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Safety Assessment (safety + assessment)
Kinds of Safety Assessment Selected AbstractsEvaluation of a Non-Targeted "Omic" Approach in the Safety Assessment of Genetically Modified PlantsPLANT BIOLOGY, Issue 5 2006S. B. Metzdorff Abstract: Genetically modified plants must be approved before release in the European Union, and the approval is generally based upon a comparison of various characteristics between the transgenic plant and a conventional counterpart. As a case study, focusing on safety assessment of genetically modified plants, we here report the development and characterisation of six independently transformed Arabidopsis thaliana lines modified in the flavonoid biosynthesis. Analyses of integration events and comparative analysis for characterisation of the intended effects were performed by PCR, quantitative Real-time PCR, and High Performance Liquid Chromatography. Analysis by cDNA microarray was used as a non-targeted approach for the identification of potential unintended effects caused by the transformation. The results revealed that, although the transgenic lines possessed different types of integration events, no unintended effects were identified. However, we found that the majority of genes showing differential expression were identified as stress-related genes and that environmental conditions had a large impact on the expression of several genes, proteins, and metabolites. We suggest that the microarray approach has the potential to become a useful tool for screening of unintended effects, but state that it is crucial to have substantial information on the natural variation in traditional crops in order to be able to interpret "omics" data correctly within the framework of food safety assessment strategies of novel plant varieties, including genetically modified plant varieties. [source] Preclinical Safety Assessment: In vitro , in vivo TestingBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2000Flemming Højelse The Safety Assessment of the results with respect to predictability for humans is discussed, as well as new tests under validation. Suggestions for changes in the future of Non-Clinical Safety tests are mentioned. [source] Peginterferon alpha-2b plus ribavirin vs interferon alpha-2b plus ribavirin for chronic hepatitis C in HIV-coinfected patientsJOURNAL OF VIRAL HEPATITIS, Issue 4 2007M. Crespo Summary., Treatment of chronic hepatitis C in human immunodeficiency virus (HIV)-infected patients is associated with low response rates and high incidence of side effects. One hundred twenty-one hepatitis C virus (HCV),HIV-coinfected patients were randomized to receive interferon alpha-2b (3 MU thrice weekly; n = 61) or peginterferon alpha-2b (1.5 ,g/kg/week; n = 60), plus ribavirin (800 mg daily), for 24 (genotype 2 or 3) or 48 weeks (genotype 1 or 4). We assessed early virological response at 4, 8 and 12 weeks to predict sustained virological response (SVR). Safety assessment included frequent blood lactate measurement and relative quantitation of mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells. In intention-to-treat analysis, the SVR rate was higher in the peginterferon group (55%vs 26%; P = 0.002). The difference for HCV genotypes 1 and 4 was 45%vs 14% (P = 0.009) and 50%vs 27% (P = 0.387), respectively, and for genotype 2 or 3, 71%vs 43% (P = 0.12) Viral response at 4, 8 and 12 weeks of treatment was highly predictive of SVR. Among genotype 3 patients, 17 of 20 (85%) whose HCV RNA was already undetectable at 4 weeks had an SVR after 24 weeks of treatment. Hyperlactataemia occurred in 22 patients and was clinically significant in six, two of whom died. mtDNA decreased significantly 4,12 weeks after the start of treatment in patients developing clinically significant hyperlactataemia. Peginterferon alpha-2b plus ribavirin was more effective than interferon alpha-2b plus ribavirin in HIV-coinfected patients. Frequent monitoring of virological response may be very helpful to optimize treatment compliance, to tailor treatment duration and to minimize side effects. [source] Safety and tolerability of duloxetine in the treatment of major depressive disorder: analysis of pooled data from eight placebo-controlled clinical trialsHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2005James I. Hudson Abstract Objective To examine the safety and tolerability of the antidepressant duloxetine across multiple studies for major depressive disorder (MDD). Method Safety data were integrated from the acute phases of eight double-blind, placebo-controlled trials in which patients were randomized to duloxetine (40,120,mg/d; n,=,1139) or placebo (n,=,777) for up to 9 weeks. This data set included all acute-phase clinical trials that formed the basis of the New Drug Application (United States) or European Union submission package for duloxetine in the treatment of MDD. Two studies included continuation phases in which acute treatment responders received duloxetine or placebo for an additional 26 weeks. Safety assessments included serious adverse event reports, rates of discontinuation, spontaneously reported treatment-emergent adverse events, changes in vital signs and laboratory values, and electrocardiograms. Results The rates of serious adverse events for duloxetine- and placebo-treated patients were 0.3% and 0.6%, respectively (p,=,0.282). Adverse events led to discontinuation in 9.7% of duloxetine-treated patients, compared with 4.2% of patients receiving placebo (p,<,0.001). Treatment-emergent adverse events with an incidence for duloxetine ,,5.0% and significantly greater than placebo were nausea, dry mouth, constipation, insomnia, dizziness, fatigue, somnolence, increased sweating and decreased appetite. Mean changes in blood pressure and heart rate were small, and the incidence of increases above normal ranges was low. Duloxetine-treated patients had a mean decrease in weight of 0.5,kg compared with an increase of 0.2,kg for patients receiving placebo (p,<,0.001). No significant differences were found between duloxetine and placebo in the incidence of potentially clinically significant laboratory values at anytime while on treatment. Conclusion These results are consistent