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Safety Evaluation (safety + evaluation)
Kinds of Safety Evaluation Selected AbstractsMutagenicity and Safety Evaluation of Water Extract of,Coriander sativum,LeavesJOURNAL OF FOOD SCIENCE, Issue 1 2010Mariana Ramírez Reyes ABSTRACT:, Coriander has been used as a spice and medicinal plant for centuries. Several studies have described its biological properties and some reports have indicated its pharmacological actions in some human pathology. However, data on its toxicity and metabolism are limited or null, and no research has been conducted with mammalian cells. The purpose of this study was to evaluate the mutagenicity and safety of,Coriandrum sativum,extract. The mutagenic effects of,C. sativum,extract were evaluated by Ames test. Mutagenicity was present when the,C. sativum,extract was used in high concentrations in both tested strains (Salmonella typhimurium,TA97 and TA102). Our research showed that,C. sativum,extract reduced the cell survival of human cell lines (WRL-68 and 293Q cells) by inducing apoptosis and necrosis in the cases where extract concentration was the highest. The,C. sativum,extract altered the cell cycle; it increased the G1 phase of hepatic cells and reduced the G2+M phase in both cell lines in a dose-response manner. These results showed correlation with a reduction in the mitotic index. The extract also induced severe malformations during embryonic development. Exposure of chicken embryos to the,C. sativum,extract resulted in a dose-dependent increase of anomalies. Present results show that,C. sativum,extract reduced the axial skeleton and affected the neural tube, the somites, the cardiovascular structures, and the eye. According to the present results, the,C. sativum,aqueous extract cannot be considered safe. These results indicate that some significant adverse effects of,C. sativum,extract could be observed,in vivo. [source] Efficacy and Safety Evaluation of Ozonation to Degrade Aflatoxin in CornJOURNAL OF FOOD SCIENCE, Issue 8 2002A.D. Prudente Jr. ABSTRACT: This study determined the efficacy and safety of ozonation in degrading aflatoxin in corn. Ozonation (10 to 12 wt%) reduced aflatoxin levels by 92% and no reversion to the parent compound was observed. Ozonation had minimal effect on fatty acids of uncontaminated corn, but had significant effect on fatty acids of contaminated corn. Crude extracts showed no mutagenic potential in the Ames assay using TA98 and TA100. Clean-up using hexane increased their mutagenic potentials. Clean-up using Mycosep columns increased the mutagenic potentials 18 to 617%. Hexane extracts from ozone-treated contaminated corn had lower inhibitory effect. This suggested that a fat-soluble mutagen is being formed or natural inhibitors of mutagenicity are being destroyed. [source] Chronic Pharmacological and Safety Evaluation of HematideÔ, a PEGylated Peptidic Erythropoiesis-Stimulating Agent, in RodentsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2009Kathryn W. Woodburn To support the safety of long-term dosing of chronic renal failure patients, a comprehensive toxicology programme was implemented including rat subchronic and chronic studies. Rats were administered 0, 0.1, 1 and 10 mg/kg of Hematide every 3 weeks for 3 months via subcutaneous injection or for 6 months via intravenous injection. The dosing period was followed by a 6-week follow-up period. The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time- and dose-dependent. The pharmacology profiles were similar regardless of administration route. For example, for male rats at Day 90, subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl for 0.1, 1 and 10 mg Hematide/kg respectively, compared to 2.8, 5.7 and 7.4 g/dl increases for intravenous dosing. Histopathological changes were related to the prolonged severe polycythemia induced in normocythemic animals administered an erythropoiesis-stimulating agent. The findings included extramedullary haematopoiesis in the spleen and liver, bone marrow hypercellularity and organ congestion. Microscopic findings were reversible, demonstrating a return towards control findings within 6 weeks following cessation of dosing. Systemic exposures, based on both area under the curve (AUC) and maximum concentration (Cmax), were substantially greater for intravenous than subcutaneous administration. No Hematide-specific antibodies were detected. In conclusion, Hematide is a potent erythropoiesis-stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure. [source] Application of Genomics in Preclinical Drug Safety EvaluationBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2006Peter G. Lord Toxicologists have traditionally gathered pathological, morphological, chemical and biochemical information from in vivo studies of preclinical species in order to assess drug safety and