivo models available to test these standards. We developed a novel in vivo model to test rung and rail design. We report the feasibility and safety of the model. A device was built to simulate children hanging onto a playground bar until their hand slips off. This was defined as breakaway strength. The handle unit was mounted on a vertical cable that was mechanically raised and lowered using a linear actuator controlled by the experimenter. The unit was padded and contained a video camera that recorded the posture of the hand during each trial. Breakaway force and torque were recorded as they held onto the handle by LabView software. In addition, standard anthropometrics and grip strength were recorded. Biomedical engineering approved the device. There were 425 eligible students aged 5 years to 11 years. Of these, 93% (397) participated (212 males and 185 females). Ninety-nine percent (396 of 397) completed all three experimental stations, one declined because of fear. There were no injuries and no falls. Average time to complete the study was 22 ± 0.5 minutes. Ninety-one percent of participants were right handed; the ethnicity was representative of the local area with 79% being white. Mean ± SD height, weight, and body mass index for the 397 participants were 1.28 ± 0.11 m, 28.0 ± 8.12 kg, and 16.31 ± 2.59 kg/m², respectively. Hand size, grip strength, and maximum breakaway force increased with age. This model is safe and feasible and maybe a viable method to assess rung and rail design for playgrounds.

  12. Safety and Feasibility of Transradial Access for Visceral Interventions in Patients with Thrombocytopenia

    Titano, J. J.; Biederman, D. M.; Marinelli, B. S.; Patel, R. S.; Kim, E.; Tabori, N. E.; Nowakowski, F. S.; Lookstein, R. A.; Fischman, A. M.

    2016-01-01

    PurposeTransradial access (TRA) has shown lower morbidity and decreased bleeding complications compared to transfemoral access. This study evaluates the safety and feasibility of TRA in thrombocytopenic patients undergoing visceral interventions.Methods and MaterialsPatients who underwent visceral interventions via the radial artery with platelet count less than or equal to 50,000/µL were included in the study. Outcome variables included technical success, access site, bleeding, transfusion, and neurological complications.ResultsFrom July 1, 2012, to May 31, 2015, a total of 1353 peripheral interventions via TRA were performed, of which 85 procedures were performed in 64 patients (mean age 62.2 years) with a platelet count <50,000/µL (median 39,000/µL). Interventions included chemoembolization (n = 46), selective internal radiation therapy (n = 30), and visceral embolization (n = 9). Technical success was 97.6 % with two cases of severe vessel spasm requiring ipsilateral femoral crossover. There was no major access site, bleeding, or neurological adverse events at 30 days. Minor access site hematomas occurred in five cases (5.9 %) and were treated conservatively in all cases. Pre-procedural platelet transfusions were administered in 23 (27.1 %) cases. There was no statistically significant difference in access site or bleeding complications between the transfused and nontransfused groups.ConclusionsTransradial visceral interventions in patients with thrombocytopenia are both feasible and safe, possibly without the need for platelet transfusions.

  13. Feasibility and Safety of a Transthoracic Pneumostoma Airway Bypass in Severe Emphysema Patients.

    Snell, Gregory I; Holsworth, Lynda; Khorramnia, Sadie; Westall, Glen P; Williams, Trevor J; Marasco, Silvana; Gooi, Julian H

    2017-01-01

    Emphysema is characterised by airflow obstruction, hyperinflation, and resultant dyspnoea. It is worth investigating whether decompression improves lung mechanics and enhances quality of life (QoL). The purpose of this study was to describe the feasibility and safety of creating a transthoracic pneumostoma to enable lung reduction. A transthoracic 10-mm diameter Portaero Access Tube (Portaero™, Cupertino, CA, USA) was implanted via a third intercostal space incision in 15 severe emphysema patients [mean age 63 years, forced expiratory volume in 1 s 54% predicted, diffusing capacity for carbon monoxide 31% predicted, residual volume 246% predicted, Six-Minute Walk Test 296 m]. Four weeks later, an 8-mm Portaero Disposable Tube (3-8 cm in length) was substituted and changed daily thereafter. The targeted primary endpoints were a ≥12% increase in forced expiratory volume in 1 s and a decrease of ≥4 points in Saint George's Respiratory Questionnaire score at 6 months. Sixteen procedures were performed on 15 patients, complicated by 1 intercostal haemorrhage, 1 pneumothorax, and universal mild surgical emphysema. Early patency issues were common, but often responded to external endoscopic debridement or argon plasma laser. Three-month patency was achieved in 9 of 15 patients, and 6 of these had long-term patency (mean of 4 years). Patency was associated with potentially useful long-term improvements or stability in spirometry, residual volume, and QoL. However, the primary endpoints were not met at 6 months. The creation and maintenance of a transthoracic pneumostoma appears feasible and safe in patients with severe emphysema. Further studies refining patient selection (perhaps via chest computed tomography collateral ventilation and fissure assessments), techniques, and tube materials are suggested. © 2017 S. Karger AG, Basel.

  14. Sentinel lymph node biopsy in endometrial cancer-Feasibility, safety and lymphatic complications.

    Geppert, Barbara; Lönnerfors, Céline; Bollino, Michele; Persson, Jan

    2018-03-01

    To compare the rate of lymphatic complications in women with endometrial cancer undergoing sentinel lymph node biopsy versus a full pelvic and infrarenal paraaortic lymphadenectomy, and to examine the overall feasibility and safety of the former. A prospective study of 188 patients with endometrial cancer planned for robotic surgery. Indocyanine green was used to identify the sentinel lymph nodes. In low-risk patients the lymphadenectomy was restricted to removal of sentinel lymph nodes whereas in high-risk patients also a full lymphadenectomy was performed. The impact of the extent of the lymphadenectomy on the rate of complications was evaluated. The bilateral detection rate of sentinel lymph nodes was 96% after cervical tracer injection. No intraoperative complication was associated with the sentinel lymph node biopsy per se. Compared with hysterectomy alone, the additional average operative time for removal of sentinel lymph nodes was 33min whereas 91min were saved compared with a full pelvic and paraaortic lymphadenectomy. Sentinel lymph node biopsy alone resulted in a lower incidence of leg lymphedema than infrarenal paraaortic and pelvic lymphadenectomy (1.3% vs 18.1%, p=0.0003). The high feasibility, the absence of intraoperative complications and the low risk of lymphatic complications supports implementing detection of sentinel lymph nodes in low-risk endometrial cancer patients. Given that available preliminary data on sensitivity and false negative rates in high-risk patients are confirmed in further studies, we also believe that the reduction in lymphatic complications and operative time strongly motivates the sentinel lymph node concept in high-risk endometrial cancer. Copyright © 2017. Published by Elsevier Inc.

  15. Feasibility and Safety of Endovascular Stripping of Totally Implantable Venous Access Devices

    Heye, Sam; Maleux, Geert; Goossens, G. A.; Vaninbroukx, Johan; Jerôme, M.; Stas, M.

    2012-01-01

    Purpose: To evaluate the safety and feasibility of percutaneous stripping of totally implantable venous access devices (TIVAD) in case of catheter-related sleeve and to report a technique to free the catheter tip from vessel wall adherence. Materials and Methods: A total of 37 stripping procedures in 35 patients (14 men, 40%, and 21 women, 60%, mean age 53 ± 14 years) were reviewed. Totally implantable venous access devices were implanted because of malignancy in most cases (85.7%). Catheter-related sleeve was confirmed as cause of persistent catheter dysfunction despite instillation of thrombolytics. A technique to mobilize the catheter tip from the vessel wall was used when stripping with the snare catheter was impossible. Technical success, complication rate, and outcome were noted. Results: A total of 55.9% (n = 19) of the 34 technically successful procedures (91.9%) could be done with the snare catheter. In 15 cases (44.1%), additional maneuvers to free the TIVAD’s tip from the vessel wall were needed. Success rate was not significantly lower before (72.4%) than after (96.7%) implementation of the new technique (P = 0.09). No complications were observed. Follow-up was available in 67.6% of cases. Recurrent catheter dysfunction was found in 17 TIVADs (78.3%) at a mean of 137.7 days and a median of 105 days. Conclusions: Stripping of TIVADs is technically feasible and safe, with an overall success rate of 91.9%. Additional endovascular techniques to mobilize the distal catheter tip from the wall of the superior vena cava or right atrium to allow encircling the TIVAD tip with the snare catheter may be needed in 44.1% of cases.

  16. Safety and Feasibility of Transradial Access for Visceral Interventions in Patients with Thrombocytopenia

    Titano, J. J., E-mail: joseph.titano@mountsinai.org; Biederman, D. M., E-mail: derek.biederman@mountsinai.org; Marinelli, B. S., E-mail: brett.marinelli@exchange.mssm.edu; Patel, R. S., E-mail: rahul.patel@mountsinai.org; Kim, E., E-mail: edward.kim@mountsinai.org; Tabori, N. E., E-mail: nora.tabori@mountsinai.org; Nowakowski, F. S., E-mail: scott.nowakowski@mountsinai.org; Lookstein, R. A., E-mail: robert.lookstein@mountsinai.org; Fischman, A. M., E-mail: aaron.fischman@mountsinai.org [Icahn School of Medicine at Mount Sinai, Department of Interventional Radiology (United States)

    2016-05-15

    PurposeTransradial access (TRA) has shown lower morbidity and decreased bleeding complications compared to transfemoral access. This study evaluates the safety and feasibility of TRA in thrombocytopenic patients undergoing visceral interventions.Methods and MaterialsPatients who underwent visceral interventions via the radial artery with platelet count less than or equal to 50,000/µL were included in the study. Outcome variables included technical success, access site, bleeding, transfusion, and neurological complications.ResultsFrom July 1, 2012, to May 31, 2015, a total of 1353 peripheral interventions via TRA were performed, of which 85 procedures were performed in 64 patients (mean age 62.2 years) with a platelet count <50,000/µL (median 39,000/µL). Interventions included chemoembolization (n = 46), selective internal radiation therapy (n = 30), and visceral embolization (n = 9). Technical success was 97.6 % with two cases of severe vessel spasm requiring ipsilateral femoral crossover. There was no major access site, bleeding, or neurological adverse events at 30 days. Minor access site hematomas occurred in five cases (5.9 %) and were treated conservatively in all cases. Pre-procedural platelet transfusions were administered in 23 (27.1 %) cases. There was no statistically significant difference in access site or bleeding complications between the transfused and nontransfused groups.ConclusionsTransradial visceral interventions in patients with thrombocytopenia are both feasible and safe, possibly without the need for platelet transfusions.

  17. Safety and feasibility of the robotic platform in the management of surgical sequelae of chronic pancreatitis.

    Hamad, Ahmad; Zenati, Mazen S; Nguyen, Trang K; Hogg, Melissa E; Zeh, Herbert J; Zureikat, Amer H

    2018-02-01

    The application of minimally invasive surgery to chronic pancreatitis (CP) procedures is uncommon. Our objective was to report the safety and feasibility of the robotic approach in the treatment of surgical sequelae of CP, and provide insights into the technique, tricks, and pitfalls associated with the application of robotics to this challenging disease entity. A retrospective review of a prospectively maintained database of patients undergoing robotic-assisted resections and/or drainage procedures for CP at the University of Pittsburgh between May 2009 and January 2017 was performed. A video of a robotic Frey procedure is also shown. Of 812 robotic pancreatic resections and reconstructions 39 were for CP indications. These included 11 total pancreatectomies [with and without auto islet transplantation], 8 Puestow procedures, 4 Frey procedures, 6 pancreaticoduodenectomies, and 10 distal pancreatectomies. Median age was 49, and 41% of the patients were female. The most common etiology for CP was idiopathic pancreatitis (n = 16, 46%). Median operative time was 324 min with a median estimated blood loss of 250 ml. None of the patients required conversion to laparotomy. A Clavien III-IV complication rate was experienced by 5 (13%) patients, including one reoperation. Excluding the eleven patients who underwent TP, rate of clinically relevant postoperative pancreatic fistula was 7% (Grade B = 2, Grade C = 0). No 30 or 90 day mortalities were recorded. The median length of hospital stay was 7 days. Use of the robotic platform is safe and feasible when tackling complex pancreatic resections for sequelae of chronic pancreatitis.

  18. Safety and Feasibility of Using the Second-Generation Pillcam Colon Capsule to Assess Active Colonic Crohn's Disease

    D'Haens, Geert; Löwenberg, Mark; Samaan, Mark A.; Franchimont, Denis; Ponsioen, Cyriel; van den Brink, Gijs R.; Fockens, Paul; Bossuyt, Peter; Amininejad, Leila; Rajamannar, Gopalan; Lensink, Elsemieke M.; van Gossum, Andre M.

    2015-01-01

    The second-generation Pillcam Colon Capsule Endoscope (PCCE-2; Given Imaging Ltd, Yoqneam, Israel) is an ingestible capsule for visualization of the colon. We performed a multicenter pilot study to assess its safety and feasibility in evaluating the severity of Crohn's disease (CD). In a prospective

  19. [Post-marketing drug safety-risk management plan(RMP)].

    Ezaki, Asami; Hori, Akiko

    2013-03-01

    The Guidance for Risk Management Plan(RMP)was released by the Ministry of Health, Labour and Welfare in April 2012. The RMP consists of safety specifications, pharmacovigilance plans and risk minimization action plans. In this paper, we outline post-marketing drug safety operations in PMDA and the RMP, with examples of some anticancer drugs.

  20. The role of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) in monitoring drug safety

    Boyd, Ian W.

    2002-01-01

    The Australian adverse drug reaction reporting system is acknowledged as one of the best in the world. Despite its small population of less than 20 million people, Australia's current ADR reporting rate of over 12000 reports per year places it in the top few nations in terms of reports per capita. The ADRAC program has been in operation for over 30 years. Australia was a founding member of the WHO International Drug Monitoring Programme which commenced in 1968 and currently there are about 153000 reports in the ADRAC database. Reports from health professionals have uncovered a number of significant safety problems over the years. Of particular importance are flucloxacillin-induced hepatitis, amoxycillin/clavulanate-induced hepatitis, and the association of cystitis with tiaprofenic acid. The number and quality of the reports has allowed an understanding of the characteristics of the reactions and, using ADRAC reporters as a major source of cases, case-control studies have been completed which have identified risk factors. ADRAC's review of Australian reports has highlighted many important associations that have been disseminated through the Australian Adverse Drug Reactions Bulletin

  1. From Drug Safety to Drug Security: A Contemporary Shift in the Policing of Health.

    Hornberger, Julia

    2018-01-29

    The counterfeiting of medication is increasingly seen as a major threat to health, especially in the light of both the everyday reliance on and a broadening of world-wide access to pharmaceuticals. Exaggerated or real, this threat has inaugurated, this article argues, a shift from a drug safety regime to a drug security regime that governs the flow of pharmaceuticals and brings together markets, police, and health actors in new ways. This entails a shift from soft disciplinary means aimed at incremental and continued inclusion of defaulters, to one of drastically sovereign measures of exclusion and banishment aimed at fake goods and the people associated with them, in the name of health. Through a multi-sited ethnographic study, this article shows how such new drug security efforts play themselves out especially in (South) Africa, highlighting a modus operandi of spectacular performativity and of working through suspicion and association rather than factuality, producing value less so for those in need of health than for a petty security industry itself. © 2018 by the American Anthropological Association.

  2. Feasibility and Safety Assessment for Advanced Reactor Concepts Using Vented Fuel

    Klein, Andrew; Lenhof, Renae; Deason, Wesley; Harter, Jackson

    2015-01-01

    Recent interest in fast reactor technology has led to renewed analysis of past reactor concepts such as Gas Fast Reactors and Sodium Fast Reactors. In an effort to make these reactors more economic, the fuel is required to stay in the reactor for extended periods of time; the longer the fuel stays within the core, the more fertile material is converted into usable fissile material. However, as burnup of the fuel-rod increases, so does the internal pressure buildup due to gaseous fission products. In order to reach the 30 year lifetime requirements of some reactor designs, the fuel pins must have a vented-type design to allow the buildup of fission products to escape. The present work aims to progress the understanding of the feasibility and safety issues related to gas reactors that incorporate vented fuel. The work was separated into three different work-scopes: 1. Quantitatively determine fission gas release from uranium carbide in a representative helium cooled fast reactor; 2. Model the fission gas behavior, transport, and collection in a Fission Product Vent System; and, 3. Perform a safety analysis of the Fission Product Vent System. Each task relied on results from the previous task, culminating in a limited scope Probabilistic Risk Assessment (PRA) of the Fission Product Vent System. Within each task, many key parameters lack the fidelity needed for comprehensive or accurate analysis. In the process of completing each task, the data or methods that were lacking were identified and compiled in a Gap Analysis included at the end of the report.

  3. Efficacy, Safety, and Feasibility of the Morphine Microdose Method in Community-Based Clinics.

    Wilkes, Denise M; Orillosa, Susan J; Hustak, Erik C; Williams, Courtney G; Doulatram, Gulshan R; Solanki, Daneshvari R; Garcia, Eduardo A; Huang, Li-Yen M

    2017-06-13

    The goal of this study was to assess the success of the morphine microdose method in a community pain clinic setting by monitoring follow-up frequency, dose escalation, and monotherapy/polytherapy ratio. The morphine microdose method involves a pretrial reduction or elimination of systemic opioids followed by a period of abstinence. Intrathecal (IT) morphine is then started at doses of less than 0.2 mg per day. Systemic opioid abstinence is then continued after pump implant and IT morphine monotherapy. Retrospective review of medical records. Private and academic pain clinic practices. Chronic noncancer pain patients. We reviewed the charts of 60 patients who had completed a microdose regimen and had an IT pump implanted between June 11, 2008, and October 11, 2014. During IT therapy, dose change over time, pain scores, side effects, max dose, and duration were recorded. The majority of patients (35/60, 58%) were successfully managed solely on morphine microdose monotherapy. These patients did not require additional oral therapy. There was a significant reduction in mean pain scores, from 7.4 ± 0.32 before microdose therapy to 4.8 ± 0.3 after microdose therapy. Microdose therapy achieved analgesia, improved safety, and avoided systemic side effects. The safety of IT therapy was increased by using a lower concentration (2 mg/mL) and lower daily doses (microdose therapy was feasible, safe, and cost-effective in the outpatient setting. 2017 American Academy of Pain Medicine. This work is written by US Government employees and is in the public domain in the US.

  4. Feasibility and Safety Assessment for Advanced Reactor Concepts Using Vented Fuel

    Klein, Andrew [Oregon State Univ., Corvallis, OR (United States). Nuclear Engineering and Radiation Health Physics; Matthews, Topher [Oregon State Univ., Corvallis, OR (United States); Lenhof, Renae [Oregon State Univ., Corvallis, OR (United States); Deason, Wesley [Oregon State Univ., Corvallis, OR (United States); Harter, Jackson [Oregon State Univ., Corvallis, OR (United States)

    2015-01-16

    Recent interest in fast reactor technology has led to renewed analysis of past reactor concepts such as Gas Fast Reactors and Sodium Fast Reactors. In an effort to make these reactors more economic, the fuel is required to stay in the reactor for extended periods of time; the longer the fuel stays within the core, the more fertile material is converted into usable fissile material. However, as burnup of the fuel-rod increases, so does the internal pressure buildup due to gaseous fission products. In order to reach the 30 year lifetime requirements of some reactor designs, the fuel pins must have a vented-type design to allow the buildup of fission products to escape. The present work aims to progress the understanding of the feasibility and safety issues related to gas reactors that incorporate vented fuel. The work was separated into three different work-scopes: 1. Quantitatively determine fission gas release from uranium carbide in a representative helium cooled fast reactor; 2. Model the fission gas behavior, transport, and collection in a Fission Product Vent System; and, 3. Perform a safety analysis of the Fission Product Vent System. Each task relied on results from the previous task, culminating in a limited scope Probabilistic Risk Assessment (PRA) of the Fission Product Vent System. Within each task, many key parameters lack the fidelity needed for comprehensive or accurate analysis. In the process of completing each task, the data or methods that were lacking were identified and compiled in a Gap Analysis included at the end of the report.

  5. Safety and feasibility of liver resection with continued antiplatelet therapy using aspirin.

    Monden, Kazuteru; Sadamori, Hiroshi; Hioki, Masayoshi; Ohno, Satoshi; Saneto, Hiromi; Ueki, Toru; Yabushita, Kazuhisa; Ono, Kazumi; Sakaguchi, Kousaku; Takakura, Norihisa

    2017-07-01

    Aspirin is widely used for the secondary prevention of ischemic stroke and cardiovascular disease. Perioperative aspirin may decrease thrombotic morbidity, but may also increase hemorrhagic morbidity. In particular, liver resection carries risks of bleeding, leading to higher risks of hemorrhagic morbidity. Our institution has continued aspirin therapy perioperatively in patients undergoing liver resection. This study examined the safety and feasibility of liver resection while continuing aspirin. We retrospectively evaluated 378 patients who underwent liver resection between January 2010 and January 2016. Patients were grouped according to preoperative aspirin prescription: patients with aspirin therapy (aspirin users, n = 31); and patients without use of aspirin (aspirin non-users, n = 347). Aspirin users were significantly older (P aspirin users than among aspirin non-users, no significant difference was identified. No postoperative hemorrhage was seen among aspirin users. Liver resection can be safely performed while continuing aspirin therapy without increasing hemorrhagic morbidity. Our results suggest that interruption of aspirin therapy is unnecessary for patients undergoing liver resection. © 2017 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  6. da Vinci robot-assisted keyhole neurosurgery: a cadaver study on feasibility and safety.

    Marcus, Hani J; Hughes-Hallett, Archie; Cundy, Thomas P; Yang, Guang-Zhong; Darzi, Ara; Nandi, Dipankar

    2015-04-01

    The goal of this cadaver study was to evaluate the feasibility and safety of da Vinci robot-assisted keyhole neurosurgery. Several keyhole craniotomies were fashioned including supraorbital subfrontal, retrosigmoid and supracerebellar infratentorial. In each case, a simple durotomy was performed, and the flap was retracted. The da Vinci surgical system was then used to perform arachnoid dissection towards the deep-seated intracranial cisterns. It was not possible to simultaneously pass the 12-mm endoscope and instruments through the keyhole craniotomy in any of the approaches performed, limiting visualization. The articulated instruments provided greater dexterity than existing tools, but the instrument arms could not be placed in parallel through the keyhole craniotomy and, therefore, could not be advanced to the deep cisterns without significant clashing. The da Vinci console offered considerable ergonomic advantages over the existing operating room arrangement, allowing the operating surgeon to remain non-sterile and seated comfortably throughout the procedure. However, the lack of haptic feedback was a notable limitation. In conclusion, while robotic platforms have the potential to greatly enhance the performance of transcranial approaches, there is strong justification for research into next-generation robots, better suited to keyhole neurosurgery.

  7. Feasibility and safety of endoscopic submucosal dissection for lower rectal tumors with hemorrhoids.

    Tanaka, Shinwa; Toyonaga, Takashi; Morita, Yoshinori; Hoshi, Namiko; Ishida, Tsukasa; Ohara, Yoshiko; Yoshizaki, Tetsuya; Kawara, Fumiaki; Umegaki, Eiji; Azuma, Takeshi

    2016-07-21

    To evaluate the feasibility and safety of endoscopic submucosal dissection (ESD) for lower rectal lesions with hemorrhoids. The outcome of ESD for 23 lesions with hemorrhoids (hemorrhoid group) was compared with that of 48 lesions without hemorrhoids extending to the dentate line (non-hemorrhoid group) during the same study period. Median operation times (ranges) in the hemorrhoid and non-hemorrhoid groups were 121 (51-390) and 130 (28-540) min. The en bloc resection rate and the curative resection rate in the hemorrhoid group were 96% and 83%, and they were 100% and 90% in the non-hemorrhoid group, respectively. In terms of adverse events, perforation and postoperative bleeding did not occur in both groups. In terms of the clinical course of hemorrhoids after ESD, the rate of complete recovery of hemorrhoids after ESD in lesions with resection of more than 90% was significantly higher than that in lesions with resection of less than 90%. ESD on lower rectal lesions with hemorrhoids could be performed safely, similarly to that on rectal lesions extending to the dentate line without hemorrhoids. In addition, all hemorrhoids after ESD improved to various degrees, depending on the resection range.

  8. Cervical cancer prevention: safety, acceptability, and feasibility of a single-visit approach in Accra, Ghana.

    Blumenthal, Paul D; Gaffikin, Lynne; Deganus, Sylvia; Lewis, Robbyn; Emerson, Mark; Adadevoh, Sydney

    2007-04-01

    The purpose of this study was to assess the safety and acceptability of a single-visit approach to cervical cancer prevention combining visual inspection of the cervix with acetic acid wash (VIA) and cryotherapy. The study was observational. Nine clinicians were trained in VIA and cryotherapy. Over 18 months 3665 women were VIA-tested. If positive and eligible, cryotherapy was offered immediately. Treated women were followed-up at 3 months and 1 year. The test-positive rate was 13.2%. Of those eligible, 70.2% and 21% received immediate or delayed treatment, respectively. No major complications were recorded, and 5.6% presented for a perceived problem post-cryotherapy. Among those treated over 90% expressed satisfaction with their experience, and 96% had an indentifiable squamo-columnar junction. Only 2.6% (6/232) were test positive, 1-year posttreatment. A single-visit approach using VIA and cryotherapy proved to be safe, acceptable, and feasible in an urban African setting.

  9. Feasibility and safety of extended adjuvant temozolomide beyond six cycles for patients with glioblastoma.

    Hsieh, S Yp; Chan, D Tm; Kam, M Km; Loong, H Hf; Tsang, W K; Poon, D Mc; Ng, S Cp; Poon, W S

    2017-12-01

    Temozolomide is the first chemotherapeutic agent proven effective for patients with newly diagnosed glioblastoma. The drug is well tolerated for its low toxicity. The current standard practice is concomitant chemoradiotherapy for 6 weeks followed by 6 cycles of adjuvant temozolomide. Some Caucasian studies have suggested that patients might benefit from extended adjuvant cycles of temozolomide (>6 cycles) to lengthen both progression-free survival and overall survival. In the present study, we compared differences in survival and toxicity profile between patients who received conventional 6-cycle temozolomide and those who received more than 6 cycles of temozolomide. Patients with newly diagnosed glioblastoma without progressive disease and completed concomitant chemoradiotherapy during a 4-year period were studied. Progression-free survival was compared using Kaplan-Meier survival curves. t Test, U test, and correlation were chosen accordingly to examine the impact of age, extent of resection, MGMT promoter methylation status and adjuvant cycles on progression-free survival. For factors with a P value of cycles of temozolomide (n=7) and 43.4 months for those who received more than 6 cycles (n=7) [P=0.007, log-rank test]. Two patients in the former group and one in the latter group encountered grade 1 toxicity and recovered following dose adjustment. Cycles of adjuvant temozolomide were correlated with progression-free survival (P=0.016, hazard ratio=0.68). Extended cycles of temozolomide are safe and feasible for Chinese patients with disease responsive to temozolomide.

  10. Prescription for antibiotics at drug shops and strategies to improve quality of care and patient safety

    Mbonye, Anthony K; Buregyeya, Esther; Rutebemberwa, Elizeus

    2016-01-01

    OBJECTIVES: The main objective of this study was to assess practices of antibiotic prescription at registered drug shops with a focus on upper respiratory tract infections among children in order to provide data for policy discussions aimed at improving quality of care and patient safety......-line drug for treatment of pneumonia in children according to the guidelines. CONCLUSIONS: There is urgent need to regulate drug shop practices of prescribing and selling antibiotics, for the safety of patients seeking care at these outlets....

  11. Drug education in bolivian schools: A feasibility study for cross-cultural application of a preventive curricular unit

    Gonzalez, Gerardo M.; Moreno, Veronica Kaune

    1995-11-01

    The purpose of this study was to test the feasibility of adapting and implementing in La Paz, Bolivia a drug education course originally developed for use in the middle schools in the United States. On the basis of teacher and student evaluations, it was concluded that the unit is a viable, culturally relevant and effective method of drug education in the public and private schools in La Paz. Implications for the prevention of other health-related problems and for implementation of a demandreduction strategy to prevent drug abuse throughout the Americas are discussed.

  12. 77 FR 10666 - Pipeline Safety: Post Accident Drug and Alcohol Testing

    2012-02-23

    ... 199 [Docket No. PHMSA-2011-0335] Pipeline Safety: Post Accident Drug and Alcohol Testing AGENCY... operators of Liquefied Natural Gas (LNG) facilities to conduct post- accident drug and alcohol tests of..., operators must drug and alcohol test each covered employee whose performance either contributed to the...

  13. Intravenous recombinant tissue plasminogen activator for acute ischemic stroke: a feasibility and safety study

    Sadeghi-Hokmabadi E

    2016-10-01

    Full Text Available Elyar Sadeghi-Hokmabadi, Mehdi Farhoudi, Aliakbar Taheraghdam, Mazyar Hashemilar, Daryous Savadi-Osguei, Reza Rikhtegar, Kaveh Mehrvar, Ehsan Sharifipour, Parisa Youhanaee, Reshad Mirnour Neurosciences Research Center, Neurology Department, Tabriz University of Medical Sciences, Tabriz, East Azerbaijan, Iran Background: In developing countries, intravenous thrombolysis (IVT is available at a limited number of centers. This study aimed to assess the feasibility and safety of IVT at Tabriz Imam Reza Hospital. Methods: In a prospective study, over a 55-month period, any patient at the hospital for whom stroke code had been activated was enrolled in the study. Data on demographic characteristics, stroke risk factors, admission blood pressure, blood tests, findings of brain computed tomography (CT scans, time of symtom onset, time of arrival to the emergency department, time of stroke code activation, time of CT scan examination, and the time of recombinant tissue plasminogen activator administration were recorded. National Institutes of Health Stroke Scale assessments were performed before IVT bolus, at 36 hours, at either 7 days or discharge (which ever one was earlier, and at 3-month follow-up. Brain CT scans were done for all patients before and 24 hours after the treatment. Results: Stroke code was activated for 407 patients and IVT was done in 168 patients. The rate of functional independence (modified Rankin Scale [mRS] 0–1 at 3 months was 39.2% (62/158. The mortality rate at day 7 was 6% (10/168. Hemorrhagic transformation was noted in 16 patients (9.5%. Symptomatic intracranial hemorrhage occurred in 5 (3%, all of which were fatal. One case of severe urinary bleeding and one other fatal case of severe angioedema were observed. Conclusion: During the first 4–5 years of administration of IVT in the hospital, it was found to be feasible and safe, but to increase the efficacy, poststroke care should be more organized and a stroke center

  14. Feasibility, safety, acceptability, and functional outcomes of playing Nintendo Wii Fit Plus™ for frail elderly: study protocol for a feasibility trial.

    Gomes, Gisele Cristine Vieira; Bacha, Jéssica Maria Ribeiro; do Socorro Simões, Maria; Lin, Sumika Mori; Viveiro, Larissa Alamino Pereira; Varise, Eliana Maria; Filho, Wilson Jacob; Pompeu, José Eduardo

    2017-01-01

    Frailty can be defined as a medical syndrome with multiple causes and contributors, characterized by diminished strength and endurance and reduced physiological function that increases the vulnerability to develop functional dependency and/or death. Studies have shown that the most commonly studied exercise protocol for frail older adults is the multimodal training. Interactive video games (IVGs) involve tasks in virtual environments that combine physical and cognitive demands in an attractive and challenging way. The aim of this study will be to evaluate the feasibility, safety, acceptability, and functional outcomes of playing Nintendo Wii Fit Plus TM (NWFP) for frail older adults. The study is a randomized controlled, parallel group, feasibility trial. Participants will be randomly assigned to the experimental group (EG) and control group (CG). The EG will participate in 14 training sessions, each lasting 50 min, twice a week. In each training session, the participants will play five games, with three attempts at each game. The first attempt will be performed with the assistance of a physical therapist to correct the movements and posture of the patients and subsequent attempts will be performed independently. Scores achieved in the games will be recorded. The participants will be evaluated by a blinded physical therapist at three moments: before and after intervention and 30 days after the end of the intervention (follow-up). We will assess the feasibility, acceptability, safety, and clinical outcomes (postural control, gait, cognition, quality of life, mood, and fear of falling). Due to the deficiencies in multiple systems, studies have shown that multimodal interventions including motor-cognitive stimulation can improve the mobility of frail elderly adults. IVGs, among them the NWFP, are considered as a multimodal motor-cognitive intervention that can potentially improve motor and cognitive functions in the frail elderly. However, there is still no evidence

  15. Drug waste minimisation and cost-containment in Medical Oncology: Two-year results of a feasibility study

    Mansutti Mauro

    2008-04-01

    Full Text Available Abstract Background Cost-containment strategies are required to face the challenge of rising drug expenditures in Oncology. Drug wastage leads to economic loss, but little is known about the size of the problem in this field. Methods Starting January 2005 we introduced a day-to-day monitoring of drug wastage and an accurate assessment of its costs. An internal protocol for waste minimisation was developed, consisting of four corrective measures: 1. A rational, per pathology distribution of chemotherapy sessions over the week. 2. The use of multi-dose vials. 3. A reasonable rounding of drug dosages. 4. The selection of the most convenient vial size, depending on drug unit pricing. Results Baseline analysis focused on 29 drugs over one year. Considering their unit price and waste amount, a major impact on expense was found to be attributable to six drugs: cetuximab, docetaxel, gemcitabine, oxaliplatin, pemetrexed and trastuzumab. The economic loss due to their waste equaled 4.8% of the annual drug expenditure. After the study protocol was started, the expense due to unused drugs showed a meaningful 45% reduction throughout 2006. Conclusion Our experience confirms the economic relevance of waste minimisation and may represent a feasible model in addressing this issue. A centralised unit of drug processing, the availability of a computerised physician order entry system and an active involvement of the staff play a key role in allowing waste reduction and a consequent, substantial cost-saving.

  16. The Feasibility and Safety of Surgery in Patients Receiving Immune Checkpoint Inhibitors: A Retrospective Study

    Alexandra W. Elias

    2017-06-01

    Full Text Available Immune checkpoint inhibitors (ICI are revolutionizing care for cancer patients. The list of malignancies for which the Food and Drug Administration is granting approval is rapidly increasing. Furthermore, there is a concomitant increase in clinical trials incorporating ICI. However, the safety of ICI in patients undergoing surgery remains unclear. Herein, we assessed the safety of ICI in the perioperative setting at a single center. We conducted a retrospective review of patients who underwent planned surgery while receiving ICI in the perioperative setting from 2012 to 2016. We collected 30-day postoperative morbidity and mortality utilizing the Clavien–Dindo classification system. We identified 17 patients who received perioperative ICI in 22 operations. Patients were diagnosed with melanoma (n = 14, renal cell carcinoma (n = 2, and urothelial carcinoma (n = 1. Therapies included pembrolizumab (n = 10, ipilimumab (n = 5, atezolizumab (n = 5, and ipilimumab/nivolumab (n = 2. Procedures included cutaneous/subcutaneous resection (n = 6, lymph node resection (n = 5, small bowel resection (n = 5, abdominal wall resection (n = 3, other abdominal surgery (n = 3, orthopedic surgery (n = 1, hepatic resection (n = 1, and neurosurgery (n = 2. There were no Grade III–IV Clavien–Dindo complications. There was one death secondary to ventricular fibrillation in the setting of coronary artery disease. ICI appear safe in the perioperative setting, involving multiple different types of surgery, and likely do not need to be stopped in the perioperative setting. Further studies are warranted to confirm these findings.

  17. Office-based esophageal dilation in head and neck cancer: Safety, feasibility, and cost analysis.

    Howell, Rebecca J; Schopper, Melissa A; Giliberto, John Paul; Collar, Ryan M; Khosla, Sid M

    2018-02-08

    To review experience, safety, and cost of office-based esophageal dilation in patients with history of head and neck cancer (HNCA). The medical records of patients undergoing esophageal dilation in the office were retrospectively reviewed between August 2015 and May 2017. Patients were given nasal topical anesthesia. Next, a transnasal esophagoscopy (TNE) was performed. If the patient tolerated TNE, we proceeded with esophageal dilation using Seldinger technique with the CRE™ Boston Scientific (Boston Scientific Corp., Marlborough, MA) balloon system. Patients were discharged directly from the outpatient clinic. Forty-seven dilations were performed in 22 patients with an average of 2.1 dilations/patient (range 1-10, standard deviation [SD] ± 2.2). Seventeen patients (77%) were male. The average age was 67 years (range 35-78 years, SD ± 8.5). The most common primary site of cancer was oral cavity/oropharynx (n = 10), followed by larynx (n = 6). All patients (100%) had history of radiation treatment. Four patients were postlaryngectomy. The indication for esophageal dilation was esophageal stricture and progressive dysphagia. All dilations occurred in the proximal esophagus. There were no major complications. Three focal, superficial lacerations occurred. Two patients experienced mild, self-limited epistaxis. One dilation was poorly tolerated due to discomfort. One patient required pain medication postprocedure. Office-based esophageal dilation generated $15,000 less in health system charges compared to traditional operating room dilation on average per episode of care. In patients with history of HNCA and radiation, office-based TNE with esophageal dilation appears safe, well-tolerated, and cost-effective. In a small cohort, the technique has low complication rate and is feasible in an otolaryngology outpatient office setting. 4. Laryngoscope, 2018. © 2018 The American Laryngological, Rhinological and Otological Society, Inc.

  18. Implementation of enhanced recovery programme for laparoscopic distal pancreatectomy: feasibility, safety and cost analysis.

    Richardson, John; Di Fabio, Francesco; Clarke, Hannah; Bajalan, Mohammed; Davids, Joe; Abu Hilal, Mohammed

    2015-01-01

    The adoption of laparoscopy for distal pancreatectomy has proven to substantially improve short-term outcomes. Stress response after major surgery can be further minimized within an enhanced recovery programme (ERP). However, data on the potential benefit of an ERP for laparoscopic distal pancreatectomy are still lacking. The aim was to assess the feasibility, safety and cost of ERP for patients undergoing laparoscopic distal pancreatectomy. This is a case-control study from a Tertiary University Hospital. Sixty-six consecutive patients who underwent laparoscopic distal pancreatectomy were analyzed. Twenty-two patients were enrolled for the ERP and compared with previous consecutive 44 patients managed traditionally (1:2 ratio). Operative details, post-operative outcome and cost analysis were compared in the two groups. Patients enrolled in the ERP had similar intraoperative blood loss (median 165 ml vs. 200 ml; p = 0.176), operation time (225 min vs. 210 min; p = 0.633), time to remove naso-gastric tube (1 vs. 1 day; p = 0.081) but significantly shorter time to mobilization (median 1 vs. 2 days; p = 0.0001), start solid diet (2 vs. 3 days; p = 0004), and pass stools (3 vs. 5 days; p = 0.002) compared to the control group. Median length of stay was significantly shorter in the ERP group (3 vs. 6 days; p pancreatectomy with significant earlier return to normal gut function, reduced length of stay and cost saving. Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  19. Safety and feasibility of percutaneous vertebroplasty with radioactive {sup 153}Sm PMMA in an animal model

    Lu Jun [Department of Radiotherapy, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Deng Jinglan, E-mail: dengjinglan@gmail.com [Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Zhao Haitao [Department of Radiology, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Shi Mei [Department of Radiotherapy, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Wang Jing [Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Zhao Lina [Department of Radiotherapy, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China)

    2011-05-15

    Purpose: We investigated the safety and feasibility of the combination of samarium-153-ethylenediamine tetramethylene phosphonate ({sup 153}Sm-EDTMP)-incorporated bone cement (BC) with percutaneous vertebroplasty (PVP) in dogs. Methods and materials: {sup 153}Sm-EDTMP-incorporated BC was prepared by combining solid {sup 153}Sm-EDTMP and polymethylmethacrylate (PMMA) immediately before PVP. It was then injected into the vertebrae of four healthy mongrel dogs (two males and two females) by PVP under CT guidance. Each dog was subjected to five PVP sessions at a {sup 153}Sm-EDTMP dose of 30-70 mCi. The suppressive effect of local injection of {sup 153}Sm-EDTMP on the hematopoietic system was evaluated through counting of peripheral blood cells. Distribution of {sup 153}Sm-EDTMP-incorporated BC and the status of tissues adjacent to injected vertebrae were evaluated with SPECT, CT and MRI. Histopathology was carried out to assess the influence of PVP on the vertebra and adjacent tissues at the microscopic level. Results: PVP was done successfully, and all dogs exhibited normal behavior and stable physical signs after procedures. {sup 153}Sm-EDTMP-incorporated BC was concentrated mainly in target vertebrae, and the peripheral blood cells remained within normal range. The spinal cord and tissues around BC did not exhibit signs of injury even when the dosage of {sup 153}Sm-EDTMP increased from 30 mCi to 70 mCi. Conclusion: A dose lower than 70 mCi of {sup 153}Sm is safe when it was injected into vertebrae. {sup 153}Sm-EDTMP-incorporated BC did not influence the effect of PVP. This means might strengthen anti-tumor activity locally for vertebra with osseous metastasis without damaging adjacent tissues.

  20. Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers.

    Ryszard M Pluta

    Full Text Available BACKGROUND: Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. METHODOLOGY: Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075 between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21-56 years were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr. Clinical, physiologic and laboratory data before, during and after infusion were analyzed. FINDINGS: The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. CONCLUSION: Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. CLINICAL TRIAL REGISTRATION INFORMATION: http

  1. Closure of tubular patent ductus arteriosus with the Amplatzer Vascular Plug IV: feasibility and safety.

    Baruteau, Alban-Elouen; Lambert, Virginie; Riou, Jean-Yves; Angel, Claude-Yves; Belli, Emre; Petit, Jérôme

    2015-01-01

    Closure of tubular patent ductus arteriosus remains a challenging procedure. Anecdotal use of Amplatzer Vascular Plug IV for tubular ductus closure has been reported but feasibility and safety in a consecutive patients' series remain unknown. We performed a monocenter prospective study at the Marie Lannelongue Hospital in Paris, France. From 2009 to 2014, a total of 47 patients (39 infants, 3 children, and 5 adults) underwent ductus closure with the Plug IV. Ductus morphology was a type E in 34 (72.3%) patients and a type C in 13 (27.7%) patients. Ductus closure occurred in 39 (83.0%) infants at a median age of seven months (range: 3-23 months) and a median weight of 6.9 kg (range: 4.1-17.0 kg). A past history of prematurity and very low birth weight was found in 33 (70.2%) of them. Twelve (25.5%) patients had pulmonary hypertension. Mean Plug IV diameter was 1.9 ± 0.1 mm larger than the mean maximal ductus diameter. Early complete closure of the ductus was obtained in all patients. Early migration of an undersized Plug IV occurred in one (2.1%) patient and was suitable for percutaneous device retrieval. After a mean follow-up of 3.4 ± 1.4 years, all patients are alive and asymptomatic, no late complication occurred. Transcatheter closure of tubular ductus with the Amplatzer Vascular Plug IV can be safe and effective, with a 100% early occlusion rate. This device, suitable for a 4F sheath, is a new alternative for tubular ductus closure in low-body-weight infants. © The Author(s) 2014.

  2. Probing cardiac repolarization reserve in drug safety assessment

    Nalos, L.

    2011-01-01

    Excessive prolongation of cardiac repolarization, manifested as QT prolongation on ECG, is common unwanted side effect of many drugs and drug candidates. Prolongation of QT interval may lead to life threatening cardiac arrhythmia – Torsade de Point (TdP). Number of drugs was withdrawn from the

  3. Use of Active-Play Video Games to Enhance Aerobic Fitness in Schizophrenia: Feasibility, Safety, and Adherence.

    Kimhy, David; Khan, Samira; Ayanrouh, Lindsey; Chang, Rachel W; Hansen, Marie C; Lister, Amanda; Ballon, Jacob S; Vakhrusheva, Julia; Armstrong, Hilary F; Bartels, Matthew N; Sloan, Richard P

    2016-02-01

    Active-play video games have been used to enhance aerobic fitness in various clinical populations, but their use among individuals with schizophrenia has been limited. Feasibility, acceptability, safety, and adherence data were obtained for use of aerobic exercise (AE) equipment by 16 individuals with schizophrenia during a 12-week AE program consisting of three one-hour exercise sessions per week. Equipment included exercise video games for Xbox 360 with Kinect motion sensing devices and traditional exercise equipment. Most participants (81%) completed the training, attending an average of 79% of sessions. The proportion of time spent playing Xbox (39%) exceeded time spent on any other type of equipment. When using Xbox, participants played 2.24±1.59 games per session and reported high acceptability and enjoyment ratings, with no adverse events. Measures of feasibility, acceptability, adherence, and safety support the integration of active-play video games into AE training for people with schizophrenia.

  4. Online availability and safety of drugs in shortage: a descriptive study of internet vendor characteristics.

    Liang, Bryan A; Mackey, Tim K

    2012-02-09

    Unprecedented drug shortages announced by the US Food and Drug Administration (FDA) have severely affected therapeutic access, patient safety, and public health. With continued shortages, patients may seek drugs online. To assess the prevalence of online marketing for current FDA shortage drugs and potential patient safety risks. We performed a descriptive study of the prevalence of online marketing for shortage drugs-that is, offers for sale of each drug, including characteristics of online drug sellers and intermediary sites marketing these drugs. Of the 72 FDA shortage-listed drugs, 68 (94%) were offered for sale online. We found 291 offers for these drugs, the vast majority (n = 207, 71.1%) by online drug sellers selling direct to consumers. Intermediary sites included data aggregators (n = 22, 8%), forum links (n = 23, 8%), and personal page data links (n = 34, 12%), as well as Flickr social media links (n = 5, 2%), all advertising drugs without a prescription. Of the 91 online drug sellers identified, 31 (34%) had more than 1 shortage drug offered for sale, representing most (n = 148, 71%) of all online drug seller sales offers. The majority of these online drug sellers (n = 21, 68%) were on the National Association of Boards of Pharmacy (NABP) Not Recommended Sites list. Finally, for shortage drugs with an online drug seller (n = 58, 85%), 53 (91%) had at least one site on the Not Recommended list and 21 (36%) had only sites on the Not Recommended list. FDA shortage drugs are widely marketed over the Internet. Suspect online drug sellers and intermediaries dominate these sales offers. As a critical risk management issue, patients, providers, and policymakers should be extremely cautious in procuring shortage drugs through Internet sourcing.

  5. 76 FR 63929 - Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Dermatologic and...

    2011-10-14

    ...] Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Dermatologic and... Administration (FDA). The meeting will be open to the public. Name of Committees: Drug Safety and Risk Management... Safe Use (ETASU) before its Drug Safety and Risk Management Advisory Committee (DSaRM). On December 1...

  6. 75 FR 17417 - Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management...

    2010-04-06

    ...] Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory... Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee. This meeting was... Drug Safety and Risk Management Advisory Committee would be held on May 12, 2010. On page 10490, in the...

  7. Online Availability and Safety of Drugs in Shortage: A Descriptive Study of Internet Vendor Characteristics

    Mackey, Tim K

    2012-01-01

    Background Unprecedented drug shortages announced by the US Food and Drug Administration (FDA) have severely affected therapeutic access, patient safety, and public health. With continued shortages, patients may seek drugs online. Objective To assess the prevalence of online marketing for current FDA shortage drugs and potential patient safety risks. Methods We performed a descriptive study of the prevalence of online marketing for shortage drugs—that is, offers for sale of each drug, including characteristics of online drug sellers and intermediary sites marketing these drugs. Results Of the 72 FDA shortage-listed drugs, 68 (94%) were offered for sale online. We found 291 offers for these drugs, the vast majority (n = 207, 71.1%) by online drug sellers selling direct to consumers. Intermediary sites included data aggregators (n = 22, 8%), forum links (n = 23, 8%), and personal page data links (n = 34, 12%), as well as Flickr social media links (n = 5, 2%), all advertising drugs without a prescription. Of the 91 online drug sellers identified, 31 (34%) had more than 1 shortage drug offered for sale, representing most (n = 148, 71%) of all online drug seller sales offers. The majority of these online drug sellers (n = 21, 68%) were on the National Association of Boards of Pharmacy (NABP) Not Recommended Sites list. Finally, for shortage drugs with an online drug seller (n = 58, 85%), 53 (91%) had at least one site on the Not Recommended list and 21 (36%) had only sites on the Not Recommended list. Conclusions FDA shortage drugs are widely marketed over the Internet. Suspect online drug sellers and intermediaries dominate these sales offers. As a critical risk management issue, patients, providers, and policymakers should be extremely cautious in procuring shortage drugs through Internet sourcing. PMID:22321731

  8. Advice on drug safety in pregnancy: are there differences between commonly used sources of information?

    Frost Widnes, Sofia K; Schjøtt, Jan

    2008-01-01

    Safety regarding use in pregnancy is not established for many drugs. Inconsistencies between sources providing drug information can give rise to confusion with possible therapeutic consequences. Therefore, it is important to measure clinically important differences between drug information sources. The objective of this study was to compare two easily accessible Norwegian sources providing advice on drug safety in pregnancy - the product monographs in the Felleskatalog (FK), published by the pharmaceutical companies, and the five regional Drug Information Centres (DICs) in Norway - in addition to assessing the frequency of questions regarding drug safety in pregnancy made to the DICs according to the Anatomical Therapeutic Chemical (ATC) classification system. Advice on drug use in pregnancy provided by the DICs in 2003 and 2005 were compared with advice in the product monographs for the respective drugs in the FK. Comparison of advice was based on categorization to one of four categories: can be used, benefit-risk assessment, should not be used, or no available information. A total of 443 drug advice were categorized. Seven out of ten of drugs frequently enquired about, according to the ATC system, were drugs acting on the nervous system (group N). For 208 (47%) of the drugs, advice differed between the DICs and FK. Advice from the FK was significantly (p drugs that were newly introduced and those that had been on the market for a longer time, advice regarding use of drugs in the first trimester and advice regarding use of drugs in the second or third trimester, or between advice provided during 2003 and during 2005. The results of this study show considerable differences between two Norwegian sources providing advice on the use of drugs in pregnancy. Based on the knowledge that healthcare providers choose sources of information in a random manner, our results may be of clinical importance. We believe that the problem with heterogeneous drug information on this

  9. Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre-clinical investigation

    Girelli, Roberto; Prejanò, Simona; Cataldo, Ivana; Corbo, Vincenzo; Martini, Lucia; Scarpa, Aldo; Claudio, Bassi

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents. The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 μs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium (MTS) assay. In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation. Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma

  10. Enhancing food safety: the role of the Food and Drug Administration

    Wallace, Robert B; Oria, Maria

    2010-01-01

    .... Food and Drug Administration's abilities to discover potential threats to food safety and prevent outbreaks of foodborne illness are hampered by impediments to efficient use of its limited resources...