with those obtained previously from smaller pooled data sets, and suggest that duloxetine is safe and well tolerated in patients with MDD. Copyright © 2005 John Wiley & Sons, Ltd. [source] Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled studyBIPOLAR DISORDERS, Issue 7 2009Magali Haas Objectives:, To evaluate the efficacy, safety, and tolerability of risperidone monotherapy for the treatment of an acute mixed or manic episode in children and adolescents with bipolar I disorder. Methods:, This randomized, placebo-controlled, double-blind, 3-arm study (N = 169) included children and adolescents (ages 10,17 years) with a DSM-IV diagnosis of bipolar I disorder, experiencing a manic or mixed episode. Study participants were randomized to placebo (n = 58), risperidone 0.5,2.5 mg/day (n = 50), or risperidone 3,6 mg/day (n = 61) for 3 weeks. The primary efficacy measure was change in Young Mania Rating Scale (YMRS) total score from baseline to end point. Safety assessments included adverse event (AE) monitoring and scores on extrapyramidal symptom rating scales. Results:, Improvement in mean YMRS total score was significantly greater in risperidone-treated subjects than in placebo-treated subjects [mean change (SD) ,9.1 (11.0) for placebo; ,18.5 (9.7) for risperidone 0.5,2.5 mg (p < 0.001); ,16.5 (10.3) for risperidone 3,6 mg (p < 0.001)]. The most common risperidone-associated AEs were somnolence, headache, and fatigue. Mean (SD) weight gain was 0.7 (1.9) kg, 1.9 (1.7) kg, and 1.4 (2.4) kg in the placebo, risperidone 0.5,2.5 mg, and risperidone 3,6 mg groups, respectively, during this 3-week study. Conclusions:, At daily doses of 0.5,2.5 mg and 3,6 mg, risperidone was effective and well tolerated in children and adolescents experiencing acute manic or mixed episodes of bipolar I disorder. Results indicate that risperidone 0.5,2.5 mg has a better benefit,risk profile than risperidone 3,6 mg. [source] Risperidone in the treatment of disruptive behavioural symptoms in children with autistic and other pervasive developmental disordersCHILD: CARE, HEALTH AND DEVELOPMENT, Issue 2 2005Richard ReadingArticle first published online: 16 FEB 200 Risperidone in the treatment of disruptive behavioural symptoms in children with autistic and other pervasive developmental disorders . SheaS, TurgayA, CarrollA, SchulzM, OrlikH, SmithI & DunbarF. ( 2004 ) Pediatrics , 114 , e634 , e641 . Objective To investigate the efficacy and safety of risperidone for the treatment of disruptive behavioural symptoms in children with autism and other pervasive developmental disorders (PDD). Methods In this 8-week, randomized, double-blinded, placebo-controlled trial, risperidone/placebo solution (0.01,0.06 mg/kg/day) was administered to 79 children who were aged 5,12 years and had PDD. Behavioural symptoms were assessed using the Aberrant Behaviour Checklist (ABC), Nisonger Child Behaviour Rating Form and Clinical Global Impression-Change. Safety assessments included vital signs, electrocardiogram, extrapyramidal symptoms, adverse events and laboratory tests. Results Subjects who were taking risperidone (mean dosage: 0.04 mg/kg/day; 1.17 mg/day) experienced a significantly greater mean decrease on the irritability subscale of the ABC (primary endpoint) compared with those who were taking placebo. By study endpoint, risperidone-treated subjects exhibited a 64% improvement over baseline in the irritability score almost double that of placebo-treated subjects (31%). Risperidone-treated subjects also exhibited significantly greater decreases on the other four subscales of the ABC; on the conduct problem, insecure/anxious, hyperactive and overly sensitive subscales of the Nisonger Child Behaviour Rating Form (parent version); and on the Visual Analog Scale of the most troublesome symptom. More risperidone-treated subjects (87%) showed global improvement in their condition compared with the placebo group (40%). Somnolence, the most frequently reported adverse event, was noted in 72.5% vs. 7.7% of subjects (risperidone vs. placebo) and seemed manageable with dose/dose-schedule modification. Risperidone-treated subjects experienced statistically significantly greater increases in weight (2.7 vs. 1.0 kg), pulse rate and systolic blood pressure. Extrapyramidal symptoms scores were comparable between groups. Conclusions Risperidone was well-tolerated and efficacious in treating behavioural symptoms associated with PDD in children. [source] Horizontal Roadway Curvature Computation Algorithm Using Vision TechnologyCOMPUTER-AIDED CIVIL AND INFRASTRUCTURE ENGINEERING, Issue 2 2010Yichang (James) Tsai However, collecting such data is time-consuming, costly, and dangerous using traditional, manual surveying methods. It is especially difficult to perform such manual measurement when roadways have high traffic volumes. Thus, it would be valuable for transportation agencies if roadway curvature data could be computed from photographic images taken using low-cost digital cameras. This is the first article that develops an algorithm using emerging vision technology to acquire horizontal roadway curvature data from roadway images to perform roadway safety assessment. The proposed algorithm consists of four steps: (1) curve edges image processing, (2) mapping edge positions from an image domain to the real-world domain, (3) calibrating camera parameters, and (4) calculating the curve radius and center from curve points. The proposed algorithm was tested on roadways having various levels of curves and using different image sources to demonstrate its capability. The ground truth curvatures for two cases were also collected to evaluate the error of the proposed algorithm. The test results are very promising, and the computed curvatures are especially accurate for curves of small radii (less than 66 m/200 ft) with less than 1.0% relative errors with respect to the ground truth data. The proposed algorithm can be used as an alternative method that complements the traditional measurement methods used by state DOTs to collect roadway curvature data. [source] Are we reaching the limits or our ability to detect skin effects with our current testing and measuring methods for consumer products?CONTACT DERMATITIS, Issue 6 