to determine how new drugs can be safely administered to the human patient population. In recent years the emerging "-omics" technologies have been developed and integrated into preclinical studies in order to better assess drug safety by gaining information on the cellular and molecular events underlying adverse drug reactions. Genomics approaches in particular have become readily available and are being applied in several stages of drug development. The burgeoning literature on what has become known as "toxicogenomics" has for the most part highlighted successful applications of gene expression profiling in predictive toxicology, enabling decisions to be made on the developability of a compound early in the drug development process. It is also becoming apparent that toxicogenomic approaches are good starting points to develop experiments designed to gain a mechanistic insight into drug toxicities within and across species. Gene expression arrays permit the measurement of responses of essentially all the genes in the entire genome to be monitored, and knowledge of the function of the genes affected can identify the potential mechanisms to then be confirmed using conventional biochemical, toxicological and pathological approaches. As toxicologists put these technologies into practice they build up a knowledge base to better characterize toxicities at the molecular level and to make the search for much needed, novel biomarkers of toxicity more achievable. [source] Safety evaluation of sewage-sludge-derived fuels by comparison with other fuelsFIRE AND MATERIALS, Issue 4 2009Xin-Rui Li Abstract The utility of sewage sludge as a biomass fuel is taken as a new approach to recycle unwanted wastes as renewable energy and deal with global warming. However, safety caring of this new type of fuel is a premise before it is practically used in boilers. Thermal behaviors of four sludge-derived fuels which are under development were examined by several calorimeters (such as thermogravimetry/differential thermal analysis, C80 and thermal activity monitor) at temperature ramp and isothermal conditions. Heat generation at relatively low temperatures was observed. The corresponding spontaneous ignition was detected in an adiabatic spontaneous ignition tester at 80,C in some sludge species. Moreover, a certain amount of gaseous evolution was accompanied when the sludge fuels were stored at room temperature and at 60,C. Oxidation is mainly responsible for the heat and gas release from the sludge fuels. The hazards of the sewage sludge fuels were also compared with a bituminous coal and a refuse-derived fuel, which have the main feature of spontaneous ignition. Copyright © 2009 John Wiley & Sons, Ltd. [source] Impact of inter-individual differences in drug metabolism and pharmacokinetics on safety evaluationFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004J.L.C.M. Dorne Abstract Safety evaluation aims to assess the dose,response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is ,without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 100.5 (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment. [source] Safety evaluation of individual non-fried and fried sunflower oil, paraffin oil, jojoba oil and their binary mixtures on rat healthINTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 10 2008Radwan S. Farag Summary Sunflower, jojoba, paraffin oils and binary oil mixtures of sunflower, jojoba and sunflower,paraffin oils were continuously heated at 180 °C for 12 h. Aliquots of potato chips were fried in the aforementioned oil samples. Organoleptic tests were performed on fried chips and safety limits of the oil samples were measured by certain biochemical tests. Histopathological examinations of rat liver and kidney tissues were microscopically done. Organoleptic results for fried potato chips indicate that all types of chips obtained from heated oils were categorised good. Histopathological examinations indicate changes in rat tissues of liver and kidney paralleled the biochemical data. In general, the results suggest that paraffin oil alone and in mixtures with sunflower oil have to ban its use in frying processes. [source] 2265: Safety evaluation of intravitreal use of a beta2-agonist in rabbit eyesACTA OPHTHALMOLOGICA, Issue 2010J VAN CALSTER Purpose There is no known information on the use and safety of a long-acting beta-agonist, such as Clenbuterol when administered by intravitreal injection. Therefore, it is appropriate to perform this intravitreal injection in an animal model prior to start with a human experiment. The aim is to investigate the safety of an intravitreal injection of the beta2-agonist Clenbuterol in rabbit eyes. This study is in preparation of using of this molecule in human eyes. That trial will be a monocentric, academic (investigator driven) trial to investigate