  11. Laparoscopic cholecystectomy in acute gallstone pancreatitis in index hospital admission: feasibility and safety.

    Sangrasi, Ahmed Khan; Syed, Bm; Memon, Amir Iqbal; Laghari, Abdul Aziz; Talpur, K Altaf Hussain; Qureshi, Jawaid Naeem

    2014-05-01

    Acute gallstone pancreatitis is quite common throughout the globe. Conventionally definitive cholecystectomy has been delayed in index hospital admission. Since the last decade timing of cholecystectomy is gradually shifting towards the earlier phase of disease and currently gallstone pancreatitis is being evaluated as a further indication for laparoscopic cholecystectomy. There is also great concern regarding compliance of patients for definitive surgery due to poverty, ignorance and illiteracy in developing countries. The aim of this study was to assess the feasibility and safety of laparoscopic cholecystectomy as a definitive treatment in patients with mild and resolving gall stone pancreatitis. This was a prospective study from July 2009 to June 2012. Patients were diagnosed by clinical examination, biochemical tests, ultrasonography and contrast enhanced CT. Patients with mild form of the disease (Ranson Score ≤3) and who showed clinical improvement were offered laparoscopic cholecystectomy in index hospital admission. Those who were unfit for surgery were referred for endoscopic sphincterotomy. Common bile duct stones were excluded preoperatively. A total of 38 patients were admitted with acute gallstone pancreatitis in the study period. The mean age of patients was 46.3 years with male to female ratio of 11/27. 22 (57.8%) patients were selected for laparoscopic cholecystectomy and procedure was completed successfully. Ten (26.3%) patients were referred for ERCP and endoscopic sphincterotomy and 11 (28.9%) were managed by conservative treatment and went without any definitive treatment. Mean duration of time from onset of symptoms and laparoscopic cholecystectomy was 7 days (range 4-10). Mean duration of operative time was 45 minutes and hospital stay was 7 days. There was no operative mortality. No major intra-operative or post-operative complication was recorded. two patients (9%) had minor complications. Laparoscopic cholecystectomy can be safely

  12. Feasibility and safety of same-day discharge after laparoscopic radical hysterectomy for cervix cancer.

    Philp, Lauren; Covens, Allan; Vicus, Danielle; Kupets, Rachel; Pulman, Katherine; Gien, Lilian T

    2017-12-01

    To evaluate the safety and feasibility of same day-discharge (SDD) after laparoscopic radical hysterectomy for cervix cancer by determining complication rates and factors associated with post-operative admission. In this retrospective cohort study, patients undergoing laparoscopic radical hysterectomy for cervix cancer at a single institution from January 2006 to November 2015 were identified. Admitted patients were compared to same-day discharge patients. Rates of post-operative complications and readmission were analyzed and regression analysis used to determine factors associated with admission. 119 patients were identified. 75 (63%) were SDD patients (mean stay 156.7±50.2min) and 44 (37%) were admitted patients (mean stay 1.2±0.6days). Ten (13%) SDD patients sought medical attention within 30days post-operatively vs. nine (20%) admitted patients (p=0.17). Reasons SDD patients sought attention included pain (n=1), wound concerns (n=2), vaginal bleeding (n=2), DVT/VTE (n=1), fever (n=2) and fistula (n=2). All patients developed symptoms and presented between 5 and 13days post-operatively thus no complications could have been detected or prevented through initial admission. Four SDD patients were readmitted within 30days of surgery (p=0.25), two required re-operation (p=0.16). Admitted patients were older (p=0.049), had longer operations (p=0.02), increased blood loss (p=0.0004), increased intra-operative complications (p=0.001), surgery later in the day (p=0.004) and before April 2010 (p=0.001). On multivariate analysis, older age (OR1.05, p=0.03), surgery later in the day (OR 7.22, p=0.002) and presence of an intra-operative complication (OR 10.25, p=0.02) were significantly associated with admission. Same-day discharge after laparoscopic radical hysterectomy for cervix cancer is safe, with a low risk of post-operative morbidity and hospital readmission. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients

    Kristensen, L E; Jakobsen, A K; Askling, J

    2015-01-01

    OBJECTIVE: Safety data regarding the use of etoricoxib and other nonsteroidal antiinflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. Our objective was to estimate and compare rates of gastrointestinal, renovascular, and cardio......OBJECTIVE: Safety data regarding the use of etoricoxib and other nonsteroidal antiinflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. Our objective was to estimate and compare rates of gastrointestinal, renovascular...

  14. Drug and alcohol crash risk : traffic safety facts : research note.

    2015-02-01

    While the extent of use of alcohol by drivers and the risks posed by alcohol use have been well known for many decades, relatively little has been known about the use of other drugs by drivers and the associated risks. However, drug-impaired driving ...

  15. Environmental, Safety, and Health Plan for the remedial investigation/feasibility study at Oak Ridge National Laboratory, Oak Ridge, Tennessee

    1993-05-01

    This Environmental, Safety, and Health (ES ampersand H) Plan presents the concepts and methodologies to be followed during the remedial investigation/feasibility study (RI/FS) for Oak Ridge National Laboratory (ORNL) to protect the health and safety of employees, the public, and the environment. This ES ampersand H Plan acts as a management extension for ORNL and Martin Marietta Energy Systems, Inc. (Energy Systems) to direct and control implementation of the project ES ampersand H program. The subsections that follow describe the program philosophy, requirements, quality assurance measures, and methods for applying the ES ampersand H program to individual waste area grouping (WAG) remedial investigations. Hazardous work permits (HWPs) will be used to provide task-specific health and safety requirements

  16. Patient-led training on patient safety: a pilot study to test the feasibility and acceptability of an educational intervention.

    Jha, V; Winterbottom, A; Symons, J; Thompson, Z; Quinton, N; Corrado, O J; Melville, C; Watt, I; Torgerson, D; Wright, J

    2013-09-01

    Training in patient safety is an important element of medical education. Most educational interventions on patient safety training adopt a 'health-professional lens' with limited consideration on the impact of safety lapses on the patient and their families and little or no involvement of patients in the design or delivery of the training. This paper describes a pilot study to test the feasibility and acceptability of implementing a patient-led educational intervention to facilitate safety training amongst newly qualified doctors. Patients and/or carers who had experienced harm during their care shared narratives of their stories with trainees; this was followed by a focused discussion on patient safety issues exploring the causes and consequences of safety incidents and lessons to be learned from these. The intervention, which will be further tested in an NIHR-funded randomised controlled trial (RCT), was successfully implemented into an existing training programme and found acceptance amongst the patients and trainees. The pilot study proved to be a useful step in refining the intervention for the RCT including identifying appropriate outcome measures and highlighting organisational issues.

  17. Continuous Postoperative Pericardial Flushing: A Pilot Study on Safety, Feasibility, and Effect on Blood Loss

    Johan S.J. Manshanden

    2015-09-01

    Conclusions: CPPF after cardiac surgery was found to be safe and feasible in this experimental setting. The clinically relevant effect on blood loss needs to be confirmed in a randomized clinical trial.

  18. Legacy data sharing to improve drug safety assessment: the eTOX project

    Sanz, Ferran; Pognan, François; Steger-Hartmann, Thomas

    2017-01-01

    The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through...

  19. Safety, efficacy, and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis

    Egeberg, A; Ottosen, M B; Gniadecki, R

    2018-01-01

    BACKGROUND: Real-life data on newer biologic and biosimilar agents for moderate-to-severe psoriasis are lacking. OBJECTIVES: To examine safety, efficacy, and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab) and compare origina...... the long-term safety of novel biologics for psoriasis. This article is protected by copyright. All rights reserved....

  20. The Influence of Safety, Efficacy, and Medical Condition Severity on Natural versus Synthetic Drug Preference.

    Meier, Brian P; Lappas, Courtney M

    2016-11-01

    Research indicates that there is a preference for natural v. synthetic products, but the influence of this preference on drug choice in the medical domain is largely unknown. We present 5 studies in which participants were asked to consider a hypothetical situation in which they had a medical issue requiring pharmacological therapy. Participants ( N = 1223) were asked to select a natural, plant-derived, or synthetic drug. In studies 1a and 1b, approximately 79% of participants selected the natural v. synthetic drug, even though the safety and efficacy of the drugs were identical. Furthermore, participants rated the natural drug as safer than the synthetic drug, and as that difference increased, the odds of choosing the natural over synthetic drug increased. In studies 2 and 3, approximately 20% of participants selected the natural drug even when they were informed that it was less safe (study 2) or less effective (study 3) than the synthetic drug. Finally, in study 4, approximately 65% of participants chose a natural over synthetic drug regardless of the severity of a specific medical condition (mild v. severe hypertension), and this choice was predicted by perceived safety and efficacy differences. Overall, these data indicate that there is a bias for natural over synthetic drugs. This bias could have implications for drug choice and usage. © The Author(s) 2015.

  1. Pancreatic Safety of Incretin-Based Drugs - FDA and EMA Assessment

    Egan, Amy G.; Blind, Eberhard; Dunder, Kristina; de Graeff, Pieter A.; Hummer, B. Timothy; Bourcier, Todd; Rosebraugh, Curtis

    2014-01-01

    After evaluating a safety signal regarding pancreatitis and pancreatic cancer in patients using incretin-based drugs, the Food and Drug Administration and the European Medicines Agency conclude that assertions of a causal association are inconsistent with the data. With approximately 25.8 million

  2. 78 FR 71036 - Pipeline Safety: Random Drug Testing Rate; Contractor Management Information System Reporting...

    2013-11-27

    ... PHMSA-2013-0248] Pipeline Safety: Random Drug Testing Rate; Contractor Management Information System Reporting; and Obtaining Drug and Alcohol Management Information System Sign-In Information AGENCY: Pipeline... Management Information System (MIS) Data; and New Method for Operators to Obtain User Name and Password for...

  3. Drug Safety Monitoring in Children: Performance of Signal Detection Algorithms and Impact of Age Stratification

    O.U. Osokogu (Osemeke); C. Dodd (Caitlin); A.C. Pacurariu (Alexandra C.); F. Kaguelidou (Florentia); D.M. Weibel (Daniel); M.C.J.M. Sturkenboom (Miriam)

    2016-01-01

    textabstractIntroduction: Spontaneous reports of suspected adverse drug reactions (ADRs) can be analyzed to yield additional drug safety evidence for the pediatric population. Signal detection algorithms (SDAs) are required for these analyses; however, the performance of SDAs in the pediatric

  4. Assessment of pharmacovigilance approaches for monitoring the safety of antimalarial drugs in pregnancy

    Dellicour, S.O.M.C.

    2014-01-01

    Post-marketing surveillance of drugs used in pregnancy is challenging, especially in developing countries where resources for pharmacovigilance are rare. There is a need to establish simple but effective systems to monitor safety of drugs given during pregnancy in resource constrained countries.

  5. Drug safety alerts of pharmacovigilance programme of India: A scope for targeted spontaneous reporting in India

    Prasad Thota

    2018-01-01

    Conclusion: In India, spontaneous reporting of ADRs existed since 1998 under passive surveillance method, but there is an urgent need to initiate TSR, which is a complementary method to spontaneous reporting on these drug safety alerts for further regulatory action by Central Drugs Standard Control Organization.

  6. Feasibility, safety and outcomes of playing Kinect Adventures!™ for people with Parkinson's disease: a pilot study.

    Pompeu, J E; Arduini, L A; Botelho, A R; Fonseca, M B F; Pompeu, S M A A; Torriani-Pasin, C; Deutsch, J E

    2014-06-01

    To assess the feasibility, safety and outcomes of playing Microsoft Kinect Adventures™ for people with Parkinson's disease in order to guide the design of a randomised clinical trial. Single-group, blinded trial. Rehabilitation Center of São Camilo University, Brazil. Seven patients (six males, one female) with Parkinson's disease (Hoehn and Yahr Stages 2 and 3). Fourteen 60-minute sessions, three times per week, playing four games of Kinect Adventures! The feasibility and safety outcomes were patients' game performance and adverse events, respectively. The clinical outcomes were the 6-minute walk test, Balance Evaluation System Test, Dynamic Gait Index and Parkinson's Disease Questionnaire (PDQ-39). Patients' scores for the four games showed improvement. The mean [standard deviation (SD)] scores in the first and last sessions of the Space Pop game were 151 (36) and 198 (29), respectively [mean (SD) difference 47 (7), 95% confidence interval 15 to 79]. There were no adverse events. Improvements were also seen in the 6-minute walk test, Balance Evaluation System Test, Dynamic Gait Index and PDQ-39 following training. Kinect-based training was safe and feasible for people with Parkinson's disease (Hoehn and Yahr Stages 2 and 3). Patients improved their scores for all four games. No serious adverse events occurred during training with Kinect Adventures!, which promoted improvement in activities (balance and gait), body functions (cardiopulmonary aptitude) and participation (quality of life). Copyright © 2013 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

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

    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

  8. E-learning to improve the drug prescribing in the hospitalized elderly patients: the ELICADHE feasibility pilot study.

    Franchi, C; Mari, D; Tettamanti, M; Pasina, L; Djade, C D; Mannucci, P M; Onder, G; Bernabei, R; Gussoni, G; Bonassi, S; Nobili, A

    2014-08-01

    E-learning is an efficient and cost-effective educational method. This study aimed at evaluating the feasibility of an educational e-learning intervention, focused on teaching geriatric pharmacology and notions of comprehensive geriatric assessment, to improve drug prescribing to hospitalized elderly patients. Eight geriatric and internal medicine wards were randomized to intervention (e-learning educational program) or control. Clinicians of the two groups had to complete a specific per group e-learning program in 30 days. Then, ten patients (aged ≥75 years) had to be consecutively enrolled collecting clinical data at hospital admission, discharge, and 3 months later. The quality of prescription was evaluated comparing the prevalence of potentially inappropriate medications through Beer's criteria and of potential drug-drug interactions through a specific computerized database. The study feasibility was confirmed by the high percentage (90 %) of clinicians who completed the e-learning program, the recruitment, and follow-up of all planned patients. The intervention was well accepted by all participating clinicians who judged positively (a mean score of >3 points on a scale of 5 points: 0 = useless; 5 = most useful) the specific contents, the methodology applied, the clinical relevance and utility of e-learning contents and tools for the evaluation of the appropriateness of drug prescribing. The pilot study met all the requested goals. The main study is currently ongoing and is planned to finish on July 2015.

  9. Changes in the utilization of osteoporosis drugs after the 2010 FDA bisphosphonate drug safety communication

    Bander Balkhi

    2018-02-01

    Conclusions: The 2010 FDA bisphosphonates safety communication appeared to have influenced Osteoporosis utilization in Medicaid recipients. The 2010 FDA bisphosphonates safety communication was associated with a significant reduction in the utilization of bisphosphonates in the Medicaid program.

  10. CRASH - Community Road Accident System Homepage : feasibility study on a European Road Safety Information System, financially supported by the European Commission.

    Brouwer, M. Poppe, F. Blokpoel, A. & Kars, V.

    2000-01-01

    This report is the result of a feasibility study, financially supported by the European Commission. The study investigated the possibilities for the development and maintenance of a European Road Safety Information System with relevant and internationally comparable information. Recommendations on

  11. A primer of drug safety surveillance: an industry perspective. Part II: Product labeling and product knowledge.

    Allan, M C

    1992-01-01

    To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part II of this series discusses specific issues regarding product labeling, such as developing the labeling, changing the labeling, and the legal as well as commercial ramifications of the contents of the labeling. An adverse event report scenario is further analyzed and suggestions are offered for maintaining the product labeling as an accurate reflection of the drug safety surveillance data. This article also emphasizes the necessity of product knowledge in adverse event database management. Both scientific and proprietary knowledge are required. Acquiring product knowledge is a part of the day-to-day activities of drug safety surveillance. A knowledge of the history of the product may forestall adverse publicity, as shown in the illustration. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction of the components of the process. Suggestions are offered

  12. Application of the Pareto principle to identify and address drug-therapy safety issues.

    Müller, Fabian; Dormann, Harald; Pfistermeister, Barbara; Sonst, Anja; Patapovas, Andrius; Vogler, Renate; Hartmann, Nina; Plank-Kiegele, Bettina; Kirchner, Melanie; Bürkle, Thomas; Maas, Renke

    2014-06-01

    Adverse drug events (ADE) and medication errors (ME) are common causes of morbidity in patients presenting at emergency departments (ED). Recognition of ADE as being drug related and prevention of ME are key to enhancing pharmacotherapy safety in ED. We assessed the applicability of the Pareto principle (~80 % of effects result from 20 % of causes) to address locally relevant problems of drug therapy. In 752 cases consecutively admitted to the nontraumatic ED of a major regional hospital, ADE, ME, contributing drugs, preventability, and detection rates of ADE by ED staff were investigated. Symptoms, errors, and drugs were sorted by frequency in order to apply the Pareto principle. In total, 242 ADE were observed, and 148 (61.2 %) were assessed as preventable. ADE contributed to 110 inpatient hospitalizations. The ten most frequent symptoms were causally involved in 88 (80.0 %) inpatient hospitalizations. Only 45 (18.6 %) ADE were recognized as drug-related problems until discharge from the ED. A limited set of 33 drugs accounted for 184 (76.0 %) ADE; ME contributed to 57 ADE. Frequency-based listing of ADE, ME, and drugs involved allowed identification of the most relevant problems and development of easily to implement safety measures, such as wall and pocket charts. The Pareto principle provides a method for identifying the locally most relevant ADE, ME, and involved drugs. This permits subsequent development of interventions to increase patient safety in the ED admission process that best suit local needs.

  13. [Drug supply chain safety in hospitals: current data and experience of the Grenoble university hospital].

    Bedouch, P; Baudrant, M; Detavernier, M; Rey, C; Brudieu, E; Foroni, L; Allenet, B; Calop, J

    2009-01-01

    Drug supply chain safety has become a priority for public health which implies a collective process. This process associates all health professionals including the pharmacist who plays a major role. The objective of this present paper is to describe the several approaches proven effective in the reduction of drug-related problem in hospital, illustrated by the Grenoble University Hospital experience. The pharmacist gets involved first in the general strategy of hospital drug supply chain, second by his direct implication in clinical activities. The general strategy of drug supply chain combines risk management, coordination of the Pharmacy and Therapeutics Committee, selection and purchase of drugs and organisation of drug supply chain. Computer management of drug supply chain is a major evolution. Nominative drug delivering has to be a prior objective and its implementation modalities have to be defined: centralized or decentralized in wards, manual or automated. Also, new technologies allow the automation of overall drug distribution from central pharmacy and the implementation of automated drug dispensing systems into wards. The development of centralised drug preparation allows a safe compounding of high risk drugs, like cytotoxic drugs. The pharmacist should develop his clinical activities with patients and other health care professionals in order to optimise clinical decisions (medication review, drug order analysis) and patients follow-up (therapeutic monitoring, patient education, discharge consultation).

  14. Mathematical modeling of efficacy and safety for anticancer drugs clinical development.

    Lavezzi, Silvia Maria; Borella, Elisa; Carrara, Letizia; De Nicolao, Giuseppe; Magni, Paolo; Poggesi, Italo

    2018-01-01

    Drug attrition in oncology clinical development is higher than in other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development. Areas covered: Herein, the most relevant mathematical models used in clinical anticancer drug development during the last decade are described. Less recent models were considered in the review if they represent a standard for the analysis of certain types of efficacy or safety measures. Expert opinion: Several mathematical models have been proposed to predict overall survival from earlier endpoints and validate their surrogacy in demonstrating drug efficacy in place of overall survival. An increasing number of mathematical models have also been developed to describe the safety findings. Modeling has been extensively used in anticancer drug development to individualize dosing strategies based on patient characteristics, and design optimal dosing regimens balancing efficacy and safety.

  15. Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and toxicology assessments.

    McGivern, Jered V; Ebert, Allison D

    2014-04-01

    In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body and recapitulate human disease, may be an important cellular system to add to the drug development repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery and safety studies as well as some of the recent applications of stem cells in drug screening studies. We will also address some of the hurdles that need to be overcome in order to make stem cell-based approaches an efficient and effective tool in the quest to produce clinically successful drug compounds. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. The feasibility, safety and cost of infiltration anaesthesia for hernia repair. Hvidovre Hospital Hernia Group

    Callesen, T; Bech, K; Kehlet, H

    1998-01-01

    Data from 400 consecutive elective ambulatory operations for inguinal hernia under unmonitored local anaesthesia with limited pre-operative testing were prospectively obtained by the use of standardised files and questionnaires to assess the feasibility, patient satisfaction and potential cost re...

  17. Why trash don't pass? pharmaceutical licensing and safety performance of drugs.

    Banerjee, Tannista; Nayak, Arnab

    2017-01-01

    This paper examines how asymmetric information in pharmaceutical licensing affects the safety standards of licensed drugs. Pharmaceutical companies often license potential drug molecules at different stages of drug development from other pharmaceutical or biotechnology companies and complete the remaining of research stages before submitting the new drug application(NDA) to the food and drug administration. The asymmetric information associated with the quality of licensed molecules might result in the molecules which are less likely to succeed to be licensed out, while those with greater potential of success being held internally for development. We identify the NDAs submitted between 1993 and 2004 where new molecular entities were acquired through licensing. Controlling for other drug area specific and applicant firm specific factors, we investigate whether drugs developed with licensed molecules face higher probability of safety based recall and ultimate withdrawal from the market than drugs developed internally. Results suggest the opposite of Akerlof's (Q J Econ 84:488-500, 1970) lemons problem. Licensed molecules rather have less probability of facing safety based recalls and ultimate withdrawal from the market comparing to internally developed drug molecules. This suggests that biotechnology and small pharmaceutical firms specializing in pharmaceutical research are more efficient in developing good potential molecules because of their concentrated research. Biotechnology firms license out good potential molecules because it increases their market value and reputation. In addition, results suggest that both the number of previous approved drugs in the disease area, and also the applicant firms' total number of previous approvals in all disease areas reduce the probability that an additional approved drug in the same drug area will potentially be harmful.

  18. Suspected adverse drug reactions in elderly patients reported to the Committee on Safety of Medicines.

    Castleden, C M; Pickles, H

    1988-01-01

    1. Spontaneous reports of suspected adverse drug reactions (ADRs) reported to the Committee on Safety of Medicines (CSM) have been studied in relation to patient age. 2. The proportion of reports received for the elderly increased between 1965 and 1983. 3. There was a correlation between the use of drugs and the number of ADR reports. Thus age-related prescription figures for two non-steroidal anti-inflammatory drugs (NSAI) and co-trimoxazole matched ADR reports for each drug in each age grou...

  19. Drug safety data mining with a tree-based scan statistic.

    Kulldorff, Martin; Dashevsky, Inna; Avery, Taliser R; Chan, Arnold K; Davis, Robert L; Graham, David; Platt, Richard; Andrade, Susan E; Boudreau, Denise; Gunter, Margaret J; Herrinton, Lisa J; Pawloski, Pamala A; Raebel, Marsha A; Roblin, Douglas; Brown, Jeffrey S

    2013-05-01

    In post-marketing drug safety surveillance, data mining can potentially detect rare but serious adverse events. Assessing an entire collection of drug-event pairs is traditionally performed on a predefined level of granularity. It is unknown a priori whether a drug causes a very specific or a set of related adverse events, such as mitral valve disorders, all valve disorders, or different types of heart disease. This methodological paper evaluates the tree-based scan statistic data mining method to enhance drug safety surveillance. We use a three-million-member electronic health records database from the HMO Research Network. Using the tree-based scan statistic, we assess the safety of selected antifungal and diabetes drugs, simultaneously evaluating overlapping diagnosis groups at different granularity levels, adjusting for multiple testing. Expected and observed adverse event counts were adjusted for age, sex, and health plan, producing a log likelihood ratio test statistic. Out of 732 evaluated disease groupings, 24 were statistically significant, divided among 10 non-overlapping disease categories. Five of the 10 signals are known adverse effects, four are likely due to confounding by indication, while one may warrant further investigation. The tree-based scan statistic can be successfully applied as a data mining tool in drug safety surveillance using observational data. The total number of statistical signals was modest and does not imply a causal relationship. Rather, data mining results should be used to generate candidate drug-event pairs for rigorous epidemiological studies to evaluate the individual and comparative safety profiles of drugs. Copyright © 2013 John Wiley & Sons, Ltd.

  20. Nonsteroidal anti-inflammatory drug gastropathy: new avenues for safety

    Roth, Sandford

    2011-01-01

    Sanford H RothArizona Research and Education, Arthritis Laboratory, Arizona State University, Phoenix, AZ, USAAbstract: Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID) therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less...

  1. Phase Two Feasibility Study for Software Safety Requirements Analysis Using Model Checking

    Turgeon, Gregory; Price, Petra

    2010-01-01

    A feasibility study was performed on a representative aerospace system to determine the following: (1) the benefits and limitations to using SCADE , a commercially available tool for model checking, in comparison to using a proprietary tool that was studied previously [1] and (2) metrics for performing the model checking and for assessing the findings. This study was performed independently of the development task by a group unfamiliar with the system, providing a fresh, external perspective free from development bias.

  2. Feasibility, safety, acceptability, and preliminary efficacy of measurement-based care depression treatment for HIV patients in Bamenda, Cameroon.

    Pence, Brian W; Gaynes, Bradley N; Atashili, Julius; O'Donnell, Julie K; Kats, Dmitry; Whetten, Kathryn; Njamnshi, Alfred K; Mbu, Tabenyang; Kefie, Charles; Asanji, Shantal; Ndumbe, Peter

    2014-06-01

    Depression affects 18-30 % of HIV-infected patients in Africa and is associated with greater stigma, lower antiretroviral adherence, and faster disease progression. However, the region's health system capacity to effectively identify and treat depression is limited. Task-shifting models may help address this large mental health treatment gap. Measurement-Based Care (MBC) is a task-shifting model in which a Depression Care Manager guides a non-psychiatric (e.g., HIV) provider in prescribing and managing antidepressant treatment. We adapted MBC for depressed HIV-infected patients in Cameroon and completed a pilot study to assess feasibility, safety, acceptability, and preliminary efficacy. We enrolled 55 participants; all started amitriptyline 25-50 mg daily at baseline. By 12 weeks, most remained at 50 mg daily (range 25-125 mg). Median (interquartile range) PHQ-9 depressive severity scores declined from 13 (12-16) (baseline) to 2 (0-3) (week 12); 87 % achieved depression remission (PHQ-9 feasibility, safety, acceptability, and preliminary efficacy in this uncontrolled pilot study. Further research should assess whether MBC could improve adherence and HIV outcomes in this setting.

  3. Feasibility of subcutaneously implanted magnetic microarrays for site specific drug and gene targeting

    M. Babincová

    2010-01-01

    Full Text Available The magnetic nanoparticles play a crucial role as a drug carriers in the human body. The wedge like magnetic arrays creatinga strongly non-homogeneous magnetic field are considered as a useful way to focus magnetic nanoparticles functionalizedwith various drugs or genes to desired sites. The goal of this study is to develop a numerical model of drug targetingusing subcutaneously implanted magnetic microarrays. The Finite Element Method is applied to solve partial differentialequations describing electromagnetic field (Maxwell equations and motion of these particles in a given magnetic field isobtained solving set of ordinary differential equations expressed by Newton law of motion. The results are encouragingshowing the potential to target drug to the tumour cell locally, without unwanted side effects.

  4. Therapeutic drug monitoring: how to improve drug dosage and patient safety in tuberculosis treatment

    Giovanni Sotgiu

    2015-03-01

    Full Text Available In this article we describe the key role of tuberculosis (TB treatment, the challenges (mainly the emergence of drug resistance, and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and contribution of therapeutic drug monitoring (TDM is discussed in detail. Treatment success in multidrug-resistant (MDR TB cases is low (62%, with 7% failing or relapsing and 9% dying and in extensively drug-resistant (XDR TB cases is even lower (40%, with 22% failing or relapsing and 15% dying. The treatment of drug-resistant TB is also more expensive (exceeding €50 000 for MDR-TB and €160 000 for XDR-TB and more toxic if compared to that prescribed for drug-susceptible TB. Appropriate dosing of first- and second-line anti-TB drugs can improve the patient's prognosis and lower treatment costs. TDM is based on the measurement of drug concentrations in blood samples collected at appropriate times and subsequent dose adjustment according to the target concentration. The ‘dried blood spot’ technique offers additional advantages, providing the rationale for discussions regarding a possible future network of selected, quality-controlled reference laboratories for the processing of dried blood spots of difficult-to-treat patients from reference TB clinics around the world.

  5. Safety and problems in using radioactive drugs in hospitals

    Arimizu, Noboru

    1975-01-01

    The safety and the control problem of non-closed RI (radiopharmaceuticals) of which use has rapidly been increased, were studied. At present, the hospitals with an independent clinic for the nuclear medicine are very limited and many doctors, nurses and safety controllers who are working in the clinic belong to other clinics. As for the diagnosis using RI examination, the dangers of the persons who are working with radioimmunoassay, especially using Au-antigen kit were studied. Furthermore, the problems concerning the reduction of exposure dose by the use of a short half-life RI, such as sup(99m)Tc and the dangers of external exposure on the persons who use the isotope were studied. In addition, the control of RI ward for RI therapy was discussed. The author considered the specialization and fixation of doctors, nurses and technicians are becoming of necessity with the advancement of RI therapy. In addition, the necessity of training nurses for the nuclear medicine was insisted on. (Tsukamoto, Y.)

  6. Safety and problems in using radioactive drugs in hospitals

    Arimizu, N [National Inst. of Radiological Sciences, Chiba (Japan)

    1975-01-01

    The safety and the control problem of non-closed RI (radiopharmaceuticals) of which use has rapidly been increased, were studied. At present, the hospitals with an independent clinic for the nuclear medicine are very limited and many doctors, nurses and safety controllers who are working in the clinic belong to other clinics. As for the diagnosis using RI examination, the dangers of the persons who are working with radioimmunoassay, especially using Au-antigen kit were studied. Furthermore, the problems concerning the reduction of exposure dose by the use of a short half-life RI, such as sup(99m)Tc and the dangers of external exposure on the persons who use the isotope were studied. In addition, the control of RI ward for RI therapy was discussed. The author considered the specialization and fixation of doctors, nurses and technicians are becoming of necessity with the advancement of RI therapy. In addition, the necessity of training nurses for the nuclear medicine was insisted on.

  7. Safety risks with investigational drugs: Pharmacy practices and perceptions in the veterans affairs health system.

    Cruz, Jennifer L; Brown, Jamie N

    2015-06-01

    Rigorous practices for safe dispensing of investigational drugs are not standardized. This investigation sought to identify error-prevention processes utilized in the provision of investigational drug services (IDS) and to characterize pharmacists' perceptions about safety risks posed by investigational drugs. An electronic questionnaire was distributed to an audience of IDS pharmacists within the Veteran Affairs Health System. Multiple facets were examined including demographics, perceptions of medication safety, and standard processes used to support investigational drug protocols. Twenty-one respondents (32.8% response rate) from the Northeast, Midwest, South, West, and Non-contiguous United States participated. The mean number of pharmacist full-time equivalents (FTEs) dedicated to the IDS was 0.77 per site with 0.2 technician FTEs. The mean number of active protocols was 22. Seventeen respondents (81%) indicated some level of concern for safety risks. Concerns related to the packaging of medications were expressed, most notably lack of product differentiation, expiration dating, barcodes, and choice of font size or color. Regarding medication safety practices, the majority of sites had specific procedures in place for storing and securing drug supply, temperature monitoring, and prescription labeling. Repackaging bulk items and proactive error-identification strategies were less common. Sixty-seven percent of respondents reported that an independent double check was not routinely performed. Medication safety concerns exist among pharmacists in an investigational drug service; however, a variety of measures have been employed to improve medication safety practices. Best practices for the safe dispensing of investigational medications should be developed in order to standardize these error-prevention strategies.

  8. Integrated safety analysis of rolapitant with coadministered drugs from phase II/III trials

    Barbour, S; Smit, T.; Wang, X

    2017-01-01

    adverse events by use versus non-use of drug substrates of CYP2D6 or BCRP. Patients and methods: Patients were randomized to receive either 180 mg oral rolapitant or placebo approximately 1-2 hours before chemotherapy in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Data...... cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug-drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined...... for treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) during cycle 1 were pooled across the four studies and summarized in the overall population and by concomitant use/non-use of CYP2D6 or BCRP substrate drugs. Results: In the integrated safety population, 828...

  9. Feasibility, safety, and efficacy of aerobic training in pretreated patients with metastatic breast cancer: A randomized controlled trial.

    Scott, Jessica M; Iyengar, Neil M; Nilsen, Tormod S; Michalski, Meghan; Thomas, Samantha M; Herndon, James; Sasso, John; Yu, Anthony; Chandarlapaty, Sarat; Dang, Chau T; Comen, Elizabeth A; Dickler, Maura N; Peppercorn, Jeffrey M; Jones, Lee W

    2018-04-06

    The investigation of exercise training in metastatic breast cancer has received minimal attention. This study determined the feasibility and safety of aerobic training in metastatic breast cancer. Sixty-five women (age, 21-80 years) with metastatic (stage IV) breast cancer (57% were receiving chemotherapy, and >40% had ≥ 2 lines of prior therapy) were allocated to an aerobic training group (n = 33) or a stretching group (n = 32). Aerobic training consisted of 36 supervised treadmill walking sessions delivered thrice weekly between 55% and 80% of peak oxygen consumption (VO 2peak ) for 12 consecutive weeks. Stretching was matched to aerobic training with respect to location, frequency, duration, and intervention length. The primary endpoint was aerobic training feasibility, which was a priori defined as the lost to follow-up (LTF) rate (aerobic training was LTF, whereas the mean attendance rate was 63% ± 30%. The rates of permanent discontinuation and dose modification were 27% and 49%, respectively. Intention-to-treat analyses indicated improvements in PROs, which favored the attention control group (P values > .05). Per protocol analyses indicated that 14 of 33 patients (42%) receiving aerobic training had acceptable tolerability (relative dose intensity ≥ 70%), and this led to improvements in VO 2peak and functional capacity (P values Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of patients with metastatic breast cancer. The acceptable feasibility and promising benefit for select patients warrant further evaluation in a dose-finding phase 1/2 study. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

  10. Current MitraClip experience, safety and feasibility in the Netherlands

    Rahhab, Z.; Kortlandt, F. A.; Velu, J. F.; Schurer, R. A. J.; Delgado, V.; Tonino, P.; Boven, A. J.; van den Branden, B. J. L.; Kraaijeveld, A. O.; Voskuil, M.; Hoorntje, J.; van Wely, M. [=Marleen; van Houwelingen, K.; Bleeker, G. B.; Rensing, B.; Kardys, I.; Baan, J.; van der Heyden, J. A. S.; van Mieghem, N. M.

    2017-01-01

    Purpose Data on MitraClip procedural safety and efficacy in the Netherlands are scarce. We aim to provide an overview of the Dutch MitraClip experience. Methods We pooled anonymised demographic and procedural data of 1151 consecutive MitraClip patients, from 13 Dutch hospitals. Data was collected by

  11. Preventing errors in administration of parenteral drugs: the results of a four-year national patient safety program.

    Blok, C. de; Schilp, J.; Wagner, C.

    2013-01-01

    Objectives: To evaluate the implementation of a four-year national patient safety program concerning the parenteral drug administration process in the Netherlands. Methods: Structuring the preparation and administration process of parenteral drugs reduces the number of medication errors. A

  12. The Patient's Voice in Pharmacovigilance: Pragmatic Approaches to Building a Patient-Centric Drug Safety Organization.

    Smith, Meredith Y; Benattia, Isma

    2016-09-01

    Patient-centeredness has become an acknowledged hallmark of not only high-quality health care but also high-quality drug development. Biopharmaceutical companies are actively seeking to be more patient-centric in drug research and development by involving patients in identifying target disease conditions, participating in the design of, and recruitment for, clinical trials, and disseminating study results. Drug safety departments within the biopharmaceutical industry are at a similar inflection point. Rising rates of per capita prescription drug use underscore the importance of having robust pharmacovigilance systems in place to detect and assess adverse drug reactions (ADRs). At the same time, the practice of pharmacovigilance is being transformed by a host of recent regulatory guidances and related initiatives which emphasize the importance of the patient's perspective in drug safety. Collectively, these initiatives impact the full range of activities that fall within the remit of pharmacovigilance, including ADR reporting, signal detection and evaluation, risk management, medication error assessment, benefit-risk assessment and risk communication. Examples include the fact that manufacturing authorization holders are now expected to monitor all digital sources under their control for potential reports of ADRs, and the emergence of new methods for collecting, analysing and reporting patient-generated ADR reports for signal detection and evaluation purposes. A drug safety department's ability to transition successfully into a more patient-centric organization will depend on three defining attributes: (1) a patient-centered culture; (2) deployment of a framework to guide patient engagement activities; and (3) demonstrated proficiency in patient-centered competencies, including patient engagement, risk communication and patient preference assessment. Whether, and to what extent, drug safety departments embrace the new patient-centric imperative, and the methods and

  13. Safety and efficacy of generic drugs with respect to brand formulation

    Gallelli, Luca; Palleria, Caterina; De Vuono, Antonio; Mumoli, Laura; Vasapollo, Piero; Piro, Brunella; Russo, Emilio

    2013-01-01

    Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to gener...

  14. Transdermal drug delivery: feasibility for treatment of superficial bone stress fractures.

    Aghazadeh-Habashi, Ali; Yang, Yang; Tang, Kathy; Lőbenberg, Raimar; Doschak, Michael R

    2015-12-01

    Transdermal drug delivery offers the promise of effective drug therapy at selective sites of pathology whilst reducing systemic exposure to the pharmaceutical agents in off-target organs and tissues. However, that strategy is often limited to cells comprising superficial tissues of the body (rarely to deeper bony structures) and mostly indicated with small hydrophobic pharmacological agents, such as steroid hormones and anti-inflammatory gels to skin, muscle, and joints. Nonetheless, advances in transdermal liposomal formulation have rendered the ability to readily incorporate pharmacologically active hydrophilic drug molecules and small peptide biologics into transdermal dosage forms to impart the effective delivery of those bioactive agents across the skin barrier to underlying superficial tissue structures including bone, often enhanced by some form of electrical, chemical, and mechanical facilitation. In the following review, we evaluate transdermal drug delivery systems, with a particular focus on delivering therapeutic agents to treat superficial bone pain, notably stress fractures. We further introduce and discuss several small peptide hormones active in bone (such as calcitonins and parathyroid hormone) that have shown potential for transdermal delivery, often under the added augmentation of transdermal drug delivery systems that employ lipo/hydrophilicity, electric charge, and/or microprojection facilitation across the skin barrier.

  15. Feasibility of abdominal plain film images in evaluation suspected drug smuggler

    Sormaala, Markus J., E-mail: markus.sormaala@welho.com [Medical Imaging Center, Helsinki University Central Hospital, Helsinki (Finland); Salonen, Hanna-Mari, E-mail: hanna-mari.salonen@hus.fi [Medical Imaging Center, Helsinki University Central Hospital, Helsinki (Finland); Mattila, Ville M., E-mail: ville.mattila@uta.fi [Department of Orthopedic Surgery and Trauma, Tampere University Hospital, Tampere (Finland); Kivisaari, Arto, E-mail: arto.kivisaari@hus.fi [Medical Imaging Center, Helsinki University Central Hospital, Helsinki (Finland); Autti, Taina, E-mail: taina.autti@hus.fi [Medical Imaging Center, Helsinki University Central Hospital, Helsinki (Finland)

    2012-09-15

    Objective: Drug smuggling in the gastrointestinal tract has soared within the last 20 years. Though illegal substances in the gastrointestinal tract can be visualized with ultrasound, MRI and CT, the abdominal radiograph has by far remained the most frequently used way of detecting smuggled drugs. The purpose of the study was to evaluate the inter-radiologist interpretation error and the reliability of the abdominal radiograph in detecting smuggled drugs. Materials and methods: A total of 279 abdominal radiographs of suspected smugglers were classified by three radiologists as clearly positive or negative for drug smuggling. All available information about the cases was collected from the customs officers and police. Results: Out of these cases 203 (73%) were interpreted as negative and 35 (13%) as positive by all three radiologists. In 86% of the cases there was, therefore, an inter-radiological agreement in interpreting the images. In 41 (14%) cases, however, there was an inter-radiologist disagreement. Kappa-value for inter-observer variability was 0.70. Conclusions: In up to a seventh of the abdominal radiographs the interpretation can be challenging even for an experienced radiologist. False positive interpretation can lead to innocent passengers being detained in vain. As negatively interpreted images usually result in releasing of the suspect, there is no way of knowing how many false negative occur. This makes the abdominal radiograph a suboptimal examination, and low dose CT should be considered as the screening modality for gastrointestinal drug smugglers.

  16. Feasibility of abdominal plain film images in evaluation suspected drug smuggler

    Sormaala, Markus J.; Salonen, Hanna-Mari; Mattila, Ville M.; Kivisaari, Arto; Autti, Taina

    2012-01-01

    Objective: Drug smuggling in the gastrointestinal tract has soared within the last 20 years. Though illegal substances in the gastrointestinal tract can be visualized with ultrasound, MRI and CT, the abdominal radiograph has by far remained the most frequently used way of detecting smuggled drugs. The purpose of the study was to evaluate the inter-radiologist interpretation error and the reliability of the abdominal radiograph in detecting smuggled drugs. Materials and methods: A total of 279 abdominal radiographs of suspected smugglers were classified by three radiologists as clearly positive or negative for drug smuggling. All available information about the cases was collected from the customs officers and police. Results: Out of these cases 203 (73%) were interpreted as negative and 35 (13%) as positive by all three radiologists. In 86% of the cases there was, therefore, an inter-radiological agreement in interpreting the images. In 41 (14%) cases, however, there was an inter-radiologist disagreement. Kappa-value for inter-observer variability was 0.70. Conclusions: In up to a seventh of the abdominal radiographs the interpretation can be challenging even for an experienced radiologist. False positive interpretation can lead to innocent passengers being detained in vain. As negatively interpreted images usually result in releasing of the suspect, there is no way of knowing how many false negative occur. This makes the abdominal radiograph a suboptimal examination, and low dose CT should be considered as the screening modality for gastrointestinal drug smugglers

  17. Randomized Controlled Study on Safety and Feasibility of Transfusion Trigger Score of Emergency Operations

    De-Xing Liu

    2015-01-01

    Conclusions: Peri-operative Transfusion Trigger Score-E evaluation scheme is used to guide the application of RBC. There are no differences in the recent prognosis of patients with the traditional transfusion guidelines. This scheme is safe; Compared with doctor experience-based subjective assessment, the scoring scheme was closer to patient physiological needs for transfusion and more reasonable; Utilization rate and the per capita consumption of RBC are obviously declined, which has clinical significance and is feasible. Based on the abovementioned three points, POTTS-E scores scheme is safe, reasonable, and practicable and has the value for carrying out multicenter and large sample clinical researches.

  18. Pharmacovigilance in Crisis: Drug Safety at a Crossroads.

    Price, John

    2018-05-01

    Pharmacovigilance (PV) is under unprecedented stress from fundamental changes in a booming pharmaceutical industry, from the challenges of creating and maintaining an increasingly complex PV system in a globally diverse regulatory environment, and from unpredicted consequences of historical PV cost-reduction strategies. At the same time, talent availability lags demand, and many PV professionals may no longer be finding personal fulfillment in their careers. The situation creates risks for companies. Advantages and disadvantages of potential strategies to address this increasing problem at a corporate and industry level and in collaboration with regulatory agencies are discussed, as well as opportunities to adopt new technologies, including artificial intelligence and machine-learning to automate pharmacovigilance operations. These approaches would address burdensome and wasteful effort assuring regulatory compliance and free up resources to support the original mission of PV as an important public health activity and to reinvest in the development of new drugs. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

  19. Current MitraClip experience, safety and feasibility in the Netherlands

    Rahhab, Z.; Kortlandt, F.A.; Velu, J.F.; Schurer, R.A.J.; Delgado, V.; Tonino, P.; Boven, A.J. van; Branden, B.J.L. Van den; Kraaijeveld, A.O.; Voskuil, M.; Hoorntje, J.; Wely, M.H. van; Houwelingen, K. van; Bleeker, G.B.; Rensing, B.

    2017-01-01

    PURPOSE: Data on MitraClip procedural safety and efficacy in the Netherlands are scarce. We aim to provide an overview of the Dutch MitraClip experience. METHODS: We pooled anonymised demographic and procedural data of 1151 consecutive MitraClip patients, from 13 Dutch hospitals. Data was collected by product specialists in collaboration with local operators. Effect on mitral regurgitation was intra-procedurally assessed by transoesophageal echocardiography. Technical success and device succe...

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

    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.

  1. The Expected Net Present Value of Developing Weight Management Drugs in the Context of Drug Safety Litigation.

    Chawla, Anita; Carls, Ginger; Deng, Edmund; Tuttle, Edward

    2015-07-01

    Following withdrawals, failures, and significant litigation settlements, drug product launches in the anti-obesity category slowed despite a large and growing unmet need. Litigation concerns, a more risk-averse regulatory policy, and the difficulty of developing a product with a compelling risk-benefit profile in this category may have limited innovators' expected return on investment and restricted investment in this therapeutic area. The objective of the study was to estimate perceived manufacturer risk associated with product safety litigation and increased development costs vs. revenue expectations on anticipated return on investment and to determine which scenarios might change a manufacturer's investment decision. Expected net present value of a weight-management drug entering pre-clinical trials was calculated for a range of scenarios representing evolving expectations of development costs, revenue, and litigation risk over the past 25 years. These three factors were based on published estimates, historical data, and analogs from other therapeutic areas. The main driver in expected net present value calculations is expected revenue, particularly if one assumes that litigation risk and demand are positively correlated. Changes in development costs associated with increased regulatory concern with potential safety issues for the past 25 years likely did not impact investment decisions. Regulatory policy and litigation risk both played a role in anti-obesity drug development; however, product revenue-reflecting efficacy at acceptable levels of safety-was by far the most important factor. To date, relatively modest sales associated with recent product introductions suggest that developing a product that is sufficiently efficacious with an acceptable level of safety continues to be the primary challenge in this market.

  2. Drug packaging in 2014: authorities should direct more efforts towards medication safety.

    2015-05-01

    In 2014, Prescrire examined the packaging quality of about 250 drugs. A few advances stand out, mainly involving recent drugs, but on the whole, the situation is worrisome in terms of medication safety. Although pharmaceutical companies and drug regulatory agencies seem to be taking more account of the risk of accidental poisoning in children, the level of protection remains low overall in the absence of stringent measures on the part of the authorities. New drugs too often have poor-quality or even dangerous packaging at the time of their market introduction. And the packaging quality of older drugs is disturbing. Pharmaceutical companies no longer invest in the packaging of these products, and agencies often fail to take advantage of the opportunities provided by their reassessment to improve the situation. The inappropriate labelling of certain injectable drugs remains a source of medication errors, sometimes resulting in very serious consequences. In 2014, signs of progress in the packaging of several drugs show that its role in medication safety is better appreciated. But the persistence of dangers in the pharmaceuticals market, created by "unfinished", overly complex or poor-quality packaging, raises the question of the responsibility of pharmaceutical companies and agencies for past and present accidents.

  3. FDA drug safety communications: a narrative review and clinical considerations for older adults.

    Marcum, Zachary A; Vande Griend, Joseph P; Linnebur, Sunny A

    2012-08-01

    The US Food and Drug Administration (FDA) has new regulatory authorities intended to enhance drug safety monitoring in the postmarketing period. This has resulted in an increase in communication from the FDA in recent years about the safety profile of certain drugs. It is important to stay abreast of the current literature on drug risks to effectively communicate these risks to patients, other health care providers, and the general public. To summarize 4 new FDA drug safety communications by describing the evidence supporting the risks and the clinical implications for older adults. The FDA Web site was reviewed for new drug safety communications from May 2011 to April 2012 that would be relevant to older adults. Approved labeling for each drug or class was obtained from the manufacturer, and PubMed was searched for primary literature that supported the drug safety concern. FDA drug safety communications for 4 drugs were chosen because of the potential clinical importance in older adults. A warning for citalopram was made because of potential problems with QT prolongation in patients taking less than 40 mg per day. The evidence suggests minor changes in QT interval. Given the flat dose-response curve in treating depression with citalopram, the new 20-mg/d maximum dose in older adults is sensible. Another warning was made for proton pump inhibitors (PPIs) and an increased risk of Clostridium difficile infection. A dose-response relationship was found for this drug risk. With C. difficile infections on the rise in older adults, along with other safety risks of PPI therapy, PPIs should only be used in older adults indicated for therapy for the shortest duration possible. In addition, a warning about dabigatran was made. There is strong evidence from a large clinical trial, as well as case reports, of increased bleeding risk in older adults taking dabigatran, especially in older adults with decreased renal function. This medication should be used with caution in older

  4. Use of nonsteroidal anti-inflammatory drugs among healthy people and specific cerebrovascular safety

    Fosbøl, Emil L; Olsen, Anne-Marie Schjerning; Olesen, Jonas Bjerring

    2014-01-01

    BACKGROUND: Nonsteroidal anti-inflammatory drugs can increase bleeding and thrombosis, but little is known about the cerebrovascular safety of these drugs, especially among healthy people. AIMS: The aim of this study was to examine the risk of ischemic and hemorrhagic stroke associated with the use...... stroke). RESULTS: We selected 1,028,437 healthy individuals (median age 39 years). At least one nonsteroidal anti-inflammatory drug was claimed by 44·7% of the study population, and the drugs were generally used for a short period of time and in low doses. High-dose ibuprofen and diclofenac were......·35-3·42)]. CONCLUSIONS: In healthy individuals, use of commonly available nonsteroidal anti-inflammatory drugs such as ibuprofen, diclofenac, and naproxen was associated with increased risk of stroke....