2005Miranda A. Farage Testing for potential adverse skin effects is a key part of both the overall safety assessment for many consumer products and the evaluation of potential product improvements in mildness. Whilst modern tissue and paper products (i.e. facial tissues, catamenial products, baby wipes and baby and adult diapers) are inherently very mild to skin, current test methodology may not be robust enough to evaluate future improvements in such products. This article provides a commentary on several technologies we have been exploring to improve the sensitivity of test methods for tissue and paper products. The focus has been on three approaches: (i) further exaggerating exposure conditions using novel approaches to sample application, (ii) increasing the sensitivity of the manner in which we score for irritant effects, either visually or via instrumentation and (iii) quantitatively measuring additional endpoints, i.e. subjective sensory effects. [source] A strategy to reduce the numbers of fish used in acute ecotoxicity testing of pharmaceuticalsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2003Thomas H. Hutchinson Abstract The pharmaceutical industry gives high priority to animal welfare in the process of drug discovery and safety assessment. In the context of environmental assessments of active pharmaceutical ingredients (APIs), existing U.S. Food and Drug Administration and draft European regulations may require testing of APIs for acute ecotoxicity to algae, daphnids, and fish (base-set ecotoxicity data used to derive the predicted no-effect concentration [PNECwater] from the most sensitive of three species). Subject to regulatory approval, it is proposed that testing can be moved from fish median lethal concentration (LC50) testing (typically using ,42 fish/API) to acute threshold tests using fewer fish (typically 10 fish/API). To support this strategy, we have collated base-set ecotoxicity data from regulatory studies of 91 APIs (names coded for commercial reasons). For 73 of the 91 APIs, the algal median effect concentration (EC50) and daphnid EC50 values were lower than or equal to the fish LC50 data. Thus, for approximately 80% of these APIs, algal and daphnid acute EC50 data could have been used in the absence offish LC50 data to derive PNECwater values. For the other 18 APIs, use of an acute threshold test with a step-down factor of 3.2 is predicted to give comparable PNECwater outcomes. Based on this preliminary scenario of 91 APIs, this approach is predicted to reduce the total number offish used from 3,822 to 1,025 (,73%). The present study, although preliminary, suggests that the current regulatory requirement for fish LC50 data regarding APIs should be succeeded by fish acute threshold (step-down) test data, thereby achieving significant animal welfare benefits with no loss of data for PNECwater estimates. [source] Beneficial lactobacilli in food and feed: long-term use, biodiversity and proposals for specific and realistic safety assessmentsFEMS MICROBIOLOGY REVIEWS, Issue 4 2006Marion Bernardeau Abstract Lactobacilli have played a crucial role in the production of fermented products for millennia. Their probiotic effects have recently been studied and used in new products. Isolated cases of lactobacillemia have been reported in at-risk populations, but lactobacilli present an essentially negligible biological risk. We analyzed the current European guidelines for safety assessment in food/feed and conclude that they are not relevant for the Lactobacillus genus. We propose new specific guidelines, beginning by granting a ,long-standing presumption of safety' status to Lactobacillus genus based on its long history of safe use. Then, based on the available body of knowledge and intended use, only such tests as are useful will be necessary before attributing ,qualified presumption of safety' status. [source] New data for sandwich panels on the correlation between the SBI test method and the room corner reference scenarioFIRE AND MATERIALS, Issue 1 2005Jesper Axelsson Abstract Assessment of the fire behaviour of sandwich panels is continuously under discussion. The fire behaviour of these panels is a combination of material characteristics such as the core material and mechanical behaviour of the panels such as joints, dilations etc. The use of small or intermediate scale tests can be questioned for such types of products. Within the proposed European product standard for sandwich panels (prEN 14509) the intermediate scale test method SBI (EN 13823) has been suggested as the fire test method to certify panels. The standard does, however, use quite an artificial mounting procedure, which does not fully reflect the end-use conditions of the panels. In a previous research project conducted by Nordtest it was shown that the correlation between the SBI test method and both the ISO 9705 and ISO 13784 part 1 was insufficient. The test data produced for the SBI test method, however, did not use the above mentioned mounting technique. In this article new data for a number of products are added to the database using the mounting procedure of the product standard. The data are compared with the previous data and show that the mounting method of the product standard results in slightly more severe conditions but that there are still discrepancies with the full-scale test results. The data also show an unacceptable level of repeatability due to the fact that small dilations result in a wide variation of classification result. The new data together with the old data show once more that it is dangerous to make a fire safety assessment of a sandwich panel based on small or intermediate scale tests. Copyright © 2004 John Wiley & Sons, Ltd. [source] Safety pharmacology in the nonclinical assessment of new medicinal products: definition, place, interest and difficultiesFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2002Jean-Roger Claude Until the year 2000 there was no internationally-accepted definition for the terms used in nonclinical pharmacology (primary, secondary pharmacodynamics, discovery, safety pharmacology, etc). Now, after ICH5 (San Diego, November 2000), a harmonisation of the nomenclature is adopted: safety pharmacology is defined