the safety and efficacy of an intravitreal beta2-agonist in patients with persistent subfoveal fluid after retinal detachment surgery. Approval of the ethics committee for the human trial has already been obtained, pending a re-evaluation after the results of the animal study will be known. Methods An intravitreal injection of 0,1 ml solution containing 0.08µg Clenbuterol or 0.1ml NaCl 0.9% was given in 10 eyes of 10 rabbits. The distribution occurred at random and was masked. A masked investigator examined both eyes after 1, 3 and 7 days (biomicroscopy, intraocular pression and ophthalmoscopy). After one week, the rabbits were sacrificed, the eyes enucleated and fixated for histopathological examination and electron microscopy by a masked investigator. Cell death was monitored by a DNase type I/II activity assay. Results There was no clinical or histopathological difference between the clenbuterol and the control group. Conclusion Clenbuterol is not toxic for the retina of rabbit eyes after intravitreal injection. It can be considered for the use in human eyes. Final approval of the ethics committee for the human trial is awaited. [source] Safety evaluation of intravitreal use of a beta2-agonist in rabbit eyesACTA OPHTHALMOLOGICA, Issue 2009J VAN CALSTER Purpose There is no known information on the use and safety of a long-acting beta-agonist, such as Clenbuterol when administered by intravitreal injection. Therefore, it is appropriate to perform this intravitreal injection in an animal model prior to start with a human experiment. The aim is to investigate the safety of an intravitreal injection of the beta2-agonist Clenbuterol in rabbit eyes. This study is in preparation of using of this molecule in human eyes. That trial will be a monocentric, academic (investigator driven) trial to investigate the safety and efficacy of an intravitreal beta2-agonist in patients with persistent subfoveal fluid after retinal detachment surgery. Approval of the ethics committee for the human trial has already been obtained, pending a re-evaluation after the results of the animal study will be known. Methods 5 rabbits will receive an injection of 0.1 ml solution containing 0.08µg Clenbuterol in one eye and an injection of 0.1ml NaCl 0.9% in the other eye. Since the volume of an adult rabbit eye is only one third of an adult human eye, the achieved concentration with be three time the concentration suggested for use in a human eye. [source] Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: A pilot studyINFLAMMATORY BOWEL DISEASES, Issue 2 2001Dr. Bruce E. Sands Abstract We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis. [source] Clinical efficacy and safety of oral terbinafine in fungal mycetomaINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 2 2006Bassirou N'Diaye MD Objectives, An open-label study was performed to assess the efficacy and safety of terbinafine in the treatment of eumycetoma. Methods, Single-center, open-label study, including 27 patients with signs and symptoms of eumycetoma which had developed within 5 years and was confirmed by mycological examination. The intention-to-treat population (n = 23) received 500 mg of terbinafine bid for 24,48 weeks. Efficacy evaluations included clinical signs and symptoms (e.g. sinuses open or closed, degree of tumefaction, and emission of grains either present or absent); mycological examinations from Week 24 onwards; and investigators' overall assessment of efficacy (cure, improved since baseline, unchanged since baseline, or deterioration since baseline). Safety evaluations included monitoring of adverse events, laboratory assessments, vital signs and physical examinations. Results, Good clinical improvement was seen in patients who completed the study (n = 20). Tumefaction was absent or improved in 80% of patients; sinuses were closed in 50% of patients, and grain emissions were absent in 65% of patients. Of the 16 patients who had repeat mycological assessment, four (25%) were mycologically cured. In the investigators' overall opinion at the end of the study, five (25%) were cured and 11 (55%) were clinically improved. The majority of adverse events reported were mild to moderate, and consistent with the known tolerability profile of terbinafine. Conclusion, High-dose terbinafine (1000 mg/day) is well tolerated and clinically effective in patients with eumycetoma, a difficult-to-treat subcutaneous mycoses. [source] Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled studyINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 1 2001Johannes Ring MD Background Chronic idiopathic urticaria (CIU) is the most common type of chronic urticaria, and pruritus is the most prominent symptom. Antihistamines are the first-line treatment for CIU. Sedation and anticholinergic adverse effects are often experienced with the first-generation