  5. A feasibility study on the extended cycle from the point of view of Non-LOCA safety analysis

    Lee, Chul Sin; Kim, Hee Chul; Kim, Jeong Jin; Baek, Seung Su; Lee, Byung Il; Jeon, Tae Hyun; Lee, Jeong Chan

    1996-06-01

    Extended cycle operation has many advantages as compared with standard cycle operation (12 months) from the viewpoint of operators' exposure to radiation dose, man-power for maintenance and the production of nuclear waste. And it is more economic than the standard cycle operation. If the extended cycle operation is adopted in the CE type nuclear plant, the effective management and enhancement of operation capability could be expected. A feasibility study on the extended cycle operation should be performed. The purpose of this technical report is to perform safety analysis using the design data for Yonggwang Nuclear Plant (YGN) 3 and 4 extended cycle operation and to evaluate qualitatively and quantitatively the safety related design basis events to verify the satisfaction of the safety criteria. Boron dilution and steam line break accidents were found to be most influenced by the change of physics data due to the adaptation of the extended cycle operation. For boron dilution accident, source range monitor ratio of 3.07 for YGN 3 cycle 2 was decreased to 2.92. The 3D reactivity feedback effect due to the local heatup in the vicinity of stuck CEA was credited in the analysis of steam line break. No return-to-power occurred for the steam line break with offsite power available and return-to-power occurred for the steam line break with loss of offsite power. For the steam line break with loss of offsite power, the safety margin was preserved with respect to fuel performance (DNB and LHGR) despite the return-to-power. 6 tabs., 10 figs., 5 refs. (Author) .new

  6. Safety pharmacology of sibutramine mesylate, an anti-obesity drug.

    Kim, Eun-Joo; Park, Eun-Kyung; Suh, Kwee-Hyun

    2005-03-01

    Sibutramine mesylate is a new anti-obesity drug. It is a crystalline salt of sibutramine developed to improve the solubility of sibutramine hydrochloride. Methanesulfonic acid was used as a salt-forming acid instead of hydrochloric acid, resulting in a greatly improved solubility of 1000 mg/mL in water. Sibutramine mesylate was administered orally to ICR mice, Sprague-Dawley rats, and beagle dogs at dose levels of 1.15, 3.45, and 11.50 mg/kg to measure its effects on the central nervous system (CNS), general behaviour, cardiovascular-respiratory system and the other organ systems. Following administration of sibutramine mesylate, spontaneous locomotor activity was significantly increased from 120 min to 24 hours at 3.45 mg/kg and from 30 min to 24 hours at 11.50 mg/kg. Furthermore, there were a decrease in hexobarbital-induced sleep time, an increase in respiratory rate at 120 min, increases in intestinal transport capacity and gastric pH at 11.50 mg/kg, and decreases in gastric volume and total acidity at 3.45 and 11.50 mg/kg. However sibutramine mesylate caused no effects on general behaviour, motor coordination, body temperature, analgesia, convulsion, blood pressure, heart rate, electrocardiogram, cardiac functions of the isolated rat heart, isolated smooth muscles and renal function. Based on the above results, it was concluded that sibutramine mesylate caused effects on the spontaneous locomotor activity, hexobarbital-induced sleep time, respiration, gastrointestinal transport, and gastric secretion at a dose level of 3.45 mg/kg or greater but caused no effects on other general pharmacological reactions.

  7. Investigating the feasibility of temperature-controlled accelerated drug release testing for an intravaginal ring.

    Externbrink, Anna; Clark, Meredith R; Friend, David R; Klein, Sandra

    2013-11-01

    The objective of the present study was to investigate if temperature can be utilized to accelerate drug release from Nuvaring®, a reservoir type intravaginal ring based on polyethylene vinyl acetate copolymer that releases a constant dose of contraceptive steroids over a duration of 3 weeks. The reciprocating holder apparatus (USP 7) was utilized to determine real-time and accelerated etonogestrel release from ring segments. It was demonstrated that drug release increased with increasing temperature which can be attributed to enhanced drug diffusion. An Arrhenius relationship of the zero-order release constants was established, indicating that temperature is a valid parameter to accelerate drug release from this dosage form and that the release mechanism is maintained under these accelerated test conditions. Accelerated release tests are particularly useful for routine quality control to assist during batch release of extended release formulations that typically release the active over several weeks, months or even years, since they can increase the product shelf life. The accelerated method should therefore be able to discriminate between formulations with different release characteristics that can result from normal manufacturing variance. In the case of Nuvaring®, it is well known that the process parameters during the extrusion process strongly influence the polymeric structure. These changes in the polymeric structure can affect the permeability which, in turn, is reflected in the release properties. Results from this study indicate that changes in the polymeric structure can lead to a different temperature dependence of the release rate, and as a consequence, the accelerated method can become less sensitive to detect changes in the release properties. When the accelerated method is utilized during batch release, it is therefore important to take this possible restriction into account and to evaluate the accelerated method with samples from non

  8. Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke.

    Dawson, Jesse; Pierce, David; Dixit, Anand; Kimberley, Teresa J; Robertson, Michele; Tarver, Brent; Hilmi, Omar; McLean, John; Forbes, Kirsten; Kilgard, Michael P; Rennaker, Robert L; Cramer, Steven C; Walters, Matthew; Engineer, Navzer

    2016-01-01

    Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke. Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5-second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl-Meyer Assessment-Upper Extremity). Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl-Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, -0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl-Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6). This study suggests that VNS paired with rehabilitation is feasible and has not raised safety concerns. Additional studies of VNS in adults with chronic stroke will now be performed. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01669161. © 2015 The Authors.

  9. Catheter-Based Measurements of Absolute Coronary Blood Flow and Microvascular Resistance: Feasibility, Safety, and Reproducibility in Humans.

    Xaplanteris, Panagiotis; Fournier, Stephane; Keulards, Daniëlle C J; Adjedj, Julien; Ciccarelli, Giovanni; Milkas, Anastasios; Pellicano, Mariano; Van't Veer, Marcel; Barbato, Emanuele; Pijls, Nico H J; De Bruyne, Bernard

    2018-03-01

    The principle of continuous thermodilution can be used to calculate absolute coronary blood flow and microvascular resistance (R). The aim of the study is to explore the safety, feasibility, and reproducibility of coronary blood flow and R measurements as measured by continuous thermodilution in humans. Absolute coronary flow and R can be calculated by thermodilution by infusing saline at room temperature through a dedicated monorail catheter. The temperature of saline as it enters the vessel, the temperature of blood and saline mixed in the distal part of the vessel, and the distal coronary pressure were measured by a pressure/temperature sensor-tipped guidewire. The feasibility and safety of the method were tested in 135 patients who were referred for coronary angiography. No significant adverse events were observed; in 11 (8.1%) patients, bradycardia and concomitant atrioventricular block appeared transiently and were reversed immediately on interruption of the infusion. The reproducibility of measurements was tested in a subgroup of 80 patients (129 arteries). Duplicate measurements had a strong correlation both for coronary blood flow (ρ=0.841, P <0.001; intraclass correlation coefficient=0.89, P <0.001) and R (ρ=0.780, P <0.001; intraclass correlation coefficient=0.89, P <0.001). In Bland-Altman plots, there was no significant bias or asymmetry. Absolute coronary blood flow (in L/min) and R (in mm Hg/L/min or Wood units) can be safely and reproducibly measured with continuous thermodilution. This approach constitutes a new opportunity for the study of the coronary microcirculation. © 2018 American Heart Association, Inc.

  10. Feasibility study on floating nuclear power plant (2). Safety design study of FNPP. Contract research

    Yabuuchi, Noriaki; Shimazaki, Junya; Ochiai, Masaaki [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Takahashi, Masao [Niigata Engineering Co. Ltd., Tokyo (Japan); Nakazawa, Toshio [Japan Atomic Energy Research Inst., Oarai, Ibaraki (Japan). Oarai Research Establishment; Sato, Kazuo [Ishikawajima-Harima Heavy Industries Co. Ltd., Tokyo (Japan)

    2001-02-01

    In the previous report of 'Conceptual Design Study of FNPP (Floating Nuclear Power Plant)', a design study on a concept for FNPP, which is sited off the sea coast on the open sea with water depth of 20m and it is moored on protected sea by the breakwater was conducted and the floating platform guarded by the breakwater was found to be stable enough to install the nuclear power plant from analysis simulating the movement of the platform due to sea wave or wind. In this report, studies on a basic safety design concept of the FNPP, setting natural phenomena for design condition, required safety functions and a review on dynamic analysis of the large floating structure are presented. The studies revealed that the stability of the floating platform is an essential issue for the FNPP soundness, and the design base natural phenomena such as S1 and S2-class storm including S1 and S2-class earthquake should be considered in evaluation of the stability of the floating platform, and it is one of key technical subjects how to set the magnitude of these storm in application of design evaluation on each FNPP case. (J.P.N.)

  11. Dobutamine stress MRI. Part I. Safety and feasibility of dobutamine cardiovascular magnetic resonance in patients suspected of myocardial ischemia

    Kuijpers, Dirkjan; Janssen, Caroline H.C.; Oudkerk, Matthijs; Dijkman, Paul R.M. van

    2004-01-01

    The aim of the study was to evaluate safety and feasibility of dobutamine cardiovascular magnetic resonance (CMR) in patients with proven or suspected coronary artery disease. Dobutamine CMR was evaluated retrospectively in 400 consecutive patients with suspicion of myocardial ischemia. Dobutamine was infused using an incremental protocol up to 40 μg/kg body weight per minute. All anti-anginal medication was stopped 4 days before the CMR study and infusion time of dobutamine was 6 min per stage. Hemodynamic data, CMR findings and side effects were reported. Patients with contraindications to CMR (metallic implants and claustrophobia) were excluded from analysis. Dobutamine CMR was successfully performed in 355 (89%) patients. Forty-five (11%) patients could not be investigated adequately because of non-cardiac side effects in 29 (7%) and cardiac side effects in 16 (4%) patients. Hypotension (1.5%) and arrhythmias (1%) were the most frequent cardiac side effects. One patient developed a severe complication (ventricular fibrillation) at the end of the study. There were no myocardial infarctions or fatal complications of the stress test. The most frequent non-cardiac side effects were nausea, vomiting and claustrophobia. Age >70 years, prior myocardial infarction and rest wall motion abnormalities showed no significant differences with side effects (P>0.05). Dobutamine CMR is safe and feasible in patients with suspicion of myocardial ischemia. (orig.)

  12. Feasibility and Safety of Overtubes for PEG-Tube Placement in Patients with Head and Neck Cancer

    Crispin O. Musumba

    2015-01-01

    Full Text Available Background. Percutaneous endoscopic gastrostomy (PEG placement using the “pull” technique is commonly utilized for providing nutritional support in head and neck cancer (HNC patients, but it may be complicated by peristomal metastasis in up to 3% of patients. Overtube-assisted PEG placement might reduce this risk. However, this technique has not been systemically studied for this purpose to date. Methods. Retrospective analysis of consecutive patients with HNC who underwent overtube-assisted PEG placement at Westmead Hospital, Australia, between June 2011 and December 2013. Data were extracted from patients’ endoscopy reports and case notes. We present our technique for PEG insertion and discuss the feasibility and safety of this method. Results. In all 53 patients studied, the PEG tubes were successfully placed using 25 cm long flexible overtubes, in 89% prophylactically (before commencing curative chemoradiotherapy, and in 11% reactively (for treatment of tumor related dysphagia or weight loss. During a median follow-up period of 16 months, 3 (5.7% patients developed peristomal infection and 3 others developed self-limiting peristomal pain. There were no cases of overtube-related adverse events or overt cutaneous metastases observed. Conclusions. Overtube-assisted PEG placement in patients with HNC is a feasible, simple, and safe technique and might be effective for preventing cutaneous metastasis.

  13. Dobutamine stress MRI. Part I. Safety and feasibility of dobutamine cardiovascular magnetic resonance in patients suspected of myocardial ischemia.

    Kuijpers, Dirkjan; Janssen, Caroline H C; van Dijkman, Paul R M; Oudkerk, Matthijs

    2004-10-01

    The aim of the study was to evaluate safety and feasibility of dobutamine cardiovascular magnetic resonance (CMR) in patients with proven or suspected coronary artery disease. Dobutamine CMR was evaluated retrospectively in 400 consecutive patients with suspicion of myocardial ischemia. Dobutamine was infused using an incremental protocol up to 40 microg/kg body weight per minute. All anti-anginal medication was stopped 4 days before the CMR study and infusion time of dobutamine was 6 min per stage. Hemodynamic data, CMR findings and side effects were reported. Patients with contraindications to CMR (metallic implants and claustrophobia) were excluded from analysis. Dobutamine CMR was successfully performed in 355 (89%) patients. Forty-five (11%) patients could not be investigated adequately because of non-cardiac side effects in 29 (7%) and cardiac side effects in 16 (4%) patients. Hypotension (1.5%) and arrhythmias (1%) were the most frequent cardiac side effects. One patient developed a severe complication (ventricular fibrillation) at the end of the study. There were no myocardial infarctions or fatal complications of the stress test. The most frequent non-cardiac side effects were nausea, vomiting and claustrophobia. Age >70 years, prior myocardial infarction and rest wall motion abnormalities showed no significant differences with side effects (P>0.05). Dobutamine CMR is safe and feasible in patients with suspicion of myocardial ischemia. Copyright 2004 Springer-Verlag

  14. Dobutamine stress MRI. Part I. Safety and feasibility of dobutamine cardiovascular magnetic resonance in patients suspected of myocardial ischemia

    Kuijpers, Dirkjan [State University and Academic Hospital Groningen, Department of Radiology, Groningen (Netherlands); Bronovo Hospital, Department of Radiology and Cardiology, Bronovolaan 1, P.O. Box 96900, The Hague (Netherlands); Janssen, Caroline H.C.; Oudkerk, Matthijs [State University and Academic Hospital Groningen, Department of Radiology, Groningen (Netherlands); Dijkman, Paul R.M. van [Bronovo Hospital, Department of Radiology and Cardiology, Bronovolaan 1, P.O. Box 96900, The Hague (Netherlands)

    2004-10-01

    The aim of the study was to evaluate safety and feasibility of dobutamine cardiovascular magnetic resonance (CMR) in patients with proven or suspected coronary artery disease. Dobutamine CMR was evaluated retrospectively in 400 consecutive patients with suspicion of myocardial ischemia. Dobutamine was infused using an incremental protocol up to 40 {mu}g/kg body weight per minute. All anti-anginal medication was stopped 4 days before the CMR study and infusion time of dobutamine was 6 min per stage. Hemodynamic data, CMR findings and side effects were reported. Patients with contraindications to CMR (metallic implants and claustrophobia) were excluded from analysis. Dobutamine CMR was successfully performed in 355 (89%) patients. Forty-five (11%) patients could not be investigated adequately because of non-cardiac side effects in 29 (7%) and cardiac side effects in 16 (4%) patients. Hypotension (1.5%) and arrhythmias (1%) were the most frequent cardiac side effects. One patient developed a severe complication (ventricular fibrillation) at the end of the study. There were no myocardial infarctions or fatal complications of the stress test. The most frequent non-cardiac side effects were nausea, vomiting and claustrophobia. Age >70 years, prior myocardial infarction and rest wall motion abnormalities showed no significant differences with side effects (P>0.05). Dobutamine CMR is safe and feasible in patients with suspicion of myocardial ischemia. (orig.)

  15. Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy

    Lee Young-Ho

    2012-03-01

    Full Text Available Abstract Backgrounds We conducted a pilot study of the infusion of intravenous autologous cord blood (CB in children with cerebral palsy (CP to assess the safety and feasibility of the procedure as well as its potential efficacy in countering neurological impairment. Methods Patients diagnosed with CP were enrolled in this study if their parents had elected to bank their CB at birth. Cryopreserved CB units were thawed and infused intravenously over 10~20 minutes. We assessed potential efficacy over 6 months by brain magnetic resonance imaging (MRI-diffusion tensor imaging (DTI, brain perfusion single-photon emission computed tomography (SPECT, and various evaluation tools for motor and cognitive functions. Results Twenty patients received autologous CB infusion and were evaluated. The types of CP were as follows: 11 quadriplegics, 6 hemiplegics, and 3 diplegics. Infusion was generally well-tolerated, although 5 patients experienced temporary nausea, hemoglobinuria, or urticaria during intravenous infusion. Diverse neurological domains improved in 5 patients (25% as assessed with developmental evaluation tools as well as by fractional anisotropy values in brain MRI-DTI. The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. Conclusions Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP.

  16. Safety, feasibility, and acceptability of visual inspection with acetic acid and immediate treatment with cryotherapy in rural Laos.

    Phongsavan, Keokedthong; Phengsavanh, Alongkone; Wahlström, Rolf; Marions, Lena

    2011-09-01

    To assess the safety, acceptability, and feasibility of visual inspection with acetic acid (VIA) followed by immediate treatment with cryotherapy as a single-visit approach for the prevention of cervical cancer among women in rural Laos. In 2009, women from 2 provinces in Laos were recruited for cervical cancer screening using VIA. If the inspection of the cervix showed a well-defined acetowhite lesion close to the os, immediate cryotherapy was offered. Of the 1926 women who were included, 134 (7.0%) tested positive on VIA. Of these, 113 (84.3%) underwent immediate cryotherapy and none declined treatment. One year after immediate cryotherapy, 77 (68.1%) women returned for a follow-up assessment and 68 (88.3%) were now VIA-negative. There was no report of a major complication during or after treatment. The acceptance of both VIA and cryotherapy was high. Visual inspection with acetic acid is a simple test that requires minimal infrastructure and expenditure. Integration of VIA with cryotherapy at the primary care level may constitute a feasible program for the prevention of cervical cancer in Laos. Copyright © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  17. The nuts and bolts of pills and portions: the functions of a drug safety working group.

    Nath, Noleen S; Jones, Ellen H; Stride, Peter; Premaratne, Manuja; Thaker, Darshit; Lim, Ivan

    2011-11-01

    Hospitalised patients commonly experience adverse drug events (ADEs) and medication errors. Runciman reported that ADEs in hospitals account for 20% of reported adverse events and contribute to 27% of deaths where death followed an adverse event. Hughes recommends multidisciplinary hospital drug committees to assess performance and raise standards. The new Code of Conduct of the Medical Board of Australia recommends participation in systems for surveillance and monitoring of adverse events, and to improve patient safety. We describe the functions and role of a Drug Safety Working Group (DSWG) in a suburban hospital, which aims to audit and promote a culture of prescribing and medication administration that is prudent and cautious to minimise the risk of harm to patients. We believe that regular prescription monitoring and feedback to Resident Medical Officers (RMOs) improves medication management in our hospital.

  18. Metabolic drug interactions - the impact of prescribed drug regimens on the medication safety.

    Fialova, D.; Vrbensky, K.; Topinkova, E.; Vlcek, J.; Soerbye, L.W.; Wagner, C.; Bernabei, R.

    2005-01-01

    Background and objective: Risk/benefit profile of prescribed drug regimens is unkown. Over 60% of commonly used medications interact on metabolic pathways (cytochrom P450 (CYP450), uridyl-glucuronyl tranferasis (UGT I, II) and P-glycoprotein (PGP) transport). Using an up-to-date knowledge on

  19. The practice of pre-marketing safety assessment in drug development.

    Chuang-Stein, Christy; Xia, H Amy

    2013-01-01

    The last 15 years have seen a substantial increase in efforts devoted to safety assessment by statisticians in the pharmaceutical industry. While some of these efforts were driven by regulations and public demand for safer products, much of the motivation came from the realization that there is a strong need for a systematic approach to safety planning, evaluation, and reporting at the program level throughout the drug development life cycle. An efficient process can help us identify safety signals early and afford us the opportunity to develop effective risk minimization plan early in the development cycle. This awareness has led many pharmaceutical sponsors to set up internal systems and structures to effectively conduct safety assessment at all levels (patient, study, and program). In addition to process, tools have emerged that are designed to enhance data review and pattern recognition. In this paper, we describe advancements in the practice of safety assessment during the premarketing phase of drug development. In particular, we share examples of safety assessment practice at our respective companies, some of which are based on recommendations from industry-initiated working groups on best practice in recent years.

  20. 76 FR 64354 - Burden of Food and Drug Administration Food Safety Modernization Act Fee Amounts on Small...

    2011-10-18

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0529] Burden of Food and Drug Administration Food Safety Modernization Act Fee Amounts on Small Business... amounts on small business, as set forth in the FDA Food Safety Modernization Act (FSMA). In particular...

  1. 76 FR 45818 - Burden of Food and Drug Administration Food Safety Modernization Act Fee Amounts on Small...

    2011-08-01

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0529] Burden of Food and Drug Administration Food Safety Modernization Act Fee Amounts on Small Business... burden of fee amounts on small business, as set forth in the FDA Food Safety Modernization Act (FSMA...

  2. A modular, prospective, semi-automated drug safety monitoring system for use in a distributed data environment.

    Gagne, Joshua J; Wang, Shirley V; Rassen, Jeremy A; Schneeweiss, Sebastian

    2014-06-01

    The aim of this study was to develop and test a semi-automated process for conducting routine active safety monitoring for new drugs in a network of electronic healthcare databases. We built a modular program that semi-automatically performs cohort identification, confounding adjustment, diagnostic checks, aggregation and effect estimation across multiple databases, and application of a sequential alerting algorithm. During beta-testing, we applied the system to five databases to evaluate nine examples emulating prospective monitoring with retrospective data (five pairs for which we expected signals, two negative controls, and two examples for which it was uncertain whether a signal would be expected): cerivastatin versus atorvastatin and rhabdomyolysis; paroxetine versus tricyclic antidepressants and gastrointestinal bleed; lisinopril versus angiotensin receptor blockers and angioedema; ciprofloxacin versus macrolide antibiotics and Achilles tendon rupture; rofecoxib versus non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) and myocardial infarction; telithromycin versus azithromycin and hepatotoxicity; rosuvastatin versus atorvastatin and diabetes and rhabdomyolysis; and celecoxib versus ns-NSAIDs and myocardial infarction. We describe the program, the necessary inputs, and the assumed data environment. In beta-testing, the system generated four alerts, all among positive control examples (i.e., lisinopril and angioedema; rofecoxib and myocardial infarction; ciprofloxacin and tendon rupture; and cerivastatin and rhabdomyolysis). Sequential effect estimates for each example were consistent in direction and magnitude with existing literature. Beta-testing across nine drug-outcome examples demonstrated the feasibility of the proposed semi-automated prospective monitoring approach. In retrospective assessments, the system identified an increased risk of myocardial infarction with rofecoxib and an increased risk of rhabdomyolysis with cerivastatin years

  3. Morsleben repository - Interdependence of technical feasibility and functionality of geotechnical barriers and safety case development

    Wollrath, Juergen; Mauke, Ralf; Mohlfeld, Matthias; Niemeyer, Matthias; Becker, Dirk-Alexander

    2014-01-01

    Based on a selection procedure whereby ten existing mines had been taken into consideration, the Morsleben repository for radioactive waste (ERAM) was built in a former mine for potash and rock salt production. The specific concerns and objectives of a repository for radioactive waste could not be taken into account when the mine was built at the beginning of the last century. Irrespective of this, altogether about 37 000 m 3 of low-level and intermediate-level radioactive waste was stored in several areas of the mine between 1971 and 1991 and from 1994 to 1998. In the scope of the ongoing licensing procedure, the safety of the 'historically grown' repository needs to be demonstrated for the phase after it has been sealed. (authors)

  4. Feasibility, safety and image quality of cardiac FDG studies during hyperinsulinaemic-euglycaemic clamping

    Bax, Jeroen J.; Visser, Frans C.; Lingen, Arthur van; Visser, Cees A.; Poldermans, Don; Elhendy, Abdou; Boersma, Eric

    2002-01-01

    Fluorine-18 fluorodeoxyglucose (FDG) imaging for the assessment of myocardial viability has become an integral part of the diagnostic and prognostic work-up of patients with ischaemic cardiomyopathy. To ensure good image quality, in particular in patients with diabetes mellitus, hyperinsulinaemic-euglycaemic clamping has been proposed. In this study we evaluated the safety and the image quality of cardiac FDG imaging during clamping in a large group of patients, including a subgroup with diabetes mellitus. The incidence of viability (on both a segment and a patient basis) was also determined for patients with and without diabetes mellitus. The safety and image quality of cardiac FDG studies during clamping were evaluated in 131 patients, including 19 with diabetes mellitus. Image quality was assessed visually and quantitatively using heart-to-lung (H/L), heart-to-liver (H/Li) and myocardium-to-background (M/B) ratios. Blood samples were drawn at baseline and at the time of FDG injection to determine levels of glucose, free fatty acids and insulin. The metabolic circumstances were optimal for FDG imaging: high insulin levels, low free fatty acid levels and glucose levels in the normal range (levels of substrates were comparable between patients with and patients without diabetes mellitus). No serious side-effects occurred in any patient. Image quality (assessed visually) was good in all patients. The quantitative parameters of image quality (H/L, H/Li and M/B) were comparable between patients with and patients without diabetes mellitus. The incidence of viability was high: 38% of patients without and 58% of patients with diabetes mellitus had substantial viability despite contractile dysfunction. It is concluded that cardiac FDG imaging during clamping is safe and provides excellent image quality, including in patients with diabetes mellitus. The incidence of viability is high, in particular in patients with diabetes mellitus. (orig.)

  5. Feasibility and safety of electrochemotherapy (ECT in the pancreas: a pre-clinical investigation

    Girelli Roberto

    2015-06-01

    Full Text Available Background. Pancreatic ductal adenocarcinoma (PDAC is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT, thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents.

  6. Two-port cholecystectomy maintains safety and feasibility in benign gallbladder diseases: a comparative study.

    Lee, Sang Chul; Choi, Byeong-Jo; Kim, Say-June

    2014-01-01

    In an effort to overcome the limitations of single-port laparoscopic cholecystectomy (LC) while preserving the cosmetic benefits of reduced ports cholecystectomy, we have developed a 2-port LC that allows for the full, unrestricted use of 4 laparoscopic instruments. We retrospectively analyzed data of patients who had undergone either 4-port LC or 2-port LC for benign gallbladder diseases between March 2007 and March 2013. Two incisions of 2-port LC were composed of an umbilical incision as the manner of single-port laparoscopic surgery and a 5-mm epigastric incision. These two incisions were utilized for comfortable bimanual manipulation under the liver-elevated vision provided by a liver retractor. During the study period, 766 patients underwent LC; 263 (34.3%) started with 4-port LC, and 503 (65.7%) started with 2-port LC. Of patients started with 2-port LC, 486 patients (96.6%) was ended up with 2-port without open conversion or addition of port(s). The two groups had similar operative time, open conversion rate, incidence of complications, analgesic requirement, and length of postoperative hospital stay. Multivariate analyses revealed that the independent factors related to prolonged operative time (≥ 90 th percentile) in 2-port LC were the presence of cholecystitis (odds ratio [OR] 2.412, 95% CI 1.246-4.668, p = 0.009) and admission through the emergency department (OR 2.132, 95% CI 1.135-4.004, p = 0.019). This study suggests that 2-port LC for benign gallbladder diseases is as safe and feasible as 4-port LC when it is performed by surgeons trained in conventional laparoscopic techniques. Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

  7. The feasibility of modelling coupled processes in safety analysis of spent nuclear fuel disposal

    Rasilainen, K. [VTT Energy, Espoo (Finland); Luukkonen, A.; Niemi, A.; Poellae, J. [VTT Communities and Infrastructure, Espoo (Finland); Olin, M. [VTT Chemical Technology, Espoo (Finland)

    1999-07-01

    The potential of applying coupled modelling in the Finnish safety analysis programme has been reviewed. The study focused on the migration of radionuclides escaping from a spent fuel repository planned to be excavated in fractured bedrock. Two effects that can trigger various couplings in and around a spent fuel repository in Finland were studied in detail; namely heat generation in the spent fuel and the presence of deep, saline groundwaters. The latter have been observed in coastal areas. A systematic survey of the requirements of coupled modelling identified features that render such migration calculations a challenging task. In groundwater flow modelling there appears to be wide ranging uncertainty related to conceptualisation of flow systems and to the corresponding input data. In terms of migration related chemistry there appear to be large gaps in the underlying thermodynamic database for geochemical systems. Rock mechanical predictions are heavily dependent on knowing the location, structure and properties of dominant fractures; information which is extremely difficult to obtain. Conduction and convection of heat is understood well in principle. On the basis of this review, it appears that coupled migration modelling may not yet be at the stage of development that would allow its use as a standard modelling tool in performance assessments. However, a firmer basis for the conclusions reached can only be obtained after a systematic modelling exercise on a relevant and real migration problem has been carried out. (orig.)

  8. The feasibility of modelling coupled processes in safety analysis of spent nuclear fuel disposal

    Rasilainen, K.; Luukkonen, A.; Niemi, A.; Poellae, J.; Olin, M.

    1999-01-01

    The potential of applying coupled modelling in the Finnish safety analysis programme has been reviewed. The study focused on the migration of radionuclides escaping from a spent fuel repository planned to be excavated in fractured bedrock. Two effects that can trigger various couplings in and around a spent fuel repository in Finland were studied in detail; namely heat generation in the spent fuel and the presence of deep, saline groundwaters. The latter have been observed in coastal areas. A systematic survey of the requirements of coupled modelling identified features that render such migration calculations a challenging task. In groundwater flow modelling there appears to be wide ranging uncertainty related to conceptualisation of flow systems and to the corresponding input data. In terms of migration related chemistry there appear to be large gaps in the underlying thermodynamic database for geochemical systems. Rock mechanical predictions are heavily dependent on knowing the location, structure and properties of dominant fractures; information which is extremely difficult to obtain. Conduction and convection of heat is understood well in principle. On the basis of this review, it appears that coupled migration modelling may not yet be at the stage of development that would allow its use as a standard modelling tool in performance assessments. However, a firmer basis for the conclusions reached can only be obtained after a systematic modelling exercise on a relevant and real migration problem has been carried out. (orig.)

  9. Safety and efficacy of generic drugs with respect to brand formulation.

    Gallelli, Luca; Palleria, Caterina; De Vuono, Antonio; Mumoli, Laura; Vasapollo, Piero; Piro, Brunella; Russo, Emilio

    2013-12-01

    Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to generic formulations. In conclusion, the use of generic drugs could be related with an increased days of disease (time to relapse) or might lead to a therapeutic failure; on the other hand, a higher drug concentration might expose patients to an increased risk of dose-dependent side-effects.

  10. Level of Evidence Associated with FDA Safety Communications with Drug Labeling Changes: 2010-2014

    Benjamin Hixon

    2017-02-01

    Full Text Available Purpose: Approximately 800,000 safety reports are submitted to the FDA annually, however, only significant issues generate drug safety communications (DSC. The purpose of this study was to determine the type of clinical evidence used to warrant a change in drug labeling for drugs with DSC between January 1, 2010 and December 31, 2014. Methods: Selected data was obtained from the FDA website. The primary endpoint of the study was the frequency of the types of clinical evidence used in FDA communications, as reported through the FDA DSC. Results were evaluated via descriptive statistics, and chi-squared for nominal data. Results: A total of 2521 drug safety labeling changes were identified and 99 (3.9% of safety communications met the inclusion criteria. The majority of the labeling changes were associated with single agents (83.8%. The three most frequently reported labeling changes were warnings (68.7%, precautions (58.6%, and patient package insert/medication guide (23.2%. Case reports resulted in the greatest number of documented literature types (n = 791, followed by randomized controlled trials (n = 76, and case control/cohort studies (n = 74. Significantly more evidence for DSCs were classified as Level of Evidence B (LOE B, 68.6%, compared to LOE A (17.1%, and LOE C (14.1% (p = 0.007. Conclusions: The majority of drug labeling change initiators was associated with LOE equivalent to B. Practitioners should evaluate data associated with labeling changes to determine how to interpret the information for their patients. Conflict of Interest We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the manuscript, including grants (pending or received, employment, gifts, stock holdings or options, honoraria, consultancies, expert testimony, patents and royalties.   Type: Original Research

  11. 76 FR 20686 - Draft Guidance for Industry on Safety Labeling Changes; Implementation of the Federal Food, Drug...

    2011-04-13

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0164] Draft Guidance for Industry on Safety Labeling Changes; Implementation of the Federal Food, Drug, and Cosmetic Act; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and...

  12. 75 FR 36427 - Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management...

    2010-06-25

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0001] Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION: Notice. This notice...

  13. Randomized Controlled Study on Safety and Feasibility of Transfusion Trigger Score of Emergency Operations.

    Liu, De-Xing; Liu, Jin; Zhang, Fan; Zhang, Qiu-Ying; Xie, Mian; Zhu, Zhao-Qiong

    2015-07-05

    totally (100%) conformed to the requirements of the transfusion guideline to RBC infusion, which was higher than that of the control group (81.25%), P differences in utilization rates of autologous blood of the two groups; the utilization rates of allogeneic RBC, total allogeneic RBC and total RBC were 48.48%, 51.5%, and 75.7% in POTTS-E group, which were lower than those of the control group (84.3%, 84.3%, and 96.8%) P groups were all lower than those of control group (4.0 [2.0, 4.0], 4.0 [2.0, 6.0] and 5.8 [2.7, 8.2]), P used to guide the application of RBC. There are no differences in the recent prognosis of patients with the traditional transfusion guidelines. This scheme is safe; Compared with doctor experience-based subjective assessment, the scoring scheme was closer to patient physiological needs for transfusion and more reasonable; Utilization rate and the per capita consumption of RBC are obviously declined, which has clinical significance and is feasible. Based on the abovementioned three points, POTTS-E scores scheme is safe, reasonable, and practicable and has the value for carrying out multicenter and large sample clinical researches.

  14. Effects of organizational safety practices and perceived safety climate on PPE usage, engineering controls, and adverse events involving liquid antineoplastic drugs among nurses.

    DeJoy, David M; Smith, Todd D; Woldu, Henok; Dyal, Mari-Amanda; Steege, Andrea L; Boiano, James M

    2017-07-01

    Antineoplastic drugs pose risks to the healthcare workers who handle them. This fact notwithstanding, adherence to safe handling guidelines remains inconsistent and often poor. This study examined the effects of pertinent organizational safety practices and perceived safety climate on the use of personal protective equipment, engineering controls, and adverse events (spill/leak or skin contact) involving liquid antineoplastic drugs. Data for this study came from the 2011 National Institute for Occupational Safety and Health (NIOSH) Health and Safety Practices Survey of Healthcare Workers which included a sample of approximately 1,800 nurses who had administered liquid antineoplastic drugs during the past seven days. Regression modeling was used to examine predictors of personal protective equipment use, engineering controls, and adverse events involving antineoplastic drugs. Approximately 14% of nurses reported experiencing an adverse event while administering antineoplastic drugs during the previous week. Usage of recommended engineering controls and personal protective equipment was quite variable. Usage of both was better in non-profit and government settings, when workers were more familiar with safe handling guidelines, and when perceived management commitment to safety was higher. Usage was poorer in the absence of specific safety handling procedures. The odds of adverse events increased with number of antineoplastic drugs treatments and when antineoplastic drugs were administered more days of the week. The odds of such events were significantly lower when the use of engineering controls and personal protective equipment was greater and when more precautionary measures were in place. Greater levels of management commitment to safety and perceived risk were also related to lower odds of adverse events. These results point to the value of implementing a comprehensive health and safety program that utilizes available hazard controls and effectively communicates

  15. The impact of medicinal drugs on traffic safety: a systematic review of epidemiological studies.

    Orriols, Ludivine; Salmi, Louis-Rachid; Philip, Pierre; Moore, Nicholas; Delorme, Bernard; Castot, Anne; Lagarde, Emmanuel

    2009-08-01

    To evaluate the quality of epidemiological research into effects of medicinal drugs on traffic safety and the current knowledge in this area. The bibliographic search was done in Medline electronic database using the keywords: ((accident* or crash*) and traffic and drug*) leading to 1141 references. Additional references were retrieved from the Safetylit website and the reference lists of selected studies. Original articles published in English or French, between 1 April 1979 and 31 July 2008, were considered for inclusion. We excluded descriptive studies, studies limited to alcohol or illicit drug involvement and investigations of injuries other than from traffic crashes. Studies based on laboratory tests, driving simulators or on-the-road driving tests were also excluded. Eligible studies had to evaluate the causal relationship between the use of medicinal drugs and the risk of traffic crashes. Study quality was assessed by two independent experts, according to a grid adapted from the strengthening the reporting of observational studies in epidemiology (STROBE) statement. Twenty two studies of variable methodological quality were included. Definition of drug exposure varied across studies and depended on the data sources. Potential confounding due to the interaction between the effects of the medicinal drug and disease-related symptoms was often not controlled. The risk of motor-vehicle crashes related to benzodiazepines has been amply studied and demonstrated. Results for other medicinal drugs remain controversial. There is a need for large studies, investigating the role of individual substances in the risk of road traffic crashes. Copyright 2009 John Wiley & Sons, Ltd.

  16. Holes in the safety net: a case study of access to prescription drugs and specialty care.

    Stanley, Ava; Cantor, Joel C; Guarnaccia, Peter

    2008-07-01

    The health care safety net in the United States is intended to fill gaps in health care services for uninsured and other vulnerable populations. This paper presents a case study of New Brunswick, NJ, a small city rich in safety net resources, to examine the adequacy of the American model of safety net care. We find substantial gaps in access to care despite the presence of a medical school, an abundance of primary care and specialty physicians, two major teaching hospitals, a large federally qualified health center and other safety net resources in this community of about 50,000 residents. Using a blend of random-digit-dial and area probability sampling, a survey of 595 households was conducted in 2001 generating detailed information about the health, access to care, demographic and other characteristics of 1,572 individuals. Confirming the great depth of the New Brunswick health care safety net, the survey showed that more than one quarter of local residents reported a hospital or community clinic as their usual source of care. Still, barriers to prescription drugs were reported for 11.0% of the area population and more than two in five (42.8%) local residents who perceived a need for specialty care reported difficulty getting those services. Bivariate analyses show significantly elevated risk of access problems among Hispanic and black residents, those in poor health, those relying on hospital and community clinics or with no usual source of care, and those living at or below poverty. In multivariate analysis, lack of health insurance was the greatest risk factor associated with both prescription drug and specialty access problems. Few local areas can claim the depth of safety net resources as New Brunswick, NJ, raising serious concerns about the adequacy of the American safety net model, especially for people with complex and chronic health care needs.

  17. Initial experience with a robotically operated video optical telescopic-microscope in cranial neurosurgery: feasibility, safety, and clinical applications.

    Gonen, Lior; Chakravarthi, Srikant S; Monroy-Sosa, Alejandro; Celix, Juanita M; Kojis, Nathaniel; Singh, Maharaj; Jennings, Jonathan; Fukui, Melanie B; Rovin, Richard A; Kassam, Amin B

    2017-05-01

    OBJECTIVE The move toward better, more effective optical visualization in the field of neurosurgery has been a focus of technological innovation. In this study, the authors' objectives are to describe the feasibility and safety of a new robotic optical platform, namely, the robotically operated video optical telescopic-microscope (ROVOT-m), in cranial microsurgical applications. METHODS A prospective database comprising patients who underwent a cranial procedure between April 2015 and September 2016 was queried, and the first 200 patients who met the inclusion criteria were selected as the cohort for a retrospective chart review. Only adults who underwent microsurgical procedures in which the ROVOT-m was used were considered for the study. Preoperative, intraoperative, and postoperative data were retrieved from electronic medical records. The authors address the feasibility and safety of the ROVOT-m by studying various intraoperative variables and by reporting perioperative morbidity and mortality, respectively. To assess the learning curve, cranial procedures were categorized into 6 progressively increasing complexity groups. The main categories of pathology were I) intracerebral hemorrhages (ICHs); II) intraaxial tumors involving noneloquent regions or noncomplex extraaxial tumors; III) intraaxial tumors involving eloquent regions; IV) skull base pathologies; V) intraventricular lesions; and VI) cerebrovascular lesions. In addition, the entire cohort was evenly divided into early and late cohorts. RESULTS The patient cohort comprised 104 female (52%) and 96 male (48%) patients with a mean age of 56.7 years. The most common pathological entities encountered were neoplastic lesions (153, 76.5%), followed by ICH (20, 10%). The distribution of cases by complexity categories was 11.5%, 36.5%, 22%, 20%, 3.5%, and 6.5% for Categories I, II, II, IV, V, and VI, respectively. In all 200 cases, the surgical goal was achieved without the need for intraoperative conversion

  18. Nintendo Wii Fit as an adjunct to physiotherapy following lower limb fractures: preliminary feasibility, safety and sample size considerations.

    McPhail, S M; O'Hara, M; Gane, E; Tonks, P; Bullock-Saxton, J; Kuys, S S

    2016-06-01

    The Nintendo Wii Fit integrates virtual gaming with body movement, and may be suitable as an adjunct to conventional physiotherapy following lower limb fractures. This study examined the feasibility and safety of using the Wii Fit as an adjunct to outpatient physiotherapy following lower limb fractures, and reports sample size considerations for an appropriately powered randomised trial. Ambulatory patients receiving physiotherapy following a lower limb fracture participated in this study (n=18). All participants received usual care (individual physiotherapy). The first nine participants also used the Wii Fit under the supervision of their treating clinician as an adjunct to usual care. Adverse events, fracture malunion or exacerbation of symptoms were recorded. Pain, balance and patient-reported function were assessed at baseline and discharge from physiotherapy. No adverse events were attributed to either the usual care physiotherapy or Wii Fit intervention for any patient. Overall, 15 (83%) participants completed both assessments and interventions as scheduled. For 80% power in a clinical trial, the number of complete datasets required in each group to detect a small, medium or large effect of the Wii Fit at a post-intervention assessment was calculated at 175, 63 and 25, respectively. The Nintendo Wii Fit was safe and feasible as an adjunct to ambulatory physiotherapy in this sample. When considering a likely small effect size and the 17% dropout rate observed in this study, 211 participants would be required in each clinical trial group. A larger effect size or multiple repeated measures design would require fewer participants. Copyright © 2015 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

  19. Safety and feasibility of modified chair-yoga on functional outcome among elderly at risk for falls

    Mary Lou Galantino

    2012-01-01

    Full Text Available Falls are among the most common problems affecting older adults. At least 50% of those over the age of 80 fall annually. The goal of this pilot study was to assess the safety and feasibility of structured yoga in an elderly population with fall risk. Seniors at risk for falls were identified and enrolled in a single arm pilot trial. A chair based yoga program was provided twice a week for 8 weeks. The program was designed from previously published pilot data. A battery of validated instruments was administered at baseline and week eight and was used to identify which instruments may be sensitive to change as a result of a yoga program. Among sixteen seniors (median age of 88 with a previous history of falls, 87% provided data for assessment at the end of the intervention. Two patients withdrew, one due to a fall outside the institution and the other due to lack of time and interest. There were no adverse events during the yoga sessions. Paired-t tests compared pre-post changes and gains were noted in Fear of Falling (5.27 to 2.60; P = 0.029 and SPPB sit to stand subscale (0.31 to 1.00; P =.022. Improved trends were noted in anxiety and the timed up and go assessments. We found the modified chair-yoga program is safe and recruitment is feasible. Our data suggests that yoga may be beneficial in improving mobility and reducing fear of falling which warrants additional research via randomized controlled trial.

  20. Does the Early Adopter of Drugs Exist? A Population Based Study of General Practitioners’ Prescribing of New Drugs.20 th International Conference on Pharmacoepiemiology and Risk Management. Bordeaux, France. Pharmacoepidemiology and Drug Safety, 2004;13:Sl 1:158

    Dybdahl, Torben; Andersen, Morten; Søndergaard, Jens

    2004-01-01

    20 th International Conference on Pharmacoepiemiology and Risk Management. Bordeaux, France. Pharmacoepidemiology and Drug Safety, 2004;13:Sl 1:158......20 th International Conference on Pharmacoepiemiology and Risk Management. Bordeaux, France. Pharmacoepidemiology and Drug Safety, 2004;13:Sl 1:158...

  1. Pressure-controlled intermittent coronary sinus occlusion (PICSO) in acute ST-segment elevation myocardial infarction: results of the Prepare RAMSES safety and feasibility study

    van de Hoef, Tim P.; Nijveldt, Robin; van der Ent, Martin; Neunteufl, Thomas; Meuwissen, Martijn; Khattab, Ahmed; Berger, Rudolf; Kuijt, Wichert J.; Wykrzykowska, Joanna; Tijssen, Jan G. P.; van Rossum, Albert C.; Stone, Gregg W.; Piek, Jan J.

    2015-01-01

    Pressure-controlled intermittent coronary sinus occlusion (PICSO) may improve myocardial perfusion after pPCI. We evaluated the safety and feasibility of PICSO after pPCI for STEMI, and explored its effects on infarct size and myocardial function. Thirty patients were enrolled following successful

  2. Permitting product liability litigation for FDA-approved drugs and devices promotes patient safety.

    Kesselheim, A S

    2010-06-01

    In 2008 and 2009, the Supreme Court reviewed the question of whether patients injured by dangerous prescription drugs or medical devices can bring tort lawsuits against pharmaceutical and device manufacturers. The Court ruled that claims against device manufacturers were preempted while claims against pharmaceutical manufacturers were not. The threat of product liability lawsuits promotes patient safety by encouraging manufacturers to take greater responsibility in providing clear warnings about known adverse effects of their products.

  3. Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: myocardial and infectious adverse reactions as application cases.

    Wang, Kejian; Weng, Zuquan; Sun, Liya; Sun, Jiazhi; Zhou, Shu-Feng; He, Lin

    2015-02-13

    Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure-activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. In the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. [Investigation of the cognition and behavior on drug safety in Beijing middle school students].

    Cheng, Y C; Pan, Y P; Zhang, Y; Pan, Y T; Ding, C Y; Cao, Y; Zhuo, L; Fang, R F; Gao, A Y; Guo, J; Li, A J; Fu, Q; Ma, J; Zhan, S Y

    2017-12-18

    To understand the cognition and behavior of drug safety in Beijing middle school students and provide advice for relevant education. A cross-sectional survey using paper questionnaires was carried out on the student body of nine Beijing middle schools. Multi-stage proportionate stratified cluster sampling was adopted to enroll participants. In addition to demographic questions, the questionnaire included 17 questions assessing the cognition and behavior of safe drug use, prioritizing questions that aligned with the health education guideline for primary and secondary school students from Chinese Ministry of Education. Descriptive statistical methods were applied using the SAS 9.2 software. Of the 4 220 students investigated, 2 097(49.7%) were males and 2 123(50.3%) were females. The average age was (14.3±1.7) years. 2 030(48.1%) students were from downtown areas, 1 511(35.8%) were from urban-rural linking areas and 679(16.1%) were from rural areas. Half (51.5%) of the respondents were junior high school students, and the others were from senior high schools (34.2%) and vocational high schools (14.3%). Most of the students (89.6%) lived off campus. The awareness rate of drug safety knowledge was 74.4%, the median score of drug safety behavior was 4 points (full score was 5 points) and there was a statistically positive correlation between the two (Spearman's correlation coefficient was 0.156, Pmiddle school students is good, but problems still exist in medication adherence, the management of expired drugs and the antibiotics cognition, which need to be fixed through specific, pointed way of education. And more efforts should be made to improve the cognition in rural regions, vocational high schools and on campus students.

  5. Safety and feasibility of chronic transvenous phrenic nerve stimulation for treatment of central sleep apnea in heart failure patients.

    Zhang, Xilong; Ding, Ning; Ni, Buqing; Yang, Bing; Wang, Hong; Zhang, Shi-Jiang

    2017-03-01

    Central sleep apnea (CSA) is common in patients with heart failure (HF) and is associated with poor quality of life and prognosis. Early acute studies using transvenous phrenic nerve stimulation (PNS) to treat CSA in HF have shown a significantly reduction of CSA and improvement of key polysomnographic parameters. In this study, we evaluated the safety of and efficiency chronic transvenous PNS with an implanted neurostimulator in HF patients with CSA. This study was a prospective, nonrandomized evaluation of unilateral transvenous PNS in eight HF patients with CSA. The stimulation lead, which connected to a proprietary neurostimulator, was positioned in either the left pericardiophrenic or right brachiocephalic vein. Monitoring during implantation and 6-monthly follow-ups were performed. Six of the implanted eight patients completed the study (one was lost to follow-up; one died from pneumonia). Neither side effects nor adverse events related to stimulation occurred. During the 6-monthly follow-ups, one patient had a lead dislodgement in the first month and the lead was subsequently repositioned. No additional lead dislodgements occurred. There were no significant changes in sleep habits, appetite, bleeding or infections. Compared with the parameters before stimulator implantation, there were significant improvement in apnea-hypopnea index, central apnea index, left ventricular ejection fraction and 6-min walk distance (all P < 0.01). Use of chronic transvenous PNS appears to be safe and feasible in HF patients with CSA. Large multicenter studies are needed to confirm safety and efficacy in this population. © 2015 John Wiley & Sons Ltd.

  6. Balanced Propofol Sedation in Patients Undergoing EUS-FNA: A Pilot Study to Assess Feasibility and Safety

    N. Pagano

    2011-01-01

    Full Text Available Introduction and aims. Balanced propofol sedation (BPS administered by gastroenterologists has gained popularity in endoscopic procedures. Few studies exist about the safety of this approach during endosonography with fine needle aspiration (EUS-FNA. We assessed the safety of BPS in EUS-FNA. Materials and methods. 112 consecutive patients, referred to our unit to perform EUS-FNA, from February 2008 to December 2009, were sedated with BPS. A second gastroenterologist administered the drugs and monitorized the patient. Results. All the 112 patients (62 males, mean age 58.35 completed the examination. The mean dose of midazolam and propofol was, respectively, of 2.1 mg (range 1–4 mg and 350 mg (range 180–400. All patients received oxygen with a mean flux of 4 liter/minute (range 2–6 liters/minute. The mean recovery time after procedure was 25 minutes (range 18–45 minutes. No major complications related to sedation were registered during all procedures. The oxygen saturation of all patients never reduced to less than 85%. Blood systolic pressure during and after the procedure never reduced to less than 100 mmHg. Conclusions. In our experience BPS administered by non-anaesthesiologists provided safe and successful sedation in patients undergoing EUS-FNA.

  7. The complications of controlling agency time discretion: FDA review deadlines and postmarket drug safety.

    Carpenter, Daniel; Chattopadhyay, Jacqueline; Moffitt, Susan; Nall, Clayton

    2012-01-01

    Public agencies have discretion on the time domain, and politicians deploy numerous policy instruments to constrain it. Yet little is known about how administrative procedures that affect timing also affect the quality of agency decisions. We examine whether administrative deadlines shape decision timing and the observed quality of decisions. Using a unique and rich dataset of FDA drug approvals that allows us to examine decision timing and quality, we find that this administrative tool induces a piling of decisions before deadlines, and that these “just-before-deadline” approvals are linked with higher rates of postmarket safety problems (market withdrawals, severe safety warnings, safety alerts). Examination of data from FDA advisory committees suggests that the deadlines may impede quality by impairing late-stage deliberation and agency risk communication. Our results both support and challenge reigning theories about administrative procedures, suggesting they embody expected control-expertise trade-offs, but may also create unanticipated constituency losses.