as the studies that investigate the potential undesirable pharmacodynamic effects of a medicinal product on physiological functions in relationship to exposure. Consequently, safety pharmacology studies are a part of the safety assessment for a new product, in the same way than toxicological studies, and a basic battery of tests (core battery) has to be conducted prior to the first administration to humans. Safety pharmacology studies are of peculiar interest: they show a good predictive potential for humans, they do not require a large number of laboratory animals, long-term studies, large amount of products and they are more dynamic and more flexible than toxicological studies. Nevertheless, many difficulties occur for the implementation in industry, related to practical and/or scientific problems: location of the studies, routine activity for the pharmacologists, sometimes difficulties in the relationship between toxicologists and pharmacologists, adaptation to the GLP requirements, elaboration of an early relevant scientific programme, necessity to go to contract-labs or to academic research for unusual or for up to date methods, etc. To conclude, a retrospective timetable of the regulatory evolution for the last 10 years will be provided, as an illustration of the worldwide progress in the concept of `harmonisation' for the assessment of new medicinal products. [source] Development of the DYNA3D simulation code with automated fracture procedure for brick elementsINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 14 2003Ala Tabiei Abstract Numerical simulation of cracked structures is an important aspect in structural safety assessment. In recent years, there has been an increasing rate of development of numerical codes for modelling fracture procedure. The subject of this investigation is implementing automated fracture models in the DYNA3D non-linear explicit finite element code to simulate pseudo 3D crack growth procedure. The implemented models have the capabilities of simulating automatic crack propagation without user intervention. The implementation is carried on solid elements. The methodology of implementing fracture models is described. An element deletion-and-replacement remeshing procedure is proposed for updating the explicit geometric description of evolving cracks. Fracture parameters such as stress intensity factors, energy release rates and crack tip opening angle are evaluated. The maximum circumferential stress criterion is used to predict the direction of crack advancement. Seven crack problems are presented to verify the effectiveness of the methodology. Mesh sensitivity and loading rate effects are studied in the validation of the presented procedure. Copyright © 2003 John Wiley & Sons, Ltd. [source] Kenosha County Falls Prevention Study: A Randomized, Controlled Trial of an Intermediate-Intensity, Community-Based Multifactorial Falls InterventionJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 4 2007Jane E. Mahoney MD OBJECTIVES: To decrease the rate of falls in high-risk community-dwelling older adults. DESIGN: Randomized, controlled trial. SETTING: Community-based. PARTICIPANTS: Three hundred forty-nine adults aged 65 and older with two falls in the previous year or one fall in the previous 2 years with injury or balance problems. INTERVENTION: Subjects received two in-home visits from a trained nurse or physical therapist who assessed falls risk factors using an algorithm. The intervention consisted of recommendations to the subject and their primary physician, referrals to physical therapy and other providers, 11 monthly telephone calls, and a balance exercise plan. Control subjects received a home safety assessment. MEASUREMENTS: The primary outcome was rate of falls per year in the community. Secondary outcomes included all-cause hospitalizations and nursing home admissions per year. RESULTS: There was no difference in rate of falls between the intervention and control groups (rate ratio (RR)=0.81, P=.27). Nursing home days were fewer in the intervention group (10.3 vs 20.5 days, P=.04). Intervention subjects with a Mini-Mental State Examination (MMSE) score of 27 or less had a lower rate of falls (RR=0.55; P=.05) and, if they lived with someone, had fewer hospitalizations (RR=0.44, P=.05), nursing home admissions (RR=0.15, P=.003), and nursing home days (7.5 vs 58.2, P=.008). CONCLUSION: This multifactorial intervention did not decrease falls in at-risk community-living adults but did decrease nursing home utilization. There was evidence of efficacy in the subgroup who had an MMSE score of 27 or less and lived with a caregiver, but validation is required. [source] A Randomized, Controlled Trial of Fall Prevention Programs and Quality of Life in Older FallersJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 4 2007Mau-Roung Lin PhD OBJECTIVES: To compare the effects of three fall-prevention programs (education (ED), home safety assessment and modification (HSAM), and exercise training (ET)) on quality of life (QOL), functional balance and gait, activities of daily living (ADLs), fear of falling, and depression in adults aged 65 and older. DESIGN: A 4-month randomized trial. SETTING: Randomized, controlled trial. PARTICIPANTS: One hundred fifty participants who had experienced a recent fall. MEASUREMENTS: QOL was assessed according to the brief version of the World Health Organization Quality of Life instrument (WHOQOL-BREF), functional balance and gait according to functional reach and Tinetti balance and gait, ADLs according to the Older Americans Resources and Services questionnaire, fear of falling according to a visual analog scale, and depression level according to the Geriatric Depression Scale. RESULTS: The score changes for the ET group were 2.1 points greater on the physical domain (95% confidence interval (CI)=,1.2,5.3), 3.8 points greater on the psychological domain (95% CI=0.7,7.0), and for the WHOQOL-BREF, 3.4 points greater on the social domain (95% CI=0.7,6.1) and 3.2 points greater on the environmental domain (95% CI=0.6,5.7) than for the ED group. The score change for each domain of the WHOQOL-BREF for the HSAM group was greater than that for the ED group, although these results were not