antihistamines and there is a risk of cardiovascular adverse effects and drug interactions with some second-generation agents. Hence, new treatment options are needed. Desloratadine is a new, potent, nonsedating antihistamine that has an excellent cardiovascular safety profile. Methods This was a multicenter, randomized, double-blind, placebo-controlled study designed to determine the efficacy and safety of desloratadine in the treatment of moderate-to-severe CIU. A total of 190 patients, aged 12,79 years, with at least a 6-week history of CIU and who were currently experiencing a flare of at least moderate severity, were randomly assigned to therapy with desloratadine 5 mg or placebo once daily for 6 weeks. Twice daily, patients rated the severity of CIU symptoms (pruritus, number of hives, and size of largest hive), as well as the impact of CIU symptoms on sleep and daily activity. Patients and investigators jointly evaluated therapeutic response and overall condition. Safety evaluations included the incidence of treatment-emergent adverse events, discontinuations due to adverse events, and changes from baseline in vital signs, laboratory parameters, and ECG intervals. Results Desloratadine was superior to placebo in controlling pruritus and total symptoms after the first dose and maintained this superiority to the end of the study. Measures of sleep, daily activity, therapeutic response, and global CIU status were also significantly better with desloratadine after the first dose; these clinical benefits were also maintained throughout the 6-week study. No significant adverse events occured. Conclusions Desloratadine 5 mg daily is a safe and effective treatment for CIU with significant benefits within 24 h and maintained through the treatment period. [source] Safety characteristics of gadobenate dimeglumine: Clinical experience from intra- and interindividual comparison studies with gadopentetate dimeglumineJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 6 2006Frank G. Shellock PhD Abstract Purpose To evaluate the safety and tolerability of gadobenate dimeglumine (Gd-BOPTA) relative to that of gadopentetate dimeglumine (Gd-DTPA) in patients and volunteers undergoing MRI for various clinical conditions. Materials and Methods A total of 924 subjects were enrolled in 10 clinical trials in which Gd-BOPTA was compared with Gd-DTPA. Of these subjects, 893 were patients with known or suspected disease and 31 were healthy adult volunteers. Of the 893 patients, 174 were pediatric subjects (aged two days to 17 years) referred for MRI of the brain or spine. Safety evaluations included monitoring vital signs, laboratory values, and adverse events (AE). Results The rate of AE in adults was similar between the two agents (Gd-BOPTA: 51/561, 9.1%; Gd-DTPA: 33/472, 7.0%; P = 0.22). In parallel-group studies in which subjects were randomized to either agent, the rate of AE was 10.9% for Gd-BOPTA and 7.9% for Gd-DTPA (P = 0.21). In the subset of subjects receiving both agents in intraindividual crossover trials, the rate of AE was 8.0% for Gd-BOPTA and 8.5% for Gd-DTPA (P = 0.84). Results of other safety assessments (laboratory tests, vital signs) were similar for the two agents. Conclusion The safety profile of Gd-BOPTA is similar to Gd-DTPA in patients and volunteers. Both compounds are equally well-tolerated in patients with various disease states undergoing MRI. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc. [source] Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critiqueJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2009Professor K.D. Rainsford Abstract Objectives Chondroitin sulphate (CS) has attracted much interest over the past two decades or so as a biological agent for use in the relief of pain and joint symptoms in osteoarthritis. Earlier clinical investigations produced variable, if encouraging results. This variability was partly due to limitations on the study designs and the lack of availability of standardized CS. Recently, high quality and fully standardized CS (Condrosulf) has become available and its effects have been studied in large-scale osteoarthritis trials, which are discussed here. Key findings There is now evidence for symptom - and structure-modifying (radio-logically-observed) effects. These studies show that CS (a) has slow onset of response and that relief of pain may not be like that of the direct analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs), (b) there are indications of reduced need for intake of analgesics (e.g. NSAIDs) in patients taking CS, and (c) quality of life and cost-benefits may be associated with use of CS. Safety evaluations show that the incidence of adverse reactions is low. Pharmacokinetic studies indicate that although oral absorption is relatively fast CS has moderate oral bioavailability (15,24%) and that depolymerised