  8. Feasibility of ecological momentary assessment to study mood and risk behavior among young people who inject drugs.

    Mackesy-Amiti, Mary E; Boodram, Basmattee

    2018-04-16

    To test the acceptability and feasibility of ecological momentary assessment (EMA) of mood and injection risk behavior among young people who inject drugs (PWID), using mobile phones. Participants were 185 PWID age 18-35 recruited from two sites of a large syringe service program in Chicago. After completing a baseline interview, participants used a mobile phone app to respond to momentary surveys on mood, substance use, and injection risk behavior for 15 days. Participants were assigned to receive surveys 4, 5, or 6 times per day. Participants were 68% male, 61% non-Hispanic white, 24% Hispanic, and 5% non-Hispanic Black. Out of 185 participants, 8% (n = 15) failed to complete any EMA assessments. Among 170 EMA responders, the mean number of days reporting was 10 (SD 4.7), the mean proportion of assessments completed was 0.43 (SD 0.27), and 76% (n = 130) completed the follow-up interview. In analyses adjusted for age and race/ethnicity, women were more responsive than men to the EMA surveys in days reporting (IRR = 1.33, 95% CI 1.13-1.56), and total number of surveys completed (IRR = 1.51, 95% CI 1.18-1.93). Homeless participants responded on fewer days (IRR = 0.76, 95% CI 0.64-0.90) and completed fewer surveys (IRR = 0.70, 95% CI 0.54-0.91), and were less likely to return for follow-up (p = 0.016). EMA responsiveness was not significantly affected by the number of assigned daily assessments. This study demonstrated high acceptability and feasibility of EMA among young PWID, with up to 6 survey prompts per day. However, homelessness significantly hampered successful participation. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. [Evaluation of the safety of innovative drugs against viruses and infectious agents].

    Kobayashi, Tetsu; Yusa, Keisuke; Kawasaki, Nana

    2013-01-01

    Recently, several novel cellular therapy products and biological drugs are being developed to treat various previously untreatable diseases. One of the most important issues regarding these innovations is how to ensure safety over infectious agents, including viruses and prions, in the earliest treatments with these products. The object of this study is a risk assessment of cases of human infectious with the agents and to present a sample risk management plan based on a collaboration among the National Institute of Health Sciences, universities, marketing authorization holders, and scientific societies. There are three subjects of study: (1) the viral safety of cellular therapy products, (2) the viral safety of biological drugs, and (3) the safety of prions. In this report, we describe the objects of the study, the project members, the study plan outline, and the ongoing plans. The results of the viral risk identification and the risk analysis of cellular therapy products will also be described, based on a review of the literature and case reports obtained during the first year of this project.

  10. Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

    Wang, Kejian, E-mail: kejian.wang.bio@gmail.com [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai (China); Weng, Zuquan [Japan National Institute of Occupational Safety and Health, Kawasaki (Japan); Sun, Liya [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai (China); Sun, Jiazhi; Zhou, Shu-Feng [Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL (United States); He, Lin, E-mail: helin@Bio-X.com [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai (China)

    2015-02-13

    Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. In the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.

  11. Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

    Wang, Kejian; Weng, Zuquan; Sun, Liya; Sun, Jiazhi; Zhou, Shu-Feng; He, Lin

    2015-01-01

    Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. In the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development

  12. Drug monitoring in child and adolescent psychiatry for improved efficacy and safety of psychopharmacotherapy

    Fegert Jörg M

    2009-04-01

    Full Text Available Abstract Most psychotropic drugs used in the treatment of children and adolescents are applied "off label" with a direct risk of under- or overdosing and a delayed risk of long-term side effects. The selection of doses in paediatric psychiatric patients requires a consideration of pharmacokinetic parameters and the development of central nervous system, and warrants specific studies in children and adolescents. Because these are lacking for most of the psychotropic drugs applied in the Child and Adolescent and Psychiatry, therapeutic drug monitoring (TDM is a valid tool to optimise pharmacotherapy and to enable to adjust the dosage of drugs according to the characteristics of the individual patient. Multi-centre TDM studies enable the identification of age- and development-dependent therapeutic ranges of blood concentrations and facilitate a highly qualified standardized documentation in the child and adolescent health care system. In addition, they will provide data for future research on psychopharmacological treatment in children and adolescents, as a baseline for example for clinically relevant interactions with various co-medications. Therefore, a German-Austrian-Swiss "Competence Network on Therapeutic Drug Monitoring in Child and Adolescent Psychiatry" was founded 1 introducing a comprehensive internet data base for the collection of demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents.

  13. Suspected adverse drug reactions in elderly patients reported to the Committee on Safety of Medicines.

    Castleden, C M; Pickles, H

    1988-10-01

    1. Spontaneous reports of suspected adverse drug reactions (ADRs) reported to the Committee on Safety of Medicines (CSM) have been studied in relation to patient age. 2. The proportion of reports received for the elderly increased between 1965 and 1983. 3. There was a correlation between the use of drugs and the number of ADR reports. Thus age-related prescription figures for two non-steroidal anti-inflammatory drugs (NSAI) and co-trimoxazole matched ADR reports for each drug in each age group. 4. The reported ADR was more likely to be serious or fatal in the elderly. 5. The commonest ADRs reported for the elderly affected the gastrointestinal (GIT) and haemopoietic systems, where more reports were received than would be expected from prescription figures. 6. The drug suspected of causing a GIT reaction was a NSAI in 75% of the reports. 7. Ninety-one per cent of fatal reports of GIT bleeds and perforations associated with NSAI drugs were in patients over 60 years of age.

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

    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.

  15. Ayurpharmacoepidemiology en Route to Safeguarding Safety and Efficacy of Ayurvedic Drugs in Global Outlook

    Debnath, Parikshit; Banerjee, Subhadip; Adhikari, Anjan; Debnath, Pratip K.

    2016-01-01

    Ayurpharmacoepidemiology is a new field developed by synergy of the fields of clinical pharmacology, epidemiology, and ayurveda. It will use the effects of ayurvedic medicinal products on large populations to describe and analyze the practices, evaluate the safety and efficacy, and carry out medicoeconomic evaluations. Good pharmacoepidemiology practices in ayurveda is projected to assist with issues of ayurpharmacoepidemiologic research. The embraced good pharmacoepidemiology practices guideline in this viewpoint will be able to provide valuable evidence about the health effects of ayurvedic herbs/drugs and consider different fields like pharmacovigilance, pharmacoeconomics, and drug discovery with ayurvedic reverse pharmacology approach, also pass out significant data for further basic sciences study in ayurveda biology, ayurgenomics, ayurnutrigenomics, and systems biology. Several unanswered questions about ayurvedic drug use and informed interventions or policies that can be addressed by informatics database, which will eventually demonstrate the credibility and rationality of ayurceuticals in the future. PMID:26721554

  16. Anti-Obesity Drugs: A Review about Their Effects and Safety

    Jun Goo Kang

    2012-02-01

    Full Text Available The current recommendations for the treatment of obese people include increased physical activity and reduced calories intake. When the behavioral approach is not sufficient, a pharmacologic treatment is recommended. In past years, numerous drugs have been approved for the treatment of obesity; however, most of them have been withdrawn from the market because of their adverse effects. In fact, amphetamine, rimonabant and sibutramine licenses have been withdrawn due to an increased risk of psychiatric disorders and non-fatal myocardial infarction or stroke. Even if orlistat is not as effective as other drugs in reducing body weight, orlistat is presently the only available choice for the treatment of obesity because of its safety for cardiovascular events and positive effects on diabetic control. Hopefully, more effective and better tolerated anti-obesity drugs will be developed through an improved understanding of the multiple mechanisms and complex physiological systems targeting appetite.

  17. Enabling social listening for cardiac safety monitoring: Proceedings from a drug information association-cardiac safety research consortium cosponsored think tank.

    Seifert, Harry A; Malik, Raleigh E; Bhattacharya, Mondira; Campbell, Kevin R; Okun, Sally; Pierce, Carrie; Terkowitz, Jeffrey; Turner, J Rick; Krucoff, Mitchell W; Powell, Gregory E

    2017-12-01

    This white paper provides a summary of the presentations and discussions from a think tank on "Enabling Social Listening for Cardiac Safety Monitoring" trials that was cosponsored by the Drug Information Association and the Cardiac Safety Research Consortium, and held at the White Oak headquarters of the US Food and Drug Administration on June 3, 2016. The meeting's goals were to explore current methods of collecting and evaluating social listening data and to consider their applicability to cardiac safety surveillance. Social listening is defined as the act of monitoring public postings on the Internet. It has several theoretical advantages for drug and device safety. First, these include the ability to detect adverse events that are "missed" by traditional sources and the ability to detect adverse events sooner than would be allowed by traditional sources, both by affording near-real-time access to data from culturally and geographically diverse sources. Social listening can also potentially introduce a novel patient voice into the conversation about drug safety, which could uniquely augment understanding of real-world medication use obtained from more traditional methodologies. Finally, it can allow for access to information about drug misuse and diversion. To date, the latter 2 of these have been realized. Although regulators from the Food and Drug Administration and the United Kingdom's Medicines and Healthcare Products Regulatory Agency participated in the think tank along with representatives from industry, academia, and patient groups, this article should not be construed to constitute regulatory guidance. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Safety studies of homoeopathic drugs in acute, sub-acute and chronic toxicity in rats

    Surender Singh

    2017-01-01

    Full Text Available Background: Homoeopathic drugs are frequently recommended in day to day life as therapeutic agents by homoeopathic practitioners. However, safety of homoeopathic drugs remains a challenge because of the high variability of chemical components involved. Aim: The objective of the present study was to investigate the acute, subacute, and chronic oral toxicity of different homoeopathic drugs (Ferrum phosphoricum 3X, Ferrum phosphoricum 6X, Calcarea phosphoricum 6X, and Magnesium phosphoricum 6X in experimental models. Materials and Methods: In acute oral toxicity study, homoeopathic drugs were administered orally at 2000mg/kg body weight, and animals were observed for toxic symptoms till 10 days as per the OECD guidelines. For subacute and chronic toxicity study, homoeopathic drugs were administered for 28 and 180 days, respectively, as per the OECD guidelines. At the end of 28 and 180 days, the animals were sacrificed and toxicity parameters were assessed. Histopathological evaluation of different organs was also performed to assess any toxicity. Results: In acute toxicity study, no mortality was found at a dose of 2000 mg/kg which indicates that oral LD50of homoeopathic drugs were more than 2000 mg/kg. The administration of drugs at a dose of 70 mg/kg body weight for 28 and 180 days did not produce any significant change in haematological and biochemical parameters of male and female rats as compared to normal control group. No pathological changes were observed in histology of various organs of treated rats as compared to normal control animals. Conclusion: These homoeopathic drugs are safe & produce no toxicity when administered for longer duration.

  19. Social Media Impact of the Food and Drug Administration's Drug Safety Communication Messaging About Zolpidem: Mixed-Methods Analysis.

    Sinha, Michael S; Freifeld, Clark C; Brownstein, John S; Donneyong, Macarius M; Rausch, Paula; Lappin, Brian M; Zhou, Esther H; Dal Pan, Gerald J; Pawar, Ajinkya M; Hwang, Thomas J; Avorn, Jerry; Kesselheim, Aaron S

    2018-01-05

    The Food and Drug Administration (FDA) issues drug safety communications (DSCs) to health care professionals, patients, and the public when safety issues emerge related to FDA-approved drug products. These safety messages are disseminated through social media to ensure broad uptake. The objective of this study was to assess the social media dissemination of 2 DSCs released in 2013 for the sleep aid zolpidem. We used the MedWatcher Social program and the DataSift historic query tool to aggregate Twitter and Facebook posts from October 1, 2012 through August 31, 2013, a period beginning approximately 3 months before the first DSC and ending 3 months after the second. Posts were categorized as (1) junk, (2) mention, and (3) adverse event (AE) based on a score between -0.2 (completely unrelated) to 1 (perfectly related). We also looked at Google Trends data and Wikipedia edits for the same time period. Google Trends search volume is scaled on a range of 0 to 100 and includes "Related queries" during the relevant time periods. An interrupted time series (ITS) analysis assessed the impact of DSCs on the counts of posts with specific mention of zolpidem-containing products. Chow tests for known structural breaks were conducted on data from Twitter, Facebook, and Google Trends. Finally, Wikipedia edits were pulled from the website's editorial history, which lists all revisions to a given page and the editor's identity. In total, 174,286 Twitter posts and 59,641 Facebook posts met entry criteria. Of those, 16.63% (28,989/174,286) of Twitter posts and 25.91% (15,453/59,641) of Facebook posts were labeled as junk and excluded. AEs and mentions represented 9.21% (16,051/174,286) and 74.16% (129,246/174,286) of Twitter posts and 5.11% (3,050/59,641) and 68.98% (41,138/59,641) of Facebook posts, respectively. Total daily counts of posts about zolpidem-containing products increased on Twitter and Facebook on the day of the first DSC; Google searches increased on the week of the

  20. The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety.

    Heal, D J; Cheetham, S C; Smith, S L

    2009-12-01

    Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

  1. Randomized controlled trial of Family Nurture Intervention in the NICU: assessments of length of stay, feasibility and safety.

    Welch, Martha G; Hofer, Myron A; Stark, Raymond I; Andrews, Howard F; Austin, Judy; Glickstein, Sara B; Ludwig, Robert J; Myers, Michael M

    2013-09-24

    While survival rates for preterm infants have increased, the risk for adverse long-term neurodevelopmental and behavioral outcomes remains very high. In response to the need for novel, evidence-based interventions that prevent such outcomes, we have assessed Family Nurture Intervention (FNI), a novel dual mother-infant intervention implemented while the infant is in the Neonatal Intensive Care Unit (NICU). Here, we report the first trial results, including the primary outcome measure, length of stay in the NICU and, the feasibility and safety of its implementation in a high acuity level IV NICU. The FNI trial is a single center, parallel-group, randomized controlled trial at Morgan Stanley Children's Hospital for mothers and their singleton or twin infants of 26-34 weeks gestation. Families were randomized to standard care (SC) or (FNI). FNI was implemented by nurture specialists trained to facilitate affective communication between mother and infant during specified calming interactions. These interactions included scent cloth exchange, sustained touch, vocal soothing and eye contact, wrapped or skin-to-skin holding, plus family-based support interactions. A total of 826 infants born between 26 and 34 weeks during the 3.5 year study period were admitted to the NICU. After infant and mother screening plus exclusion due to circumstances that prevented the family from participating, 373 infants were eligible for the study. Of these, we were unable to schedule a consent meeting with 56, and consent was withheld by 165. Consent was obtained for 150 infants from 115 families. The infants were block randomized to groups of N = 78, FNI and N = 72, SC. Sixteen (9.6%) of the randomized infants did not complete the study to home discharge, 7% of those randomized to SC and 12% of FNI infants. Mothers in the intervention group engaged in 3 to 4 facilitated one- to two-hour sessions/week. Intent to treat analyses revealed no significant difference between groups in

  2. Safety aspects of protease inhibitors for chronic hepatitis C: adverse events and drug-to-drug interactions

    Rosângela Teixeira

    Full Text Available The standard of care therapy of chronic hepatitis C with the combination of pegylated interferon and ribavirin for 24 or 48 weeks was a remarkable accomplishment of the past decade. However, sustained virological responses rates of about 80% (genotypes 2-3 and 50% (geno 3 type 1 were not satisfactory especially for patients infected with genotype 1. Important advances in the biology of HCV have made possible the development of the direct-acting antiviral agents boceprevir and telaprevir with substantial increase in the rates of sustained virological response with shorter duration of therapy for a large number of patients. However, the complexity of triple therapy is higher and several new side effects are expected suggesting greater expertise in the patient management. Anemia and disgeusia are frequent with boceprevir while cutaneous rash, ranging from mild to severe, is expected with telaprevir. Higher risk of drug-drug interactions demand further clinical consideration of the previous well-known adverse events of pegylated interferon and ribavirin. Identification and prompt management of these potential new problems with boceprevir and telaprevir are crucial in clinical practice for optimizing treatment and assuring safety outcomes to HCV-genotype 1 patients.

  3. Safety aspects of protease inhibitors for chronic hepatitis C: adverse events and drug-to-drug interactions

    Rosângela Teixeira

    2013-04-01

    Full Text Available The standard of care therapy of chronic hepatitis C with the combination of pegylated interferon and ribavirin for 24 or 48 weeks was a remarkable accomplishment of the past decade. However, sustained virological responses rates of about 80% (genotypes 2-3 and 50% (geno 3 type 1 were not satisfactory especially for patients infected with genotype 1. Important advances in the biology of HCV have made possible the development of the direct-acting antiviral agents boceprevir and telaprevir with substantial increase in the rates of sustained virological response with shorter duration of therapy for a large number of patients. However, the complexity of triple therapy is higher and several new side effects are expected suggesting greater expertise in the patient management. Anemia and disgeusia are frequent with boceprevir while cutaneous rash, ranging from mild to severe, is expected with telaprevir. Higher risk of drug-drug interactions demand further clinical consideration of the previous well-known adverse events of pegylated interferon and ribavirin. Identification and prompt management of these potential new problems with boceprevir and telaprevir are crucial in clinical practice for optimizing treatment and assuring safety outcomes to HCV-genotype 1 patients.

  4. Thermal safety of ultrasound-enhanced ocular drug delivery: A modeling study

    Nabili, Marjan; Geist, Craig; Zderic, Vesna

    2015-01-01

    Purpose: Delivery of sufficient amounts of therapeutic drugs into the eye for treatment of various ocular diseases is often a challenging task. Ultrasound was shown to be effective in enhancing ocular drug delivery in the authors’ previous in vitro and in vivo studies. Methods: The study reported here was designed to investigate the safety of ultrasound application and its potential thermal effects in the eye using PZFlex modeling software. The safety limit in this study was set as a temperature increase of no more than 1.5 °C based on regulatory recommendations and previous experimental safety studies. Acoustic and thermal specifications of different human eye tissues were obtained from the published literature. The tissues of particular interest in this modeling safety study were cornea, lens, and the location of optic nerve in the posterior eye. Ultrasound application was modeled at frequencies of 400 kHz–1 MHz, intensities of 0.3–1 W/cm 2 , and exposure duration of 5 min, which were the parameters used in the authors’ previous drug delivery experiments. The baseline eye temperature was 37 °C. Results: The authors’ results showed that the maximal tissue temperatures after 5 min of ultrasound application were 38, 39, 39.5, and 40 °C in the cornea, 39.5, 40, 42, and 43 °C in the center of the lens, and 37.5, 38.5, and 39 °C in the back of the eye (at the optic nerve location) at frequencies of 400, 600, 800 kHz, and 1 MHz, respectively. Conclusions: The ocular temperatures reached at higher frequencies were considered unsafe based on current recommendations. At a frequency of 400 kHz and intensity of 0.8 W/cm 2 (parameters shown in the authors’ previous in vivo studies to be optimal for ocular drug delivery), the temperature increase was small enough to be considered safe inside different ocular tissues. However, the impact of orbital bone and tissue perfusion should be included in future modeling efforts to determine the safety of this

  5. Thermal safety of ultrasound-enhanced ocular drug delivery: A modeling study

    Nabili, Marjan, E-mail: mnabili@gwmail.gwu.edu [Department of Electrical and Computer Engineering, The George Washington University, 800 22nd Street NW, Room 5000, Washington, DC 20052 (United States); Geist, Craig, E-mail: cgeist@mfa.gwu.edu, E-mail: zderic@gwu.edu [Department of Ophthalmology, The George Washington University, 2150 Pennsylvania Avenue NW, Floor 2A, Washington, DC 20037 (United States); Zderic, Vesna, E-mail: cgeist@mfa.gwu.edu, E-mail: zderic@gwu.edu [Department of Biomedical Engineering, The George Washington University, 800 22nd Street NW, Room 6670, Washington, DC 20052 (United States)

    2015-10-15

    Purpose: Delivery of sufficient amounts of therapeutic drugs into the eye for treatment of various ocular diseases is often a challenging task. Ultrasound was shown to be effective in enhancing ocular drug delivery in the authors’ previous in vitro and in vivo studies. Methods: The study reported here was designed to investigate the safety of ultrasound application and its potential thermal effects in the eye using PZFlex modeling software. The safety limit in this study was set as a temperature increase of no more than 1.5 °C based on regulatory recommendations and previous experimental safety studies. Acoustic and thermal specifications of different human eye tissues were obtained from the published literature. The tissues of particular interest in this modeling safety study were cornea, lens, and the location of optic nerve in the posterior eye. Ultrasound application was modeled at frequencies of 400 kHz–1 MHz, intensities of 0.3–1 W/cm{sup 2}, and exposure duration of 5 min, which were the parameters used in the authors’ previous drug delivery experiments. The baseline eye temperature was 37 °C. Results: The authors’ results showed that the maximal tissue temperatures after 5 min of ultrasound application were 38, 39, 39.5, and 40 °C in the cornea, 39.5, 40, 42, and 43 °C in the center of the lens, and 37.5, 38.5, and 39 °C in the back of the eye (at the optic nerve location) at frequencies of 400, 600, 800 kHz, and 1 MHz, respectively. Conclusions: The ocular temperatures reached at higher frequencies were considered unsafe based on current recommendations. At a frequency of 400 kHz and intensity of 0.8 W/cm{sup 2} (parameters shown in the authors’ previous in vivo studies to be optimal for ocular drug delivery), the temperature increase was small enough to be considered safe inside different ocular tissues. However, the impact of orbital bone and tissue perfusion should be included in future modeling efforts to determine the safety

  6. Best practices: an electronic drug alert program to improve safety in an accountable care environment.

    Griesbach, Sara; Lustig, Adam; Malsin, Luanne; Carley, Blake; Westrich, Kimberly D; Dubois, Robert W

    2015-04-01

    The accountable care organization (ACO), one of the most promising and talked about new models of care, focuses on improving communication and care transitions by tying potential shared savings to specific clinical and financial benchmarks. An important factor in meeting these benchmarks is an ACO's ability to manage medications in an environment where medical and pharmacy care has been integrated. The program described in this article highlights the critical components of Marshfield Clinic's Drug Safety Alert Program (DSAP), which focuses on prioritizing and communicating safety issues related to medications with the goal of reducing potential adverse drug events. Once the medication safety concern is identified, it is reviewed to evaluate whether an alert warrants sending prescribers a communication that identifies individual patients or a general communication to all physicians describing the safety concern. Instead of basing its decisions regarding clinician notification about drug alerts on subjective criteria, the Marshfield Clinic's DSAP uses an internally developed scoring system. The scoring system includes criteria developed from previous drug alerts, such as level of evidence, size of population affected, severity of adverse event identified or targeted, litigation risk, available alternatives, and potential for duration of medication use. Each of the 6 criteria is assigned a weight and is scored based upon the content and severity of the alert received.  In its first 12 months, the program targeted 6 medication safety concerns involving the following medications: topiramate, glyburide, simvastatin, citalopram, pioglitazone, and lovastatin. Baseline and follow-up prescribing data were gathered on the targeted medications. Follow-up review of prescribing data demonstrated that the DSAP provided quality up-to-date safety information that led to changes in drug therapy and to decreases in potential adverse drug events. In aggregate, nearly 10,000 total

  7. Safety and effectiveness of drug therapy for the acutely agitated patient (Part 2

    Gianluca Airoldi

    2013-04-01

    Full Text Available Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the second in a 2-part series is to review published data on the efficacy and safety of antipsychotic medications currently available for managing situations of this type. Arrhythmias caused by QT-prolonging drugs occur infrequently, and multiple factors are often involved, including concomitant use of other drugs affecting the same pathway (most antipsychotic drugs prolong the QT interval by blocking potassium IKr current in HERG channels of myocardial cells, electrolyte disorders and, possibly, genetic predisposition. Judicious use of typical antipsychotics (mainly haloperidol and benzodiazepines (mainly lorazepam, given intramuscularly alone or in combination, has proved to be safe and effective for controlling acute motor agitation related to psychiatric illness; cocaine, methamphetamine, and ethanol toxicity; ethanol withdrawal; and other factors. They are still widely used and are particularly useful when limited data are available on the patient’s history of cardiovascular disease, current use of medication, and/or the likelihood of illicit drug or alcohol intoxication; when the diagnosis involves medical comorbidity or intoxication; or when there is no specific treatment (e.g., personality disorders, learning disabilities, mental retardation, organic brain damage. If rapid tranquillization is necessary before a formal diagnosis can be made and there are uncertainties regarding the patient’s medical history, lorazepam is often considered the first-line drug of choice. In

  8. Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients.

    Buckley, Lorrene A; Salunke, Smita; Thompson, Karen; Baer, Gerri; Fegley, Darren; Turner, Mark A

    2018-02-05

    A public workshop entitled "Challenges and strategies to facilitate formulation development of pediatric drug products" focused on current status and gaps as well as recommendations for risk-based strategies to support the development of pediatric age-appropriate drug products. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary, panel, and case-study breakout sessions. By enabling practical and meaningful discussion between scientists representing the diversity of involved disciplines (formulators, nonclinical scientists, clinicians, and regulators) and geographies (eg, US, EU), the Excipients Safety workshop session was successful in providing specific and key recommendations for defining paths forward. Leveraging orthogonal sources of data (eg. food industry, agro science), collaborative data sharing, and increased awareness of the existing sources such as the Safety and Toxicity of Excipients for Paediatrics (STEP) database will be important to address the gap in excipients knowledge needed for risk assessment. The importance of defining risk-based approaches to safety assessments for excipients vital to pediatric formulations was emphasized, as was the need for meaningful stakeholder (eg, patient, caregiver) engagement. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Zero-inflated Poisson model based likelihood ratio test for drug safety signal detection.

    Huang, Lan; Zheng, Dan; Zalkikar, Jyoti; Tiwari, Ram

    2017-02-01

    In recent decades, numerous methods have been developed for data mining of large drug safety databases, such as Food and Drug Administration's (FDA's) Adverse Event Reporting System, where data matrices are formed by drugs such as columns and adverse events as rows. Often, a large number of cells in these data matrices have zero cell counts and some of them are "true zeros" indicating that the drug-adverse event pairs cannot occur, and these zero counts are distinguished from the other zero counts that are modeled zero counts and simply indicate that the drug-adverse event pairs have not occurred yet or have not been reported yet. In this paper, a zero-inflated Poisson model based likelihood ratio test method is proposed to identify drug-adverse event pairs that have disproportionately high reporting rates, which are also called signals. The maximum likelihood estimates of the model parameters of zero-inflated Poisson model based likelihood ratio test are obtained using the expectation and maximization algorithm. The zero-inflated Poisson model based likelihood ratio test is also modified to handle the stratified analyses for binary and categorical covariates (e.g. gender and age) in the data. The proposed zero-inflated Poisson model based likelihood ratio test method is shown to asymptotically control the type I error and false discovery rate, and its finite sample performance for signal detection is evaluated through a simulation study. The simulation results show that the zero-inflated Poisson model based likelihood ratio test method performs similar to Poisson model based likelihood ratio test method when the estimated percentage of true zeros in the database is small. Both the zero-inflated Poisson model based likelihood ratio test and likelihood ratio test methods are applied to six selected drugs, from the 2006 to 2011 Adverse Event Reporting System database, with varying percentages of observed zero-count cells.

  10. Complicating factors in safety testing of drug metabolites: Kinetic differences between generated and preformed metabolites

    Prueksaritanont, Thomayant; Lin, Jiunn H.; Baillie, Thomas A.

    2006-01-01

    This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models

  11. Exploiting heterogeneous publicly available data sources for drug safety surveillance: computational framework and case studies.

    Koutkias, Vassilis G; Lillo-Le Louët, Agnès; Jaulent, Marie-Christine

    2017-02-01

    Driven by the need of pharmacovigilance centres and companies to routinely collect and review all available data about adverse drug reactions (ADRs) and adverse events of interest, we introduce and validate a computational framework exploiting dominant as well as emerging publicly available data sources for drug safety surveillance. Our approach relies on appropriate query formulation for data acquisition and subsequent filtering, transformation and joint visualization of the obtained data. We acquired data from the FDA Adverse Event Reporting System (FAERS), PubMed and Twitter. In order to assess the validity and the robustness of the approach, we elaborated on two important case studies, namely, clozapine-induced cardiomyopathy/myocarditis versus haloperidol-induced cardiomyopathy/myocarditis, and apixaban-induced cerebral hemorrhage. The analysis of the obtained data provided interesting insights (identification of potential patient and health-care professional experiences regarding ADRs in Twitter, information/arguments against an ADR existence across all sources), while illustrating the benefits (complementing data from multiple sources to strengthen/confirm evidence) and the underlying challenges (selecting search terms, data presentation) of exploiting heterogeneous information sources, thereby advocating the need for the proposed framework. This work contributes in establishing a continuous learning system for drug safety surveillance by exploiting heterogeneous publicly available data sources via appropriate support tools.

  12. Feasibility and Safety of Transradial Arterial Approach for Simultaneous Right and Left Vertebral Artery Angiographic Studies and Stenting

    Yip, H.-K.; Youssef, Ali A.; Chang, W.-N.; Lu, C.-H.; Yang, C.-H.; Chen, S.-M.; Wu, C.-J.

    2007-01-01

    Objectives. This study investigated whether the transradial artery (TRA) approach using a 6-French (F) Kimny guiding catheter for right vertebral artery (VA) angiographic study and stenting is safe and effective for patients with significant VA stenosis. Background. The TRA approach is commonly performed worldwide for both diagnostic cardiac catheterization and catheter-based coronary intervention. However, to our knowledge, the safety and feasibility of left and right VA angiographic study and stenting, in the same procedure, using the TRA approach for patients with brain ischemia have not been reported. Methods. The study included 24 consecutive patients (22 male, 2 female; age, 63-78 years). Indications for VA angiographic study and stenting were (1) prior stroke or symptoms related to vertebrobasilar ischemia and (2) an asymptomatic but vertebral angiographic finding of severe stenosis (>70%). A combination of the ipsilateral and retrograde-engagement technique, which involved a looping 6-F Kimny guiding catheter, was utilized for VA angiographic study. For VA stenting, an ipsilateral TRA approach with either a Kimny guiding catheter or a left internal mammary artery guiding catheter was utilized in 22 patients and retrograde-engagement technique in 2 patients. Results. A technically successful procedure was achieved in all patients, including left VA stenting in 15 patients and right VA stenting in 9 patients. The mean time for stenting (from engagement to stent deployment) was 12.7 min. There were no vascular complications or mortality. However, one patient suffered from a transient ischemic attack that resolved within 3 h. Conclusion. We conclude that TRA access for both VA angiographic study and VA stenting is safe and effective, and provides a simple and useful clinical tool for patients unsuited for femoral arterial access

  13. Feasibility and safety of adenosine cardiovascular magnetic resonance in patients with MR conditional pacemaker systems at 1.5 Tesla.

    Klein-Wiele, Oliver; Garmer, Marietta; Urbien, Rhyan; Busch, Martin; Kara, Kaffer; Mateiescu, Serban; Grönemeyer, Dietrich; Schulte-Hermes, Michael; Garbrecht, Marc; Hailer, Birgit

    2015-12-22

    Cardiovascular Magnetic Resonance (CMR) with adenosine stress is a valuable diagnostic tool in coronary artery disease (CAD). However, despite the development of MR conditional pacemakers CMR is not yet established in clinical routine for pacemaker patients with known or suspected CAD. A possible reason is that adenosine stress perfusion for ischemia detection in CMR has not been studied in patients with cardiac conduction disease requiring pacemaker therapy. Other than under resting conditions it is unclear whether MR safe pacing modes (paused pacing or asynchronous mode) can be applied safely because the effect of adenosine on heart rate is not precisely known in this entity of patients. We investigate for the first time feasibility and safety of adenosine stress CMR in pacemaker patients in clinical routine and evaluate a pacing protocol that considers heart rate changes under adenosine. We retrospectively analyzed CMR scans of 24 consecutive patients with MR conditional pacemakers (mean age 72.1 ± 11.0 years) who underwent CMR in clinical routine for the evaluation of known or suspected CAD. MR protocol included cine imaging, adenosine stress perfusion and late gadolinium enhancement. Pacemaker indications were sinus node dysfunction (n = 18) and second or third degree AV block (n = 6). Under a pacing protocol intended to avoid competitive pacing on the one hand and bradycardia due to AV block on the other no arrhythmia occurred. Pacemaker stimulation was paused to prevent competitive pacing in sinus node dysfunction with resting heart rate >45 bpm. Sympatho-excitatory effect of adenosine led to a significant acceleration of heart rate by 12.3 ± 8.3 bpm (p pacemakers. Heart rate response to adenosine has to be considered for the choice of pacing modes during CMR.

  14. Morphometric analysis of the cervical facets and the feasibility, safety, and effectiveness of Goel inter-facet spacer distraction technique

    Abhidha Shah

    2014-01-01

    Full Text Available Aim: Quantitative anatomy of the facets of the sub-axial cervical spine was performed. The purpose of the evaluation was to determine the feasibility of insertion of Goel inter-facetal articular spacers in the sub-axial cervical spine. Only few studies detailing the morphometry of the facets are available in the literature. Materials and Methods: Ten cervical vertebrae from C3 to C7 with a total of 20 facets were evaluated by the author. The anatomic parameters studied were the height, width, thickness, shape, orientation, and inclination of each of the superior and inferior facets. The alterations in a number of intervertebral segmental distances were measured before and after spacer insertion. The distance of the inferior facet from the foramen tranversarium, spinal canal, and neural foramina was measured to assess safety of spacer insertion with respect to the vertebral artery and neural structures. Results: The height, width and thickness of the superior facets from C3 to C7 ranged from 6 to 12 mm, 8 to 12 mm, and 2.5 to 6 mm, respectively. The inferior facets had an average height of 10.5 mm, average width of 11.2 mm and average thickness of 3.5 mm. The inclination of the superior facets with respect to the transverse plane ranged from 22° to 45° and that of the inferior facets ranged from 29° to 53°. The distance of the anterior margin of the inferior facet from the posterior border of the foramen transversium ranged from 5 to 7 mm. This distance was maximum at C3 level, then decreased at C4 and remained constant from C5 to C7. Conclusion: This anatomic evaluation aided in understanding the morphology of the cervical facets and the suitability of the cervical facetal articular cavity for insertion of spacers.

  15. Human rights vs. Public safety -- When can you test your workers for drugs?

    Kossowan, B. L.

    2002-06-01

    Legislative and regulatory aspects of drug testing of employees vs. public safety are discussed. While in Canada federal and provincial laws concerning human rights take precedence over public safety issues, laws and regulations vary from province to province, therefore there is good reason for concern about uncertainty. To compound the uncertainty, certain relevant laws of the United States are different (generally more stringent than corresponding Canadian laws), consequently there is the possibility that certain American companies might feel justified in refusing to do business with Canadian firms that do not follow their rigid standards. The conclusion is that while the situation may be clear enough in a legal situation, it does not always work equally well in practice. Unfortunately, at the present time there is not a whole lot of guidance available for companies to manage the workplace in a practical sense.

  16. Long-Term Safety of Drug-Eluting and Bare-Metal Stents

    Palmerini, Tullio; Benedetto, Umberto; Biondi-Zoccai, Giuseppe

    2015-01-01

    BACKGROUND: Previous meta-analyses have investigated the relative safety and efficacy profiles of different types of drug-eluting stents (DES) and bare-metal stents (BMS); however, most prior trials in these meta-analyses reported follow-up to only 1 year, and as such, the relative long-term safety....... RESULTS: Fifty-one trials that included a total of 52,158 randomized patients with follow-up duration ≥3 years were analyzed. At a median follow-up of 3.8 years, cobalt-chromium everolimus-eluting stents (EES) were associated with lower rates of mortality, definite stent thrombosis (ST), and myocardial...... infarction than BMS, paclitaxel-eluting stents (PES), and sirolimus-eluting stents (SES) and less ST than BES. Phosphorylcholine-based zotarolimus-eluting stents had lower rates of definite ST than SES and lower rates of myocardial infarction than BMS and PES. The late rates of target...

  17. Evaluation of Electronic Healthcare Databases for Post-Marketing Drug Safety Surveillance and Pharmacoepidemiology in China.

    Yang, Yu; Zhou, Xiaofeng; Gao, Shuangqing; Lin, Hongbo; Xie, Yanming; Feng, Yuji; Huang, Kui; Zhan, Siyan

    2018-01-01

    Electronic healthcare databases (EHDs) are used increasingly for post-marketing drug safety surveillance and pharmacoepidemiology in Europe and North America. However, few studies have examined the potential of these data sources in China. Three major types of EHDs in China (i.e., a regional community-based database, a national claims database, and an electronic medical records [EMR] database) were selected for evaluation. Forty core variables were derived based on the US Mini-Sentinel (MS) Common Data Model (CDM) as well as the data features in China that would be desirable to support drug safety surveillance. An email survey of these core variables and eight general questions as well as follow-up inquiries on additional variables was conducted. These 40 core variables across the three EHDs and all variables in each EHD along with those in the US MS CDM and Observational Medical Outcomes Partnership (OMOP) CDM were compared for availability and labeled based on specific standards. All of the EHDs' custodians confirmed their willingness to share their databases with academic institutions after appropriate approval was obtained. The regional community-based database contained 1.19 million people in 2015 with 85% of core variables. Resampled annually nationwide, the national claims database included 5.4 million people in 2014 with 55% of core variables, and the EMR database included 3 million inpatients from 60 hospitals in 2015 with 80% of core variables. Compared with MS CDM or OMOP CDM, the proportion of variables across the three EHDs available or able to be transformed/derived from the original sources are 24-83% or 45-73%, respectively. These EHDs provide potential value to post-marketing drug safety surveillance and pharmacoepidemiology in China. Future research is warranted to assess the quality and completeness of these EHDs or additional data sources in China.

  18. Working towards consensus on methods used to elicit participant-reported safety data in uncomplicated malaria clinical drug studies: a Delphi technique study.

    Mandimika, Nyaradzo; Barnes, Karen I; Chandler, Clare I R; Pace, Cheryl; Allen, Elizabeth N

    2017-01-28

    Eliciting adverse event (AE) and non-study medication data reports from clinical research participants is integral to evaluating drug safety. However, using different methods to question participants yields inconsistent results, compromising the interpretation, comparison and pooling of data across studies. This is particularly important given the widespread use of anti-malarials in vulnerable populations, and their increasing use in healthy, but at-risk individuals, as preventive treatment or to reduce malaria transmission. Experienced and knowledgeable anti-malarial drug clinical researchers were invited to participate in a Delphi technique study, to facilitate consensus on what are considered optimal (relevant, important and feasible) methods, tools, and approaches for detecting participant-reported AE and non-study medication data in uncomplicated malaria treatment studies. Of 72 invited, 25, 16 and 10 panellists responded to the first, second and third rounds of the Delphi, respectively. Overall, 68% (68/100) of all questioning items presented for rating achieved consensus. When asking general questions about health, panellists agreed on the utility of a question/concept about any change in health, taking care to ensure that such questions/concepts do not imply causality. Eighty-nine percent (39/44) of specific signs and symptoms questions were rated as optimal. For non-study medications, a general question and most structured questioning items were considered an optimal approach. The use of mobile phones, patient diaries, rating scales as well as openly engaging with participants to discuss concerns were also considered optimal complementary data-elicitation tools. This study succeeded in reaching consensus within a section of the anti-malarial drug clinical research community about using a general question concept, and structured questions for eliciting data about AEs and non-study medication reports. The concepts and items considered in this Delphi to be

  19. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis.

    Trelle, Sven; Reichenbach, Stephan; Wandel, Simon; Hildebrand, Pius; Tschannen, Beatrice; Villiger, Peter M; Egger, Matthias; Jüni, Peter

    2011-01-11

    To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs. Network meta-analysis. Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data. All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility. The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data. 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death. Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

  20. Pharmacovigilance and drug safety in Calabria (Italy): 2012 adverse events analysis.

    Giofrè, Chiara; Scicchitano, Francesca; Palleria, Caterina; Mazzitello, Carmela; Ciriaco, Miriam; Gallelli, Luca; Paletta, Laura; Marrazzo, Giuseppina; Leporini, Christian; Ventrice, Pasquale; Carbone, Claudia; Saullo, Francesca; Rende, Pierandrea; Menniti, Michele; Mumoli, Laura; Chimirri, Serafina; Patanè, Marinella; Esposito, Stefania; Cilurzo, Felisa; Staltari, Orietta; Russo, Emilio; De Sarro, Giovambattista

    2013-12-01

    Pharmacovigilance (PV) is designed to monitor drugs continuously after their commercialization, assessing and improving their safety profile. The main objective is to increase the spontaneous reporting of adverse drug reactions (ADRs), in order to have a wide variety of information. The Italian Drug Agency (Agenzia Italiana del Farmaco [AIFA]) is financing several projects to increase reporting. In Calabria, a PV information center has been created in 2010. We obtained data using the database of the National Health Information System AIFA relatively to Italy and Calabria in the year 2012. Descriptive statistics were performed to analyze the ADRs. A total number of 461 ADRs have been reported in the year 2012 with an increase of 234% compared with 2011 (138 reports). Hospital doctors are the main source of this reporting (51.62%). Sorafenib (Nexavar(®)), the combination of amoxicillin/clavulanic acid and ketoprofen represent the drugs most frequently reported causing adverse reactions. Adverse events in female patients (61.83%) were more frequently reported, whereas the age groups "41-65" (39.07%) and "over 65" (27.9%) were the most affected. Calabria has had a positive increase in the number of ADRs reported, although it has not yet reached the gold standard set by World Health Organization (about 600 reports), the data have shown that PV culture is making inroads in this region and that PV projects stimulating and increasing PV knowledge are needed.

  1. Pharmacovigilance and drug safety 2011 in Calabria (Italy: Adverse events analysis

    Francesca Scicchitano

    2012-01-01

    Full Text Available Background : Pharmacovigilance assesses the safety profile of drugs. Its main aim is the increase of spontaneous reporting of adverse drug reactions (ADRs. The Italian Drug Agency (AIFA; Agenzia Italiana del Farmaco is financing several projects to the aim of increasing reporting, and in Calabria a Pharmacovigilance Information Centre has been created. Materials and Methods: We analyzed the AIFA database relatively to Calabria in the year 2011 and we have analyzed ADRs using descriptive statistics. We have also collected a questionnaire-based interview in order to describe the background knowledge in the field. Results : Regarding the number of AIFA reported ADRs from Calabria, a 38% increase (138 vs. 100 in comparison to 2010 was evidenced. Hospital Doctors represent the main source of signaling (71.7 %. Ketoprofene and the combination amoxicillin/clavulanic acid represent the most frequently reported drugs causing ADRs. Our questionnaires indicated that despite the health professionals have met at least once an ADR only a small percentage of them was reported to the authorities (37%. There is a very good knowledge of the ADR concept and reporting system (90% of interviewed distinguish an ADR and knows how to report it, and there is a strong interest in participating to training courses in the field (95% are interested. Conclusions : Despite Calabria has had a positive increase in the number of reported ADRs, the total number is very low and the pharmacovigilance culture is far from being achieved in this region.

  2. Pharmacovigilance and drug safety 2011 in Calabria (Italy): Adverse events analysis.

    Scicchitano, Francesca; Giofrè, Chiara; Palleria, Caterina; Mazzitello, Carmela; Ciriaco, Miriam; Gallelli, Luca; Paletta, Laura; Marrazzo, Giuseppina; De Fazio, Salvatore; Menniti, Michele; Curia, Rubens; Arena, Concetta; Chimirri, Serafina; Patanè, Marinella; Esposito, Stefania; Cilurzo, Felisa; Staltari, Orietta; Russo, Emilio; De Sarro, Giovambattista

    2012-09-01

    Pharmacovigilance assesses the safety profile of drugs. Its main aim is the increase of spontaneous reporting of adverse drug reactions (ADRs). The Italian Drug Agency (AIFA; Agenzia Italiana del Farmaco) is financing several projects to the aim of increasing reporting, and in Calabria a Pharmacovigilance Information Centre has been created. We analyzed the AIFA database relatively to Calabria in the year 2011 and we have analyzed ADRs using descriptive statistics. We have also collected a questionnaire-based interview in order to describe the background knowledge in the field. Regarding the number of AIFA reported ADRs from Calabria, a 38% increase (138 vs. 100) in comparison to 2010 was evidenced. Hospital Doctors represent the main source of signaling (71.7 %). Ketoprofene and the combination amoxicillin/clavulanic acid represent the most frequently reported drugs causing ADRs. Our questionnaires indicated that despite the health professionals have met at least once an ADR only a small percentage of them was reported to the authorities (37%). There is a very good knowledge of the ADR concept and reporting system (90% of interviewed distinguish an ADR and knows how to report it), and there is a strong interest in participating to training courses in the field (95% are interested). Despite Calabria has had a positive increase in the number of reported ADRs, the total number is very low and the pharmacovigilance culture is far from being achieved in this region.

  3. Feasibility, safety and effectiveness of combining home based malaria management and seasonal malaria chemoprevention in children less than 10 years in Senegal

    Tine, Roger C K; Ndour, Cheikh T; Faye, Babacar

    2014-01-01

    Home-based management of malaria (HMM) may improve access to diagnostic testing and treatment with artemisinin combination therapy (ACT). In the Sahel region, seasonal malaria chemoprevention (SMC) is now recommended for the prevention of malaria in children. It is likely that combinations...... of antimalarial interventions can reduce the malaria burden. This study assessed the feasibility, effectiveness and safety of combining SMC and HMM delivered by community health workers (CHWs)....

  4. Long-term safety and feasibility of three-vessel multimodality intravascular imaging in patients with ST-elevation myocardial infarction

    Taniwaki, Masanori; Radu, Maria D; Garcia-Garcia, Hector M

    2015-01-01

    We assessed the feasibility and the procedural and long-term safety of intracoronary (i.c) imaging for documentary purposes with optical coherence tomography (OCT) and intravascular ultrasound (IVUS) in patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary PCI in the s......We assessed the feasibility and the procedural and long-term safety of intracoronary (i.c) imaging for documentary purposes with optical coherence tomography (OCT) and intravascular ultrasound (IVUS) in patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary PCI...... in the setting of IBIS-4 study. IBIS4 (NCT00962416) is a prospective cohort study conducted at five European centers including 103 STEMI patients who underwent serial three-vessel coronary imaging during primary PCI and at 13 months. The feasibility parameter was successful imaging, defined as the number...... of pullbacks suitable for analysis. Safety parameters included the frequency of peri-procedural complications, and major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction (MI) and any clinically-indicated revascularization at 2 years. Clinical outcomes were compared...

  5. Type I error probability spending for post-market drug and vaccine safety surveillance with binomial data.

    Silva, Ivair R

    2018-01-15

    Type I error probability spending functions are commonly used for designing sequential analysis of binomial data in clinical trials, but it is also quickly emerging for near-continuous sequential analysis of post-market drug and vaccine safety surveillance. It is well known that, for clinical trials, when the null hypothesis is not rejected, it is still important to minimize the sample size. Unlike in post-market drug and vaccine safety surveillance, that is not important. In post-market safety surveillance, specially when the surveillance involves identification of potential signals, the meaningful statistical performance measure to be minimized is the expected sample size when the null hypothesis is rejected. The present paper shows that, instead of the convex Type I error spending shape conventionally used in clinical trials, a concave shape is more indicated for post-market drug and vaccine safety surveillance. This is shown for both, continuous and group sequential analysis. Copyright © 2017 John Wiley & Sons, Ltd.

  6. Pharmacokinetics in Drug Discovery: An Exposure-Centred Approach to Optimising and Predicting Drug Efficacy and Safety.

    Reichel, Andreas; Lienau, Philip

    2016-01-01

    The role of pharmacokinetics (PK) in drug discovery is to support the optimisation of the absorption, distribution, metabolism and excretion (ADME) properties of lead compounds with the ultimate goal to attain a clinical candidate which achieves a concentration-time profile in the body that is adequate for the desired efficacy and safety profile. A thorough characterisation of the lead compounds aiming at the identification of the inherent PK liabilities also includes an early generation of PK/PD relationships linking in vitro potency and target exposure/engagement with expression of pharmacological activity (mode-of-action) and efficacy in animal studies. The chapter describes an exposure-centred approach to lead generation, lead optimisation and candidate selection and profiling that focuses on a stepwise generation of an understanding between PK/exposure and PD/efficacy relationships by capturing target exposure or surrogates thereof and cellular mode-of-action readouts in vivo. Once robust PK/PD relationship in animal PD models has been constructed, it is translated to anticipate the pharmacologically active plasma concentrations in patients and the human therapeutic dose and dosing schedule which is also based on the prediction of the PK behaviour in human as described herein. The chapter outlines how the level of confidence in the predictions increases with the level of understanding of both the PK and the PK/PD of the new chemical entities (NCE) in relation to the disease hypothesis and the ability to propose safe and efficacious doses and dosing schedules in responsive patient populations. A sound identification of potential drug metabolism and pharmacokinetics (DMPK)-related development risks allows proposing of an effective de-risking strategy for the progression of the project that is able to reduce uncertainties and to increase the probability of success during preclinical and clinical development.

  7. Nonclinical safety biomarkers of drug-induced vascular injury: current status and blueprint for the future.

    Mikaelian, Igor; Cameron, Mark; Dalmas, Deidre A; Enerson, Bradley E; Gonzalez, Raymond J; Guionaud, Silvia; Hoffmann, Peter K; King, Nicholas M P; Lawton, Michael P; Scicchitano, Marshall S; Smith, Holly W; Thomas, Roberta A; Weaver, James L; Zabka, Tanja S

    2014-06-01

    Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI. © 2014 by The Author(s).