statistically significant. The ET group also had greater improvements in functional reach, Tinetti balance and gait, and fear of falling than the ED group. CONCLUSION: The QOL outcome supports the superiority of ET over the other two interventions in older people who have recently fallen. This finding also parallels those gathered from the functional measures. [source] Drug substances presented as sulfonic acid salts: overview of utility, safety and regulationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2009David P. Elder Abstract Objectives Controlling genotoxic impurities represents a significant challenge to both industry and regulators. The potential for formation of genotoxic short-chain alkyl esters of sulfonic acids during synthesis of sulfonic acid salts is a long-standing regulatory concern. This review provides a general overview of the utility of sulfonic acids as salt-forming moieties and discusses strategies for effectively minimizing the potential for alkyl sulfonate formation during the synthesis and processing of sulfonate salt active pharmaceutical ingredients. The potential implications of the recent establishment of a substantial human threshold dose for ethyl methanesulfonate for the safety assessment of alkyl sulfonates in general are also discussed. Key findings The formation of alkyl sulfonates requires highly acidic conditions, possibly combined with long reaction times and/or elevated temperatures, to generate significant amounts, and these conditions are most unlikely to be present in the synthesis of active pharmaceutical ingredient sulfonate salts. It is possible to design salt formation conditions, using a short-chain alcohol as solvent, to manufacture sulfonate salts that are essentially free of alkyl sulfonate impurities. Processes using non-acidic conditions such as ethanol recrystallization or wet granulation should not raise any concerns of alkyl sulfonate formation. Summary An understanding of the mechanism of formation of alkyl sulfonates is critical in order to avoid restricting or over-controlling sulfonic acid salts, which have many technical advantages as pharmaceutical counterions. Recent regulatory acceptance of a human threshold limit dose of 2 mg/kg per day for ethyl methanesulfonate, indicating that its toxicological risks have previously been considerably overestimated, could signal the beginning of the end over safety concerns on alkyl sulfonate residues, thus removing a major constraint from the exploitation of sulfonic acid counterions. [source] The definition, source, manifestation and assessment of unintended effects in genetically modified plantsJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 14 2008Ping-Jian Deng Abstract At present, there is consensus among many relevant international agencies that unintended effects should be paid particular attention in the process of edible safety assessment of genetically modified plants (GMPs) and their products, especially in regard to some long-term and potential food safety issues. However, with respect to the current risk assessment of GMPs, serious dissension on the apprehension of unintended effects exists. The present paper interprets and systematically analyses this dissension in order to review development on the definition, source and manifestation of unintended effects in GMPs. First, differences in the various concepts of unintended effect are discussed and compared. Then the mechanisms whereby unintended effects may arise during GMP breeding are analysed and the main unexpected variation manifestations in GMPs are presented. With regard to the safety assessment of unintended effects in GMPs, the current evaluation strategy, detection methods and several assessment cases are expounded. In addition, the unique assessment standard for unintended effects in GMPs in China is outlined. Copyright © 2008 Society of Chemical Industry [source] Approaches in the safety evaluations of veterinary antimicrobial agents in food to determine the effects on the human intestinal microfloraJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2005C. E. CERNIGLIA The administration of antimicrobial agents to livestock creates potential for antibiotic residues to enter the food supply and be consumed by humans. Therefore, as a process of food animal drug registration, national regulatory agencies and international committees evaluate data regarding the chemical, microbiologic, pharmacokinetic, pharmacodynamic, pharmacologic, toxicologic, and antimicrobial properties of veterinary drugs to assess the safety of ingested antimicrobial residues to consumers. Currently, European, Australian and United States guidelines for veterinary drug registration require a safety assessment of microbiologic hazards from consumption of antimicrobial residues taking into account the potentially adverse effects on human intestinal microflora. The main concerns addressed are selection of resistant bacteria in the gastrointestinal tract and disruption of the colonization barrier of the resident intestinal microflora. Current requirements differ among national agencies. Efforts are ongoing internationally to review and harmonize approaches and test methods and protocols for application to these microbiologic safety evaluations of antimicrobial drug residues in food. This review describes the background to current regulatory approaches used in applying in vitro and in vivo methods to set a microbiologic acceptable daily intake for residues in food derived from animals treated with an antimicrobial agent. This paper also examines the current research needs to support these evaluations. [source] Evaluation of a Non-Targeted "Omic" Approach in the Safety Assessment of Genetically Modified PlantsPLANT BIOLOGY, Issue 5 2006S. B. Metzdorff Abstract: Genetically modified plants must be approved before release in the European Union, and the approval is generally based upon a comparison of various characteristics between the transgenic plant and a conventional counterpart. As a case study, focusing on safety assessment of genetically modified plants, we here report the development and characterisation of six independently transformed Arabidopsis thaliana lines modified in the flavonoid biosynthesis. Analyses