and degraded CS that is evident after absorption, together with CS itself, may take some time to accumulate in target joints. The pharmacodynamic actions of CS indicate that it has anti-inflammatory effects that include multiple actions involving reduction of catabolic reactions and enhanced anabolic (proteoglycan) synthetic reactions in cartilage and may block osteoclast activation in bone. Further studies are required to (a) establish the effects of depolymerised and degraded CS on degradation of cartilage and bone in vitro, and (b) MRI and other investigations of the effects in osteoarthritis of long-term CS treatment. Summary The findings from this review show there may be potential value of CS in reducing the dependence on intake of NSAIDs and analgesics in patients with osteoarthritis, while at the same time having favourable safety. [source] Biphasic insulin aspart vs. human insulin in adolescents with type 1 diabetes on multiple daily insulin injectionsPEDIATRIC DIABETES, Issue 1 2006Henrik Mortensen Abstract:, The aim was to compare clinical efficacy and safety of two treatment regimens: biphasic insulin aspart (BIAsp) injected at all three meals plus neutral protamine Hagedorn (NPH) insulin at bedtime vs. a human insulin regimen, premixed human insulin at breakfast and soluble insulin at lunch and dinner and NPH at bedtime. A total of 167 adolescents (80 males and 87 females) with type 1 diabetes was included in the trial (multinational, randomized, open-label, and parallel group). Each subject received either of two treatment regimens for a 4-month period. BIAsp was injected immediately before main meals, human insulin products 30 min before meals, and NPH at night. Glycemic control was monitored by eight-point evaluations (after 6 and 16 wks) and hemoglobin A1c (HbA1c) (after 2, 6, and 16 wks). Safety evaluations included adverse events and incidence of hypoglycemic episodes. HbA1c (mean ± SD) after 4 months on BIAsp (9.39 ± 0.14) was not significantly different from that with human insulin (9.30 ± 0.15). The average postprandial glucose increment in the BIAsp group was about half the increment in the human insulin group; the difference not statistically significant. The body mass index (BMI) increased in both groups, but significantly (p = 0.005) less in the BIAsp group. However, in males on BIAsp, the BMI decreased compared with those on human insulin (p = 0.007). No significant group differences were found for the rate of hypoglycemic episodes. We concluded that the BIAsp regimen was associated with similar glycemic control and similar incidence of hypoglycemic episodes as human insulin. However, the BIAsp regimen caused a significantly smaller increase in BMI, particularly in males, compared with the human insulin regimen. [source] A short course of BG9588 (anti,CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritisARTHRITIS & RHEUMATISM, Issue 3 2003Dimitrios T. Boumpas Objective CD40,CD40 ligand (CD40L) interactions play a significant role in the production of autoantibodies and tissue injury in lupus nephritis. We performed an open-label, multiple-dose study to evaluate the safety, efficacy, and pharmacokinetics of BG9588, a humanized anti-CD40L antibody, in patients with proliferative lupus nephritis. The primary outcome measure was 50% reduction in proteinuria without worsening of renal function. Methods Twenty-eight patients with active proliferative lupus nephritis were scheduled to receive 20 mg/kg of BG9588 at biweekly intervals for the first 3 doses and at monthly intervals for 4 additional doses. Safety evaluations were performed on all patients. Eighteen patients receiving at least 3 doses were evaluated for efficacy. Results The study was terminated prematurely because of thromboembolic events occurring in patients in this and other BG9588 protocols (2 myocardial infarctions in this study). Of the 18 patients for whom efficacy could be evaluated, 2 had a 50% reduction in proteinuria without worsening of renal function. Mean reductions of 38.9% (P < 0.005), 50.1% (P < 0.005), and 25.3% (P < 0.05) in anti,double-stranded DNA (anti-dsDNA) antibody titers were observed at 1, 2, and 3 months, respectively, after the last treatment. There was a significant increase in serum C3 concentrations at 1 month after the last dose (P < 0.005), and hematuria disappeared in all 5 patients with significant hematuria at baseline. There were no statistically significant reductions in lymphocyte count or serum immunoglobulin, anticardiolipin antibody, or rubella IgG antibody concentrations after therapy. Conclusion A short course of BG9588 treatment in patients with proliferative lupus nephritis reduces anti-dsDNA antibodies, increases C3 concentrations, and decreases hematuria, suggesting that the drug has immunomodulatory action. Additional studies will be needed to