  8. Safety and feasibility of atrial fibrillation ablation using Amigo® system versus manual approach: A pilot study

    Antonio Scarà

    2018-03-01

    Full Text Available Background: The Amigo® Remote Catheter System is a relatively new robotic system for catheter navigation. This study compared feasibility and safety using Amigo (RCM versus manual catheter manipulation (MCM to treat paroxysmal atrial fibrillation (PAF. Contact force (CF and force-time integral (FTI values obtained during pulmonary vein isolation (PVI ablation were compared. Methods: Forty patients were randomly selected for either RCM (20 or MCM (20. All were studied with the Thermocool® SmartTouch® force-sensing catheter (STc. Contact Force (CF, Force Time Integral (FTI and procedure-related data, were measured/stored in the CARTO®3. Results: All cases achieved complete PVI without major complications. Mean CF was significantly higher in the RCM group (13.3 ± 7.7 g in RCM vs. 12.04 ± 7.42 g in MCM p < 0.001, as was overall mean FTI (425.6 gs ± 199.6 gs with RCM and 407.5 gs ± 288.0 gs in MCM (p = 0.007 and was more likely to fall into the optimal FTI range (400-1000 using RCM (66.1% versus 49.1%, p < 0.001. FTI was significantly more likely to fall within the optimal range in each PV, as was CF within its optimal range in the right PVs, but trended higher in the left PVs. Freedom from atrial tachyarrhythmia was 90.0% for the RCM and 70.0% for the MCM group (p = 0,12 at 540 days follow-up. Conclusions: This pilot study suggests that use of the Amigo RCM system, with STc catheter, seems to be safe and effective for PVI ablation in paroxysmal AF patients. A not statistically significant favorable trend was observed for RCM in term of AF-free survival. Keywords: Atrial fibrillation, Catheter ablation, Remote robotic ablation

  9. Feasibility of a computer-delivered driver safety behavior screening and intervention program initiated during an emergency department visit.

    Murphy, Mary; Smith, Lucia; Palma, Anton; Lounsbury, David; Bijur, Polly; Chambers, Paul; Gallagher, E John

    2013-01-01

    Injuries from motor vehicle crashes are a significant public health problem. The emergency department (ED) provides a setting that may be used to screen for behaviors that increase risk for motor vehicle crashes and provide brief interventions to people who might otherwise not have access to screening and intervention. The purpose of the present study was to (1) assess the feasibility of using a computer-assisted screening program to educate ED patients about risky driving behaviors, (2) evaluate patient acceptance of the computer-based traffic safety educational intervention during an ED visit, and (3) assess postintervention changes in risky driving behaviors. Pre/posteducational intervention involving medically stable adult ED patients in a large urban academic ED serving over 100,000 patients annually. Patients completed a self-administered, computer-based program that queried patients on risky driving behaviors (texting, talking, and other forms of distracted driving) and alcohol use. The computer provided patients with educational information on the dangers of these behaviors and data were collected on patient satisfaction with the program. Staff called patients 1 month post-ED visit for a repeat query. One hundred forty-nine patients participated, and 111 completed 1-month follow up (75%); the mean age was 39 (range: 21-70), 59 percent were Hispanic, and 52 percent were male. Ninety-seven percent of patients reported that the program was easy to use and that they were comfortable receiving this education via computer during their ED visit. All driving behaviors significantly decreased in comparison to baseline with the following reductions reported: talking on the phone, 30 percent; aggressive driving, 30 percent; texting while driving, 19 percent; drowsy driving, 16 percent; driving while multitasking, 12 percent; and drinking and driving, 9 percent. Overall, patients were very satisfied receiving educational information about these behaviors via computer

  10. Impact of regulatory guidances and drug regulation on risk minimization interventions in drug safety: a systematic review.

    Nkeng, Lenhangmbong; Cloutier, Anne-Marie; Craig, Camille; Lelorier, Jacques; Moride, Yola

    2012-07-01

    Therapeutic risk management has received growing interest in recent years, particularly since the publication of regulatory guidances in 2005 and 2006, paralleled with a change in drug regulation. The characteristics of risk minimization interventions (RMIs) that have been implemented or approved remain inadequately explored. The aim of this study was to review RMIs published in the literature or posted on regulatory agency websites over the past 10 years, and to assess whether publication of regulatory guidances on risk management is associated with changes in the number and types of interventions. Sources were searched for RMIs published/posted between 1 January 2000 and 31 December 2009. For the literature search, MEDLINE and EMBASE databases were used using key words related to drug safety (i.e. 'drug toxicity') and the individual RMI names. The website review involved searches of major regulatory authority websites such as the European Medicines Agency, US FDA, Health Canada, the UK's Medicines and Healthcare products Regulatory Agency, Japan's Pharmaceutical and Medical Devices Agency and Australia's Therapeutic Goods Administration. The following eligibility criteria were applied for inclusion in the review: published/posted between the years 2000 and 2009, inclusive; involving drug products; use in humans; and involving RMIs, or tools used to increase the reporting of adverse events (AEs). Natural healthcare products, devices, diagnostic chemicals, pregnancy registries without follow-up, medication errors and products not used as therapy for illness were not retained. For each source, the following characteristics were extracted: nature of the intervention, target population, therapeutic area, AE(s) of special interest, country/regulatory agency and year of publication. A total of 119 unique interventions were identified in the literature (54 published in 2000-4 and 65 published in 2005-9). Interventions included educational material (n = 37; 31%), black

  11. Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

    Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

    2013-11-01

    Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

  12. Considerations for the nonclinical safety evaluation of antibody drug conjugates for oncology.

    Roberts, Stanley A; Andrews, Paul A; Blanset, Diann; Flagella, Kelly M; Gorovits, Boris; Lynch, Carmel M; Martin, Pauline L; Kramer-Stickland, Kimberly; Thibault, Stephane; Warner, Garvin

    2013-12-01

    Antibody drug conjugates (ADCs) include monoclonal antibodies that are linked to cytotoxic small molecules. A number of these agents are currently being developed as anti-cancer agents designed to improve the therapeutic index of the cytotoxin (i.e., cytotoxic small molecule or cytotoxic agent) by specifically delivering it to tumor cells. This paper presents primary considerations for the nonclinical safety evaluation of ADCs and includes strategies for the evaluation of the entire ADC or the various individual components (i.e., antibody, linker or the cytotoxin). Considerations are presented on how to design a nonclinical safety assessment program to identify the on- and off-target toxicities to enable first-in-human (FIH) studies. Specific discussions are also included that provide details as to the need and how to conduct the studies for evaluating ADCs in genetic toxicology, tissue cross-reactivity, safety pharmacology, carcinogenicity, developmental and reproductive toxicology, biotransformation, toxicokinetic monitoring, bioanalytical assays, immunogenicity testing, test article stability and the selection of the FIH dose. Given the complexity of these molecules and our evolving understanding of their properties, there is no single all-encompassing nonclinical strategy. Instead, each ADC should be evaluated on a case-by-case scientifically-based approach that is consistent with ICH and animal research guidelines. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance.

    Schadt, Simone; Bister, Bojan; Chowdhury, Swapan K; Funk, Christoph; Hop, Cornelis E C A; Humphreys, W Griffith; Igarashi, Fumihiko; James, Alexander D; Kagan, Mark; Khojasteh, S Cyrus; Nedderman, Angus N R; Prakash, Chandra; Runge, Frank; Scheible, Holger; Spracklin, Douglas K; Swart, Piet; Tse, Susanna; Yuan, Josh; Obach, R Scott

    2018-06-01

    Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. Together with technological advances, these events have led to a general shift of focus toward earlier human metabolism studies using high-resolution mass spectrometry and to a reduction in animal radiolabel absorption/distribution/metabolism/excretion studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industry. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Environmental, Safety, and Health Plan for the remedial investigation/feasibility study at Oak Ridge National Laboratory, Oak Ridge, Tennessee. Revision 1, Environmental Restoration Program

    Davis, C. M.; El-Messidi, O. E.; Cowser, D. K.; Kannard, J. R.; Carvin, R. T.; Will, III, A. S.; Clark, Jr., C.; Garland, S. B.

    1993-05-01

    This Environmental, Safety, and Health (ES&H) Plan presents the concepts and methodologies to be followed during the remedial investigation/feasibility study (RI/FS) for Oak Ridge National Laboratory (ORNL) to protect the health and safety of employees, the public, and the environment. This ES&H Plan acts as a management extension for ORNL and Martin Marietta Energy Systems, Inc. (Energy Systems) to direct and control implementation of the project ES&H program. The subsections that follow describe the program philosophy, requirements, quality assurance measures, and methods for applying the ES&H program to individual waste area grouping (WAG) remedial investigations. Hazardous work permits (HWPs) will be used to provide task-specific health and safety requirements.

  15. Strategy for a consistent selection of radionuclide migration parameters for the Belgian safety and feasibility case-1

    Bruggeman, C.; Maes, N.; Salah, S.; Brassinnes, S.; Van Geet, M.

    2010-01-01

    Document available in extended abstract form only. The purpose of this presentation is to describe the strategy for the selection of retention and migration parameters for safety-relevant nuclides that was developed in the framework of the Belgian Safety and Feasibility Case SFC-1. A geochemical database containing state-of-the-art retention and migration parameters of all safety-relevant radionuclides, is ideally based on a thermodynamic understanding and an ability to accurately describe the geochemical and transport behaviour of all these radionuclides under the geochemical conditions that are considered for a reference host formation. In Belgium, this reference formation is Boom Clay. The parameters will be used in Performance Assessment (PA) calculations, and therefore must also be adapted to PA models. Since these models currently use only a four parameters for every radionuclide, the whole geochemical and transport behaviour must be comprised to a very limited parameter set that describe on the one hand chemical retention within the Boom Clay formation, and on the other hand transport through the Boom Clay formation. Chemical retention considers two concepts: 1) a concentration limit (S), which represents the mobile concentration of a nuclide present in the aqueous phase under undisturbed far field Boom Clay conditions; 2) a retardation (R/Kd) factor, which represents the uptake of a mobile nuclide by the inorganic and organic phases present in the Boom Clay formation. For mobility/migration two additional concepts are introduced: 3) the diffusion accessible porosity (η), which is the total physical space available for transport of a nuclide. The maximum value of η is limited by the water content of the formation; 4) the pore diffusion coefficient (Dp), which represents the transport velocity of a nuclide in a diffusion-dominated system. Within the framework of SFC-1, primary focus is laid on the compilation of parameter ranges, instead of individual &apos

  16. Safety of Therapeutic Fever Induction in Cancer Patients Using Approved PAMP Drugs

    Uwe Rudolf Max Reuter

    2018-04-01

    Full Text Available William Coley, between 1895 and 1936, treated hundreds of cancer patients using infusions of fever inducing bacerial extracts. Similar experiments were done by Klyuyeva and co-workers in the 1940ies in Russia using trypanosoma extracts. Many remissions and cures were reported. We have conjectured that pathogen associated molecular pattern substances (PAMP are the molecular explanation for the beneficial treatments in both groups. We could show that a combination of PAMP can eradicate solid tumours in cancer mice if applied several times. Accordingly, we suggested to combine PAMP containing approved drugs to treat cancer patients using a protocol similar to the old fever induction regimen. In this retrospective phase-1 study we report on the fever induction capacity and safety of applications of bacterial extracts, combinations of bacterial extracts with approved drugs, and combinations of approved drugs in 131 mainly cancer patients. Adverse reactions were those which can be expected during a feverish infection and mild. Over 523 fever inductions, no severe adverse reaction was observed.

  17. Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature

    M. Varenna

    2013-10-01

    Full Text Available The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction.

  18. A safety and tolerability study of differently-charged nanoparticles for local pulmonary drug delivery

    Harush-Frenkel, Oshrat; Bivas-Benita, Maytal; Nassar, Taher; Springer, Chaim; Sherman, Yoav; Avital, Avraham; Altschuler, Yoram; Borlak, Jurgen; Benita, Simon

    2010-01-01

    Nanoparticle (NP) based drug delivery systems provide promising opportunities in the treatment of lung diseases. Here we examined the safety and tolerability of pulmonary delivered NPs consisting of PEG-PLA as a function of particle surface charge. The rationale for such a comparison should be attributed to the differential pulmonary toxicity of positively and negatively charged PEG-PLA NP. Thus, the local and systemic effects of pulmonary administered NPs were investigated following 5 days of daily endotracheal instillation to BALB/c mice that were euthanized on the eighth or nineteenth day of the experiment. We collected bronchoalveolar lavages and studied hematological as well as histochemistry parameters. Notably, the cationic stearylamine based PEG-PLA NPs elicited increased local and systemic toxic effects both on the eighth and nineteenth day. In contrast, anionic NPs of similar size were much better tolerated with local inflammatory effects observed only on the eighth experimental day after pulmonary instillation. No systemic toxicity effect was observed although a moderate change was noted in the platelet count that was not considered to be of clinical significance. No pathological observations were detected in the internal organs following instillation of anionic NPs. Overall these observations suggest that anionic PEG-PLA NPs are useful pulmonary drug carriers that should be considered as a promising therapeutic drug delivery system.

  19. Comparison of the safety information on drug labels in three developed countries: The USA, UK and Canada

    Thamir M. Alshammari

    2017-12-01

    Full Text Available The safety information on drug labels of a company marketing the same drugs in different countries is sometimes different. The aim of the present study is to understand the differences in the volume and content of safety information on the drug labels from the same manufacturers in three developed countries: the United States of America (USA, the United Kingdom (UK and Canada. This study involved the calculation of the proportion of total safety information (PSI and of contraindications (PCI in comparison to all information on the label and the percentage of boxed warnings (PBW among the 100 labels studied from each country. The PSI on the labels of different countries is different with USA labels bearing lesser value PSI and UK labels bearing higher value PSI. The qualitative information provided on these drug labels from each country in ‘contraindications’ sections, ‘boxed/serious warnings’ and ‘overdosage’ sections presented differences in the information provided on most of the labels. We have found distinct differences between the safety information available on drug labels in terms of volume and content. We conclude that the safety information for the same products should be standardised across all countries.

  20. The impact of assay technology as applied to safety assessment in reducing compound attrition in drug discovery.

    Thomas, Craig E; Will, Yvonne

    2012-02-01

    Attrition in the drug industry due to safety findings remains high and requires a shift in the current safety testing paradigm. Many companies are now positioning safety assessment at each stage of the drug development process, including discovery, where an early perspective on potential safety issues is sought, often at chemical scaffold level, using a variety of emerging technologies. Given the lengthy development time frames of drugs in the pharmaceutical industry, the authors believe that the impact of new technologies on attrition is best measured as a function of the quality and timeliness of candidate compounds entering development. The authors provide an overview of in silico and in vitro models, as well as more complex approaches such as 'omics,' and where they are best positioned within the drug discovery process. It is important to take away that not all technologies should be applied to all projects. Technologies vary widely in their validation state, throughput and cost. A thoughtful combination of validated and emerging technologies is crucial in identifying the most promising candidates to move to proof-of-concept testing in humans. In spite of the challenges inherent in applying new technologies to drug discovery, the successes and recognition that we cannot continue to rely on safety assessment practices used for decades have led to rather dramatic strategy shifts and fostered partnerships across government agencies and industry. We are optimistic that these efforts will ultimately benefit patients by delivering effective and safe medications in a timely fashion.

  1. The principle of safety evaluation in medicinal drug - how can toxicology contribute to drug discovery and development as a multidisciplinary science?

    Horii, Ikuo

    2016-01-01

    Pharmaceutical (drug) safety assessment covers a diverse science-field in the drug discovery and development including the post-approval and post-marketing phases in order to evaluate safety and risk management. The principle in toxicological science is to be placed on both of pure and applied sciences that are derived from past/present scientific knowledge and coming new science and technology. In general, adverse drug reactions are presented as "biological responses to foreign substances." This is the basic concept of thinking about the manifestation of adverse drug reactions. Whether or not toxic expressions are extensions of the pharmacological effect, adverse drug reactions as seen from molecular targets are captured in the category of "on-target" or "off-target", and are normally expressed as a biological defense reaction. Accordingly, reactions induced by pharmaceuticals can be broadly said to be defensive reactions. Recent molecular biological conception is in line with the new, remarkable scientific and technological developments in the medical and pharmaceutical areas, and the viewpoints in the field of toxicology have shown that they are approaching toward the same direction as well. This paper refers to the basic concept of pharmaceutical toxicology, the differences for safety assessment in each stage of drug discovery and development, regulatory submission, and the concept of scientific considerations for risk assessment and management from the viewpoint of "how can multidisciplinary toxicology contribute to innovative drug discovery and development?" And also realistic translational research from preclinical to clinical application is required to have a significant risk management in post market by utilizing whole scientific data derived from basic and applied scientific research works. In addition, the significance for employing the systems toxicology based on AOP (Adverse Outcome Pathway) analysis is introduced, and coming challenges on precision

  2. Feasibility, safety, and potential demand of emergent brain magnetic resonance imaging of patients with cardiac implantable electronic devices

    Maki Ono

    2017-10-01

    Conclusions: Our study found the potential demand of brain MRI of patients with CIEDs in emergency situations compared with scheduled scanning, which was shown to be feasible and safe for the diagnosis and treatment of an acute stroke.

  3. Drug research methodology. Volume 1, The alcohol-highway safety experience and its applicability to other drugs

    1980-03-01

    This report presents the findings of a workshop concerning the alcohol and highway safety experience, which includes research efforts to define the drinking-driving problem and societal responses to reduce the increased highway safety risk attributab...

  4. A systematic review and meta-analysis of the safety, feasibility and effect of exercise in women with stage II+ breast cancer.

    Singh, Ben; Spence, Rosalind R; Steele, Megan L; Sandler, Carolina X; Peake, Jonathan M; Hayes, Sandra C

    2018-05-03

    To systematically evaluate the safety, feasibility and effect of exercise among women with stage II+ breast cancer. CINAHL, Cochrane, Ebscohost, MEDLINE, Pubmed, ProQuest Health and Medical Complete, ProQuest Nursing and Allied Health Source, Science Direct and SPORTDiscus were searched for articles published prior to March 1, 2017. Randomised, controlled, exercise trials involving at least 50% of women diagnosed with stage II+ breast cancer were included. Risk of bias was assessed and adverse event severity was classified using the Common Terminology Criteria. Feasibility was evaluated by computing median (range) recruitment, withdrawal and adherence rates. Meta-analyses were performed to evaluate exercise safety and effects on health outcomes only. The influence of intervention characteristics (mode, supervision, duration and timing) on exercise outcomes were also explored. There were no differences in adverse events between exercise and usual care (risk difference: feasibility outcomes were similar, irrespective of exercise mode, supervision, duration, or timing. Effects of exercise for quality of life, fitness, fatigue, strength, anxiety, depression, body mass index and waist circumference compared with usual care were significant (standardised mean difference range: 0.17-0.77, pfeasibility and effects of exercise for those with stage II+ breast cancer, suggesting that national and international exercise guidelines appear generalizable to women with local, regional and distant breast cancer. Copyright © 2018. Published by Elsevier Inc.

  5. Effects of acute exercise on drug craving, self-esteem, mood and affect in adults with poly-substance dependence: Feasibility and preliminary findings.

    Ellingsen, Maren Mikkelsen; Johannesen, Sunniva Launes; Martinsen, Egil W; Hallgren, Mats

    2018-06-04

    Novel treatments for substance use disorders are needed. Acute bouts of exercise can improve mood states in non-clinical populations, but effects in those with poly-substance dependence are understudied. We examined the feasibility and short-term effects of three types of exercise on drug cravings, self-esteem, mood and positive/negative affect in nine poly-drug-dependent inpatients. Using a cross-over design, changes in the four study outcomes were assessed immediately before exercise and on four separate occasions post-exercise (immediately after, then at 1, 2 and 4 h post-exercise) enabling patterns of change over time (analysis of covariance) to be observed. Participants were willing and able to engage in different non-laboratory based exercises. Football was associated with non-significant short-term reductions in drug cravings. A similar trend was seen for circuit-training, but not walking. Football and circuit-training were associated with brief improvements in mood and positive/negative affect. No adverse events were reported. Football, circuit training and walking are feasible therapeutic activities for inpatients with poly-substance dependence. Controlled trials are needed to determine the long-term effects of these activities. © 2018 Australasian Professional Society on Alcohol and other Drugs.

  6. Technical feasibility and reliability of passive safety systems for nuclear power plants. Proceedings of an advisory group meeting

    1996-12-01

    The meeting provided an overview of the key issues on passive safety. Technical problems which may affect future deployment, and the operating experience of passive systems and components, as well as, definitions of passive safety terms, were discussed. Advantages and disadvantages of passive systems were also highlighted. The philosophy behind different passive safety systems was presented and the range of possibility between fully passive and fully active systems was discussed. Refs, figs, tabs

  7. Technical feasibility and reliability of passive safety systems for nuclear power plants. Proceedings of an advisory group meeting

    NONE

    1996-12-01

    The meeting provided an overview of the key issues on passive safety. Technical problems which may affect future deployment, and the operating experience of passive systems and components, as well as, definitions of passive safety terms, were discussed. Advantages and disadvantages of passive systems were also highlighted. The philosophy behind different passive safety systems was presented and the range of possibility between fully passive and fully active systems was discussed. Refs, figs, tabs.

  8. Safety and effectiveness of drug therapy for the acutely agitated patient (Part I

    Gianluca Airoldi

    2013-04-01

    Full Text Available Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the first in a 2-part series is to review the extensive safety data published on the antipsychotic medications currently available for managing situations of this type, including older neuroleptics like haloperidol, chlorpromazine, and pimozide as well as a number of the newer atypical antipsychotics (olanzapine, risperidone, ziprasidone. Particular attention is focused on the ability of these drugs to lengthen the QT interval in surface electrocardiograms. This adverse effect is of major concern, especially in light of the reported relation between QT interval and the risk of sudden death. In patients with the congenital long-QT syndrome, a long QT interval is associated with a fatal paroxysmal ventricular arrhythmia knownas torsades de pointes. Therefore, careful evaluation of the QT-prolonging properties and arrhythmogenic potential of antipsychotic drugs is urgently needed. Clinical assessment of drug-induced QT-interval prolongation is strictly dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. Unfortunately, measurement imprecision and natural variability preclude a simple use of the actually measured QT interval as a surrogate marker of drug-induced proarrhythmia. Because the QT interval changes with heart rate, a rate-corrected QT interval (QTc is commonly used when evaluating a drug’s effect. In clinical settings, themost widely used formulas for rate-correction are those of Bazett (QTc=QT/RR^0.5 and Fridericia

  9. The Internet and drug safety: what are the implications for pharmacovigilance?

    Cobert, B; Silvey, J

    1999-02-01

    Use of the Internet is becoming widespread throughout the world. Its use in the domain of drug safety and pharmacovigilance is spreading rapidly. Governments and industry have taken the lead in developing extensive web sites. The US Food and Drug Administration (FDA), the European Agency for the Evaluation of Medicinal Products (EMEA) and other agencies have developed sites containing enormous amounts of information both on pharmacovigilance in general and on specific drugs in particular. Under the US 'Freedom of Information Act' the FDA has put major parts of its adverse event database on line. Regulatory documents are also available from the FDA site or from hyperlinks described in the site. The US Center for Drug Evaluation and Research updates its site most days and maintains a free automated e-mail announcement service of these updates. Similarly, the EMEA updates its site frequently and publishes extensive material including regulatory documents, guidelines, European Public Assessment Reports on newly approved medications and other useful information. A free update service by e-mail is also available. Although English is the primary language used on the EMEA site, some of the information is available in other languages. Pharmaceutical companies are not using the Internet for pharmacovigilance yet. Rather, the Internet is being used for promotion of their products and for informing consumers on general information on diseases, for financial and investor data and for employment opportunities, etc. Other organisations such as lobbies, consumer groups and medical journals are also beginning to use the Internet. The electronic transmission of safety information, using the standards developed by the International Conference on Harmonization, is currently being tested for the transmission of individual patient adverse event information between companies and governments. In addition, the FDA has begun to accept adverse events from healthcare providers and consumers

  10. Feasibility of applying the life history calendar in a population of chronic opioid users to identify patterns of drug use and addiction treatment.

    Fikowski, Jill; Marchand, Kirsten; Palis, Heather; Oviedo-Joekes, Eugenia

    2014-01-01

    Uncovering patterns of drug use and treatment access is essential to improving treatment for opioid dependence. The life history calendar (LHC) could be a valuable instrument for capturing time-sensitive data on lifetime patterns of drug use and addiction treatment. This study describes the methodology applied when collecting data using the LHC in a sample of individuals with long-term opioid dependence and aims to identify specific factors that impact the feasibility of administering the LHC interview. In this study, the LHC allowed important events such as births, intimate relationships, housing, or incarcerations to become reference points for recalling details surrounding drug use and treatment access. The paper concludes that the administration of the LHC was a resource-intensive process and required special attention to interviewer training and experience with the study population. These factors should be considered and integrated into study plans by researchers using the LHC in addiction research.

  11. First series of total robotic hysterectomy (TRH) using new integrated table motion for the da Vinci Xi: feasibility, safety and efficacy.

    Giannini, Andrea; Russo, Eleonora; Mannella, Paolo; Palla, Giulia; Pisaneschi, Silvia; Cecchi, Elena; Maremmani, Michele; Morelli, Luca; Perutelli, Alessandra; Cela, Vito; Melfi, Franca; Simoncini, Tommaso

    2017-08-01

    To present the first case series of total robotic hysterectomy (TRH), using integrated table motion (ITM), which is a new feature comprising a unique operating table by Trumpf Medical that communicates wirelessly with the da Vinci Xi surgical system. ITM has been specifically developed to improve multiquadrant robotic surgery such as that conducted in colorectal surgery. Between May and October 2015, a prospective post-market study was conducted on ITM in the EU in 40 cases from different specialties. The gynecological study group comprised 12 patients. Primary endpoints were ITM feasibility, safety and efficacy. Ten patients underwent TRH. Mean number of ITM moves was three during TRH; there were 31 instances of table moves in the ten procedures. Twenty-eight of 31 ITM moves were made to gain internal exposure. The endoscope remained inserted during 29 of the 31 table movements (94%), while the instruments remained inserted during 27 of the 31 moves (87%). No external instrument collisions or other problems related to the operating table were noted. There were no ITM safety-related observations and no adverse events. This preliminary study demonstrated the feasibility, safety and efficacy of ITM for the da Vinci Xi surgical system in TRH. ITM was safe, with no adverse events related to its use. Further studies will be useful to define the real role and potential benefit of ITM in gynecological surgery.

  12. Spillover Effects of Drug Safety Warnings on Preventive Health Care Use

    Daysal, N. Meltem; Orsini, Chiara

    2015-01-01

    We examine how new medical information on drug safety impacts preventive health care use. We exploit the release of the findings of the Women’s Health Initiative Study (WHIS) – the largest randomized controlled trial of women’s health – which demonstrated in 2002 the health risks associated...... with the long-term use of hormone replacement therapy (HRT). We first show that, after the release of the WHIS findings, HRT use dropped sharply among post-menopausal women. We then estimate the spillover effects of the WHIS findings on preventive care by means of a difference-in-differences methodology...... comparing changes in preventive care use among 60 to 69 year-old women (who have high rates of HRT use) with the change among women aged 75 and above (who have much lower rates of HRT use). Using data from the Behavioral Risk Factor Surveillance System for the period 1998–2007, we find that women aged 60...

  13. Open-label extension studies: do they provide meaningful information on the safety of new drugs?

    Day, Richard O; Williams, Kenneth M

    2007-01-01

    The number of open-label extension studies being performed has increased enormously in recent years. Often it is difficult to differentiate between these extension studies and the double-blind, controlled studies that preceded them. If undertaken primarily to gather more patient-years of exposure to the new drug in order to understand and gain confidence in its safety profile, open-label extension studies can play a useful and legitimate role in drug development and therapeutics. However, this can only occur if the open-label extension study is designed, executed, analysed and reported competently. Most of the value accrued in open-label extension studies is gained from a refinement in the perception of the expected incidence of adverse effects that have most likely already been identified as part of the preclinical and clinical trial programme. We still have to rely heavily on post-marketing safety surveillance systems to alert us to type B (unpredictable) adverse reactions because open-label extension studies are unlikely to provide useful information about these types of often serious and relatively rare adverse reactions. Random allocation into test and control groups is needed to produce precise incidence data on pharmacologically expected, or type A, adverse effects. Some increased confidence about incidence rates might result from the open-label extension study; however, as these studies are essentially uncontrolled and biased, the data are not of great value. Other benefits have been proposed to be gained from open-label extension studies. These include ongoing access to an effective but otherwise unobtainable medicine by the volunteers who participated in the phase III pivotal trials. However, there are unappreciated ethical issues about the appropriateness of enrolling patients whose response to previous treatment is uncertain, largely because treatment allocation in the preceding randomised, double-blind, controlled trial has not been revealed at the

  14. Revenue sources for financing transportation safety activities in Virginia : phase three, feasibility of a surcharge on traffic fines.

    1981-01-01

    Senate Bill 85, an action of the 1978 General Assembly, amended the Code of Virginia to provide, in part, that the Division of Highway Safety be succeeded by the newly created Department of Transportation Safety effective July 1, 1978. In its Declara...

  15. Drug Repositioning of Proton Pump Inhibitors for Enhanced Efficacy and Safety of Cancer Chemotherapy

    Kenji Ikemura

    2017-12-01

    Full Text Available Proton pump inhibitors (PPIs, H+/K+-ATPase inhibitors, are the most commonly prescribed drugs for the treatment of gastroesophageal reflux and peptic ulcer diseases; they are highly safe and tolerable. Since PPIs are frequently used in cancer patients, studies investigating interactions between PPIs and anticancer agents are of particular importance to achieving effective and safe cancer chemotherapy. Several studies have revealed that PPIs inhibit not only the H+/K+-ATPase in gastric parietal cells, but also the vacuolar H+-ATPase (V-ATPase overexpressed in tumor cells, as well as the renal basolateral organic cation transporter 2 (OCT2 associated with pharmacokinetics and/or renal accumulation of various drugs, including anticancer agents. In this mini-review, we summarize the current knowledge regarding the impact of PPIs on the efficacy and safety of cancer chemotherapeutics via inhibition of targets other than the H+/K+-ATPase. Co-administration of clinical doses of PPIs protected kidney function in patients receiving cisplatin and fluorouracil, presumably by decreasing accumulation of cisplatin in the kidney via OCT2 inhibition. In addition, co-administration or pretreatment with PPIs could inhibit H+ transport via the V-ATPase in tumor cells, resulting in lower extracellular acidification and intracellular acidic vesicles to enhance the sensitivity of the tumor cells to the anticancer agents. In the present mini-review, we suggest that PPIs enhance the efficacy and safety of anticancer agents via off-target inhibition (e.g., of OCT2 and V-ATPase, rather than on-target inhibition of the H+/K+-ATPase. The present findings should provide important information to establish novel supportive therapy with PPIs during cancer chemotherapy.

  16. The feasibility and safety of thoracoscopic surgery under epidural and/or local anesthesia for spontaneous pneumothorax: a meta-analysis.

    Chen, Wei; Zhang, Chenlei; Wang, Gebang; Li, Zhengjun; Wang, Hailong; Liu, Hongxu

    2017-09-01

    The aim of this study was to compare thoracoscopic surgery for spontaneous pneumothorax under epidural and/or local anesthesia (ELA) with that under general anesthesia and prove the feasibility and safety of thoracoscopic surgery under ELA for spontaneous pneumothorax. Relevant studies were searched in five databases from their date of publication to June 2016. We collected and analyzed the data concerning operative time, hospital stay, complications, air leak, recurrence and perioperative mortality. A forest plot was performed to compare the differences between the two groups. There were no significant differences between the ELA group and the general anesthesia (GA) group in operative time, hospital stay, complications, air leak or recurrence. There were 6 deaths reported in two studies. However, patients in the ELA group had significantly shorter global operating room time. Our study demonstrated that ELA, in comparison with GA, is feasible and safe for thoracoscopic surgery of spontaneous pneumothorax.

  17. Cardiopulmonary Exercise Testing in Patients with Asymptomatic or Equivocal Symptomatic Aortic Stenosis: Feasibility, Reproducibility, Safety and Information Obtained on Exercise Physiology.

    van Le, Douet; Jensen, Gunnar Vagn Hagemann; Carstensen, Steen; Kjøller-Hansen, Lars

    2016-01-01

    The aim of this study was to determine the feasibility, reproducibility, safety and information obtained on exercise physiology from cardiopulmonary exercise testing (CPX) in patients with aortic stenosis. Patients with an aortic valve area (AVA) exercise, lower peak heart rate and FEV1, and higher VE/VCO2, but not by AVA index. Equivocal symptomatic status and a low gradient but high valvulo-arterial impedance were associated with a lower pVO2, but not with an inability to increase stroke volume. In total, 18 patients were referred for valve replacement. At 1 year, no cardiovascular deaths had occurred. CPX was feasible and reproducible and provided comprehensive data on exercise physiology. A CPX-guided treatment strategy was safe up to 1 year. © 2015 S. Karger AG, Basel.

  18. Specialty pharmacies and other restricted drug distribution systems: financial and safety considerations for patients and health-system pharmacists.

    Kirschenbaum, Bonnie E

    2009-12-15

    To discuss the role of restricted drug distribution systems in the implementation of risk evaluation and mitigation strategies (REMS), health-system pharmacists' concerns associated with the use of specialty pharmacies and other restricted drug distribution systems, reimbursement policies for high-cost specialty drugs, supply chain models for traditional and specialty drugs, and emerging trends in the management of and reimbursement for specialty pharmaceuticals. Restricted drug distribution systems established by pharmaceutical manufacturers, specialty pharmacies, or other specialty suppliers may be a component of REMS, which are required by the Food and Drug Administration for the management of known or potential serious risks from certain drugs. Concerns of health-system pharmacists using specialty suppliers include access to pharmaceuticals, operational challenges, product integrity, financial implications, continuity of care, and patient safety. An ambulatory care patient taking a specialty drug product from home to a hospital outpatient clinic or inpatient setting for administration, a practice known as "brown bagging," raises concerns about product integrity and institutional liability. An institution's finances, tolerance for liability, and ability to skillfully manage the processes involved often determine its choice between an approach that prohibits brown bagging but is costly and one that permits the practice under certain conditions and is less costly. The recent shift from a traditional supply chain model to a specialty pharmacy supply chain model for high-cost pharmaceuticals has the potential to increase pharmaceutical costs for health systems. A dialogue is needed between health-system pharmacists and group purchasing organizations to address the latter's role in mitigating the financial implications of this change and to help clarify the safety issues. Some health plans have shifted part of the cost of expensive drugs to patients by establishing a

  19. Comparing Safety and Efficacy of "Third-Generation" Antiepileptic Drugs: Long-Term Extension and Post-marketing Treatment.

    Kwok, Charlotte S; Johnson, Emily L; Krauss, Gregory L

    2017-11-01

    Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

  20. Safety and feasibility of transcranial direct current stimulation (tDCS) combined with sensorimotor retraining in chronic low back pain: a protocol for a pilot randomised controlled trial.

    Ouellette, Adam Louis; Liston, Matthew B; Chang, Wei-Ju; Walton, David M; Wand, Benedict Martin; Schabrun, Siobhan M

    2017-08-21

    Chronic low back pain (LBP) is a common and costly health problem yet current treatments demonstrate at best, small effects. The concurrent application of treatments with synergistic clinical and mechanistic effects may improve outcomes in chronic LBP. This pilot trial aims to (1) determine the feasibility, safety and perceived patient response to a combined transcranial direct current stimulation (tDCS) and sensorimotor retraining intervention in chronic LBP and (2) provide data to support a sample size calculation for a fully powered trial should trends of effectiveness be present. A pilot randomised, assessor and participant-blind, sham-controlled trial will be conducted. Eighty participants with chronic LBP will be randomly allocated to receive either (1) active tDCS + sensorimotor retraining or (2) sham tDCS + sensorimotor retraining. tDCS (active or sham) will be applied to the primary motor cortex for 20 min immediately prior to 60 min of supervised sensorimotor retraining twice per week for 10 weeks. Participants in both groups will complete home exercises three times per week. Feasibility, safety, pain, disability and pain system function will be assessed immediately before and after the 10-week intervention. Analysis of feasibility and safety will be performed using descriptive statistics. Statistical analyses will be conducted based on intention-to-treat and per protocol and will be used to determine trends for effectiveness. Ethical approval has been gained from the institutional human research ethics committee (H10184). Written informed consent will be provided by all participants. Results from this pilot study will be submitted for publication in peer-reviewed journals. ACTRN12616000624482. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  1. TryCYCLE: A Prospective Study of the Safety and Feasibility of Early In-Bed Cycling in Mechanically Ventilated Patients.

    Michelle E Kho

    Full Text Available The objective of this study was to assess the safety and feasibility of in-bed cycling started within the first 4 days of mechanical ventilation (MV to inform a future randomized clinical trial.We conducted a 33-patient prospective cohort study in a 21-bed adult academic medical-surgical intensive care unit (ICU in Hamilton, ON, Canada. We included adult patients (≥ 18 years receiving MV who walked independently pre-ICU. Our intervention was 30 minutes of in-bed supine cycling 6 days/week in the ICU. Our primary outcome was Safety (termination, measured as events prompting cycling termination; secondary Safety (disconnection or dislodgement outcomes included catheter/tube dislodgements. Feasibility was measured as consent rate and fidelity to intervention. For our primary outcome, we calculated the binary proportion and 95% confidence interval (CI.From 10/2013-8/2014, we obtained consent from 34 of 37 patients approached (91.9%, 33 of whom received in-bed cycling. Of those who cycled, 16(48.4% were female, the mean (SD age was 65.8(12.2 years, and APACHE II score was 24.3(6.7; 29(87.9% had medical admitting diagnoses. Cycling termination was infrequent (2.0%, 95% CI: 0.8%-4.9% and no device dislodgements occurred. Cycling began a median [IQR] of 3 [2, 4] days after ICU admission; patients received 5 [3, 8] cycling sessions with a median duration of 30.7 [21.6, 30.8] minutes per session. During 205 total cycling sessions, patients were receiving invasive MV (150 [73.1%], vasopressors (6 [2.9%], sedative or analgesic infusions (77 [37.6%] and dialysis (4 [2.0%].Early cycling within the first 4 days of MV among hemodynamically stable patients is safe and feasible. Research to evaluate the effect of early cycling on patient function is warranted.Clinicaltrials.gov: NCT01885442.

  2. Feasibility of a Video-Based Advance Care Planning Website to Facilitate Group Visits among Diverse Adults from a Safety-Net Health System.

    Zapata, Carly; Lum, Hillary D; Wistar, Emily; Horton, Claire; Sudore, Rebecca L

    2018-02-20

    Primary care providers in safety-net settings often do not have time to discuss advance care planning (ACP). Group visits (GV) may be an efficient means to provide ACP education. To assess the feasibility and impact of a video-based website to facilitate GVs to engage diverse adults in ACP. Feasibility pilot among patients who were ≥55 years of age from two primary care clinics in a Northern California safety-net setting. Participants attended two 90-minute GVs and viewed the five steps of the movie version of the PREPARE website ( www.prepareforyourcare.org ) concerning surrogates, values, and discussing wishes in video format. Two clinician facilitators were available to encourage participation. We assessed pre-to-post ACP knowledge, whether participants designated a surrogate or completed an advance directive (AD), and acceptability of GVs and PREPARE materials. We conducted two GVs with 22 participants. Mean age was 64 years (±7), 55% were women, 73% nonwhite, and 55% had limited literacy. Knowledge improved about surrogate designation (46% correct pre vs. 85% post, p = 0.01) and discussing decisions with others (59% vs. 90%, p = 0.01). Surrogate designation increased (48% vs. 85%, p = 0.01) and there was a trend toward AD completion (9% vs. 24%, p = 0.21). Participants rated the GVs and PREPARE materials a mean of 8 (±3.1) on a 10-point acceptability scale. Using the PREPARE movie to facilitate ACP GVs for diverse adults in safety net, primary care settings is feasible and shows potential for increasing ACP engagement.

  3. Predicting Drug Safety and Communicating Risk: Benefits of a Bayesian Approach.

    Lazic, Stanley E; Edmunds, Nicholas; Pollard, Christopher E

    2018-03-01

    Drug toxicity is a major source of attrition in drug discovery and development. Pharmaceutical companies routinely use preclinical data to predict clinical outcomes and continue to invest in new assays to improve predictions. However, there are many open questions about how to make the best use of available data, combine diverse data, quantify risk, and communicate risk and uncertainty to enable good decisions. The costs of suboptimal decisions are clear: resources are wasted and patients may be put at risk. We argue that Bayesian methods provide answers to all of these problems and use hERG-mediated QT prolongation as a case study. Benefits of Bayesian machine learning models include intuitive probabilistic statements of risk that incorporate all sources of uncertainty, the option to include diverse data and external information, and visualizations that have a clear link between the output from a statistical model and what this means for risk. Furthermore, Bayesian methods are easy to use with modern software, making their adoption for safety screening straightforward. We include R and Python code to encourage the adoption of these methods.

  4. Toxicological study on the safety of DTPA as a drug, (1)

    Fukuda, Satoshi; Iida, Haruzo

    1983-01-01

    In order to clarify the safety of Ca-DTPA and Zn-DTPA recommended to use as drugs in the therapeutic removal of incorporated radionuclides from the human body, the teratological study on these two agents was carried out in rats as one of a series of the toxicological tests. The teratological effects of DTPA were observed because the fetus is highly susceptible to any drug. The pregnant females of Wistar rat were injected subcutaneously daily on days 9-13 of gestation with 1, 6, 12, 24 and 36 H.D. (H.D. = human dose, 1 H.D. = 30μmol/kg body weight) of Ca-DTPA or Zn-DTPA, respectively. In the dams, no toxic effects were observed. In the fetuses, the decrease of the survival rate was observed in only the group injected daily with 36 H.D. of Ca-DTPA. Some cases of gross defects of fetuses: the exencephaly, microphthalmia, anophthalmia and fusion of ribs were observed in the groups injected daily with 12, 24 and 36 H.D. of Ca-DTPA. The results obtained show that Ca-DTPA should not be given to a pregnant woman. However, no toxic effects of either Ca-DTPA or Zn-DTPA observed in the dams ana of Zn-DTPA even in the fetuses indicate that these agents can be used by a radiation worker who usually is an adult man. (author)

  5. Toxicological study on the safety of DTPA as a drug, (1). Teratological study in the rat

    Fukuda, Satoshi; Iida, Haruzo (National Inst. of Radiological Sciences, Chiba (Japan))

    1983-03-01

    In order to clarify the safety of Ca-DTPA and Zn-DTPA recommended to use as drugs in the therapeutic removal of incorporated radionuclides from the human body, the teratological study on these two agents was carried out in rats as one of a series of the toxicological tests. The teratological effects of DTPA were observed because the fetus is highly susceptible to any drug. The pregnant females of Wistar rat were injected subcutaneously daily on days 9-13 of gestation with 1, 6, 12, 24 and 36 H.D. (H.D. = human dose, 1 H.D. = 30..mu..mol/kg body weight) of Ca-DTPA or Zn-DTPA, respectively. In the dams, no toxic effects were observed. In the fetuses, the decrease of the survival rate was observed in only the group injected daily with 36 H.D. of Ca-DTPA. Some cases of gross defects of fetuses: the exencephaly, microphthalmia, anophthalmia and fusion of ribs were observed in the groups injected daily with 12, 24 and 36 H.D. of Ca-DTPA. The results obtained show that Ca-DTPA should not be given to a pregnant woman. However, no toxic effects of either Ca-DTPA or Zn-DTPA observed in the dams or of Zn-DTPA even in the fetuses indicate that these agents can be used by a radiation worker who usually is an adult man.

  6. Efficacy and safety of immunomodulatory drugs in patients with anterior uveitis

    Gómez-Gómez, Alejandro; Loza, Estíbaliz; Rosario, Maria Piedad; Espinosa, Gerard; de Morales, José M. García Ruiz; Herreras, Jose M.; Muñoz-Fernández, Santiago; Cordero-Coma, Miguel

    2017-01-01

    Abstract Background: To assess the efficacy and safety of immunomodulatory drugs in patients with noninfectious anterior uveitis (AU). Methods: Systematic review of studies were retrieved from Medline (1961 to March 2016), Embase (1961 to March 2016), and Cochrane Library (up to March 2016), and a complementary hand search was also performed. The selection criteria were as follows: (population) noninfectious AU patients, adults; (intervention) immunomodulatory drugs (any dose, regimen, route of administration, duration of treatment); (outcome) control of inflammation, steroid-sparing effect, AU flares, adverse events, and so on; (study design) systematic literature reviews, randomized controlled trials, and observational studies. The study quality was assessed using the Jadad scale and according to The Oxford Centre for Evidence-based Medicine (update 2009). Results: We included 13 studies of moderate-poor quality, with a mean duration from 5 months to 20 years, and number of AU patients ranging from 9 to 274. Patient's demographic and clinical characteristics were very heterogeneous. In most cases, uveitis anatomic classification criteria and outcomes definitions were unclear. Some of the studies only included AU patients with a systemic disease associated, mostly spondyloarthritis, others, mixed populations (idiopathic and systemic disease associated patients), and in some articles this data is not described. We found that methotrexate, cyclosporine A, azathioprine, adalimumab, and golimumab might prevent AU flares, improve ocular inflammation and visual acuity, and decrease systemic steroids doses. Conclusions: Although there is a lack of robust evidence, methotrexate, cyclosporine A, azathioprine, adalimumab, and golimumab might be effective in AU patients. PMID:29049193

  7. Efficacy and safety of immunomodulatory drugs in patients with anterior uveitis: A systematic literature review.

    Gómez-Gómez, Alejandro; Loza, Estíbaliz; Rosario, Maria Piedad; Espinosa, Gerard; Morales, José M García Ruiz de; Herreras, Jose M; Muñoz-Fernández, Santiago; Cordero-Coma, Miguel

    2017-10-01

    To assess the efficacy and safety of immunomodulatory drugs in patients with noninfectious anterior uveitis (AU). Systematic review of studies were retrieved from Medline (1961 to March 2016), Embase (1961 to March 2016), and Cochrane Library (up to March 2016), and a complementary hand search was also performed. The selection criteria were as follows: (population) noninfectious AU patients, adults; (intervention) immunomodulatory drugs (any dose, regimen, route of administration, duration of treatment); (outcome) control of inflammation, steroid-sparing effect, AU flares, adverse events, and so on; (study design) systematic literature reviews, randomized controlled trials, and observational studies. The study quality was assessed using the Jadad scale and according to The Oxford Centre for Evidence-based Medicine (update 2009). We included 13 studies of moderate-poor quality, with a mean duration from 5 months to 20 years, and number of AU patients ranging from 9 to 274. Patient's demographic and clinical characteristics were very heterogeneous. In most cases, uveitis anatomic classification criteria and outcomes definitions were unclear. Some of the studies only included AU patients with a systemic disease associated, mostly spondyloarthritis, others, mixed populations (idiopathic and systemic disease associated patients), and in some articles this data is not described. We found that methotrexate, cyclosporine A, azathioprine, adalimumab, and golimumab might prevent AU flares, improve ocular inflammation and visual acuity, and decrease systemic steroids doses. Although there is a lack of robust evidence, methotrexate, cyclosporine A, azathioprine, adalimumab, and golimumab might be effective in AU patients.

  8. Pharmaceutical quality of "party pills" raises additional safety concerns in the use of illicit recreational drugs.

    Young, Simon A; Thrimawithana, Thilini R; Antia, Ushtana; Fredatovich, John D; Na, Yonky; Neale, Peter T; Roberts, Amy F; Zhou, Huanyi; Russell, Bruce

    2013-06-14

    To determine the content and release kinetics of 1-benzylpiperazine (BZP) and 1-(3-trifluoromethyl-phenyl)piperazine (TFMPP) from "party pill" formulations. From these data, the possible impact of pharmaceutical quality upon the safety of such illicit formulations may be inferred. The amount of BZP and TFMPP in party pill formulations was determined using a validated HPLC method. The in-vitro release kinetics of selected party pill brands were determined using a USP dissolution apparatus (75 rpm, 37.5 degrees Celsius). The release data were then fitted to a first order release model using PLOT software and the time taken to achieve 90% release reported. Many of the tested party pill brands contained amounts of BZP and TFMPP that varied considerably from that stated on the packaging; including considerable TFMPP content in some brands not labelled to contain this drug. Dissolution studies revealed that there was considerable variability in the release kinetics between brands; in one case 90% release required >30 minutes. Lack of quality control in party pill manufacture may have led to the toxic effects reported by users unaware of the true content and release of drug from pills. More stringent regulation in the manufacture and quality control of "new generation party pills" is essential to the harm reduction campaign.

  9. Field validity and feasibility of four techniques for the detection of Trichuris in simians: a model for monitoring drug efficacy in public health?

    Bruno Levecke

    Full Text Available BACKGROUND: Soil-transmitted helminths, such as Trichuris trichiura, are of major concern in public health. Current efforts to control these helminth infections involve periodic mass treatment in endemic areas. Since these large-scale interventions are likely to intensify, monitoring the drug efficacy will become indispensible. However, studies comparing detection techniques based on sensitivity, fecal egg counts (FEC, feasibility for mass diagnosis and drug efficacy estimates are scarce. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, the ether-based concentration, the Parasep Solvent Free (SF, the McMaster and the FLOTAC techniques were compared based on both validity and feasibility for the detection of Trichuris eggs in 100 fecal samples of nonhuman primates. In addition, the drug efficacy estimates of quantitative techniques was examined using a statistical simulation. Trichuris eggs were found in 47% of the samples. FLOTAC was the most sensitive technique (100%, followed by the Parasep SF (83.0% [95% confidence interval (CI: 82.4-83.6%] and the ether-based concentration technique (76.6% [95% CI: 75.8-77.3%]. McMaster was the least sensitive (61.7% [95% CI: 60.7-62.6%] and failed to detect low FEC. The quantitative comparison revealed a positive correlation between the four techniques (Rs = 0.85-0.93; p<0.0001. However, the ether-based concentration technique and the Parasep SF detected significantly fewer eggs than both the McMaster and the FLOTAC (p<0.0083. Overall, the McMaster was the most feasible technique (3.9 min/sample for preparing, reading and cleaning of the apparatus, followed by the ether-based concentration technique (7.7 min/sample and the FLOTAC (9.8 min/sample. Parasep SF was the least feasible (17.7 min/sample. The simulation revealed that the sensitivity is less important for monitoring drug efficacy and that both FLOTAC and McMaster were reliable estimators. CONCLUSIONS/SIGNIFICANCE: The results of this study

  10. Feasibility study and uncertainties in the validation of an existing safety-related control circuit with the ISO 13849-1:2006 design standard

    Jocelyn, Sabrina; Baudoin, James; Chinniah, Yuvin; Charpentier, Philippe

    2014-01-01

    In industry, machine users and people who modify or integrate equipment often have to evaluate the safety level of a safety-related control circuit that they have not necessarily designed. The modifications or integrations may involve work to make an existing machine that does not comply with normative or regulatory specifications safe. However, how can a circuit performing a safety function be validated a posteriori? Is the validation exercise feasible? What are the difficulties and limitations of such a procedure? The aim of this article is to answer these questions by presenting a validation study of a safety function of an existing machine. A plastic injection molding machine is used for this study, as well as standard ISO 13849-1:2006. Validation consists of performing an a posteriori (post-design) estimation of the performance level of the safety function. The procedure is studied for two contexts of use of the machine: in industry, and in laboratory. The calculations required by the ISO standard were done using Excel, followed by SIStema software. It is shown that, based on the context of use, the estimated performance level was different for the same safety-related circuit. The variability in the results is explained by the assumptions made by the person undertaking the validation without the involvement of the machine designer. - Highlights: • Validation of the performance level of a safety function is undertaken. • An injection molding machine and ISO 13849-1:2006 standard are used for the procedure. • The procedure is undertaken for two contexts of use of the machine. • In this study, the performance level depends on the context of use. • The assumptions made throughout the study partially explain this difference

  11. Efficacy, safety and tolerability of sildenafil in Brazilian hypertensive patients on multiple antihypertensive drugs

    Denilson C. Albuquerque

    2005-08-01

    Full Text Available OBJECTIVE: To evaluate the efficacy, safety and tolerability of sildenafil among Brazilian patients with hypertension treated with combinations of anti-hypertensive drugs. MATERIALS AND METHODS: One hundred twenty hypertensive men aged 30 to 81 years old under treatment with 2 or more anti-hypertensive drugs and with erectile dysfunction (ED lasting for at least 6 months were enrolled at 7 research centers in Brazil. Patients were randomized to receive treatment with either sildenafil or placebo taken 1 hour before sexual intercourse (initial dose of 50 mg, adjusted to 25 mg or 100 mg according to efficacy and toxicity. During the following 8 weeks, patients were evaluated regarding vital signs, adverse events, therapeutic efficacy, satisfaction with treatment and use of concurrent medications. RESULTS: The primary evaluation of efficacy, which was based on responses to questions 3 and 4 of the International Index of Erectile Function, showed significant differences regarding treatment with sildenafil (p = 0.0002 and p < 0.0001, respectively. In the assessment of global efficacy, 87% of the patients treated with sildenafil reported improved erections, as compared with 37% of patients given placebos (p < 0.0001. The other secondary evaluations supported the results favoring sildenafil. The most frequent adverse events among patients treated with sildenafil were headaches (11.4%, vasodilation (11.4% and dyspepsia (6.5%. There were no significant changes in blood pressure measurements in both groups. CONCLUSION: Sildenafil is efficacious and safe for the treatment of hypertensive patients with ED who receive concurrent combinations of anti-hypertensive drugs.