of integration events and comparative analysis for characterisation of the intended effects were performed by PCR, quantitative Real-time PCR, and High Performance Liquid Chromatography. Analysis by cDNA microarray was used as a non-targeted approach for the identification of potential unintended effects caused by the transformation. The results revealed that, although the transgenic lines possessed different types of integration events, no unintended effects were identified. However, we found that the majority of genes showing differential expression were identified as stress-related genes and that environmental conditions had a large impact on the expression of several genes, proteins, and metabolites. We suggest that the microarray approach has the potential to become a useful tool for screening of unintended effects, but state that it is crucial to have substantial information on the natural variation in traditional crops in order to be able to interpret "omics" data correctly within the framework of food safety assessment strategies of novel plant varieties, including genetically modified plant varieties. [source] Glutathione- S -transferase pi as a model protein for the characterisation of chemically reactive metabolitesPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 2 2008Rosalind E. Jenkins Dr. Abstract Chemically reactive metabolites (CRMs) are thought to be responsible for a number of adverse drug reactions through modification of critical proteins. Methods that defined the chemistry of protein modification at an early stage would provide invaluable tools for drug safety assessment. Here, human GST pi (GSTP) was exploited as a model target protein to determine the chemical, biochemical and functional consequences of exposure to the hepatotoxic CRM of paracetamol (APAP), N -acetyl- p -benzoquinoneimine (NAPQI). Site-specific, dose-dependent modification of Cys47 in native and His-tagged GSTP was revealed by MS, and correlated with inhibition of glutathione (GSH) conjugating activity. In addition, the adaptation of iTRAQ labelling technology to define precisely the quantitative relationship between covalent modification and protein function is described. Multiple reaction monitoring (MRM)-MS of GSTP allowed high sensitivity detection of modified peptides at physiological levels of exposure. Finally, a bioengineered mutant cytochrome P450 with a broad spectrum of substrate specificities was used in an in vitro reaction system to bioactivate APAP: in this model, GSTP trapped the CRM and exhibited both reduced enzyme activity and site-specific modification of the protein. These studies provide the foundation for the development of novel test systems to predict the toxicological potential of CRMs produced by new therapeutic agents. [source] Prevention of Vomiting After Tonsillectomy in Children: Granisetron Versus RamosetronTHE LARYNGOSCOPE, Issue 2 2001Yoshitaka Fujii MD Abstract Objective/Hypothesis Granisetron, a selective 5-hydroxytryptamine type 3 receptor antagonist, is effective for the prevention of vomiting after tonsillectomy in children. Ramosetron (Nasea; Yamanouchi; Tokyo, Japan), another new antagonist of 5-hydroxytryptamione type 3 receptor, has more potent and longer-acting properties than granisetron (Kytril; Smith Kline Beecham, London, UK) against cisplatin-induced emesis. This study was undertaken to compare the efficacy and safety of granisetron and ramosetron for the prevention of vomiting after pediatric tonsillectomy. Study Design Prospective, randomized, double-blinded study. Methods Ninety pediatric patients, aged 4 to 10 years, received intravenously granisetron 40 ,g/kg or ramosetron 6 ,g/kg (n = 45 each) at the end of surgery. The same standard general anesthetic technique and postoperative analgesia were used throughout. Emetic episodes and safety assessment were performed during the first 24-hour period and the next 24-hour period after anesthesia. Results The rates of patients being emesis-free during the period from 0 to 24 hours after anesthesia were 89% with granisetron and 93% with ramosetron, respectively (P = .357); the corresponding rates during the period from 24 to 48 hours after anesthesia were 71% and 93%, respectively (P = .006). No clinically serious adverse events attributable to the study drugs were observed in any of the groups. Conclusion Ramosetron is a better antiemetic than granisetron for the long-term prevention of postoperative vomiting in children undergoing general anesthesia for tonsillectomy. [source] A STEPWISE CONFIDENCE INTERVAL PROCEDURE BASED ON AN ASYMMETRIC LOSS FUNCTION WITH APPLICATIONS TO TOXICOLOGICAL EVALUATIONAUSTRALIAN & NEW ZEALAND JOURNAL OF STATISTICS, Issue 1 2010Jian Tao Summary The purpose of toxicological studies is a safety assessment of compounds (e.g. pesticides, pharmaceuticals, industrial chemicals and food additives) at various dose levels. Because a mistaken declaration that a really non-equivalent dose is equivalent could have dangerous consequences, it is important to adopt reliable statistical methods that can properly control the family-wise error rate. We propose a new stepwise confidence interval procedure for toxicological evaluation based on an asymmetric loss function. The new procedure is shown to be reliable in the sense that the corresponding family-wise error rate is well controlled at or below the pre-specified nominal level. Our simulation results show that the new procedure is to be preferred over the classical confidence interval procedure and the stepwise procedure based on Welch's approximation in terms of practical equivalence/safety. The implementation and significance of the new procedure are illustrated with two real data sets: one from a reproductive toxicological study on Nitrofurazone in Swiss CD-1 mice, and the other from a toxicological study on Aconiazide. [source] Home safety assessment in the prevention of falls among older peopleAUSTRALIAN AND NEW ZEALAND JOURNAL OF PUBLIC HEALTH, Issue 5 2000Nancye Peel Objective:Home safety assessment was examined as part of a randomised trial of falls prevention interventions among older community dwellers. Method:Falls prevention strategies, including education and