  12. Safety

    1998-01-01

    A brief account of activities carried out by the Nuclear power plants Jaslovske Bohunice in 1997 is presented. These activities are reported under the headings: (1) Nuclear safety; (2) Industrial and health safety; (3) Radiation safety; and Fire protection

  13. Asymmetrical flow field-flow fractionation with on-line detection for drug transfer studies: a feasibility study

    Hinna, A.; Steiniger, F.; Hupfeld, S.

    2014-01-01

    Knowledge about drug retention within colloidal carriers is of uppermost importance particularly if drug targeting is anticipated. The aim of the present study was to evaluate asymmetrical flow field-flow fractionation (AF4) with on-line UV/VIS drug quantification for its suitability to determine...... both release and transfer of drug from liposomal carriers to a model acceptor phase consisting of large liposomes. The hydrophobic porphyrin 5,10,15,20-tetrakis(4-hydroxyphenyl)21H,23H-porphine (p-THPP), a fluorescent dye with an absorbance maximum in the visible range and structural similarity...... channel geometries. Drug quantification by on-line absorbance measurements was established by comprehensive evaluation of the size-dependent turbidity contribution in on-line UV/VIS detection and by comparison with off-line results obtained for the respective dye-loaded donor formulations (dissolved...

  14. The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study.

    Meijer, Willemijn M; Cornel, Martina C; Dolk, Helen; de Walle, Hermien E K; Armstrong, Nicola C; de Jong-van den Berg, Lolkje T W

    2006-09-01

    European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than 1 million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance. The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996-2000 was summarised for 15 out of 25 responding full members. Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries. Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry.

  15. First-in-Human Ultrasound Molecular Imaging With a VEGFR2-Specific Ultrasound Molecular Contrast Agent (BR55) in Prostate Cancer: A Safety and Feasibility Pilot Study.

    Smeenge, Martijn; Tranquart, François; Mannaerts, Christophe K; de Reijke, Theo M; van de Vijver, Marc J; Laguna, M Pilar; Pochon, Sibylle; de la Rosette, Jean J M C H; Wijkstra, Hessel

    2017-07-01

    BR55, a vascular endothelial growth factor receptor 2 (VEGFR2)-specific ultrasound molecular contrast agent (MCA), has shown promising results in multiple preclinical models regarding cancer imaging. In this first-in-human, phase 0, exploratory study, we investigated the feasibility and safety of the MCA for the detection of prostate cancer (PCa) in men using clinical standard technology. Imaging with the MCA was performed in 24 patients with biopsy-proven PCa scheduled for radical prostatectomy using a clinical ultrasound scanner at low acoustic power. Safety monitoring was done by physical examination, blood pressure and heart rate measurements, electrocardiogram, and blood sampling. As first-in-human study, MCA dosing and imaging protocol were necessarily fine-tuned along the enrollment to improve visualization. Imaging data were correlated with radical prostatectomy histopathology to analyze the detection rate of ultrasound molecular imaging with the MCA. Imaging with MCA doses of 0.03 and 0.05 mL/kg was adequate to obtain contrast enhancement images up to 30 minutes after administration. No serious adverse events or clinically meaningful changes in safety monitoring data were identified during or after administration. BR55 dosing and imaging were fine-tuned in the first 12 patients leading to 12 subsequent patients with an improved MCA dosing and imaging protocol. Twenty-three patients underwent radical prostatectomy. A total of 52 lesions were determined to be malignant by histopathology with 26 (50%) of them seen during BR55 imaging. In the 11 patients that were scanned with the improved protocol and underwent radical prostatectomy, a total of 28 malignant lesions were determined: 19 (68%) were seen during BR55 ultrasound molecular imaging, whereas 9 (32%) were not identified. Ultrasound molecular imaging with BR55 is feasible with clinical standard technology and demonstrated a good safety profile. Detectable levels of the MCA can be reached in patients

  16. A comprehensive review of assay methods to determine drugs in breast milk and the safety of breastfeeding when taking drugs.

    Fríguls, Bibiana; Joya, Xavier; García-Algar, Oscar; Pallás, C R; Vall, Oriol; Pichini, Simona

    2010-06-01

    Most of the licit and illicit drugs consumed by the breastfeeding woman pass into the milk and can modify the production, volume and composition of the milk, as well as hypothetically have short- and long-term harmful effects on the infant. There is much confusion in the scientific community regarding this issue: should a woman breastfeed her baby while continuing to use prescription drugs and/or drugs of abuse? There are many case reports of clinically significant toxicity in breast-fed infants from some substances used by mothers (such as irritability, vomiting, sedation, respiratory depression, shock), but there are too few data on studies conducted in breastfeeding women and their infants to make a realistic risk assessment. The objective measurement of a drug and/or metabolites in maternal milk is the first step when investigating the amount of drug excreted in milk and subsequently calculating the daily dose administered to the breast-fed infant. The present review reports the analytical methods developed to detect different drugs in the breast milk, listing the principal characteristics and validation parameters, advantages and disadvantages. Furthermore, the mechanisms of drug transfer into breast milk are discussed, the correlation between the concentration of the drug in breast milk and potential adverse outcomes on the infant are described for each drug, and suggested harm minimization strategies and approved breastfeeding recommendations are indicated.

  17. The algorithmic performance of J-Tpeak for drug safety clinical trial.

    Chien, Simon C; Gregg, Richard E

    The interval from J-point to T-wave peak (JTp) in ECG is a new biomarker able to identify drugs that prolong the QT interval but have different ion channel effects. If JTp is not prolonged, the prolonged QT may be associated with multi ion channel block that may have low torsade de pointes risk. From the automatic ECG measurement perspective, accurate and repeatable measurement of JTp involves different challenges than QT. We evaluated algorithm performance and JTp challenges using the Philips DXL diagnostic 12/16/18-lead algorithm. Measurement of JTp represents a different use model. Standard use of corrected QT interval is clinical risk assessment on patients with cardiac disease or suspicion of heart disease. Drug safety trials involve a very different population - young healthy subjects - who commonly have J-waves, notches and slurs. Drug effects include difficult and unusual morphology such as flat T-waves, gentle notches, and multiple T-wave peaks. The JTp initiative study provided ECGs collected from 22 young subjects (11 males and females) in randomized testing of dofetilide, quinidine, ranolazine, verapamil and placebo. We compare the JTp intervals between DXL algorithm and the FDA published measurements. The lead wise, vector-magnitude (VM), root-mean-square (RMS) and principal-component-analysis (PCA) representative beats were used to measure JTp and QT intervals. We also implemented four different methods for T peak detection for comparison. We found that JTp measurements were closer to the reference for combined leads RMS and PCA than individual leads. Differences in J-point location led to part of the JTp measurement difference because of the high prevalence of J-waves, notches and slurs. Larger differences were noted for drug effect causing multiple distinct T-wave peaks (Tp). The automated algorithm chooses the later peak while the reference was the earlier peak. Choosing among different algorithmic strategies in T peak measurement results in the

  18. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    Cros, C., E-mail: caroline.cros@hotmail.co.uk [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Moors, J. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Lainee, P. [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France); Valentin, J.P. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two

  19. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    Cros, C.; Skinner, M.; Moors, J.; Lainee, P.; Valentin, J.P.

    2012-01-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I Na ) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I Na , this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E max 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two out of three

  20. 77 FR 44256 - Draft Guidance for Industry and Food and Drug Administration Staff; Safety Considerations for 510...

    2012-07-27

    ...] Draft Guidance for Industry and Food and Drug Administration Staff; Safety Considerations for 510(k... serious and sometimes fatal consequences to patients. This guidance provides recommendations to 510(k... unintended connections between enteral and nonenteral devices. This draft guidance is not final nor is it in...

  1. Data-driven drug safety signal detection methods in pharmacovigilance using electronic primary care records: A population based study

    Shang-Ming Zhou

    2017-04-01

    Data-driven analytic methods are a valuable aid to signal detection of ADEs from large electronic health records for drug safety monitoring. This study finds the methods can detect known ADE and so could potentially be used to detect unknown ADE.

  2. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Fang Zheng

    Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  3. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Zheng, Fang; Zhan, Chang-Guo

    2012-01-01

    A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC) value in brain (denoted by AUC2(∞)) required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE) can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞). The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  4. Feasibility of Exploiting Celution^ System in Autologous Cell Therapy in Dokkyo Medical University Hospital:Safety and Reproducibility

    Ken-ichi, Inoue; Hiroshi, Nomura; Ryoichi, Sohma; Kazumi, Akimoto; Naohiko, Kobayashi; Takao, Kamai; Tomonori, Yamanishi; Isao, Taguchi; Hiroki, Asato; Teruo, Inoue; Tomoyuki, Mitsumori; Hideki, Iwaguro; Ken-ichiro, Yoshida; Research Support Center, Dokkyo Medical University School Of Medicine:Center For Regenerative Medicine, Dokkyo Medical University School Of Medicine; Center For Regenerative Medicine, Dokkyo Medical University School Of Medicine:Department Of Plastic And Reconstructive Surgery, Dokkyo Medical University School Of Medicine

    2014-01-01

    In 2012, we established the Center for Regenerative Medicine in Dokkyo Medical University Hospital, and are now preparing the necessary equipment and preclinical evidence for cell therapy. Liposuction is a commonly used procedure in plastic surgery and the lipoaspirate is discarded as a medical waste. However, the lipoaspirate is known to contain abundant mesenchymal stem cells, and thus, it is currently one of the most feasible options of regenerative medicine. Several ongoing clinical trial...

  5. Cooking Healthy, Eating Smart (CHES): Evaluating the feasibility of using volunteers to deliver nutrition and food safety education to rural older adults

    Getty, Morgan

    Due to their limited resources, rural, older adults in the United States are at risk for poor diet-related health outcomes. Nutrition education is a key component in improving health outcomes in older adults. Cooking Healthy, Eating Smart (CHES) is a nine-lesson curriculum designed to teach rural, older adults culturally appropriate nutrition and food safety information. Funding to hire health professionals to deliver such a curriculum is limited, presenting the need to explore a less expensive mode of dissemination. In this community-based, participatory research study, a formative evaluation and feasibility study were conducted to examine the use of volunteers to deliver a nutrition and food safety curriculum to rural, older adults in South Carolina. Seven focus groups were conducted with members of the South Carolina Family and Community Leaders (SCFCL) and members of the American Association of Retired Persons (AARP) in the four regions of South Carolina to explore barriers and facilitators of volunteers delivering CHES (N=65 participants). The focus group findings informed the development of the volunteer training manual. A comparative case study method was used to examine the feasibility of a volunteer-based approach by observing and describing the delivery of CHES by two groups of volunteers in SC. The case study findings, including volunteer knowledge change, self-efficacy change, curriculum experience, program experience, and project team observations of volunteers indicated that using volunteers to deliver CHES is a plausible approach with the assistance of paid staff or project team members.

  6. Safety and feasibility of transcranial direct current stimulation in amyotrophic lateral sclerosis - a pilot study with a single subject experimental design.

    Madhavan, Sangeetha; Sivaramakrishnan, Anjali; Bond, Sam; Jiang, Qin Li

    2018-02-28

    Transcranial direct current stimulation (tDCS) has been explored as a neuromodulatory tool to prime motor function in several neurological disorders. Studies using tDCS in amyotrophic lateral sclerosis (ALS) are limited. We investigated the safety, feasibility and effects of long-term tDCS in an individual with ALS. A 36-year-old male diagnosed with clinically definite ALS received 12 sessions each of anodal, sham, and cathodal tDCS. Outcome measures included disease progression (revised ALS functional rating scale (ALSFRS-R)), clinical measures of endurance and mobility, and corticomotor excitability. No adverse events or change in disease progression were noticed during the study. Small improvement in gait speed (15% increase) was noticed with anodal tDCS only. This case study demonstrates the safety and feasibility of long-term facilitatory and inhibitory tDCS on a single participant with ALS. This study serves as a guideline for implementing tDCS in future ALS trials.

  7. The use of in-situ simulation to improve safety in the plastic surgery office: a feasibility study.

    Shapiro, Fred E; Pawlowski, John B; Rosenberg, Noah M; Liu, Xiaoxia; Feinstein, David M; Urman, Richard D

    2014-01-01

    Simulation-based interventions and education can potentially contribute to safer and more effective systems of care. We utilized in-situ simulation to highlight safety issues, regulatory requirements, and assess perceptions of safety processes by the plastic surgery office staff. A high-fidelity human patient simulator was brought to an office-based plastic surgery setting to enact a half-day full-scale, multidisciplinary medical emergency. Facilitated group debriefings were conducted after each scenario with special consideration of the principles of team training, communication, crisis management, and adherence to evidence-based protocols and regulatory standards. Abbreviated AHRQ Medical Office Safety Culture Survey was completed by the participants before and after the session. The in-situ simulations had a high degree of acceptance and face validity according to the participants. Areas highlighted by the simulation sessions included rapid communication, delegation of tasks, location of emergency materials, scope of practice, and logistics of transport. The participant survey indicated greater awareness of patient safety issues following participation in simulation and debriefing exercises in 3 areas (P issue (100% vs 75%), openness to ideas about improving office processes (100% vs 88%), and the need to discuss ways to prevent errors from recurring (88% vs 62%). Issues of safety and regulatory compliance can be assessed in an office-based setting through the short-term (half-day) use of in-situ simulation with facilitated debriefing and the review of audiovisual recordings by trained facilities inspectors.

  8. "FIND Technology": investigating the feasibility, efficacy and safety of controller-free interactive digital rehabilitation technology in an inpatient stroke population: study protocol for a randomized controlled trial.

    Bird, M L; Cannell, J; Callisaya, M L; Moles, E; Rathjen, A; Lane, K; Tyson, A; Smith, S

    2016-04-16

    Stroke results in significant disability, which can be reduced by physical rehabilitation. High levels of repetition and activity are required in rehabilitation, but patients are typically sedentary. Using clinically relevant and fun computer games may be one way to achieve increased activity in rehabilitation. A single-blind randomized controlled trial will be conducted to evaluate the feasibility, efficacy and safety of novel stroke-specific rehabilitation software. This software uses controller-free client interaction and inertial motion sensors. Elements of feasibility include recruitment into the trial, ongoing participation (adherence and dropout), perceived benefit, enjoyment and ease of use of the games. Efficacy will be determined by measuring activity and using upper-limb tasks as well as measures of balance and mobility. The hypothesis that the intervention group will have increased levels of physical activity within rehabilitation and improved physical outcomes compared with the control group will be tested. Results from this study will provide a basis for discussion of feasibility of this interactive video technological solution in an inpatient situation. Differences in activity levels between groups will be the primary measure of efficacy. It will also provide data on measures of upper-limb function, balance and mobility. ACTRN12614000427673 . Prospectively registered 17 April 2014.

  9. Patient centric drug product design in modern drug delivery as an opportunity to increase safety and effectiveness.

    Stegemann, Sven

    2018-06-01

    The advances in drug delivery technologies have enabled pharmaceutical scientists to deliver a drug through various administration routes and optimize the drug release and absorption. The wide range of drug delivery systems and dosage forms represent a toolbox of technology for the development of pharmaceutical drug products but might also be a source of medication errors and nonadherence. Patient centric drug product development is being suggested as an important factor to increase therapeutic outcomes. Areas covered: Patients have impaired health and potentially disabilities and they are not medical or pharmaceutical experts but are requested to manage complex therapeutic regimens. As such the application of technology should also serve to reduce complexity, build on patients' intuition and ease of use. Patients form distinct populations based on the targeted disease, disease cluster or age group with specific characteristics or therapeutic contexts. Expert opinion: Establishing a target product and patient profile is essential to guide drug product design development. Including the targeted patient populations in the process is a prerequisite to achieve patient-centric pharmaceutical drug product design. Addressing the needs early on in the product design process, will create more universal design, avoiding the necessity for multiple product presentations to cover the different patient populations.

  10. How do pharmaceutical companies handle consumer adverse drug reaction reports? An overview based on a survey of French drug safety managers and officers.

    Fleuranceau-Morel, P

    2002-01-01

    It is surprising to see how consumer Adverse Drug Reaction (ADR) reports have been continuously increasing for the last few years in Europe. This probably results from the influence of United States (US) market where the patients feels justified in telephoning the pharmaceutical companies directly with queries regarding their treatment. The growing number of alternative sources of information (e.g. health and popular magazines, spots on radio and TV etc.) to which a consumer is exposed has added to this growth too. The changing relationship between patients and doctors may also contribute to this phenomenon. It is then interesting to evaluate the way pharmaceutical companies currently deal with consumer ADR reports. The management of consumer ADR reporting was investigated by means of a questionnaire sent to 46 French drug safety managers and drug safety officers (DSOs) of multinational pharmaceutical companies. The analysis of the survey stressed the fact that pharmaceutical companies should be prepared to face up to an increase in the number of consumer ADR reports. It clearly appears that the consumers who telephone to register side-effects should be forwarded to a trained DSO with medical or pharmaceutical background and the communication skills acquired through specific training. This person should also be able to release adequate product information validated by his/her own company. The influence of the US market seems to be changing the way pharmaceutical companies deal with consumer ADR reports. Nowadays, these reports are entered into a drug safety database by most of the companies without previously having contacted the patient's general practitioner (GP) or specialist for medical confirmation. Lastly, the drug safety managers and DSOs consulted have divided opinions about the usefulness of call centres and e-mails as tools for ADR reporting. But both tools are globally rejected by the pharmaceutical companies as a reliable means of reporting. As stated

  11. Applicability and feasibility of systematic review for performing evidence-based risk assessment in food and feed safety

    Aiassa, E.; Higgins, J.P.T.; Frampton, G. K.

    2015-01-01

    for answering questions in health care, and can be implemented to minimise biases in food and feed safety risk assessment. However, no methodological frameworks exist for refining risk assessment multi-parameter models into questions suitable for systematic review, and use of meta-analysis to estimate all......Food and feed safety risk assessment uses multi-parameter models to evaluate the likelihood of adverse events associated with exposure to hazards in human health, plant health, animal health, animal welfare and the environment. Systematic review and meta-analysis are established methods...... parameters in the risk model. This approach to planning and prioritising systematic review seems to have useful implications for producing evidence-based food and feed safety risk assessment....

  12. Safety and Feasibility of a Ketamine Package to Support Emergency and Essential Surgery in Kenya when No Anesthetist is Available: An Analysis of 1216 Consecutive Operative Procedures.

    Burke, Thomas F; Suarez, Sebastian; Sessler, Daniel I; Senay, Ayla; Yusufali, Taha; Masaki, Charles; Guha, Moytrayee; Rogo, Debora; Jani, Pankaj; Nelson, Brett D; Rogo, Khama

    2017-12-01

    Lack of access to emergency and essential surgery is widespread in low- and middle-income countries. Scarce anesthesia services contribute to this unmet need. The aim of this study was to evaluate the safety and feasibility of the Every Second Matters for Emergency and Essential Surgery-Ketamine (ESM-Ketamine) package for emergency and essential procedures when no anesthetist was available. From November 2013 to September 2017, the ESM-Ketamine package was used for patients requiring emergency or life-improving surgeries in fifteen selected facilities across Kenya when no anesthetist was available. A mixed-methods approach was used to assess safety and feasibility of the ESM-Ketamine package, including demand, acceptability, and practicality. The primary outcome was ketamine-related adverse events. Key-informant interviews captured perceptions of providers, hospital administrators, and surgeons/proceduralists. Non-anesthetist mid-level providers used ESM-Ketamine for 1216 surgical procedures across the fifteen study facilities. The median ketamine dose was 2.1 mg/kg. Brief (30 s) oxygen desaturations occurred in seven patients (0.6%). There were 157 (13%) reported cases of hallucinations and agitation which were treated with diazepam. All patients recovered uneventfully, and no ketamine-related deaths were reported. Twenty-seven key-informant interviews showed strong support for the program with four main themes: financial considerations, provision of services, staff impact, and scaling considerations. The ESM-Ketamine package appears safe and feasible and is capable of expanding access to emergency and essential surgeries in rural Kenya when no anesthetist is available.

  13. Examining the safety of menstrual cups among rural primary school girls in western Kenya: observational studies nested in a randomised controlled feasibility study.

    Juma, Jane; Nyothach, Elizabeth; Laserson, Kayla F; Oduor, Clifford; Arita, Lilian; Ouma, Caroline; Oruko, Kelvin; Omoto, Jackton; Mason, Linda; Alexander, Kelly T; Fields, Barry; Onyango, Clayton; Phillips-Howard, Penelope A

    2017-05-04

    Examine the safety of menstrual cups against sanitary pads and usual practice in Kenyan schoolgirls. Observational studies nested in a cluster randomised controlled feasibility study. 30 primary schools in a health and demographic surveillance system in rural western Kenya. Menstruating primary schoolgirls aged 14-16 years participating in a menstrual feasibility study. Insertable menstrual cup, monthly sanitary pads or 'usual practice' (controls). Staphylococcus aureus vaginal colonization, Escherichia coli growth on sampled used cups, toxic shock syndrome or other adverse health outcomes. Among 604 eligible girls tested, no adverse event or TSS was detected over a median 10.9 months follow-up. S. aureus prevalence was 10.8%, with no significant difference over intervention time or between groups. Of 65  S.aureus positives at first test, 49 girls were retested and 10 (20.4%) remained positive. Of these, two (20%) sample isolates tested positive for toxic shock syndrome toxin-1; both girls were provided pads and were clinically healthy. Seven per cent of cups required replacements for loss, damage, dropping in a latrine or a poor fit. Of 30 used cups processed for E. coli growth, 13 (37.1%, 95% CI 21.1% to 53.1%) had growth. E. coli growth was greatest in newer compared with established users (53%vs22.2%, p=0.12). Among this feasibility sample, no evidence emerged to indicate menstrual cups are hazardous or cause health harms among rural Kenyan schoolgirls, but large-scale trials and post-marketing surveillance should continue to evaluate cup safety. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  14. Systematic review and meta-analysis of feasibility, safety, and efficacy of a novel procedure: associating liver partition and portal vein ligation for staged hepatectomy.

    Schadde, Erik; Schnitzbauer, Andreas A; Tschuor, Christoph; Raptis, Dimitri A; Bechstein, Wolf O; Clavien, Pierre-Alain

    2015-09-01

    Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel strategy to resect liver tumors despite the small size of the liver remnant. It is an hepatectomy in two stages, with PVL and parenchymal transection during the first stage, which induces rapid growth of the remnant liver exceeding any other technique. Despite high postoperative morbidity and mortality in most reports, the technique was adopted by a number of surgeons. This systematic review explores current data regarding the feasibility, safety, and oncologic efficacy of ALPPS; the search strategy has been published online. A meta-analysis of hypertrophy, feasibility (ALPPS stage 2 performed), mortality, complications, and R0 (complete) resection was performed. A literature search revealed a total of 13 publications that met the search criteria, reporting data from 295 patients. Evidence levels were low, with the highest Oxford evidence level being 2c. The most common indication was colorectal liver metastasis in 203 patients. Hypertrophy in the meta-analysis was 84 %, feasibility (ALPPS stage 2 performed) 97 % (CI 94-99 %), 90-day mortality 11 % (CI 8-16 %), and complications grade IIIa or higher occured in 44 % (CI 38-50 %) of patients. A standardized reporting format for complications is lacking despite the widespread use of the Clavien-Dindo classification. Oncological outcome is not well-documented. The most common topics in the selected studies published were technical feasibility and indications for the procedures. Publication bias due to case-series and single-center reports is common. A systematic exploration of this novel operation with a rigid methodology, such as registry analyses and a randomized controlled trial, is highly advised.

  15. Cardiovascular safety of non-steroidal anti-inflammatory drugs among healthy individuals

    Fosbøl, Emil Loldrup; Køber, Lars; Torp-Pedersen, Christian

    2010-01-01

    Studies have raised concern on the cardiovascular safety of NSAIDs. We studied safety of NSAID therapy in a nationwide cohort of healthy individuals.......Studies have raised concern on the cardiovascular safety of NSAIDs. We studied safety of NSAID therapy in a nationwide cohort of healthy individuals....

  16. Feasibility and Safety of a Powered Exoskeleton for Assisted Walking for Persons With Multiple Sclerosis: A Single-Group Preliminary Study.

    Kozlowski, Allan J; Fabian, Michelle; Lad, Dipan; Delgado, Andrew D

    2017-07-01

    To examine the feasibility, safety, and secondary benefit potential of exoskeleton-assisted walking with one device for persons with multiple sclerosis (MS). Single-group longitudinal preliminary study with 8-week baseline, 8-week intervention, and 4-week follow-up. Outpatient MS clinic, tertiary care hospital. Participants (N=13; age range, 38-62y) were mostly women with Expanded Disability Status Scale scores ranging from 5.5 to 7.0. Exoskeleton-assisted walk training. Primary outcomes were accessibility (enrollment/screen pass), tolerability (completion/dropout), learnability (time to event for standing, walking, and sitting with little or no assistance), acceptability (satisfaction on the device subscale of the Quebec User Evaluation of Satisfaction with Assistive Technology version 2), and safety (event rates standardized to person-time exposure in the powered exoskeleton). Secondary outcomes were walking without the device (timed 25-foot walk test and 6-minute walk test distance), spasticity (Modified Ashworth Scale), and health-related quality of life (Patient-Reported Outcomes Measurement and Information System pain interference and Quality of Life in Neurological Conditions fatigue, sleep disturbance, depression, and positive affect and well-being). The device was accessible to 11 and tolerated by 5 participants. Learnability was moderate, with 5 to 15 sessions required to walk with minimal assistance. Safety was good; the highest adverse event rate was for skin issues at 151 per 1000 hours' exposure. Acceptability ranged from not very satisfied to very satisfied. Participants who walked routinely improved qualitatively on sitting, standing, or walking posture. Two participants improved and 2 worsened on ≥1 quality of life domain. The pattern of spasticity scores may indicate potential benefit. The device appeared feasible and safe for about a third of our sample, for whom routine exoskeleton-assisted walking may offer secondary benefits. Copyright

  17. Safety and feasibility of STAT RAD: Improvement of a novel rapid tomotherapy-based radiation therapy workflow by failure mode and effects analysis.

    Jones, Ryan T; Handsfield, Lydia; Read, Paul W; Wilson, David D; Van Ausdal, Ray; Schlesinger, David J; Siebers, Jeffrey V; Chen, Quan

    2015-01-01

    The clinical challenge of radiation therapy (RT) for painful bone metastases requires clinicians to consider both treatment efficacy and patient prognosis when selecting a radiation therapy regimen. The traditional RT workflow requires several weeks for common palliative RT schedules of 30 Gy in 10 fractions or 20 Gy in 5 fractions. At our institution, we have created a new RT workflow termed "STAT RAD" that allows clinicians to perform computed tomographic (CT) simulation, planning, and highly conformal single fraction treatment delivery within 2 hours. In this study, we evaluate the safety and feasibility of the STAT RAD workflow. A failure mode and effects analysis (FMEA) was performed on the STAT RAD workflow, including development of a process map, identification of potential failure modes, description of the cause and effect, temporal occurrence, and team member involvement in each failure mode, and examination of existing safety controls. A risk probability number (RPN) was calculated for each failure mode. As necessary, workflow adjustments were then made to safeguard failure modes of significant RPN values. After workflow alterations, RPN numbers were again recomputed. A total of 72 potential failure modes were identified in the pre-FMEA STAT RAD workflow, of which 22 met the RPN threshold for clinical significance. Workflow adjustments included the addition of a team member checklist, changing simulation from megavoltage CT to kilovoltage CT, alteration of patient-specific quality assurance testing, and allocating increased time for critical workflow steps. After these modifications, only 1 failure mode maintained RPN significance; patient motion after alignment or during treatment. Performing the FMEA for the STAT RAD workflow before clinical implementation has significantly strengthened the safety and feasibility of STAT RAD. The FMEA proved a valuable evaluation tool, identifying potential problem areas so that we could create a safer workflow

  18. Study protocol for the FITR Heart Study: Feasibility, safety, adherence, and efficacy of high intensity interval training in a hospital-initiated rehabilitation program for coronary heart disease.

    Taylor, Jenna; Keating, Shelley E; Leveritt, Michael D; Holland, David J; Gomersall, Sjaan R; Coombes, Jeff S

    2017-12-01

    For decades, moderate intensity continuous training (MICT) has been the cornerstone of exercise prescription for cardiac rehabilitation (CR). High intensity interval training (HIIT) is now recognized in CR exercise guidelines as an appropriate and efficient modality for improving cardiorespiratory fitness, a strong predictor of mortality. However, the clinical application of HIIT in a real world CR setting, in terms of feasibility, safety, and long-term adherence, needs further investigation to address ongoing reservations. Furthermore, studies using objective measures of exercise intensity (such as heart rate; HR) have produced variable outcomes. Therefore we propose investigating the use of subjective measures (such as rating of perceived exertion (RPE)) for prescribing exercise intensity. One hundred adults with coronary artery disease (CAD) attending a hospital-initiated CR program will be randomized to 1) HIIT: 4 × 4 min high intensity intervals at 15-18 RPE interspersed with 3-min active recovery periods or 2) MICT: usual care exercise including 40 min continuous exercise at a moderate intensity corresponding to 11-13 RPE. Primary outcome is change in exercise capacity (peak VO 2 ) following 4 weeks of exercise training. Secondary outcome measures are: feasibility, safety, exercise adherence, body composition, vascular function, inflammatory markers, intrahepatic lipid, energy intake, and dietary behavior over 12-months; and visceral adipose tissue (VAT) following 12 weeks of exercise training. This study aims to address the ongoing concerns regarding the practicality and safety of HIIT in CR programs. We anticipate study findings will lead to the development of a standardized protocol to facilitate CR programs to incorporate HIIT as a standard exercise option for appropriate patients.

  19. Feasibility and Acceptability of Screening and Brief Interventions to Address Alcohol and Other Drug Use among Patients Presenting for Emergency Services in Cape Town, South Africa

    Bronwyn Myers

    2012-01-01

    Full Text Available Despite evidence from high income countries, it is not known whether screening and brief interventions (SBI for alcohol and other drug (AOD use are feasible to implement in low and middle income countries. This paper describes the feasibility and acceptability of a peer-led SBI for AOD-using patients presenting with injuries at emergency services in Cape Town, South Africa. Data were extracted from program records on the number of eligible patients screened and the number of program refusals. A questionnaire examined preliminary responses to the intervention for 30 patients who had completed the program and 10 emergency personnel. Peer counselors were also interviewed to identify barriers to implementation. Of the 1458 patients screened, 21% (305 met inclusion criteria, of which 74% (225 were enrolled in the intervention. Of the 30 patients interviewed, most (83% found the program useful. Emergency personnel were supportive of the program but felt that visibility and reach could improve. Peer counselors identified the need for better integration of the program into emergency services and for additional training and support. In conclusion, with limited additional resources, peer-led SBIs for AOD use are feasible to conduct in South African emergency services and are acceptable to patients and emergency personnel.

  20. Sponsors’ and investigative staffs' perceptions of the current investigational new drug safety reporting process in oncology trials

    Perez, Raymond; Archdeacon, Patrick; Roach, Nancy; Goodwin, Robert; Jarow, Jonathan; Stuccio, Nina; Forrest, Annemarie

    2017-01-01

    Background/aims: The Food and Drug Administration’s final rule on investigational new drug application safety reporting, effective from 28 March 2011, clarified the reporting requirements for serious and unexpected suspected adverse reactions occurring in clinical trials. The Clinical Trials Transformation Initiative released recommendations in 2013 to assist implementation of the final rule; however, anecdotal reports and data from a Food and Drug Administration audit indicated that a majority of reports being submitted were still uninformative and did not result in actionable changes. Clinical Trials Transformation Initiative investigated remaining barriers and potential solutions to full implementation of the final rule by polling and interviewing investigators, clinical research staff, and sponsors. Methods: In an opinion-gathering effort, two discrete online surveys designed to assess challenges and motivations related to management of expedited (7- to 15-day) investigational new drug safety reporting processes in oncology trials were developed and distributed to two populations: investigators/clinical research staff and sponsors. Data were collected for approximately 1 year. Twenty-hour-long interviews were also conducted with Clinical Trials Transformation Initiative–nominated interview participants who were considered as having extensive knowledge of and experience with the topic. Interviewees included 13 principal investigators/study managers/research team members and 7 directors/vice presidents of pharmacovigilance operations from 5 large global pharmaceutical companies. Results: The investigative site’s responses indicate that too many individual reports are still being submitted, which are time-consuming to process and provide little value for patient safety assessments or for informing actionable changes. Fewer but higher quality reports would be more useful, and the investigator and staff would benefit from sponsors’“filtering” of

  1. Sponsors' and investigative staffs' perceptions of the current investigational new drug safety reporting process in oncology trials.

    Perez, Raymond; Archdeacon, Patrick; Roach, Nancy; Goodwin, Robert; Jarow, Jonathan; Stuccio, Nina; Forrest, Annemarie

    2017-06-01

    The Food and Drug Administration's final rule on investigational new drug application safety reporting, effective from 28 March 2011, clarified the reporting requirements for serious and unexpected suspected adverse reactions occurring in clinical trials. The Clinical Trials Transformation Initiative released recommendations in 2013 to assist implementation of the final rule; however, anecdotal reports and data from a Food and Drug Administration audit indicated that a majority of reports being submitted were still uninformative and did not result in actionable changes. Clinical Trials Transformation Initiative investigated remaining barriers and potential solutions to full implementation of the final rule by polling and interviewing investigators, clinical research staff, and sponsors. In an opinion-gathering effort, two discrete online surveys designed to assess challenges and motivations related to management of expedited (7- to 15-day) investigational new drug safety reporting processes in oncology trials were developed and distributed to two populations: investigators/clinical research staff and sponsors. Data were collected for approximately 1 year. Twenty-hour-long interviews were also conducted with Clinical Trials Transformation Initiative-nominated interview participants who were considered as having extensive knowledge of and experience with the topic. Interviewees included 13 principal investigators/study managers/research team members and 7 directors/vice presidents of pharmacovigilance operations from 5 large global pharmaceutical companies. The investigative site's responses indicate that too many individual reports are still being submitted, which are time-consuming to process and provide little value for patient safety assessments or for informing actionable changes. Fewer but higher quality reports would be more useful, and the investigator and staff would benefit from sponsors'"filtering" of reports and increased sponsor communication. Sponsors

  2. Feasibility and safety of early lower limb robot-assisted training in sub-acute stroke patients: a pilot study.

    Gandolfi, Marialuisa; Geroin, Christian; Tomelleri, Christopher; Maddalena, Isacco; Kirilova Dimitrova, Eleonora; Picelli, Alessandro; Smania, Nicola; Waldner, Andreas

    2017-12-01

    So far, the development of robotic devices for the early lower limb mobilization in the sub-acute phase after stroke has received limited attention. To explore the feasibility of a newly robotic-stationary gait training in sub-acute stroke patients. To report the training effects on lower limb function and muscle activation. A pilot study. Rehabilitation ward. Two sub-acute stroke inpatients and ten age-matched healthy controls were enrolled. Healthy controls served as normative data. Patients underwent 10 robot-assisted training sessions (20 minutes, 5 days/week) in alternating stepping movements (500 repetitions/session) on a hospital bed in addition to conventional rehabilitation. Feasibility outcome measures were compliance, physiotherapist time, and responses to self-report questionnaires. Efficacy outcomes were bilateral lower limb muscle activation pattern as measured by surface electromyography (sEMG), Motricity Index (MI), Medical Research Council (MRC) grade, and Ashworth Scale (AS) scores before and after training. No adverse events occurred. No significant differences in sEMG activity between patients and healthy controls were observed. Post-training improvement in MI and MRC scores, but no significant changes in AS scores, were recorded. Post-treatment sEMG analysis of muscle activation patterns showed a significant delay in rectus femoris offset (P=0.02) and prolonged duration of biceps femoris (P=0.04) compared to pretreatment. The robot-assisted training with our device was feasible and safe. It induced physiological muscle activations pattern in both stroke patients and healthy controls. Full-scale studies are needed to explore its potential role in post-stroke recovery. This robotic device may enrich early rehabilitation in subacute stroke patients by inducing physiological muscle activation patterns. Future studies are warranted to evaluate its effects on promoting restorative mechanisms involved in lower limb recovery after stroke.

  3. A feasibility trial to examine the social norms approach for the prevention and reduction of licit and illicit drug use in European University and college students

    Pischke Claudia R

    2012-10-01

    Full Text Available Abstract Background Incorrect perceptions of high rates of peer alcohol and tobacco use are predictive of increased personal use in student populations. Correcting misperceptions by providing feedback has been shown to be an effective intervention for reducing licit drug use. It is currently unknown if social norms interventions are effective in preventing and reducing illicit drug use in European students. The purpose of this paper is to describe the design of a multi-site cluster controlled trial of a web-based social norms intervention aimed at reducing licit and preventing illicit drug use in European university students. Methods/Design An online questionnaire to assess rates of drug use will be developed and translated based on existing social norms surveys. Students from sixteen universities in seven participating European countries will be invited to complete the questionnaire. Both intervention and control sites will be chosen by convenience. In each country, the intervention site will be the university that the local principal investigator is affiliated with. We aim to recruit 1000 students per site (baseline assessment. All participants will complete the online questionnaire at baseline. Baseline data will be used to develop social norms messages that will be included in a web-based intervention. The intervention group will receive individualized social norms feedback. The website will remain online during the following 5 months. After five months, a second survey will be conducted and effects of the intervention on social norms and drug use will be measured in comparison to the control site. Discussion This project is the first cross-national European collaboration to investigate the feasibility of a social norms intervention to reduce licit and prevent illicit drug use among European university students. Final trial registration number DRKS00004375 on the ‘German Clinical Trials Register’.

  4. Use of toxicogenomics in drug safety evaluation: Current status and an industry perspective.

    Vahle, John L; Anderson, Ulf; Blomme, Eric A G; Hoflack, Jean-Christophe; Stiehl, Daniel P

    2018-04-18

    Toxicogenomics held great promise as an approach to enable early detection of toxicities induced by xenobiotics; however, there remain questions regarding the impact of the discipline on pharmaceutical nonclinical safety assessment. To understand the current state of toxicogenomics in the sector, an industry group surveyed companies to determine the frequency of toxicogenomics use in in vivo studies at various stages of drug discovery and development and to assess how toxicogenomics use has evolved over time. Survey data were compiled during 2016 from thirteen pharmaceutical companies. Toxicogenomic analyses were infrequently conducted in the development phase and when performed were done to address specific mechanistic questions. Prior to development, toxicogenomics use was more frequent; however, there were significant differences in approaches among companies. Across all phases, gaining mechanistic insight was the most frequent reason cited for pursing toxicogenomics with few companies using toxicogenomics to predict toxicities. These data were consistent with the commentary submitted in response to survey questions asking companies to describe the evolution of their toxicogenomics strategy. Overall, these survey data indicate that toxicogenomics is not widely used as a predictive tool in the pharmaceutical industry but is used regularly by some companies and serves a broader role in mechanistic investigations and as a complement to other technologies. Copyright © 2018. Published by Elsevier Inc.

  5. Residues of carcinogenic animal drugs in food: difficulties in evaluation of human safety.

    Somogyi, A

    1979-01-01

    The indisputable need to intensify animal production in order to provide an adequate food supply for the world population involves the use of substances that are highly potent pharmacologically and toxicologically. The history of regulatory action with regard to such additives is similar to that for other substances: first, no regulation; next, an over-reaction; and now decisions based on judicious evaluation of scientific facts. One factor that differentiates the chemicals used in animal production from other food additives is that both the parent compounds and their metabolites appear in edible products, posing problems both for the analytical detection and safety evaluation of such residues. It would be unrealistic to propose 'zero' tolerances for these additives, even if they are carcinogenic. The benefits gained from drugs that cure and prevent infections and parasitic diseases in food-producing animals, and the fact that analytical methods can now detect very small quantities make the presence of low levels of these substances in food unobjectionable.

  6. 78 FR 22270 - Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety...

    2013-04-15

    ..., indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes... Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, for new drug...

  7. Determination of safety margins for whole blood concentrations of alcohol and nineteen drugs in driving under the influence cases.

    Kristoffersen, Lena; Strand, Dag Helge; Liane, Veronica Horpestad; Vindenes, Vigdis; Tvete, Ingunn Fride; Aldrin, Magne

    2016-02-01

    Legislative limits for driving under the influence of 20 non-alcohol drugs were introduced in Norway in February 2012. Per se limits corresponding to blood alcohol concentrations (BAC) of 0.2g/kg were established for 20 psychoactive drugs, and limits for graded sanctions corresponding to BACs of 0.5 and 1.2g/kg were determined for 13 of these drugs. This new legislation made it possible for the courts to make sentences based on the analytical results, similar to the situation for alcohol. To ensure that the reported concentration is as least as high as the true concentration, with a 99% safety level, safety margins had to be calculated for each of the substances. Diazepam, tetrahydrocannabinol (THC) and alcohol were used as model substances to establish a new model for estimating the safety margins. The model was compared with a previous used model established several years ago, by a similar yet much simpler model, and they were found to be in agreement. The measurement uncertainties depend on the standard batch used, the work list and the measurements' replicate. A Bayesian modelling approach was used to determine the parameters in the model, using a dataset of 4700 diazepam positive specimens and 5400 THC positive specimens. Different safety margins were considered for low and high concentration levels of diazepam (≤2μM (0.6mg/L) and >2μM) and THC (≤0.01μM (0.003mg/L) and >0.01μM). The safety margins were for diazepam 19.5% (≤2μM) and 34% (>2μM), for THC 19.5% (≤0.01μM) and 24.9% (>0.01μM). Concentration dependent safety margins for BAC were based on a dataset of 29500 alcohol positive specimens, and were in the range 10.4% (0.1g/kg) to 4.0% (4.0g/kg) at a 99% safety level. A simplified approach was used to establish safety margins for the compounds amphetamine, MDMA, methamphetamine, alprazolam, phenazepam, flunitrazepam, clonazepam, nitrazepam, oxazepam, buprenorphine, GHB, methadone, ketamine, cocaine, morphine, zolpidem and zopiclone. The

  8. Diagnostic feasibility and safety of CT-guided core biopsy for lung nodules less than or equal to 8 mm. A single-institution experience

    Chang, Ying-Yueh [Taipei Veterans General Hospital, Department of Radiology, Taipei (China); Chen, Chun-Ku [Taipei Veterans General Hospital, Department of Radiology, Taipei (China); National Yang-Ming University, School of Medicine, Taipei (China); National Yang-Ming University, Institute of Clinical Medicine, Taipei (China); Yeh, Yi-Chen [National Yang-Ming University, School of Medicine, Taipei (China); Taipei Veterans General Hospital, Department of Pathology and Laboratory Medicine, Taipei (China); Wu, Mei-Han [Taipei Veterans General Hospital, Department of Radiology, Taipei (China); National Yang-Ming University, School of Medicine, Taipei (China)

    2018-02-15

    This retrospective study evaluated the diagnostic yield and safety of CT-guided core biopsy of pulmonary nodules ≤8 mm. We determined the diagnostic yield and safety profile of CT-guided lung biopsies for 125 pulmonary nodules ≤8 mm. Pathological diagnoses were made by a combination of histopathological examination and imprint cytology. Results were compared with biopsy results for 134 pulmonary nodules >8 and ≤10 mm. Final diagnoses were established in 94 nodules ≤8 mm. The sensitivity, specificity and diagnostic accuracy of CT-guided core biopsy for nodules ≤8 mm were 87.1 % (61/70 nodules), 100 % (24/24) and 90.4 % (85/94), respectively. Diagnostic failure rates were comparable for nodules ≤8 mm and nodules >8 mm and ≤10 mm (9/94, 9.6 % and 7/111, 6.3 %, respectively, P=0.385). The rate of tube thoracostomy for nodules ≤8 mm was comparable to that for nodules >8 and ≤10 mm (1.6 % vs. 0.7 %, P=0.611). Nodules ≤6 mm had a higher non-diagnostic result rate of 15.4 % (6/39) than did nodules >8 and ≤10 mm (3.7 %, 5/134, P=0.017). CT-guided pulmonary biopsy is feasible for lung nodules ≤8 mm, especially those >6 mm, and has an acceptable diagnostic yield and safety profile. (orig.)

  9. The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals.

    van Meer, Peter J K; Graham, Melanie L; Schuurman, Henk-Jan

    2015-07-15

    Nonclinical studies in animals are conducted to demonstrate proof-of-concept, mechanism of action and safety of new drugs. For a large part, in particular safety assessment, studies are done in compliance with international regulatory guidance. However, animal models supporting the initiation of clinical trials have their limitations, related to uncertainty regarding the predictive value for a clinical condition. The 3Rs principles (refinement, reduction and replacement) are better applied nowadays, with a more comprehensive application with respect to the original definition. This regards also regulatory guidance, so that opportunities exist to revise or reduce regulatory guidance with the perspective that the optimal balance between scientifically relevant data and animal wellbeing or a reduction in animal use can be achieved. In this manuscript we review the connections in the triangle between nonclinical efficacy/safety studies and regulatory aspects, with focus on in vivo testing of drugs. These connections differ for different drugs (chemistry-based low molecular weight compounds, recombinant proteins, cell therapy or gene therapy products). Regarding animal models and their translational value we focus on regulatory aspects and indications where scientific outcomes warrant changes, reduction or replacement, like for, e.g., biosimilar evaluation and safety testing of monoclonal antibodies. On the other hand, we present applications where translational value has been clearly demonstrated, e.g., immunosuppressives in transplantation. Especially for drugs of more recent date like recombinant proteins, cell therapy products and gene therapy products, a regulatory approach that allows the possibility to conduct combined efficacy/safety testing in validated animal models should strengthen scientific outcomes and improve translational value, while reducing the numbers of animals necessary. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Feasibility of Capsule Endoscopy for Direct Imaging of Drug Delivery Systems in the Fasted Upper-Gastrointestinal Tract

    Pedersen, Pernille Barbre; Bar-Shalom, Daniel; Baldursdottir, Stefania

    2014-01-01

    To develop a minimally-invasive method for direct visualization of drug delivery systems in the human stomach and to compare the obtained results with an established in vitro model. The method should provide the capsule rupture, dispersion characteristics, and knowledge regarding the surrounding ...

  11. Brief Screening and Intervention for Alcohol and Drug Use in a College Student Health Clinic: Feasibility, Implementation, and Outcomes

    Amaro, Hortensia; Reed, Elizabeth; Rowe, Erin; Picci, Jennifer; Mantella, Philomena; Prado, Guillermo

    2010-01-01

    Objective: Evaluation of the Brief Alcohol Screen and Intervention in College Students (BASICS) in a university primary care setting. Participants/Methods: Undergraduates (N = 449) participated in BASICS and electronic surveys assessing frequency/quantity of alcohol and drug use, psychosocial and mental health outcomes, and demographic…

  12. Para-aortic lymphadenectomy in advanced stage cervical cancer, a protocol for comparing safety, feasibility and diagnostic accuracy of surgical staging versus PET-CT; PALDISC trial.

    Tax, Casper; Abbink, Karin; Rovers, Maroeska M; Bekkers, Ruud L M; Zusterzeel, Petra L M

    2018-01-01

    Currently, a PET-CT is used to assess the need for extended field radiotherapy of para-aortic lymph nodes (PALN) in International Federation of Gynaecology and Obstetrics (FIGO) stage IB2, IIA2-IVA (locally advanced stage) cervical cancer. A small study established a sensitivity and specificity estimate for PALN metastases of 50% (95% CI; 7-93%) and 83% (95% CI; 52-98%), respectively. Surgical staging of PALN may lead to a higher diagnostic accuracy. However, surgical staging of para-aortic lymph nodes in locally advanced stage cervical cancer is not common practice. Therefore, a phase 2 randomised controlled trial is needed to assess its safety and feasibility. In addition to standard imaging (MRI or CT scan) with PET-CT, 30 adult women with FIGO stage IB2, IIA2-IVA cervical cancer will be randomised to receive either surgical staging or usual PET-CT staging. Administering extended field radiotherapy will be based on lymphadenectomy results for the intervention group and on the PET-CT results for the control group. Follow-up visits at 0, 3, 6, 9 and 12 months will assess health-related quality of life and progression-free survival.Primary safety and feasibility outcomes of surgical staging will be assessed by calculating means with 95% confidence intervals for duration of surgery, number of complications, blood loss, nodal yield after para-aortic lymphadenectomy and treatment delay due to surgical staging. Secondary patient-centred outcomes on quality of life and first year survival will be documented and compared between the two groups. Estimates of sensitivity, specificity and negative and positive predictive values of MRI, PET-CT and surgical staging will be presented with 95% CI.. All analysis will be performed according to the intention to treat principle. This study will assess safety and feasibility, expressed as the number and severity of complications, effect on quality of life and the treatment delay due to surgically staging para-aortic lymph nodes in

  13. Self-expandable stent loaded with {sup 125}I seeds: Feasibility and safety in a rabbit model

    Guo Jinhe [Department of Radiology, Zhong-Da Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009 (China); Teng Gaojun [Department of Radiology, Zhong-Da Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009 (China)]. E-mail: gjteng@vip.sina.com; Zhu Guangyu [Department of Radiology, Zhong-Da Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009 (China); He Shicheng [Department of Radiology, Zhong-Da Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009 (China); Deng Gang [Department of Radiology, Zhong-Da Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009 (China); He Jie [Department of Radiology, Zhong-Da Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009 (China)

    2007-02-15

    Objective: To evaluate technical feasibility and acute and subacute radiotolerance of a self-expandable stent loaded with {sup 125}I seeds in the rabbit esophagus. Methods: A self-expandable stent designed for esophageal application was made of 0.16 mm nitinol wire and loaded with {sup 125}I seeds (CIAE-6711). Twenty-seven stents with three different radioactive dosages (n = 9 in each dosage group) were implanted in the esophagus of healthy rabbits, while nine stents alone were used as controls. The stents were perorally deployed into the esophagus under fluoroscopic guidance. Radiological follow-up included plain chest film, CT scan, and barium esophagography which were undertaken in all rabbits of each group at 2, 4, and 8 weeks, respectively, which were correlated to histopathological findings. The stented esophageal segments along with their adjacent tissues were harvested for histopathological examinations. Results: The stent was successfully deployed into the targeted esophageal segment in all rabbits. Neither {sup 125}I seeds dislodged from the stent during the deployment, nor they did during the follow-up period. The greatest (16.2 Gy) absorbed dose was found in the tissue 10 mm from {sup 125}I seeds at 8 weeks. Slight epithelial hyperplasia on the stent surface and submucosal inflammatory process developed at 2 weeks, which reached the peak at 8 weeks after the procedure. Significant thickness of the esophageal muscular layer was found at 8 weeks only in the groups with {sup 125}I seeds. On radiologic follow-up, moderate strictures on both ends of the stents developed at 4 weeks and became severe at 8 weeks after the procedure in all groups. Conclusion: Deployment of a self-expandable stent loaded with {sup 125}I seeds is technically feasible and safe within the first 8 weeks. Acute and subacute radiotolerance of the treated esophagus and its adjacent tissues by {sup 125}I seeds is well preserved in a healthy rabbit model.

  14. 75 FR 2926 - Pipeline Safety: Reporting Drug and Alcohol Test Results for Contractors and Multiple Operator...

    2010-01-19

    ... DEPARTMENT OF TRANSPORTATION Pipeline and Hazardous Materials Safety Administration [Docket No... Operator Identification Numbers AGENCY: Pipeline and Hazardous Materials Safety Administration (PHMSA), DOT... liquid, and carbon dioxide pipelines and liquefied natural gas facilities that the Pipeline and Hazardous...

  15. A study on the feasibility and a possible form of local residents participation in nuclear safety regulation

    Lee, Sang Hoon; Son, Moon Kyu; Kim, Seong Sook

    2003-02-01

    It is expected that the results of this study will help policy makers in the government and nuclear industry enhance the confidence of local residents and citizens in the safety of nuclear energy. It is also believed that the citizen confidence on the nuclear energy will help them implement nuclear policies more efficiently and more safely. Considering that the newly sworn-in government is to involve citizens in wide variety of policy areas, this study fits with the policy directions of the new government. Most importantly, desirable citizen participation in public decision-making is to contribute to the enhancement of the working democracy

  16. A study on the feasibility and a possible form of local residents participation in nuclear safety regulation

    Lee, Sang Hoon; Son, Moon Kyu [Korea Association for Nuclear Technology, Taejon (Korea, Republic of); Kim, Seong Sook [Shila Univ., Busan (Korea, Republic of)

    2003-02-15

    It is expected that the results of this study will help policy makers in the government and nuclear industry enhance the confidence of local residents and citizens in the safety of nuclear energy. It is also believed that the citizen confidence on the nuclear energy will help them implement nuclear policies more efficiently and more safely. Considering that the newly sworn-in government is to involve citizens in wide variety of policy areas, this study fits with the policy directions of the new government. Most importantly, desirable citizen participation in public decision-making is to contribute to the enhancement of the working democracy.

  17. Feasibility, tolerability and safety of pediatric hyperpolarized "1"2"9Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis

    Walkup, Laura L.; Watters, Erin; Ruppert, Kai; Thomen, Robert P.; Woods, Jason C.; Akinyi, Teckla G.; Cleveland, Zackary I.; Clancy, John P.

    2016-01-01

    Hyperpolarized "1"2"9Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. To assess the feasibility, safety and tolerability of hyperpolarized "1"2"9Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent "1"2"9Xe MRI, receiving up to three doses of "1"2"9Xe gas prepared by either a commercially available or a homebuilt "1"2"9Xe polarizer. Subject heart rate and SpO_2 were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. All children tolerated multiple doses of "1"2"9Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO_2 (mean -6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO_2 values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following "1"2"9Xe MRI, but all were deemed unrelated to the study. The feasibility, safety and tolerability of "1"2"9Xe MRI has been assessed in a small group of children as young as 6 years. SpO_2 changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were

  18. Feasibility, tolerability and safety of pediatric hyperpolarized {sup 129}Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis

    Walkup, Laura L.; Watters, Erin; Ruppert, Kai [Cincinnati Children' s Hospital Medical Center, Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati, OH (United States); Thomen, Robert P.; Woods, Jason C. [Cincinnati Children' s Hospital Medical Center, Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati, OH (United States); Washington University in St. Louis, Department of Physics, St. Louis, MO (United States); Akinyi, Teckla G.; Cleveland, Zackary I. [Cincinnati Children' s Hospital Medical Center, Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati, OH (United States); University of Cincinnati, Biomedical Engineering Program, Cincinnati, OH (United States); Clancy, John P. [Cincinnati Children' s Hospital Medical Center, Division of Pulmonary Medicine, Cincinnati, OH (United States)

    2016-11-15

    Hyperpolarized {sup 129}Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. To assess the feasibility, safety and tolerability of hyperpolarized {sup 129}Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent {sup 129}Xe MRI, receiving up to three doses of {sup 129}Xe gas prepared by either a commercially available or a homebuilt {sup 129}Xe polarizer. Subject heart rate and SpO{sub 2} were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. All children tolerated multiple doses of {sup 129}Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO{sub 2} (mean -6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO{sub 2} values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following {sup 129}Xe MRI, but all were deemed unrelated to the study. The feasibility, safety and tolerability of {sup 129}Xe MRI has been assessed in a small group of children as young as 6 years. SpO{sub 2} changes were consistent with the expected physiological effects of a short anoxic breath

  19. SAFETY

    Niels Dupont

    2013-01-01

    CERN Safety rules and Radiation Protection at CMS The CERN Safety rules are defined by the Occupational Health & Safety and Environmental Protection Unit (HSE Unit), CERN’s institutional authority and central Safety organ attached to the Director General. In particular the Radiation Protection group (DGS-RP1) ensures that personnel on the CERN sites and the public are protected from potentially harmful effects of ionising radiation linked to CERN activities. The RP Group fulfils its mandate in collaboration with the CERN departments owning or operating sources of ionising radiation and having the responsibility for Radiation Safety of these sources. The specific responsibilities concerning "Radiation Safety" and "Radiation Protection" are delegated as follows: Radiation Safety is the responsibility of every CERN Department owning radiation sources or using radiation sources put at its disposition. These Departments are in charge of implementing the requi...

  20. Feasibility, Safety, and Efficacy of an Alternative Schedule of Sunitinib for the Treatment of Patients with Metastatic Renal Cell Carcinoma: A Retrospective Study.

    Buti, Sebastiano; Donini, Maddalena; Bersanelli, Melissa; Gattara, Alessia; Leonardi, Francesco; Passalacqua, Rodolfo

    2017-12-01

    Standard treatment with sunitinib for patients with metastatic renal cancer provides an 'on-off' schedule (daily administration of a 50-mg capsule for 4 weeks, followed by a 2-week break; consecutive 6-week cycles). We developed an alternative intermittent schedule to reduce the toxicity and symptoms of tumor regrowth during the rest period and to allow prolonged continuation of therapy, maintaining dose intensity. The objective of this study was to provide a retrospective evaluation of the feasibility, safety, and efficacy of an alternative schedule of sunitinib in patients who did not tolerate classical treatment. Patients treated with the classical schedule with at least grade 2 toxicity or recurrence of symptoms during the rest period were switched to an alternative schedule (the same daily dose 5 consecutive days per week for 5 weeks and then the same daily dose on days 1, 3, and 5 in the sixth week; consecutive 6-week cycles). Twenty-five patients were enrolled. The median time from sunitinib initiation to schedule switch was 2.9 months. After the switch, the median therapy duration was 9.2 months. Rate of delay, corrected by cycle number, was 10% for both schedules. After the switch, 48.7% of patients obtained a toxicity reduction (hypertension -82%, stomatitis -71%, cutaneous toxicity -69%). A reduction in 'on-off symptoms' (-86%) was achieved. Overall response rate was 40% and the disease control rate was 80%. Median progression-free survival was 16.4 months and median overall survival was 41.3 months. Despite the small sample size and retrospective nature, we demonstrated the feasibility, safety, and efficacy of the alternative schedule, allowing prolonged treatment and better quality of life.

  1. Feasibility and safety of augmented-reality glass for computed tomography-assisted percutaneous revascularization of coronary chronic total occlusion: A single center prospective pilot study.

    Opolski, Maksymilian P; Debski, Artur; Borucki, Bartosz A; Staruch, Adam D; Kepka, Cezary; Rokicki, Jakub K; Sieradzki, Bartosz; Witkowski, Adam

    2017-11-01

    Percutaneous coronary intervention (PCI) of chronic total occlusion (CTO) may be facilitated by projection of coronary computed tomography angiography (CTA) datasets in the catheterization laboratory. There is no data on the feasibility and safety outcomes of CTA-assisted CTO PCI using a wearable augmented-reality glass. A total of 15 patients scheduled for elective antegrade CTO intervention were prospectively enrolled and underwent preprocedural coronary CTA. Three-dimensional and curved multiplanar CT reconstructions were transmitted to a head-mounted hands-free computer worn by interventional cardiologists during CTO PCI to provide additional information on CTO tortuosity and calcification. The results of CTO PCI using a wearable computer were compared with a time-matched prospective angiographic registry of 59 patients undergoing antegrade CTO PCI without a wearable computer. Operators' satisfaction was assessed by a 5-point Likert scale. Mean age was 64 ± 8 years and the mean J-CTO score was 2.1 ± 0.9 in the CTA-assisted group. The voice-activated co-registration and review of CTA images in a wearable computer during CTO PCI were feasible and highly rated by PCI operators (4.7/5 points). There were no major adverse cardiovascular events. Compared with standard CTO PCI, CTA-assisted recanalization of CTO using a wearable computer showed more frequent selection of the first-choice stiff wire (0% vs 40%, p augmented-reality glass is feasible and safe, and might reduce the resources required for the interventional treatment of CTO. Copyright © 2017 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.

  2. [Feasibility and relevance of an operating room safety checklist for developing countries: Study in a French hospital in Djibouti].

    Becret, A; Clapson, P; Andro, C; Chapelier, X; Gauthier, J; Kaiser, E

    2013-01-01

    The use of the World Health Organization surgical safety checklist, mandatory in operating rooms (OR) in France, significantly reduces morbidity and mortality. Our objective was to evaluate the use of this checklist in the OR of a French military hospital in Djibouti (Horn of Africa). The study was performed in three stages: a retrospective evaluation of the checklist use over the previous two months, to assess the utilization and completeness rates; provision of information to the OR staff; and thereafter, prospective evaluation for a one-month period of checklist use, the reasons for non-compliance, and the cases in which the checklist identified errors and thus prevented serious adverse events. The initial utilization rate was 49%, with only 24% complete. After staff training and during the study these rates reached 100% and 99%. The staff encountered language difficulties in 53% of cases, and an interpreter was available for 81% of them. The capacity of the surgical safety checklist to detect serious adverse events was highlighted. The utilization and completeness rates were initially worse than those observed in metropolitan French ORs, but a simple staff information program was rapidly effective. Language difficulties are frequent but an interpreter is often available, unlike in developed countries where language problems are uncommon and the availability of interpreters difficult. Moreover, this study illustrates the ability of the checklist to detect and therefore prevent potentially serious adverse events.

  3. Applicability and safety of dual-frequency ultrasonic treatment for the transdermal delivery of drugs

    Schoellhammer, Carl M.; Srinivasan, Sharanya; Barman, Ross; Mo, Stacy H.; Polat, Baris E.; Langer, Robert; Blankschtein, Daniel

    2016-01-01

    Low-frequency ultrasound presents an attractive method for transdermal drug delivery. The controlled, yet nonspecific nature of enhancement broadens the range of therapeutics that can be delivered, while minimizing necessary reformulation efforts for differing compounds. Long and inconsistent treatment times, however, have partially limited the attractiveness of this method. Building on recent advances made in this area, the simultaneous use of low- and high-frequency ultrasound is explored in a physiologically relevant experimental setup to enable the translation of this treatment to testing in vivo. Dual-frequency ultrasound, utilizing 20 kHz and 1 MHz wavelengths simultaneously, was found to significantly enhance the size of localized transport regions (LTRs) in both in vitro and in vivo models while decreasing the necessary treatment time compared to 20 kHz alone. Additionally, LTRs generated by treatment with 20 kHz + 1 MHz were found to be more permeable than those generated with 20 kHz alone. This was further corroborated with pore-size estimates utilizing hindered-transport theory, in which the pores in skin treated with 20 kHz + 1 MHz were calculated to be significantly larger than the pores in skin treated with 20 kHz alone. This demonstrates for the first time that LTRs generated with 20 kHz + 1 MHz are also more permeable than those generated with 20 kHz alone, which could broaden the range of therapeutics and doses administered transdermally. With regard to safety, treatment with 20 kHz + 1 MHz both in vitro and in vivo appeared to result in no greater skin disruption than that observed in skin treated with 20 kHz alone, an FDA-approved modality. This study demonstrates that dual-frequency ultrasound is more efficient and effective than single-frequency ultrasound and is well-tolerated in vivo. PMID:25662228

  4. Use of an Anti-Gravity Treadmill for Early Postoperative Rehabilitation After Total Knee Replacement: A Pilot Study to Determine Safety and Feasibility.

    Bugbee, William D; Pulido, Pamela A; Goldberg, Timothy; D'Lima, Darryl D

    2016-01-01

    The objective was to determine the safety, feasibility, and effects of anti-gravity gait training on functional outcomes (Knee Injury and Osteoarthritis Outcome Score [KOOS], the Timed Up and Go test [TUG], Numerical Rating Scale [NRS] for pain) with the AlterG® Anti-Gravity Treadmill® device for total knee arthroplasty (TKA) rehabilitation. Subjects (N = 30) were randomized to land-based vs anti-gravity gait training over 4 weeks of physical therapy after TKA. Adverse events, complications, and therapist satisfaction were recorded. All patients completed rehabilitation protocols without adverse events. KOOS, TUG, and NRS scores improved in both groups with no significant differences between groups. For the AlterG group, Sports/Recreation and Quality of Life subscales of the KOOS had the most improvement. At the end of physical therapy, TUG and NRS pain scores improved from 14 seconds to 8 seconds and from 2.8 to 1.1, respectively. Subjectively, therapists reported 100% satisfaction with the AlterG. This initial pilot study demonstrated that the AlterG Anti-Gravity Treadmill device was safe and feasible. While functional outcomes improved over time with use of the anti-gravity gait training, further studies are needed to define the role of this device as an alternative or adjunct to established rehabilitation protocols.

  5. Multimodal impairment-based physical therapy for the treatment of patients with post-concussion syndrome: A retrospective analysis on safety and feasibility.

    Grabowski, Patrick; Wilson, John; Walker, Alyssa; Enz, Dan; Wang, Sijian

    2017-01-01

    Demonstrate implementation, safety and feasibility of multimodal, impairment-based physical therapy (PT) combining vestibular/oculomotor and cervical rehabilitation with sub-symptom threshold exercise for the treatment of patients with post-concussion syndrome (PCS). University hospital outpatient sports medicine facility. Twenty-five patients (12-20 years old) meeting World Health Organization criteria for PCS following sport-related concussion referred for supervised PT consisting of sub-symptom cardiovascular exercise, vestibular/oculomotor and cervical spine rehabilitation. Retrospective cohort. Post-Concussion Symptom Scale (PCSS) total score, maximum symptom-free heart rate (SFHR) during graded exercise testing (GXT), GXT duration, balance error scoring system (BESS) score, and number of adverse events. Patients demonstrated a statistically significant decreasing trend (p feasibility for future clinical trials to determine viable treatment approaches to reduce symptoms and improve function while avoiding negative repercussions of physical inactivity and premature return to full activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Feasibility and safety of robot-assisted thoracic surgery for lung lobectomy in patients with non-small cell lung cancer: a systematic review and meta-analysis.

    Wei, Shiyou; Chen, Minghao; Chen, Nan; Liu, Lunxu

    2017-05-08

    The aim of this study is to evaluate the feasibility and safety of robot-assisted thoracic surgery (RATS) lobectomy versus video-assisted thoracic surgery (VATS) for lobectomy in patients with non-small cell lung cancer (NSCLC). An electronic search of six electronic databases was performed to identify relevant comparative studies. Meta-analysis was performed by pooling the results of reported incidence of overall morbidity, mortality, prolonged air leak, arrhythmia, and pneumonia between RATS and VATS lobectomy. Subgroup analysis was also conducted based on matched and unmatched cohort studies, if possible. Relative risks (RR) with their 95% confidence intervals (CI) were calculated by means of Revman version 5.3. Twelve retrospective cohort studies were included, with a total of 60,959 patients. RATS lobectomy significantly reduced the mortality rate when compared with VATS lobectomy (RR = 0.54, 95% CI 0.38-0.77; P = 0.0006), but this was not consistent with the pooled result of six matched studies (RR = 0.12, 95% CI 0.01-1.07; P = 0.06). There was no significant difference in morbidity between the two approaches (RR = 0.97, 95% CI 0.85-1.12; P = 0.70). RATS lobectomy is a feasible and safe technique and can achieve an equivalent short-term surgical efficacy when compared with VATS, but its cost effectiveness also should be taken into consideration.

  7. Feasibility and Safety of Local Treatment with Recombinant Human Tissue Factor Pathway Inhibitor in a Rat Model of Streptococcus pneumoniae Pneumonia.

    Florry E van den Boogaard

    Full Text Available Pulmonary coagulopathy is intrinsic to pulmonary injury including pneumonia. Anticoagulant strategies could benefit patients with pneumonia, but systemic administration of anticoagulant agents may lead to suboptimal local levels and may cause systemic hemorrhage. We hypothesized nebulization to provide a safer and more effective route for local administration of anticoagulants. Therefore, we aimed to examine feasibility and safety of nebulization of recombinant human tissue factor pathway inhibitor (rh-TFPI in a well-established rat model of Streptococcus (S. pneumoniae pneumonia. Thirty minutes before and every 6 hours after intratracheal instillation of S. pneumonia causing pneumonia, rats were subjected to local treatment with rh-TFPI or placebo, and sacrificed after 42 hours. Pneumonia was associated with local as well as systemic activation of coagulation. Nebulization of rh-TFPI resulted in high levels of rh-TFPI in bronchoalveolar lavage fluid, which was accompanied by an attenuation of pulmonary coagulation. Systemic rh-TFPI levels remained undetectable, and systemic TFPI activity and systemic coagulation were not affected. Histopathology revealed no bleeding in the lungs. We conclude that nebulization of rh-TFPI seems feasible and safe; local anticoagulant treatment with rh-TFPI attenuates pulmonary coagulation, while not affecting systemic coagulation in a rat model of S. pneumoniae pneumonia.

  8. The importance of Pharmacovigilance for the drug safety: Focus on cardiovascular profile of incretin-based therapy.

    Sportiello, Liberata; Rafaniello, Concetta; Scavone, Cristina; Vitale, Cristiana; Rossi, Francesco; Capuano, Annalisa

    2016-01-01

    With the recent introduction of the new European Pharmacovigilance legislation, all new drugs must be carefully monitored after admission on the European market, in order to assess the long safety profile. Currently, special attention is given to several hypoglycemic agents with recent market approval (agonists of glucagon-like peptide-1 [GLP-1] receptor and dipeptidyl peptidase 4 inhibitors [DPP-4i]), which act through the potentiation of incretin hormone signaling. Their inclusion in European additional monitoring is also due to safety problems, which seem to characterize their pharmacological class. In fact, these drugs initially showed a good tolerability profile with mainly gastrointestinal adverse events, low risk of hypoglycemia and minor effects on body weight. But, new concerns such as infections, pancreatitis, pancreatic cancer and above all cardiovascular events (especially risk of heart failure requiring hospitalization) are now arising. In this review, we highlighted aspects of the new Pharmacovigilance European dispositions, and then we investigated the tolerability profile of incretin-based therapies, in particular DPP-4 inhibitors. Notably, we focused our attention on new safety concerns, which are emerging mostly in the post-marketing period, as the cardiovascular risk profile. Evidence in literature and opinions of regulatory agencies (e.g., European Medicines Agency and Food and Drug Administration) about risks of incretin-based therapies are yet controversial, and there are many open questions in particular on cancer and cardiovascular effects. Thus, it is important to continue to monitor closely the use of these drugs in clinical practice to improve the knowledge on their long-term safety and their place in diabetes therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Community-Based Adaptive Physical Activity Program for Chronic Stroke: Feasibility, Safety, and Efficacy of the Empoli Model

    Stuart, Mary; Benvenuti, Francesco; Macko, Richard; Taviani, Antonio; Segenni, Lucianna; Mayer, Federico; Sorkin, John D.; Stanhope, Steven J.; Macellari, Velio; Weinrich, Michael

    2010-01-01

    Objective To determine whether Adaptive Physical Activity (APA-stroke), a community-based exercise program for participants with hemiparetic stroke, improves function in the community. Methods Nonrandomized controlled study in Tuscany, Italy, of participants with mild to moderate hemiparesis at least 9 months after stroke. Forty-nine participants in a geographic health authority (Empoli) were offered APA-stroke (40 completed the study). Forty-four control participants in neighboring health authorities (Florence and Pisa) received usual care (38 completed the study). The APA intervention was a community-based progressive group exercise regimen that included walking, strength, and balance training for 1 hour, thrice a week, in local gyms, supervised by gym instructors. No serious adverse clinical events occurred during the exercise intervention. Outcome measures included the following: 6-month change in gait velocity (6-Minute Timed Walk), Short Physical Performance Battery (SPPB), Berg Balance Scale, Stroke Impact Scale (SIS), Barthel Index, Hamilton Rating Scale for Depression, and Index of Caregivers Strain. Results After 6 months, the intervention group improved whereas controls declined in gait velocity, balance, SPPB, and SIS social participation domains. These between-group comparisons were statistically significant at P glucose tolerance tests were performed on a subset of participants in the intervention group. For these individuals, insulin secretion declined 29% after 6 months (P = .01). Conclusion APA-stroke appears to be safe, feasible, and efficacious in a community setting. PMID:19318465

  10. Efficacy and safety of rabeprazole in non-steroidal anti-inflammatory drug-induced ulcer in Japan.

    Mizokami, Yuji

    2009-10-28

    To investigate the efficacy and safety of rabeprazole under continuous non-steroidal anti-inflammatory drug (NSAID) administration for NSAID-induced ulcer in Japan. Subjects comprised patients undergoing NSAID treatment in whom upper gastrointestinal endoscopy revealed an ulcerous lesion (open ulcer) with diameter > or = 3 mm, who required continuous NSAID treatment. Endoscopies were performed at the start of treatment, during the treatment period, and at the conclusion (or discontinuation) of treatment. Findings were evaluated as size (maximum diameter) and stage based on the Sakita-Miwa classification. An ulcer was regarded as cured when the "white coating" was seen to have disappeared under endoscopy. As criteria for evaluating safety, all medically untoward symptoms and signs (adverse events, laboratory abnormalities, accidental symptoms, etc.) occurring after the start of rabeprazole treatment were handled as adverse events. Endoscopic cure rate in 38 patients in the efficacy analysis (endoscopic evaluation) was 71.1% (27/38). Among those 38 patients, 35 had gastric ulcer with a cure rate of 71.4% (25/35), and 3 had duodenal ulcer with a cure rate of 66.7% (2/3). Three adverse drug reactions were reported from 64 patients in the safety analysis (interstitial pneumonia, low white blood cell count and pruritus); thus, the incidence rate for adverse drug reactions was 4.7% (3/64). The treatment efficacy of rabeprazole for NSAID-induced ulcer under continuous NSAID administration was confirmed.

  11. 78 FR 10107 - Food and Drug Administration Food Safety Modernization Act: Proposed Rules To Establish Standards...

    2013-02-13

    ... AGENCY: Food and Drug Administration, HHS. ACTION: Notification of public meeting. SUMMARY: The Food and Drug Administration (FDA) is providing public meeting registration information for two FSMA related... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 1, 16, 106, 110...

  12. The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

    Marks, Louise, E-mail: louise.marks@astrazeneca.com [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Kirk, Sarah [Innovative Medicines, Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Valentin, Jean-Pierre [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom)

    2012-09-01

    Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt{sub max} and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability.

  13. The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

    Marks, Louise; Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew; Kirk, Sarah; Valentin, Jean-Pierre

    2012-01-01

    Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt max and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability. ► Haemodynamic

  14. Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy.

    Hart, Nicolas H; Newton, Robert U; Spry, Nigel A; Taaffe, Dennis R; Chambers, Suzanne K; Feeney, Kynan T; Joseph, David J; Redfern, Andrew D; Ferguson, Tom; Galvão, Daniel A

    2017-05-30

    Exercise may positively alter tumour biology through numerous modulatory and regulatory mechanisms in response to a variety of modes and dosages, evidenced in preclinical models to date. Specifically, localised and systemic biochemical alterations produced during and following exercise may suppress tumour formation, growth and distribution by virtue of altered epigenetics and endocrine-paracrine activity. Given the impressive ability of targeted mechanical loading to interfere with metastasis-driven tumour formation in human osteolytic tumour cells, it is of equal interest to determine whether a similar effect is observed in sclerotic tumour cells. The study aims to (1) establish the feasibility and safety of a combined modular multimodal exercise programme with spinal isometric training in advanced prostate cancer patients with sclerotic bone metastases and (2) examine whether targeted and supervised exercise can suppress sclerotic tumour growth and activity in spinal metastases in humans. A single-blinded, two-armed, randomised, controlled and explorative phase I clinical trial combining spinal isometric training with a modular multimodal exercise programme in 40 men with advanced prostate cancer and stable sclerotic spinal metastases. Participants will be randomly assigned to (1) the exercise intervention or (2) usual medical care. The intervention arm will receive a 3-month, supervised and individually tailored modular multimodal exercise programme with spinal isometric training. Primary endpoints (feasibility and safety) and secondary endpoints (tumour morphology; biomarker activity; anthropometry; musculoskeletal health; adiposity; physical function; quality of life; anxiety; distress; fatigue; insomnia; physical activity levels) will be measured at baseline and following the intervention. Statistical analyses will include descriptive characteristics, t-tests, effect sizes and two-way (group × time) repeated-measures analysis of variance (or analysis of

  15. Safety

    2001-01-01

    This annual report of the Senior Inspector for the Nuclear Safety, analyses the nuclear safety at EDF for the year 1999 and proposes twelve subjects of consideration to progress. Five technical documents are also provided and discussed concerning the nuclear power plants maintenance and safety (thermal fatigue, vibration fatigue, assisted control and instrumentation of the N4 bearing, 1300 MW reactors containment and time of life of power plants). (A.L.B.)

  16. Strategies for the early detection of drug-induced hepatic steatosis in preclinical drug safety evaluation studies

    Amacher, David E.

    2011-01-01

    Hepatic steatosis is characterized by the accumulation of lipid droplets in the liver. Although relatively benign, simple steatosis can eventually lead to the development of steatohepatitis, a more serious condition characterized by fibrosis, cirrhosis, and eventual liver failure if the underlying cause is not eliminated. According to the 'two hit' theory of steatohepatitis, the initial hit involves fat accumulation in the liver, and a second hit leads to inflammation and subsequent tissue injury. Because some xenobiotics target liver fatty acid metabolism, especially mitochondrial β-oxidation, it is important to avoid potential drug candidates that can contribute to either the initiation of liver steatosis or progression to the more injurious steatohepatitis. The gold standard for the detection of these types of hepatic effects is histopathological examination of liver tissue. In animal studies, these examinations are slow, restricted to a single sampling time, and limited tissue sections. Recent literature suggests that rapid in vitro screening methods can be used early in the drug R and D process to identify compounds with steatotic potential. Further, progress in the identification of potential serum or plasma protein biomarkers for these liver changes may provide additional in vivo tools to the preclinical study toxicologist. This review summarizes recent developments for in vitro screening and in vivo biomarker detection for steatotic drug candidates.

  17. Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses.

    Ocana, Alberto; Ethier, Josee-Lyne; Díez-González, Laura; Corrales-Sánchez, Verónica; Srikanthan, Amirrtha; Gascón-Escribano, María J; Templeton, Arnoud J; Vera-Badillo, Francisco; Seruga, Bostjan; Niraula, Saroj; Pandiella, Atanasio; Amir, Eitan

    2015-11-24

    Companion diagnostics aim to identify patients that will respond to targeted therapies, therefore increasing the clinical efficacy of such drugs. Less is known about their influence on safety and tolerability of targeted anti-cancer agents. Randomized trials evaluating targeted agents for solid tumors approved by the US Food and Drug Administration since year 2000 were assessed. Odds ratios (OR) and and 95% confidence intervals (CI) were computed for treatment-related death, treatment-discontinuation related to toxicity and occurrence of any grade 3/4 adverse events (AEs). The 12 most commonly reported individual AEs were also explored. ORs were pooled in a meta-analysis. Analysis comprised 41 trials evaluating 28 targeted agents. Seventeen trials (41%) utilized companion diagnostics. Compared to control groups, targeted drugs in experimental arms were associated with increased odds of treatment discontinuation, grade 3/4 AEs, and toxic death irrespective of whether they utilized companion diagnostics or not. Compared to drugs without available companion diagnostics, agents with companion diagnostics had a lower magnitude of increased odds of treatment discontinuation (OR = 1.12 vs. 1.65, p diagnostics were greatest for diarrhea (OR = 1.29 vs. 2.43, p diagnostics are associated with improved safety, and tolerability. Differences were most marked for gastrointestinal, cutaneous and neurological toxicity.

  18. Development of novel, 384-well high-throughput assay panels for human drug transporters: drug interaction and safety assessment in support of discovery research.

    Tang, Huaping; Shen, Ding Ren; Han, Yong-Hae; Kong, Yan; Balimane, Praveen; Marino, Anthony; Gao, Mian; Wu, Sophie; Xie, Dianlin; Soars, Matthew G; O'Connell, Jonathan C; Rodrigues, A David; Zhang, Litao; Cvijic, Mary Ellen

    2013-10-01

    Transporter proteins are known to play a critical role in affecting the overall absorption, distribution, metabolism, and excretion characteristics of drug candidates. In addition to efflux transporters (P-gp, BCRP, MRP2, etc.) that limit absorption, there has been a renewed interest in influx transporters at the renal (OATs, OCTs) and hepatic (OATPs, BSEP, NTCP, etc.) organ level that can cause significant clinical drug-drug interactions (DDIs). Several of these transporters are also critical for hepatobiliary disposition of bilirubin and bile acid/salts, and their inhibition is directly implicated in hepatic toxicities. Regulatory agencies took action to address transporter-mediated DDI with the goal of ensuring drug safety in the clinic and on the market. To meet regulatory requirements, advanced bioassay technology and automation solutions were implemented for high-throughput transporter screening to provide structure-activity relationship within lead optimization. To enhance capacity, several functional assay formats were miniaturized to 384-well throughput including novel fluorescence-based uptake and efflux inhibition assays using high-content image analysis as well as cell-based radioactive uptake and vesicle-based efflux inhibition assays. This high-throughput capability enabled a paradigm shift from studying transporter-related issues in the development space to identifying and dialing out these concerns early on in discovery for enhanced mechanism-based efficacy while circumventing DDIs and transporter toxicities.

  19. Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease

    Chaparro, M; Verreth, A; Lobaton, T

    2018-01-01

    OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs...... in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non......-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox...

  20. Feasibility, safety and cost of outpatient management of acute minor ischaemic stroke: a population-based study.

    Paul, Nicola L M; Koton, Silvia; Simoni, Michela; Geraghty, Olivia C; Luengo-Fernandez, Ramon; Rothwell, Peter M

    2013-03-01

    Outpatient management safely and effectively prevents early recurrent stroke after transient ischaemic attack (TIA), but this approach may not be safe in patients with acute minor stroke. To study outcomes of clinic and hospital-referred patients with TIA or minor stroke (National Institute of Health Stroke Scale score ≤3) in a prospective, population-based study (Oxford Vascular Study). Of 845 patients with TIA/stroke, 587 (69%) were referred directly to outpatient clinics and 258 (31%) directly to inpatient services. Of the 250 clinic-referred minor strokes (mean age 72.7 years), 237 (95%) were investigated, treated and discharged on the same day, of whom 16 (6.8%) were subsequently admitted to hospital within 30 days for recurrent stroke (n=6), sepsis (n=3), falls (n=3), bleeding (n=2), angina (n=1) and nursing care (n=1). The 150 patients (mean age 74.8 years) with minor stroke referred directly to hospital (median length-of-stay 9 days) had a similar 30-day readmission rate (9/150; 6.3%; p=0.83) after initial discharge and a similar 30-day risk of recurrent stroke (9/237 in clinic patients vs 8/150, OR=0.70, 0.27-1.80, p=0.61). Rates of prescription of secondary prevention medication after initial clinic/hospital discharge were higher in clinic-referred than in hospital-referred patients for antiplatelets/anticoagulants (phospital-referred minor stroke versus £743 (1794) for clinic-referred cases. Outpatient management of clinic-referred minor stroke is feasible and may be as safe as inpatient care. Rates of early hospital admission and recurrent stroke were low and uptake and maintenance of secondary prevention was high.

  1. Transportation Safety of Lithium Iron Phosphate Batteries - A Feasibility Study of Storing at Very Low States of Charge.

    Barai, Anup; Uddin, Kotub; Chevalier, Julie; Chouchelamane, Gael H; McGordon, Andrew; Low, John; Jennings, Paul

    2017-07-11

    In freight classification, lithium-ion batteries are classed as dangerous goods and are therefore subject to stringent regulations and guidelines for certification for safe transport. One such guideline is the requirement for batteries to be at a state of charge of 30%. Under such conditions, a significant amount of the battery's energy is stored; in the event of mismanagement, or indeed an airside incident, this energy can lead to ignition and a fire. In this work, we investigate the effect on the battery of removing 99.1% of the total stored energy. The performance of 8Ah C 6 /LiFePO 4 pouch cells were measured following periods of calendar ageing at low voltages, at and well below the manufacturer's recommended value. Battery degradation was monitored using impedance spectroscopy and capacity tests; the results show that the cells stored at 2.3 V exhibited no change in cell capacity after 90 days; resistance rise was negligible. Energy-dispersive X-ray spectroscopy results indicate that there was no significant copper dissolution. To test the safety of the batteries at low voltages, external short-circuit tests were performed on the cells. While the cells discharged to 2.3 V only exhibited a surface temperature rise of 6 °C, cells at higher voltages exhibited sparks, fumes and fire.

  2. Feasibility and Design of an Electronic Surgical Safety Checklist in a Teaching Hospital: A User-Based Approach.

    Kiefel, Karin; Donsa, Klaus; Tiefenbacher, Peter; Mischak, Robert; Brunner, Gernot; Sendlhofer, Gerald; Pieber, Thomas

    2018-01-01

    The Surgical Safety Checklist (SSC) is routinely used in operating rooms (OR) but its acceptance is low. One promising way to improve acceptance of the SSC and thus quality of patient care is digitalization. To investigate how a digitalization of the SSC could be implemented in a teaching hospital. Based on the identified user requirements we designed a first user interface (UI). We performed a literature review, identified user perceptions and requirements during 12 interviews including a standardized questionnaire in surgical departments at the University Hospital Graz (Austria). Subsequently a first prototype of a UI was designed. Seven different approaches for digital SSC were identified in literature. Our interviews showed that 90% of the participants had a positive attitude towards a digitalization of SSC. The most favoured version of a digitalized SSC was a tablet-based client-server system with integration in the EHR and projection on an OR monitor. Digitalization of the SSC is requested by medical and nursing personnel. Based on the identified user requirements we designed a process oriented UI of a digital SSC.

  3. Stereotactic body radiation therapy for liver metastases from colorectal cancer: analysis of safety, feasibility, and early outcomes

    Marie-Adele Sorel Kress

    2012-02-01

    Full Text Available Introduction: Colorectal cancer (CRC is the 3rd leading cause of cancer-related death in the U.S. Many patients with CRC develop hepatic metastases as the sole site of metastases. Historical treatment options were limited to resection or conventional radiation therapy. Stereotactic body radiation therapy (SBRT has emerged as a rational treatment approach. This study reviews our experience with SBRT for patients with liver metastases from CRC.Material and Methods: Fourteen histologically confirmed hepatic CRC metastases in 11 consecutive patients were identified between November, 2004 and June, 2009 at Georgetown University. All patients underwent CT-based treatment planning; a few also had MRI or PET/CT. All patients had fiducial markers placed under CT guidance and were treated using the CyberKnife system. Treatment response and toxicities were examined; survival and local control were evaluated.Results: Most patients were treated to a single hepatic lesion (n=8, with a few treated to 2 lesions (n=3. Median treatment volume was 99.7 cm3, and lesions were treated to a median BED10 of 49.7 Gy (range: 28 – 100.8 Gy. Median follow-up was 21 months; median survival was 16.1 months, with 2-year actuarial survival of 25.7%. One-year local control was 72%. Among patients with post-treatment imaging, 8 had stable disease (80% and 2 had progressive disease (20% at first follow-up. The most common grade 1-2 acute toxicities included nausea and alterations in liver function tests; there was one grade 3 toxicity (elevated bilirubin, and no grade 4-5 toxicities.Discussion: SBRT is safe and feasible for the treatment of limited hepatic metastases from CRC. Our results compare favorably with outcomes from previous studies of SBRT. Further studies are needed to better define patient eligibility, study the role of combined modality treatment, optimize treatment parameters, and characterize quality of life after treatment.

  4. Safety assessment of an anti-obesity drug (sibutramine): a retrospective cohort study.

    Tyczynski, Jerzy E; Oleske, Denise M; Klingman, David; Ferrufino, Cheryl P; Lee, Won Chan

    2012-08-01

    the UK [Germany: HR 0.47 (95% CI 0.17, 1.26), 0.43 (0.23, 0.81) and 0.44 (0.26, 0.75), respectively; UK: HR 0.44 (0.15, 1.31), 0.63 (0.25, 1.60) and 0.54 (0.27, 1.10), respectively]. Regardless of whether or not the model controlled for prior CV disease (CVD), the direction and statistical significance of the differences did not change. In the sensitivity analyses including only those without a history of CVD in the 365 days prior to the index date there was no increased risk of CV events in either Germany or the UK. This study offers a framework for the safety assessment of anti-obesity drugs using an observational epidemiological study design. Large electronic health databases were used to construct retrospective cohorts to examine the risk in a population using one specific anti-obesity drug. Use of sibutramine in general practice settings was not found to increase the risk of acute CV events.

  5. The Safety and Feasibility of Image-Guided BrainPath-Mediated Transsulcul Hematoma Evacuation: A Multicenter Study.

    Labib, Mohamed A; Shah, Mitesh; Kassam, Amin B; Young, Ronald; Zucker, Lloyd; Maioriello, Anthony; Britz, Gavin; Agbi, Charles; Day, J D; Gallia, Gary; Kerr, Robert; Pradilla, Gustavo; Rovin, Richard; Kulwin, Charles; Bailes, Julian

    2017-04-01

    Subcortical injury resulting from conventional surgical management of intracranial hemorrhage may counteract the potential benefits of hematoma evacuation. To evaluate the safety and potential benefits of a novel, minimally invasive approach for clot evacuation in a multicenter study. The integrated approach incorporates 5 competencies: (1) image interpretation and trajectory planning, (2) dynamic navigation, (3) atraumatic access system (BrainPath, NICO Corp, Indianapolis, Indiana), (4) extracorporeal optics, and (5) automated atraumatic resection. Twelve neurosurgeons from 11 centers were trained to use this approach through a continuing medical education-accredited course. Demographical, clinical, and radiological data of patients treated over 2 years were analyzed retrospectively. Thirty-nine consecutive patients were identified. The median Glasgow Coma Scale (GCS) score at presentation was 10 (range, 5-15). The thalamus/basal ganglion regions were involved in 46% of the cases. The median hematoma volume and depth were 36 mL (interquartile range [IQR], 27-65 mL) and 1.4 cm (IQR, 0.3-2.9 cm), respectively. The median time from ictus to surgery was 24.5 hours (IQR, 16-66 hours). The degree of hematoma evacuation was ≥90%, 75% to 89%, and 50% to 74% in 72%, 23%, and 5.0% of the patients, respectively. The median GCS score at discharge was 14 (range, 8-15). The improvement in GCS score was statistically significant ( P < .001). Modified Rankin Scale data were available for 35 patients. Fifty-two percent of those patients had a modified Rankin Scale score of ≤2. There were no mortalities. The approach was safely performed in all patients with a relatively high rate of clot evacuation and functional independence. Copyright © 2016 by the Congress of Neurological Surgeons

  6. 78 FR 49988 - Food and Drug Administration Food Safety Modernization Act: Proposed Rules on Foreign Supplier...

    2013-08-16

    ... help manage the safety of their global food supply chains. The purpose of the public meeting is to... electronic or written comments to FDA's Division of Dockets Management. ADDRESSES: See section II, ``How to... protect public health by helping to ensure the safety and security of the food supply. FSMA amends the...

  7. 78 FR 57320 - Food and Drug Administration Food Safety Modernization Act: Proposed Rules on Foreign Supplier...

    2013-09-18

    ... help manage the safety of their global food supply chains. The purpose of these public meetings is to... submitting either electronic or written comments to FDA's Division of Dockets Management. ADDRESSES: See..., to better protect public health by helping to ensure the safety and security of the food supply. FSMA...

  8. Home closure as a weapon in the Dutch war on drugs: Does judicial review function as a safety net?

    Bruijn, L Michelle; Vols, Michel; Brouwer, Jan G

    2018-01-01

    A widespread sense of a failing criminal justice system and increased feelings of insecurity changed the response to crime into a culture of control, which is characterized by policies that punish and exclude. In the Netherlands, these influences can be witnessed in the war on drugs where local authorities use their administrative power to close homes involved in drug-related crime. Citizens can invoke judicial review over these administrative interferences by claiming that such closure results in an unfair balance between purposes, means and consequences. This paper assesses whether judicial review functions as a safety net against losing one's home due to drug-related crime. We used doctrinal legal research methods to examine the "law in the books" and empirical legal research methods to analyse the "law in action". We used a survey to investigate how often the drug-related closure power was used in 2015, and we statistically analysed all published case law of Dutch lower courts between 2007 and 2016. The scope of the closure power broadened over the years and our data show that local authorities fiercely make use of this instrument. In 41.4% of the cases, citizens are successful in fighting the closure. While scholarly literature indicates that judicial courts function as safeguards by questioning the proportionality of administrative action, raising a proportionality defence does not necessarily result in a more favourable outcome for citizens. In fact, raising a proportionality defence makes it more likely to result in dismissal of the appeal. The stretched scope of the drug-related closure power together with the relatively low success rate of citizens who fight the loss of their home and a seemingly meaningless proportionality check show no sign of a safety net against the loss of one's home at the suit of a local authority. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Clinical Relation Extraction Toward Drug Safety Surveillance Using Electronic Health Record Narratives: Classical Learning Versus Deep Learning.

    Munkhdalai, Tsendsuren; Liu, Feifan; Yu, Hong

    2018-04-25

    Medication and adverse drug event (ADE) information extracted from electronic health record (EHR) notes can be a rich resource for drug safety surveillance. Existing observational studies have mainly relied on structured EHR data to obtain ADE information; however, ADEs are often buried in the EHR narratives and not recorded in structured data. To unlock ADE-related information from EHR narratives, there is a need to extract relevant entities and identify relations among them. In this study, we focus on relation identification. This study aimed to evaluate natural language processing and machine learning approaches using the expert-annotated medical entities and relations in the context of drug safety surveillance, and investigate how different learning approaches perform under different configurations. We have manually annotated 791 EHR notes with 9 named entities (eg, medication, indication, severity, and ADEs) and 7 different types of relations (eg, medication-dosage, medication-ADE, and severity-ADE). Then, we explored 3 supervised machine learning systems for relation identification: (1) a support vector machines (SVM) system, (2) an end-to-end deep neural network system, and (3) a supervised descriptive rule induction baseline system. For the neural network system, we exploited the state-of-the-art recurrent neural network (RNN) and attention models. We report the performance by macro-averaged precision, recall, and F1-score across the relation types. Our results show that the SVM model achieved the best average F1-score of 89.1% on test data, outperforming the long short-term memory (LSTM) model with attention (F1-score of 65.72%) as well as the rule induction baseline system (F1-score of 7.47%) by a large margin. The bidirectional LSTM model with attention achieved the best performance among different RNN models. With the inclusion of additional features in the LSTM model, its performance can be boosted to an average F1-score of 77.35%. It shows that

  10. Documentation of pediatric drug safety in manufacturers' product monographs: a cross-sectional evaluation of the canadian compendium of pharmaceuticals and specialities.

    Uppal, Navjeet K; Dupuis, Lee L; Parshuram, Christopher S

    2008-01-01

    To describe the provision of pediatric drug safety information in a national formulary of manufacturers' drug product monographs. We performed a cross-sectional evaluation of comprehensive product monographs contained in the 2005 Canadian Compendium of Pharmaceuticals and Specialities (CPS). We abstracted data describing indications for prescription, statements about pediatric safety, available preparations, and provision of dosing guidelines. For each monograph we classified pediatric safety data as either present, present but limited or absent. We then described the pediatric safety data in CPS monographs for drugs listed in the published formulary of the Hospital for Sick Children, Toronto, Ontario, Canada. A total of 2232 product monographs were screened; 684 were excluded and 1548 (66%) were further analyzed. 1462 (94%) had indications that did not exclude children. Pediatric safety information was present in 592 (38%), present but limited in 148 (10%), and absent in 808 (52%) drug monographs. Safety statements were absent in 224 (14%) drug monographs that provided both dosing guidelines and formulations suitable for administration to children, and in 214 (52%) of 411 drugs in the pediatric hospital formulary. We evaluated a widely available national source of pediatric prescribing information. Safety data for children was not mentioned in more than half of the product monographs. Moreover, the provision of safety data was discordant with indications for prescription, the availability of pediatric formulations, and dosing guidelines within the monographs, and with inclusion in a pediatric hospital formulary. Our study suggests that the presentation of pediatric safety data in drug product monographs can be improved to better inform prescribing and to optimize pharmacotherapy in children.

  11. A prospective, multicenter pilot study to investigate the feasibility and safety of a 1-year controlled exercise training after adjuvant chemotherapy in colorectal cancer patients.

    Piringer, Gudrun; Fridrik, Michael; Fridrik, Alfred; Leiherer, Andreas; Zabernigg, August; Greil, Richard; Eisterer, Wolfgang; Tschmelitsch, Jörg; Lang, Alois; Frantal, Sophie; Burgstaller, Sonja; Gnant, Michael; Thaler, Josef

    2018-04-01

    Despite advances in adjuvant chemotherapy, 20-30% of patients in stages II-III colorectal cancer will eventually relapse. Observational studies showed a reduction in relapse rate, colon cancer-specific mortality, and overall mortality by physical activity. Results from prospective randomized interventional studies to confirm these observational data are lacking. The aims of this prospective single-arm multicenter pilot study are to evaluate feasibility and safety of exercise training after adjuvant chemotherapy in colorectal cancer patients. The training was performed three times per week for 1 year and was increased gradually in three phases until reaching 18 metabolic equivalent task hours per week. Overall, 30 patients were included. The planned training intensity could be achieved in all three phases. Patients experienced a performance increase of median 35.5 watt, a weight-loss of a median of 3.0 kg, and a reduction in body fat content of median 1.0% during this exercise training. The analysis showed early study termination due to non-compliance in 10/30 patients (33.3%), disease progression in 4 patients (13.3%), and serious adverse events in 2 patients (6.7%). About half of patients (46.7%) completed the pilot study as planned. Biomarker analysis from 20 patients showed a non-significant reduction in insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2) and insulin-like growth factor binding protein 3 (IGF-BP3) levels, significant increases in adiponectin and leptin levels, and a non-significant increase in C-peptide levels. Exercise training is feasible in patients with colorectal cancer after completion of adjuvant chemotherapy. The main problem encountered during the study was compliance. To improve compliance of exercise training, several measures were adapted for the upcoming prospective randomized ABCSG C08 Exercise II study.

  12. Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial

    Brummel, N.E.; Girard, T.D.; Ely, E.W.; Pandharipande, P.P.; Morandi, A.; Hughes, C.G.; Graves, A.J.; Shintani, A.K.; Murphy, E.; Work, B.; Pun, B.T.; Boehm, L.; Gill, T.M.; Dittus, R.S.; Jackson, J.C.