awareness-raising, exercise, home modifications and medical assessment, were trialled with 252 members of the National Seniors Association. Falls outcomes were monitored using a daily calendar diary during intervention and follow-up periods. Results:The home assessment group was significantly more likely to modify their home environment than the controls (p<0.0001). Participants, regardless of group allocation, reported a significant reduction in concern about falling (p<0.0001). During the intervention, the home assessment group had lower incidence rates for falls and injuries than the control group, although differences were not significant. The lowered rates were sustained post-intervention. Conclusions:While the effect on falls incidence of a home safety intervention on its own could not be demonstrated, other benefits, including improved confidence attributable to awareness of such falls prevention measures, were recorded. Implication:The null effects of home modifications on falls prevention in this study may indicate that the program is more appropriate for the frail aged. [source] Safety of Administration of Human Butyrylcholinesterase and its Conjugates with Soman or VX in RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2010Raymond F. Genovese Rats were trained on a multiple Fixed-Ratio 32, Extinction 30 sec. (FR32, Ext30) schedule of food reinforcement and then injected (i.m.) with Hu BChE (30 mg/kg), equivalent amounts of Hu BChE,soman conjugate (GDC), Hu BChE,VX conjugate, oxotremorine (OXO) (0.316 mg/kg) or vehicle (n = 8, each group). On the day of injection and on 10 subsequent daily sessions, performance was evaluated on the FR32, Ext30 schedule. Neither conjugates nor Hu BChE produced a performance deficit under the schedule. OXO produced a substantial decrease in responding on the day of administration, with complete recovery observed on subsequent sessions. None of the treatments affected circulating acetylcholinesterase (AChE) activity when evaluated 24,72 hr after injection. The dose of Hu BChE produced a 20,000-fold increase above baseline in circulating BChE activity. Pathological evaluation of organ systems approximately 2 weeks following administration of conjugates or Hu BChE alone did not show toxicity. Taken together, these results suggest that Hu BChE , nerve agent conjugates produced following bioscavenger protection against nerve agents soman and VX do not appear to be particularly toxic. These results add to the safety assessment of Hu BChE as a bioscavenger countermeasure against nerve agent exposure. [source] The Industry View on Long-Term Toxicology Testing in Drug Development of Human PharmaceuticalsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2000Herman Van Cauteren The 1990's have seen a general acceptance that studies with a maximal duration of 6 months in rodents are all that is required for adequate safety assessment of developmental pharmaceutical agents. However, controversy has arisen concerning the most appropriate duration for chronic toxicity testing in non-rodents. Initial suggestions that 6 months duration was sufficient have been countered by findings noted in 12-month studies that were not seen in shorter-term studies. Retrospective analysis of available data eventually lead to a subsequent ICH recommendation that studies of 9 months duration would be now acceptable. However, until recently the FDA position on this recommendation was unclear and an analysis of industry practices since the ICH recommendation was made in 1997 has shown that the 9-month guideline is not widely applied. Recent clarification by the FDA will probably result in a continued but limited use of this alternative. An industry view on the future of chronic toxicology testing in rodents and non-rodents is presented. [source] Multiplicity-Adjusted Inferences in Risk Assessment: Benchmark Analysis with Quantal Response DataBIOMETRICS, Issue 1 2005Daniela K. Nitcheva Summary A primary objective in quantitative risk or safety assessment is characterization of the severity and likelihood of an adverse effect caused by a chemical toxin or pharmaceutical agent. In many cases data are not available at low doses or low exposures to the agent, and inferences at those doses must be based on the high-dose data. A modern method for making low-dose inferences is known as benchmark analysis, where attention centers on the dose at which a fixed benchmark level of risk is achieved. Both upper confidence limits on the risk and lower confidence limits on the "benchmark dose" are of interest. In practice, a number of possible benchmark risks may be under study; if so, corrections must be applied to adjust the limits for multiplicity. In this short note, we discuss approaches for doing so with quantal response data. [source] High Pressure Processing , a Database of Kinetic InformationCHEMIE-INGENIEUR-TECHNIK (CIT), Issue 8 2008R. Buckow Abstract Hydrostatic high pressure technology is relatively new to food industry and is more and more considered as an alternative to traditional preservation methods like heat processing. The inactivation of bacteria, spores, viruses and enzymes has been demonstrated in numerous papers, and various schemes for modelling the experimental inactivation data have been suggested. Although there are similarities to heat inactivation kinetics it is generally agreed that the heat process safety assessment with its typical indicator organisms cannot simply be transferred to high pressure treatment. In this paper a database is introduced which aims at the comparison of published kinetic high pressure inactivation data by using suitable mathematical modelling tools. For the sake of clarity, the functional associations of pressure, temperature and exposure time is presented by means of pressure-temperature diagrams (pT -diagrams), which show pressure-temperature combinations yielding to a desired reaction (e.g. inactivation) rate constant. Thus, the database software was particularly designed to enable the user to call up pressure-temperature dependent function equations for a number of micro-organisms, enzymes and food constituents and to visualize them in pT -diagrams for predetermined treatment times or as kinetics under predetermined