    2013-01-01

    PURPOSE Cognitive impairment after critical illness is common and debilitating. We developed a cognitive therapy program for critically ill patients and assessed the feasibility and safety of administering combined cognitive and physical therapy early during a critical illness. METHODS We randomized 87 medical and surgical ICU patients with respiratory failure and/or shock in a 1:1:2 manner to three groups: usual care, early once-daily physical therapy, or early once-daily physical therapy plus a novel, progressive, twice-daily cognitive therapy protocol. Cognitive therapy included orientation, memory, attention, and problem solving exercises, and other activities. We assessed feasibility outcomes of the early cognitive plus physical therapy intervention. At 3-months, we also assessed cognitive, functional and health-related quality of life outcomes. Data are presented as median [interquartile range] or frequency (%). RESULTS Early cognitive therapy was a delivered to 41/43 (95%) of cognitive plus physical therapy patients on 100% [92–100%] of study days beginning 1.0 [1.0–1.0] day following enrollment. Physical therapy was received by 17/22 (77%) of usual care patients, by 21/22 (95%) of physical therapy only patients and 42/43 (98%) of cognitive plus physical therapy patients on 17% [10–26%], 67% [46–87%] and 75% [59–88%] of study days, respectively. Cognitive, functional and health-related quality of life outcomes did not differ between groups at 3-month follow-up. CONCLUSIONS This pilot study demonstrates that early rehabilitation can be extended beyond physical therapy to include cognitive therapy. Future work to determine optimal patient selection, intensity of treatment and benefits of cognitive therapy in the critically ill is needed. PMID:24257969

  13. Intracardiac echo-guided radiofrequency catheter ablation of atrial fibrillation in patients with atrial septal defect or patent foramen ovale repair: a feasibility, safety, and efficacy study.

    Lakkireddy, Dhanunjaya; Rangisetty, Umamahesh; Prasad, Subramanya; Verma, Atul; Biria, Mazda; Berenbom, Loren; Pimentel, Rhea; Emert, Martin; Rosamond, Thomas; Fahmy, Tamer; Patel, Dimpi; Di Biase, Luigi; Schweikert, Robert; Burkhardt, David; Natale, Andrea

    2008-11-01

    Intracardiac Echo-Guided Radiofrequency Catheter. Patients with atrial septal defect (ASD) are at higher risk for atrial fibrillation (AF) even after repair. Transseptal access in these patients is perceived to be difficult. We describe the feasibility, safety, and efficacy of pulmonary vein antral isolation (PVAI) in these patients. We prospectively compared post-ASD/patent foramen ovale (PFO) repair patients (group I, n = 45) with age-gender-AF type matched controls (group II, n = 45). All the patients underwent PVAI through a double transseptal puncture with a roving circular mapping catheter technique guided by intracardiac echocardiography (ICE). The short-term (3 months) and long-term (12 month) failure rates were assessed. In group I, 23 (51%) had percutaneous closure devices and 22 (49%) had a surgical closure. There was no significant difference between group I and II in the baseline characteristics. Intracardiac echo-guided double transseptal access was obtained in 98% of patients in group I and in 100% of patients in group II. PVAI was performed in all patients, with right atrial flutter ablation in 7 patients in group I and in 4 patients in group II. Over a mean follow-up of 15 +/- 4 months, group I had higher short-term (18% vs 13%, P = 0.77) and long-term recurrence (24% vs 18%, P = 0.6) than group II. There was no significant difference in the perioperative complications between the two groups. Echocardiography at 3 months showed interatrial communication in 2 patients in group I and 1 patient in group II, which resolved at 12 months. Percutaneous AF ablation using double transseptal access is feasible, safe, and efficacious in patients with ASD and PFO repairs.

  14. Safety, acceptability, and feasibility of a single-visit approach to cervical-cancer prevention in rural Thailand: a demonstration project.

    Gaffikin, L; Blumenthal, P D; Emerson, M; Limpaphayom, K

    2003-03-08

    To increase screening and treatment coverage, innovative approaches to cervical-cancer prevention are being investigated in rural Thailand. We assessed the value of a single-visit approach combining visual inspection of the cervix with acetic acid wash (VIA) and cryotherapy. 12 trained nurses provided services in mobile (village health centre-based) and static (hospital-based) teams in four districts of Roi-et Province, Thailand. Over 7 months, 5999 women were tested by VIA. If they tested positive, after counselling about the benefits, potential risks, and probable side-effects they were offered cryotherapy. Data measuring safety, acceptability, feasibility, and effort to implement the programme were gathered. The VIA test-positive rate was 13.3% (798/5999), and 98.5% (609/618) of those eligible accepted immediate treatment. Overall, 756 women received cryotherapy, 629 (83.2%) of whom returned for their first follow-up visit. No major complications were recorded, and 33 (4.4%) of those treated returned for a perceived problem. Only 17 (2.2%) of the treated women needed clinical management other than reassurance about side-effects. Both VIA and cryotherapy were highly acceptable to the patients (over 95% expressed satisfaction with their experience). At their 1-year visit, the squamocolumnar junction was visible to the nurses, and the VIA test-negative rate was 94.3%. A single-visit approach with VIA and cryotherapy seems to be safe, acceptable, and feasible in rural Thailand, and is a potentially efficient method of cervical-cancer prevention in such settings.

  15. A Novel Self-Expandable, Radioactive Airway Stent Loaded with 125I Seeds: A Feasibility and Safety Study in Healthy Beagle Dog.

    Wang, Yong; Guo, Jin-He; Zhu, Guang-Yu; Zhu, Hai-Dong; Chen, Li; Lu, Jian; Wang, Chao; Teng, Gao-Jun

    2017-07-01

    Airway stent placement is an effective treatment for the immediate palliation of malignant airway obstruction. However, restenosis caused by tumor ingrowth and/or overgrowth after stenting is common. The purpose of this study was to investigate the feasibility and safety of a novel self-expandable stent loaded with 125 I seeds in healthy beagle dog. Under fluoroscopic guidance, forty-eight self-expandable airway stents loaded with 125 I seeds were perorally placed in the main trachea of 48 healthy beagle dogs, who were randomly divided into four groups (Group A: 0.3 mCi; Group B: 0.6 mCi; Group C: 0.9 mCi; Control group: 0 mCi). The estimated radiation dose was calculated using the isotropic point source approximation. Radiological follow-up examinations and histopathological examinations of stented tracheal segments and their adjacent organs and tissues were performed at 2, 4, 8, and 16 weeks following the stenting. All stents were successfully deployed in the targeted tracheal segment in the beagle dogs without procedure-related complications. Tracheal stenosis became severe gradually in all the four groups, which was not associated with the radioactivity of 125 I seeds (p > 0.05). The tracheal injury scores increased along with the higher dose of radioactive seeds which reached peak at 8 weeks and then turned back slightly at 16 weeks. The adjacent tissue did not show pathohistological changes under microscope, while mild and reversible ultrastructure changes were showed under electronic microscope. This study demonstrates that it is feasible and safe to insert this novel self-expandable airway stent loaded with 125 I seeds in healthy beagle dog.

  16. Feasibility and Safety of Intra-arterial Pericyte Progenitor Cell Delivery Following Mannitol-Induced Transient Blood-Brain Barrier Opening in a Canine Model.

    Youn, Sung Won; Jung, Keun-Hwa; Chu, Kon; Lee, Jong-Young; Lee, Soon-Tae; Bahn, Jae-jun; Park, Dong-Kyu; Yu, Jung-Suk; Kim, So-Yun; Kim, Manho; Lee, Sang Kun; Han, Moon-Hee; Roh, Jae-Kyu

    2015-01-01

    Stem cell therapy is currently being studied with a view to rescuing various neurological diseases. Such studies require not only the discovery of potent candidate cells but also the development of methods that allow optimal delivery of those candidates to the brain tissues. Given that the blood-brain barrier (BBB) precludes cells from entering the brain, the present study was designed to test whether hyperosmolar mannitol securely opens the BBB and enhances intra-arterial cell delivery. A noninjured normal canine model in which the BBB was presumed to be closed was used to evaluate the feasibility and safety of the tested protocol. Autologous adipose tissue-derived pericytes with platelet-derived growth factor receptor β positivity were utilized. Cells were administered 5 min after mannitol pretreatment using one of following techniques: (1) bolus injection of a concentrated suspension, (2) continuous infusion of a diluted suspension, or (3) bolus injection of a concentrated suspension that had been shaken by repeated syringe pumping. Animals administered a concentrated cell suspension without mannitol pretreatment served as a control group. Vital signs, blood parameters, neurologic status, and major artery patency were kept stable throughout the experiment and the 1-month posttreatment period. Although ischemic lesions were noted on magnetic resonance imaging in several mongrel dogs with concentrated cell suspension, the injection technique using repeated syringe shaking could avert this complication. The cells were detected in both ipsilateral and contralateral cortices and were more frequent at the ipsilateral and frontal locations, whereas very few cells were observed anywhere in the brain when mannitol was not preinjected. These data suggest that intra-arterial cell infusion with mannitol pretreatment is a feasible and safe therapeutic approach in stable brain diseases such as chronic stroke.

  17. The US Food and Drug Administration’s drug safety recommendations and long-acting beta2-agonist dispensing pattern changes in adult asthma patients: 2003–2012

    Zhou EH

    2017-03-01

    Full Text Available Esther H Zhou,1 Sally Seymour,2 Margie R Goulding,1 Elizabeth M Kang,1 Jacqueline M Major,1 Solomon Iyasu1 1Division of Epidemiology, Office of Surveillance and Epidemiology, 2Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA Background: Emerging safety issues associated with long-acting beta2-agonist (LABA have led to multiple regulatory activities by the US Food and Drug Administration (FDA since 2003, including Drug Safety Communications (DSCs in 2010. These DSCs had three specific recommendations for the safe use of LABA products in adult asthma treatment. Methods: We examined the initiation of LABA-containing products for adult asthma treatment using an intermittent time series approach in a claims database from 2003 to 2012. We assessed the alignment of dispensing patterns with the following 2010 FDA recommendations: 1 contraindicated use of single-ingredient (SI-LABA without an asthma controller medication (ACM; 2 a LABA should only be used when asthma is not adequately controlled on inhaled corticosteroids (ICSs or ACM; and 3 step-down asthma therapy (e.g., discontinue LABA when asthma control is achieved. Results: There were 477,922 adults (18–64 years old dispensed a new LABA during 2003–2012. Among LABA initiators, patients who initiated an SI-LABA and who did “not” have an ACM dispensed on the same date decreased from >9% in 2003 (the initial labeling change to <2% post 2010 DSCs (p-value <0.0001 in the segmented regression model. The proportion of asthma patients dispensed an ICS in 6 months prior to initiating LABA treatment did not increase. The proportion of patients with longer than 4 months of continuous treatment did not decrease over the study period. Conclusion: Although the decrease in SI-LABA initiation is consistent with FDA’s recommendations, low ICS dispensing before initiating a LABA and LABA continuation practices require further efforts

  18. Evaluation of Vaginal Drug Levels and Safety of a Locally Administered Glycerol Monolaurate Cream in Rhesus Macaques.

    Kirtane, Ameya R; Rothenberger, Meghan K; Frieberg, Abby; Nephew, Karla; Schultz-Darken, Nancy; Schmidt, Thomas; Reimann, Thomas; Haase, Ashley T; Panyam, Jayanth

    2017-07-01

    The human immunodeficiency virus epidemic affects millions of people worldwide. As women are more vulnerable to infection, female-controlled interventions can help control the spread of the disease significantly. Glycerol monolaurate (GML), an inexpensive and safe compound, has been shown to protect against simian immunodeficiency virus infection when applied vaginally. However, on account of its low aqueous solubility, fabrication of high-dose formulations of GML has proven difficult. We describe the development of a vaginal cream that could be loaded with up to 35% GML. Vaginal drug levels and safety of 3 formulations containing increasing concentrations of GML (5%w/w, 15%w/w, and 35%w/w) were tested in rhesus macaques after vaginal administration. GML concentration in the vaginal tissue increased as the drug concentration in the cream increased, with 35% GML cream resulting in tissue concentration of ∼0.5 mg/g, albeit with high interindividual variability. Compared with the vehicle control, none of the GML creams had any significant effect on the vaginal flora and cytokine (macrophage inflammatory protein 3α and interleukin 8) levels, suggesting that high-dose GML formulations do not induce local adverse effects. In summary, we describe the development of a highly loaded vaginal cream of GML, and vaginal drug levels and safety after local administration in macaques. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  19. Effect of Safety Issues with HIV Drugs on the Approval Process of Other Drugs in the Same Class An Analysis of European Public Assessment Reports : an analysis of European public assessment reports

    Arnardottir, Arna H.; Haaijer-Ruskamp, Flora M.; Straus, Sabine M. J.; de Graeff, Pieter A.; Mol, Peter G. M.

    2011-01-01

    Background: Knowledge on the safety of new medicines is limited at the time of market entry. Nearly half of all drugs used to treat HIV registered in the EU required >= 1 Direct Healthcare Professional Communication (DHPC) in the past 10 years for safety issues identified post-approval. Objective:

  20. High-intensity interval training and hyperoxia during chemotherapy: A case report about the feasibility, safety and physical functioning in a colorectal cancer patient.

    Freitag, Nils; Weber, Pia Deborah; Sanders, Tanja Christiane; Schulz, Holger; Bloch, Wilhelm; Schumann, Moritz

    2018-06-01

    We conducted a case study to examine the feasibility and safety of high-intensity interval training (HIIT) with increased inspired oxygen content in a colon cancer patient undergoing chemotherapy. A secondary purpose was to investigate the effects of such training regimen on physical functioning. A female patient (51 years; 49.1 kg; 1.65 m; tumor stage: pT3, pN2a (5/29), pM1a (HEP), L0, V0, R0) performed 8 sessions of HIIT (5 × 3 minutes at 90% of Wmax, separated by 2 minutes at 45% Wmax) with an increased inspired oxygen fraction of 30%. Patient safety, training adherence, cardiorespiratory fitness (peak oxygen uptake and maximal power output during an incremental cycle ergometer test), autonomous nervous function (i.e., heart rate variability during an orthostatic test) as well as questionnaire-assessed quality of life (EORTC QLQ-C30) were evaluated before and after the intervention.No adverse events were reported throughout the training intervention and a 3 months follow-up. While the patient attended all sessions, adherence to total training time was only 51% (102 of 200 minutes; mean training time per session 12:44 min:sec). VO2peak and Wmax increased by 13% (from 23.0 to 26.1 mL min kg) and 21% (from 83 to 100 W), respectively. Heart rate variability represented by the root mean squares of successive differences both in supine and upright positions were increased after the training by 143 and 100%, respectively. The EORTC QLQ-C30 score for physical functioning (7.5%) as well as the global health score (10.7%) improved, while social function decreased (17%). Our results show that a already short period of HIIT with concomitant hyperoxia was safe and feasible for a patient undergoing chemotherapy for colon cancer. Furthermore, the low overall training adherence of only 51% and an overall low training time per session (∼13 minutes) was sufficient to induce clinically meaningful improvements in physical functioning. However, this case also

  1. Illicit Internet availability of drugs subject to recall and patient safety consequences.

    Mackey, Tim K; Aung, Phyo; Liang, Bryan A

    2015-12-01

    Permanently recalled drugs are a public health concern if they remain accessible in violation of applicable regulation. Illicit online pharmacies act as an alternative form of access and have been associated with the sale to patients of counterfeit/falsified/fraudulent/substandard drugs. We wished to determine if permanently recalled and significantly restricted drugs were illegally marketed for sale online. The study was conducted in two phases with two objectives. The first phase attempted to identify drugs subject to permanent recall in certain major pharmaceutical markets as well as those listed as recalled or significantly restricted by the United Nations. We also examined the market authorization status of identified drugs in China and India. The second phase used structured searches on the Internet to determine if identified drugs were marketed for sale online. The World Wide Web. After identification of permanently recalled and restricted drugs we conducted Internet searches for illegal "no prescription" marketing events. We assessed the form of marketing, whether a site offered direct-to-patient sale, use of social media marketing, and the site's compliance status with external monitoring bodies. Number of recalled drugs marketed as available for purchase on the Internet. We identified 16 class I equivalent permanently recalled or restricted drugs, 56.3 % (n = 9) of which maintained market authorization in either China or India. Half (n = 8) were marketed for sale online without a prescription direct-to-patient. Use of social media marketing was mixed, with only 18.8 % (n = 3) of recalled drugs having a presence on Facebook, though 50.0 % (n = 8) had content on Twitter. We also found the majority (68.8 %, n = 11) were available and marketed for sale by vendors on the wholesale/business-to-business website alibaba.com primarily as active pharmaceutical ingredient. Despite efforts in several countries to restrict access to these drugs or permanently remove

  2. Leachables and extractables handbook: safety evaluation, qualification, and best practices applied to inhalation drug products

    Ball, Douglas J

    2012-01-01

    ...). It discusses best practices for evaluation and management of leachables and extractables throughout the pharma product lifecycle by providing practical knowledge about how and why safety thresholds were developed...

  3. The feasibility and safety of high-intensity focused ultrasound combined with low-dose external beam radiotherapy as supplemental therapy for advanced prostate cancer following hormonal therapy.

    Wu, Rui-Yi; Wang, Guo-Min; Xu, Lei; Zhang, Bo-Heng; Xu, Ye-Qing; Zeng, Zhao-Chong; Chen, Bing

    2011-05-01

    The aim of this study was to investigate the feasibility and safety of high-intensity focused ultrasound (HIFU) combined with (+) low-dose external beam radiotherapy (LRT) as supplemental therapy for advanced prostate cancer (PCa) following hormonal therapy (HT). Our definition of HIFU+LRT refers to treating primary tumour lesions with HIFU in place of reduced field boost irradiation to the prostate, while retaining four-field box irradiation to the pelvis in conventional-dose external beam radiotherapy (CRT). We performed a prospective, controlled and non-randomized study on 120 patients with advanced PCa after HT who received HIFU, CRT, HIFU+LRT and HT alone, respectively. CT/MR imaging showed the primary tumours and pelvic lymph node metastases visibly shrank or even disappeared after HIFU+LRT treatment. There were significant differences among four groups with regard to overall survival (OS) and disease-specific survival (DSS) curves (P = 0.018 and 0.015). Further comparison between each pair of groups suggested that the long-term DSS of the HIFU+LRT group was higher than those of the other three groups, but there was no significant difference between the HIFU+LRT group and the CRT group. Multivariable Cox's proportional hazard model showed that both HIFU+LRT and CRT were independently associated with DSS (P = 0.001 and 0.035) and had protective effects with regard to the risk of death. Compared with CRT, HIFU+LRT significantly decreased incidences of radiation-related late gastrointestinal (GI) and genitourinary (GU) toxicity grade ≥ II. In conclusion, long-term survival of patients with advanced PCa benefited from strengthening local control of primary tumour and regional lymph node metastases after HT. As an alternative to CRT, HIFU+LRT showed good efficacy and better safety.

  4. Feasibility and safety of on table extubation after corrective surgical repair of tetralogy of Fallot in a developing country: A case series

    Mohammad Irfan Akhtar

    2015-01-01

    Full Text Available Fast-track extubation is an established safe practice in pediatric congenital heart disease (CHD surgical patients. On table extubation (OTE in acyanotic CHD surgical patients is well established with validated safety profile. This practice is not yet reported in tetralogy of Fallot (TOF cardiac surgical repair patients in developing countries. Evidence suggests that TOF total correction patients should be extubated early, as positive pressure ventilation has a negative impact on right ventricular function and the overall increase in post-TOF repair complications such as low cardiac output state and arrhythmias. The objective of the case series was to determine the safety and feasibility of OTE in elective TOF total correction cardiac surgical patients with an integrated team approach. To the best of our knowledge, this is the first reported case series. A total of 8 elective male and female TOF patients were included. Standard anesthetic, surgical and perfusion techniques were used in these procedures. All patients were extubated in the operating room safely without any complications with the exception of one patient who continued to bleed for 3 h of postextubation at 2-3 ml/kg/h which was managed with transfusion of fresh frozen plasma at 15 mL/kg, packed red blood cells 10 mL/kg and bolus of transamine at 20 mg/kg. Apart from better surgical and bypass techniques, the most important factor leading to successful OTE was an excellent analgesia. On the basis of the case series, it is suggested to extubate selected TOF cardiac surgery repair patients on table safely with integrated multidisciplinary approach.

  5. Feasibility, safety, and economic implications of whey-recovered water in cleaning-in-place systems: A case study on water conservation for the dairy industry.

    Meneses, Yulie E; Flores, Rolando A

    2016-05-01

    Water scarcity is threatening food security and business growth in the United States. In the dairy sector, most of the water is used in cleaning applications; therefore, any attempt to support water conservation in these processes will have a considerable effect on the water footprint of dairy products. This study demonstrates the viability for recovering good quality water from whey, a highly pollutant cheese-making by-product, to be reused in cleaning-in-place systems. The results obtained in this study indicate that by using a combined ultrafiltration and reverse osmosis system, 47% of water can be recovered. This system generates protein and lactose concentrates, by-products that once spray-dried fulfill commercial standards for protein and lactose powders. The physicochemical and microbiological quality of the recovered permeate was also analyzed, suggesting suitable properties to be reused in the cleaning-in-place system without affecting the quality and safety of the product manufactured on the cleaned equipment. A cost analysis was conducted for 3 cheese manufacturing levels, considering an annual production of 1, 20, and 225 million liters of whey. Results indicate the feasibility of this intervention in the dairy industry, generating revenues of $0.18, $3.05, and $33.4 million per year, respectively. The findings provide scientific evidence to promote the safety of reuse of reconditioned water in food processing plants, contributing to building a culture of water conservation and sustainable production throughout the food supply chain. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  6. EFFICACY AND SAFETY OF LIPID-LOWERING DRUGS IN PRIMARY AND SECONDARY PREVENTION OF CARDIOVASCULAR DISEASES IN THE ELDERLY

    E. A. Ushkalova

    2016-01-01

    Full Text Available Effect of hyperlipidemia on morbidity and mortality in elderly patients is considered. Authors also cover issues of efficacy and safety of lipid-lowering therapy in primary and secondary prevention of cardiovascular diseases in patients ≥80 years of age who are the most quickly growing group of population and have the highest cardiovascular risk. They stress the need to take into account polymorbidity and polypharmacy that increase the risk of adverse reactions due to the use of both statins and their drug-drug interactions, which requires an assessment of risk/benefit ratio. In addition, there is a need for development of reliable prognostic tools to predict relevant outcomes (e.g., stroke, decrease in functionality/independence, quality of life reduction and rationales for lipid-lowering therapy in the elderly and also their adherence to treatment.

  7. Biocompatible Polymer Nanoformulation To Improve the Release and Safety of a Drug Mimic Molecule Detectable via ICP-MS.

    Ferrari, Raffaele; Talamini, Laura; Violatto, Martina Bruna; Giangregorio, Paola; Sponchioni, Mattia; Morbidelli, Massimo; Salmona, Mario; Bigini, Paolo; Moscatelli, Davide

    2017-01-03

    Fluorescent poly(ε-caprolactone)-based nanoparticles (NPs) have been synthesized and successfully loaded with a titanium organometallic compound as a mimic of a water-insoluble drug. The nature of this nanovector enabled us to combine the quantification of the metal in tissues after systemic administration in healthy immunocompetent mice by inductively coupled plasma mass spectroscopy (ICP-MS) followed by the visualization of NPs in organ sections by confocal microscopy. This innovative method of nanodrug screening has enabled us to elucidate the crucial parameters of their kinetics. The organometallic compound is a good mimic of most anticancer drugs, and this approach is an interesting starting point to design the relevance of a broad range of nanoformulations in terms of safety and targeted delivery of the cargoes.

  8. Efficacy and Safety of Drug-Eluting Stents in the Real World: 8-Year Follow-Up

    Pellegrini, Denise Oliveira, E-mail: dennizmo@yahoo.com.br; Gomes, Vitor Osório; Lasevitch, Ricardo; Smidt, Luis; Azeredo, Marco Aurélio; Ledur, Priscila; Bodanese, Rodrigo; Sinnott, Leonardo; Moriguchi, Emílio; Caramori, Paulo [Hospital São Lucas PUC, Porto Alegre, RS (Brazil)

    2014-09-15

    Drug-eluting stents have been used in daily practice since 2002, with the clear advantages of reducing the risk of target vessel revascularization and an impressive reduction in restenosis rate by 50%-70%. However, the occurrence of a late thrombosis can compromise long-term results, particularly if the risks of this event were sustained. In this context, a registry of clinical cases gains special value. To evaluate the efficacy and safety of drug-eluting stents in the real world. We report on the clinical findings and 8-year follow-up parameters of all patients that underwent percutaneous coronary intervention with a drug-eluting stent from January 2002 to April 2007. Drug-eluting stents were used in accordance with the clinical and interventional cardiologist decision and availability of the stent. A total of 611 patients were included, and clinical follow-up of up to 8 years was obtained for 96.2% of the patients. Total mortality was 8.7% and nonfatal infarctions occurred in 4.3% of the cases. Target vessel revascularization occurred in 12.4% of the cases, and target lesion revascularization occurred in 8% of the cases. The rate of stent thrombosis was 2.1%. There were no new episodes of stent thrombosis after the fifth year of follow-up. Comparative subanalysis showed no outcome differences between the different types of stents used, including Cypher®, Taxus®, and Endeavor®. These findings indicate that drug-eluting stents remain safe and effective at very long-term follow-up. Patients in the 'real world' may benefit from drug-eluting stenting with excellent, long-term results.

  9. Patient safety: numerical skills and drug calculation abilities of nursing students and registered nurses.

    McMullan, Miriam; Jones, Ray; Lea, Susan

    2010-04-01

    This paper is a report of a correlational study of the relations of age, status, experience and drug calculation ability to numerical ability of nursing students and Registered Nurses. Competent numerical and drug calculation skills are essential for nurses as mistakes can put patients' lives at risk. A cross-sectional study was carried out in 2006 in one United Kingdom university. Validated numerical and drug calculation tests were given to 229 second year nursing students and 44 Registered Nurses attending a non-medical prescribing programme. The numeracy test was failed by 55% of students and 45% of Registered Nurses, while 92% of students and 89% of nurses failed the drug calculation test. Independent of status or experience, older participants (> or = 35 years) were statistically significantly more able to perform numerical calculations. There was no statistically significant difference between nursing students and Registered Nurses in their overall drug calculation ability, but nurses were statistically significantly more able than students to perform basic numerical calculations and calculations for solids, oral liquids and injections. Both nursing students and Registered Nurses were statistically significantly more able to perform calculations for solids, liquid oral and injections than calculations for drug percentages, drip and infusion rates. To prevent deskilling, Registered Nurses should continue to practise and refresh all the different types of drug calculations as often as possible with regular (self)-testing of their ability. Time should be set aside in curricula for nursing students to learn how to perform basic numerical and drug calculations. This learning should be reinforced through regular practice and assessment.

  10. Intraarterial reteplase and intravenous abciximab for treatment of acute ischemic stroke. A preliminary feasibility and safety study in a non-human primate model

    Qureshi, Adnan I.; Suri, M. Fareed K.; Ali, Zulfiqar; Ringer, Andrew J.; Boulos, Alan S.; Guterman, Lee R.; Hopkins, L. Nelson; Nakada, Marian T.; Alberico, Ronald A.; Martin, Lisa B.E.

    2005-01-01

    We performed a preliminary feasibility and safety study using intravenous (IV) administration of a platelet glycoprotein IIb/IIIa inhibitor (abciximab) in conjunction with intraarterial (IA) administration of a thrombolytic agent (reteplase) in a primate model of intracranial thrombosis. We introduced thrombus through superselective catheterization of the intracranial segment of the internal carotid artery in 16 primates. The animals were randomly assigned to receive IA reteplase and IV abciximab (n =4), IA reteplase and IV placebo (n =4), IA placebo and IV abciximab (n =4) or IA and IV placebo (n =4). Recanalization was assessed by serial angiography during the 6-h period after initiation of treatment. Postmortem magnetic resonance (MR) imaging was performed to determine the presence of cerebral infarction or intracranial hemorrhage. Partial or complete recanalization at 6 h after initiation of treatment (decrease of two or more points in pre-treatment angiographic occlusion grade) was observed in two animals treated with IA reteplase and IV abciximab, three animals treated with IA reteplase alone and one animal treated with IV abciximab alone. No improvement in perfusion was observed in animals that received IV and IA placebo. Cerebral infarction was demonstrated on postmortem MR imaging in three animals that received IA and IV placebo and in one animal each from the groups that received IA reteplase and IV abciximab or IV abciximab alone. One animal that received IV abciximab alone had a small intracerebral hemorrhage on MR imaging. (orig.)

  11. Neuroendoscopic Resection of Intraventricular Tumors and Cysts through a Working Channel with a Variable Aspiration Tissue Resector: A Feasibility and Safety Study

    Edjah Kweku-Ebura Nduom

    2013-01-01

    Full Text Available Pure neuroendoscopic resection of intraventricular lesions through a burr hole is limited by the instrumentation that can be used with a working channel endoscope. We describe a safety and feasibility study of a variable aspiration tissue resector, for the resection of a variety of intraventricular lesions. Our initial experience using the variable aspiration tissue resector involved 16 patients with a variety of intraventricular tumors or cysts. Nine patients (56% presented with obstructive hydrocephalus. Patient ages ranged from 20 to 88 years (mean 44.2. All patients were operated on through a frontal burr hole, using a working channel endoscope. A total of 4 tumors were resected in a gross total fashion and the remaining intraventricular lesions were subtotally resected. Fifteen of 16 patients had relief of their preoperative symptoms. The 9 patients who presented with obstructive hydrocephalus had restoration of cerebrospinal fluid flow though one required a ventriculoperitoneal shunt. Three patients required repeat endoscopic resections. Use of a variable aspiration tissue resector provides the ability to resect a variety of intraventricular lesions in a safe, controlled manner through a working channel endoscope. Larger intraventricular tumors continue to pose a challenge for complete removal of intraventricular lesions.

  12. Report to the Congress on the need for, and the feasibility of, establishing a security agency within the Office of Nuclear Material Safety and Safeguards

    1976-08-01

    In response to the Congressional mandate Section 204(b)-(2) (C) of the Energy Reorganization Act of 1974, the Director of the Office of Nuclear Material Safety and Safeguards, U.S. Nuclear Regulatory Commission (NRC) has assessed the need for and the feasibility of establishing a security agency within that office for the performance of safeguards functions. The study assessed guard force effectiveness, and addressed public policy, administrative and legal issues. The study concluded that creation of a special security force within NRC would not result in a higher degree of guard force effectiveness than can be achieved through the use of private guards who have been properly trained and certified. Disparate gun laws in various states, it concluded, restrict arms possessed by both private and federal guards and private and federal transportation guards would require legislation authorizing them to bear the necessary weapons to protect nuclear material in transit. The role of reaction forces was also addressed and it was concluded that primary reliance at fixed sites should be placed on onsite protection systems; for material in transit, on invulnerability of vehicles and containers and on guard forces accompanying shipments

  13. Safety and feasibility of thallium-201 myocardial SPECT with intravenous infusion of disodium adenosine triphosphate (ATP) in the diagnosis of coronary artery disease

    Pai, Moon Sun; Park, Chan H.; Yoon, Seok Nam; Kim, Won; Kim, Han Soo [College of Medicine, Ajou Univ., Suwon (Korea, Republic of)

    1998-08-01

    ATP (adenosine triphosphate) is a potent coronary vasodilator with a rapid onset of action and a very short half-life. Myocardial perfusion scintigraphy with intravenous ATP has not yet bee sufficiently proven in the diagnosis, follow-up, and risk stratification of coronary artery disease. The purpose of this study was to evaluate the safety, feasibility and diagnostic accuracy of pharmacologic stress thallium-102 myocardial SPECT using an intravenous ATP infusion in patients with suspected coronary artery disease. Thallium-201 myocardial SPECT in 319 patients with suspected coronary artery disease were performed after the infusion of ATP (0.08 mg/min for 6 min). The adverse effects were carefully monitored. Coronary angiography was also performed within 3 weeks. Although 76.5% of he patients had some adverse effects, they were transient, mild, and well tolerated. In all patients, the ATP infusion protocol was completed and only 2 patients required aminophylline. The adverse effects were dyspnea in 63%, headache in 31%, flushing in 21%, chest pain in 14% and abdominal discomfort in 5% of the patients. The sensitivity and specificity were 80% and 90% respectively. Thallium-201 myocardial SPECT after 6 min-infusion of ATP at a rate of 0.08 mg/kg/min is safe and has a diagnostic value in detecting coronary artery disease.

  14. Safety and feasibility of thallium-201 myocardial SPECT with intravenous infusion of disodium adenosine triphosphate (ATP) in the diagnosis of coronary artery disease

    Pai, Moon Sun; Park, Chan H.; Yoon, Seok Nam; Kim, Won; Kim, Han Soo

    1998-01-01

    ATP (adenosine triphosphate) is a potent coronary vasodilator with a rapid onset of action and a very short half-life. Myocardial perfusion scintigraphy with intravenous ATP has not yet bee sufficiently proven in the diagnosis, follow-up, and risk stratification of coronary artery disease. The purpose of this study was to evaluate the safety, feasibility and diagnostic accuracy of pharmacologic stress thallium-102 myocardial SPECT using an intravenous ATP infusion in patients with suspected coronary artery disease. Thallium-201 myocardial SPECT in 319 patients with suspected coronary artery disease were performed after the infusion of ATP (0.08 mg/min for 6 min). The adverse effects were carefully monitored. Coronary angiography was also performed within 3 weeks. Although 76.5% of he patients had some adverse effects, they were transient, mild, and well tolerated. In all patients, the ATP infusion protocol was completed and only 2 patients required aminophylline. The adverse effects were dyspnea in 63%, headache in 31%, flushing in 21%, chest pain in 14% and abdominal discomfort in 5% of the patients. The sensitivity and specificity were 80% and 90% respectively. Thallium-201 myocardial SPECT after 6 min-infusion of ATP at a rate of 0.08 mg/kg/min is safe and has a diagnostic value in detecting coronary artery disease

  15. A comparative analysis of drug safety withdrawals in the UK and the US (1971-1992): implications for current regulatory thinking and policy.

    Abraham, John; Davis, Courtney

    2005-09-01

    By going beyond individual case studies and solely quantitative surveys, this paper systematically examines why there were over twice as many new prescription drugs withdrawn from the market on grounds of safety in the UK as there were in the US between 1971 and 1992. Drawing on interviews with regulators, industry scientists and others involved, and on regulatory data never before accessed outside governments and companies, five key hypotheses which might explain this difference in drug safety withdrawals are analysed. These are: (1) simply because the UK approved more new drugs than the US; (2) because of an industrial corporate strategy to seek approval of 'less safe' drugs in the UK earlier; (3) because British regulators were more vigilant at spotting post-marketing safety problems than their US counterparts; (4) because the slowness of the US in approving new drugs enabled regulators there to learn from, and avoid, safety problems that had already emerged in the UK or European market; and (5) because more stringent regulation in the US meant that they approved fewer unsafe drugs on to the market in the first place. It is concluded that the main explanation for fewer drug safety withdrawals in the US is that the regulatory agency there applied more stringent pre-market review and/or standards, which took longer than UK regulatory checks, but prevented unsafe drugs marketed in the UK from entering the US market. Contrary to the claims frequently made by the pharmaceutical industry and regulatory agencies on both sides of the Atlantic, these results imply that it is likely that acceleration of regulatory review times in the US and the UK since the early 1990s is compromising drug safety.

  16. Drug safety in pregnancy: utopia or achievable prospect? Risk information, risk research and advocacy in Teratology Information Services.

    Schaefer, Christof

    2011-03-01

    Even though from preclinical testing to drug risk labeling, the situation with drugs in pregnancy has improved substantially since the thalidomide scandal, there is still an increasing need to provide healthcare professionals and patients with updated individualized risk information for clinical decision making. For the majority of drugs, clinical experience is still insufficient with respect to their safety in pregnancy. There is often uncertainty in how to interpret the available scientific data. Based on 20 years of experience with Teratology Information Services (TIS) cooperating in the European Network of Teratology Information Services (ENTIS) methods of risk interpretation, follow-up of exposed pregnancies through the consultation process and their evaluation is discussed. Vitamin K antagonists, isotretinoin and angiotensin (AT) II-receptor-antagonists are presented as examples of misinterpretation of drug risks and subjects of research based on observational clinical data recorded in TIS. As many TIS are poorly funded, advocacy is necessary by establishing contacts with decision makers in health politics and administration, informing them of the high return in terms of health outcomes and cost savings provided by TIS as reference institutions in clinical teratology. © 2011 The Author. Congenital Anomalies © 2011 Japanese Teratology Society.

  17. A Cost Analysis of Hospitalizations for Infections Related to Injection Drug Use at a County Safety-Net Hospital in Miami, Florida

    Tookes, Hansel; Diaz, Chanelle; Li, Hua; Khalid, Rafi; Doblecki-Lewis, Susanne

    2015-01-01

    Background Infections related to injection drug use are common. Harm reduction strategies such as syringe exchange programs and skin care clinics aim to prevent these infections in injection drug users (IDUs). Syringe exchange programs are currently prohibited by law in Florida. The goal of this study was to estimate the mortality and cost of injection drug use-related bacterial infections over a 12-month period to the county safety-net hospital in Miami, Florida. Additionally, the prevalence...

  18. Suicidality and risk of suicide--definition, drug safety concerns, and a necessary target for drug development: a brief report.

    Meyer, Roger E; Salzman, Carl; Youngstrom, Eric A; Clayton, Paula J; Goodwin, Frederick K; Mann, J John; Alphs, Larry D; Broich, Karl; Goodman, Wayne K; Greden, John F; Meltzer, Herbert Y; Normand, Sharon-Lise T; Posner, Kelly; Shaffer, David; Oquendo, Maria A; Stanley, Barbara; Trivedi, Madhukar H; Turecki, Gustavo; Beasley, Charles M; Beautrais, Annette L; Bridge, Jeffrey A; Brown, Gregory K; Revicki, Dennis A; Ryan, Neal D; Sheehan, David V

    2010-08-01

    disagreement at the conference have been noted in the text. The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's encouragement of standard definitions and definable expectations for investigators and industry sponsors. Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the requirement that all central nervous system clinical drug trials must include a Columbia Classification Algorithm of Suicide Assessment (C-CASA)-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed. Copyright 2010 Physicians Postgraduate Press, Inc.

  19. Suicidality and risk of suicide--definition, drug safety concerns, and a necessary target for drug development: a consensus statement.

    Meyer, Roger E; Salzman, Carl; Youngstrom, Eric A; Clayton, Paula J; Goodwin, Frederick K; Mann, J John; Alphs, Larry D; Broich, Karl; Goodman, Wayne K; Greden, John F; Meltzer, Herbert Y; Normand, Sharon-Lise T; Posner, Kelly; Shaffer, David; Oquendo, Maria A; Stanley, Barbara; Trivedi, Madhukar H; Turecki, Gustavo; Beasley, Charles M; Beautrais, Annette L; Bridge, Jeffrey A; Brown, Gregory K; Revicki, Dennis A; Ryan, Neal D; Sheehan, David V

    2010-08-01

    . Any areas of disagreement have been noted. The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's effort to promote standard definitions and definable expectations for investigators and industry sponsors by endorsing the terminology in the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to build upon its new authority to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk within informative large health care-related databases in the United States and abroad. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the current Agency requirement that all CNS clinical drug trials must include a C-CASA-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed, and they need to be included to enable premarket assessments of the risks and benefits of medications related to suicidal ideation, suicidal behavior, and suicide in such patients. Copyright 2010 Physicians Postgraduate Press, Inc.

  20. A New Concept of a Drug Delivery System with Improved Precision and Patient Safety Features

    Florian Thoma

    2014-12-01

    Full Text Available This paper presents a novel dosing concept for drug delivery based on a peristaltic piezo-electrically actuated micro membrane pump. The design of the silicon micropump itself is straight-forward, using two piezoelectrically actuated membrane valves as inlet and outlet, and a pump chamber with a piezoelectrically actuated pump membrane in-between. To achieve a precise dosing, this micropump is used to fill a metering unit placed at its outlet. In the final design this metering unit will be made from a piezoelectrically actuated inlet valve, a storage chamber with an elastic cover membrane and a piezoelectrically actuated outlet valve, which are connected in series. During a dosing cycle the metering unit is used to adjust the drug volume to be dispensed before delivery and to control the actually dispensed volume. To simulate the new drug delivery concept, a lumped parameter model has been developed to find the decisive design parameters. With the knowledge taken from the model a drug delivery system is designed that includes a silicon micro pump and, in a first step, a silicon chip with the storage chamber and two commercial microvalves as a metering unit. The lumped parameter model is capable to simulate the maximum flow, the frequency response created by the micropump, and also the delivered volume of the drug delivery system.

  1. Monitoring drug effectiveness in kala-azar in Bihar, India: cost and feasibility of periodic random surveys vs. a health service-based reporting system.

    Malaviya, P; Singh, R P; Singh, S P; Hasker, E; Ostyn, B; Shankar, R; Boelaert, M; Sundar, S

    2011-09-01

    In 2009, a random survey was conducted in Muzaffarpur district to document the clinical outcomes of visceral leishmaniasis patients (VL) treated by the public health care system in 2008, to assess the effectiveness of miltefosine against VL. We analysed the operational feasibility and cost of such periodic random surveys as compared with health facility-based routine monitoring. A random sample of 150 patients was drawn from registers kept at Primary Health Care centres. Patient records were examined, and the patients were located at their residence. Patients and physicians were interviewed with the help of two specifically designed questionnaires by a team of one supervisor, one physician and one field worker. Costs incurred during this survey were properly documented, and vehicle log books maintained for analysis. Hundred and 39 (76.7%) of the patients could be located. Eleven patients were not traceable. Per patient, follow-up cost was US$ 15.51 and on average 2.27 patients could be visited per team-day. Human resource involvement constituted 75% of the total cost whereas involvement of physician costs 51% of the total cost. A random survey to document clinical outcomes is costly and labour intensive but gives probably the most accurate information on drug effectiveness. A health service-based retrospective cohort reporting system modelled on the monitoring system developed by tuberculosis programmes could be a better alternative. Involvement of community health workers in such monitoring would offer the additional advantage of treatment supervision and support. © 2011 Blackwell Publishing Ltd.

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

    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.

  3. Contribution of industry funded post-marketing studies to drug safety: survey of notifications submitted to regulatory agencies

    Prugger, Christof; Doshi, Peter; Ostrowski, Kerstin; Witte, Thomas; Hüsgen, Dieter; Keil, Ulrich

    2017-01-01

    Objectives To investigate the practice of post-marketing studies in Germany during a three year period and to evaluate whether these trials meet the aims specified in the German Medicinal Products Act. Design Survey of notifications submitted to German regulatory agencies before post-marketing studies were carried out, 2008-10. Setting Notifications obtained through freedom of information requests to the three authorities responsible for registering post-marketing studies in Germany. Main outcome measures Descriptive statistics of post-marketing studies, including the products under study, intended number of patients, intended number of participating physicians, proposed remunerations, study plan and protocol, and availability of associated scientific publications and reports on adverse drug reactions. Results Information was obtained from 558 studies, with a median of 600 (mean 2331, range 2-75 000) patients and 63 (270, 0-7000) participating physicians per study. The median remuneration to physicians per patient was €200 (€441, €0-€7280) (£170, £0-£6200; $215, $0-$7820), with a total remuneration cost of more than €217m for 558 studies registered over the three year period. The median remuneration per participating physician per study was €2000 (mean €19 424), ranging from €0 to €2 080 000. There was a broad range of drugs and non-drug products, of which only a third represented recently approved drugs. In many notifications, data, information, and results were, by contract, strictly confidential and the sole property of the respective sponsor. No single adverse drug reaction report could be identified from any of the 558 post-marketing studies. Less than 1% of studies could be verified as published in scientific journals. Conclusions Post-marketing studies are not improving drug safety surveillance. Sample sizes are generally too small to allow the detection of rare adverse drug reactions, and many participating physicians are

  4. Suspected Lonely Mouse Syndrome as a Cage Effect in a Drug Safety Study.

    Ye, Xiaobu; Itzoe, MariaLisa; Sarabia-Estrada, Rachel; DeTolla, Louis; Tyler, Betty M; Guarnieri, Michael

    2018-01-01

    Studies have demonstrated that buprenorphine, a front line drug for veterinary analgesia, may alleviate symptoms of chronic pain. A cage side observation protocol was used to record behavioral signs in a mouse clinical trial of extended release buprenorphine. A retrospective review of the observations for signs of pain and stress revealed that mice given a fivefold overdose of buprenorphine (16.25 mg/kg) showed lethargy and facial signs associated with stress. However, similar signs were observed in the drug-free control mice as early as Day 3 of single-cage housing. This appears to be the first report of cage effects in a clinical trial for a veterinary drug.

  5. Suspected Lonely Mouse Syndrome as a Cage Effect in a Drug Safety Study

    Xiaobu Ye

    2018-01-01

    Full Text Available Studies have demonstrated that buprenorphine, a front line drug for veterinary analgesia, may alleviate symptoms of chronic pain. A cage side observation protocol was used to record behavioral signs in a mouse clinical trial of extended release buprenorphine. A retrospective review of the observations for signs of pain and stress revealed that mice given a fivefold overdose of buprenorphine (16.25 mg/kg showed lethargy and facial signs associated with stress. However, similar signs were observed in the drug-free control mice as early as Day 3 of single-cage housing. This appears to be the first report of cage effects in a clinical trial for a veterinary drug.

  6. Applications of Dynamic Clamp to Cardiac Arrhythmia Research: Role in Drug Target Discovery and Safety Pharmacology Testing

    Francis A. Ortega

    2018-01-01

    Full Text Available Dynamic clamp, a hybrid-computational-experimental technique that has been used to elucidate ionic mechanisms underlying cardiac electrophysiology, is emerging as a promising tool in the discovery of potential anti-arrhythmic targets and in pharmacological safety testing. Through the injection of computationally simulated conductances into isolated cardiomyocytes in a real-time continuous loop, dynamic clamp has greatly expanded the capabilities of patch clamp outside traditional static voltage and current protocols. Recent applications include fine manipulation of injected artificial conductances to identify promising drug targets in the prevention of arrhythmia and the direct testing of model-based hypotheses. Furthermore, dynamic clamp has been used to enhance existing experimental models by addressing their intrinsic limitations, which increased predictive power in identifying pro-arrhythmic pharmacological compounds. Here, we review the recent advances of the dynamic clamp technique in cardiac electrophysiology with a focus on its future role in the development of safety testing and discovery of anti-arrhythmic drugs.

  7. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y.

    2014-01-01

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  8. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y., E-mail: frank.hsieh@nextcea.com

    2014-09-15

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  9. Safety of antiretroviral drugs in pregnancy and breastfeeding for mother and child

    Newell, Marie-Louise; Bunders, Madeleine J.

    2013-01-01

    Purpose of reviewThe introduction of combination ART to prevent mother-to-child-transmission (MTCT) has substantially decreased MTCT rates. However, there are concerns regarding safety of ART exposure for the mother, pregnancy outcome and infant. Changing MTCT prevention guidelines, with expanded

  10. The role of electronic healthcare record databases in paediatric drug safety surveillance: A retrospective cohort study

    S. de Bie (Sandra); P.M. Coloma (Preciosa); C. Ferrajolo (Carmen); K.M.C. Verhamme (Katia); G. Trifirò (Gianluca); M.J. Schuemie (Martijn); S.M.J.M. Straus (Sabine); R. Gini (Rosa); R.M.C. Herings (Ron); G. Mazzaglia (Giampiero); G. Picelli (Gino); A. Ghirardi (Arianna); L. Pedersen (Lars); B.H.Ch. Stricker (Bruno); J. van der Lei (Johan); M.C.J.M. Sturkenboom (Miriam)

    2015-01-01

    textabstractAim Electronic healthcare record (EHR)-based surveillance systems are increasingly being developed to support early detection of safety signals. It is unknown what the power of such a system is for surveillance among children and adolescents. In this paper we provide estimates of the

  11. Double pharmacological challenge on repolarization opens new avenues for drug safety research

    Thomsen, Morten Bækgaard

    2007-01-01

    pointes (TdP) arrhythmia. Both the pharmaceutical industry and the regulatory bodies are neglecting the available proarrhythmia models. In vitro studies have suggested that combined pharmacological hits on repolarization will produce a superior substrate for in vivo proarrhythmia, compared to the single......-drug assessment. By using consecutive pharmacological challenges, a simple model is proposed, in which combinatorial pharmacology is employed to provoke TdP in the conscious dog. The pharmaceutical industry interested in evaluating the proarrhythmic potential of their present and future drugs now has a simple...

  12. The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity

    Amacher, David E.

    2010-01-01

    Biomarkers are biometric measurements that provide critical quantitative information about the biological condition of the animal or individual being tested. In drug safety studies, established toxicity biomarkers are used along with other conventional study data to determine dose-limiting organ toxicity, and to define species sensitivity for new chemical entities intended for possible use as human medicines. A continuing goal of drug safety scientists in the pharmaceutical industry is to discover and develop better trans-species biomarkers that can be used to determine target organ toxicities for preclinical species in short-term studies at dose levels that are some multiple of the intended human dose and again later in full development for monitoring clinical trials at lower therapeutic doses. Of particular value are early, predictive, noninvasive biomarkers that have in vitro, in vivo, and clinical transferability. Such translational biomarkers bridge animal testing used in preclinical science and human studies that are part of subsequent clinical testing. Although suitable for in vivo preclinical regulatory studies, conventional hepatic safety biomarkers are basically confirmatory markers because they signal organ toxicity after some pathological damage has occurred, and are therefore not well-suited for short-term, predictive screening assays early in the discovery-to-development progression of new chemical entities (NCEs) available in limited quantities. Efforts between regulatory agencies and the pharmaceutical industry are underway for the coordinated discovery, qualification, verification and validation of early predictive toxicity biomarkers. Early predictive safety biomarkers are those that are detectable and quantifiable prior to the onset of irreversible tissue injury and which are associated with a mechanism of action relevant to a specific type of potential hepatic injury. Potential drug toxicity biomarkers are typically endogenous macromolecules in

  13. Essential Aspects in Assessing the Safety Impact of Interactions between a Drug Product and Its Associated Manufacturing System.

    Jenke, Dennis

    2012-01-01

    An emerging trend in the biotechnology industry is the utilization of plastic components in manufacturing systems for the production of an active pharmaceutical ingredient (API) or a finished drug product (FDP). If the API, the FDP, or any solution used to generate them (for example, process streams such as media, buffers, and the like) come in contact with a plastic at any time during the manufacturing process, there is the potential that substances leached from the plastic may accumulate in the API or FDP, affecting safety and/or efficacy. In this article the author develops a te