p - T conditions. In addition, the database also features a simple calculator tool which allows the user to make an entry in three of the four process conditions (pressure level, temperature level, inactivation level, dwell time) and calculate the remaining forth process condition. The database is accessible through the internet and is continuously updated on the basis of the most recent publications and own experimental data. [source] A prospective Italian survey on the safety of subcutaneous immunotherapy for respiratory allergyCLINICAL & EXPERIMENTAL ALLERGY, Issue 10 2009M. Schiappoli Summary Background Subcutaneous immunotherapy is effective for the treatment of respiratory allergy, and it is largely used in Italy, but no systematic safety assessment has been carried out so far. Objective To assess prospectively the safety of injection immunotherapy in a multicentre, real-life survey. Methods Eleven Italian allergy departments recorded the clinical characteristics of systemic reactions (SRs) due to immunotherapy. Vaccines were prescribed according to guidelines; only standardized depot extracts were used. SRs were graded according to the EAACI recommendations, and were classified as immediate or delayed. Results One thousand seven hundred and thirty-eight patients (847 males, age range 5,71) received immunotherapy from eight different manufacturers, for a total of 2038 courses (300 patients received two extracts). A total of 60 785 injections were given over a mean immunotherapy duration of 3 years. Overall, 95 reactions were observed in 57 patients (3.28%), corresponding to 4.7% of the courses and 1.56/1000 injections. Twenty-five patients experienced more than one adverse event. There were 34 grade 2, 60 grade 3 and one grade 4 reactions and no fatality. SRs occurred more frequently in patients with asthma than in patients with rhinitis alone (4.1% vs. 1.1%), and were equally distributed between the build-up and the maintenance phase. Ragweed and grass extracts caused significantly more side effects than other allergens. Conclusion In this large prospective study, the rate of SRs was low, thus confirming that injection immunotherapy has an acceptable risk/benefit ratio when prescribed and carried out according to recommendations. [source] Chapter 6: Maize with Increased Lysine (Lysine Maize,LY038)COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY, Issue 1 2008Article first published online: 30 JAN 200 ABSTRACT:, Data and information provided in this case study relate to a crop derived by modern biotechnology, in which a specific nutrient (lysine) has been increased in maize grain.Lysine maize is a feed ingredient with enhanced nutritional characteristics for poultry and swine and provides an alternative to adding supplemental lysine to diets for these animals. Lysine maize is in an advanced state of development; therefore, extensive unpublished data and information are presented to demonstrate that (1) Lysine maize,and the feeds and foods derived from it,are as safe as those derived from conventional maize,and (2) the increased lysine in Lysine maize grain produces the intended nutritional benefit for broiler chickens when compared to a diet containing conventional maize grain and a crystalline lysine supplement. These conclusions are based on a detailed molecular characterization of Lysine maize,a safety assessment of the introduced protein,a safety and nutritional assessment of the LY038 crop,and a comparison of the agronomic and phenotypic properties of maize hybrids with and without the Lysine maize trait. Although Lysine maize is a specialty crop for use in animal feed,its safety for both animals and humans must be demonstrated. Free lysine is significantly increased in Lysine maize by the introduction of the dapA gene (cordapA) from Corynebacterium glutamicum that encodes a form of dihydrodipicolinate synthase (cDHDPS) that is insensitive to lysine feedback inhibition.Analysis of lysine anabolic and catabolic pathways in maize identified 6 metabolites that might change as a consequence of the introduction of cDHDPS insensitive to lysine-feedback inhibition. The results of compositional analysis demonstrated that Lysine maize grain is comparable to conventional maize, with the exception of the intended increase in lysine and a corresponding increase in 2 products of lysine catabolism,saccha-ropine and -aminoadipic acid. Therefore, the safety and/or nutritional implication of these 3 compounds under the conditions of use were the focus of additional assessments and found to not present either a safety or nutritional problem. [source] A generalized frequency separation,strain energy damage function model for low cycle fatigue,creep life predictionFATIGUE & FRACTURE OF ENGINEERING MATERIALS AND STRUCTURES, Issue 4 2010S.-P. ZHU ABSTRACT Fatigue,creep interaction is a key factor for the failures of many engineering components and structures under high temperature and cyclic loading. These fatigue,creep life prediction issues are significant in selection, design and safety assessments of those components. Based on the frequency-modified Manson,Coffin equation and Ostergren's model, a new model for high temperature low cycle fatigue (HTLCF), a generalized frequency separation,strain energy damage function model is developed. The approach used in this model to reflect the effects of time-dependent damaging mechanisms on HTLCF life is different from those used in all the earlier models. A new strain energy damage function is used to reduce the difference between the approximate strain energy and real strain energy absorbed during the damage process. This proposed model can describe the effects of different time-dependent damaging mechanisms on HTLCF life more accurately than others. Comparing traditional frequency separation technique (FS) and strain energy frequency-modified approach (SEFS), the proposed model is widely applicable and more precise in predicting the life of fatigue,creep interaction. Experimental data from existing literature are used to demonstrate the feasibility and applicability of the proposed model. A good agreement is found between the predicted results and experimental data. [source] | |||||||||||||||||||||||||||||||||||||