evaluate its long-term effects. [source] Developmental toxicity of indium: Embryotoxicity and teratogenicity in experimental animalsCONGENITAL ANOMALIES, Issue 4 2008Mikio Nakajima ABSTRACT Indium, a precious metal classified in group 13 (IIIB) in the periodic table, has been used increasingly in the semiconductor industry. Because indium is a rare metal, technology for indium recycling from transparent conducting films for liquid crystal displays is desired, and its safety evaluation is becoming increasingly necessary. The developmental toxicity of indium in experimental animals was summarized. The intravenous or oral administration of indium to pregnant animals causes growth inhibition and the death of embryos in hamsters, rats, and mice. The intravenous administration of indium to pregnant animals causes embryonic or fetal malformation, mainly involving digit and tail deformities, in hamsters and rats. The oral administration of indium also induces fetal malformation in rats and rabbits, but requires higher doses. No teratogenicity has been observed in mice. Caudal hypoplasia, probably due to excessive cell loss by increased apoptosis in the tailbud, in the early postimplantation stage was considered to account for indium-induced tail malformation as a possible pathogenetic mechanism. Findings from in vitro experiments indicated that the embryotoxicity of indium could have direct effects on the conceptuses. Toxicokinetic studies showed that the embryonic exposure concentration was more critical than the exposure time regarding the embryotoxicity of indium. It is considered from these findings that the risk of the developmental toxicity of indium in humans is low, unless an accidentally high level of exposure or unknown toxic interaction occurs because of possible human exposure routes and levels (i.e. oral, very low-level exposure). [source] A probabilistic framework for quantification of aftershock ground-motion hazard in California: Methodology and parametric studyEARTHQUAKE ENGINEERING AND STRUCTURAL DYNAMICS, Issue 1 2009Gee Liek Yeo Abstract This paper presents a proposed method of aftershock probabilistic seismic hazard analysis (APSHA) similar to conventional ,mainshock' PSHA in that it estimates the likelihoods of ground motion intensity (in terms of peak ground accelerations, spectral accelerations or other ground motion intensity measures) due to aftershocks following a mainshock occurrence. This proposed methodology differs from the conventional mainshock PSHA in that mainshock occurrence rates remain constant for a conventional (homogeneous Poisson) earthquake occurrence model, whereas aftershock occurrence rates decrease with increased elapsed time from the initial occurrence of the mainshock. In addition, the aftershock ground motion hazard at a site depends on the magnitude and location of the causative mainshock, and the location of aftershocks is limited to an aftershock zone, which is also dependent on the location and magnitude of the initial mainshock. APSHA is useful for post-earthquake safety evaluation where there is a need to quantify the rates of occurrence of ground motions caused by aftershocks following the initial rupture. This knowledge will permit, for example, more informed decisions to be made for building tagging and entry of damaged buildings for rescue, repair or normal occupancy. Copyright © 2008 John Wiley & Sons, Ltd. [source] Strain field measurements of rubber by image analysis and design criteria for laminated rubber bearings (LRB)EARTHQUAKE ENGINEERING AND STRUCTURAL DYNAMICS, Issue 4 2004Chamindalal Sujeewa Lewangamage Abstract Although seismic isolation rubber bearings in bridges and buildings have proven to be a very effective passive method for reducing earthquake-induced forces, a detailed mechanical modeling of the rubber that is used in bearings under large strains has not been established. Therefore, a 3D model of failure behavior and the design criteria for the safety evaluation of seismic isolation bearings have not yet been developed. This paper presents: (1) correlation-based template-matching algorithms to measure large strain fields of continua; (2) a failure criterion for rubber; and (3) the design criteria for the safety evaluation of laminated algorithms, data-validation algorithms were developed and implemented to eliminate possible unrealistic displacement vectors present in the measured displacement field. The algorithms were successfully employed in the strain field measurement of LRB and rubber materials that are subjected to failure. The measured local strains for rubber material at failure were used to develop a failure criterion for rubber. The validity of the proposed criterion was evaluated by applying it to the LRB; the criterion was introduced into a 3D finite element model of LRB, compared with the experimental results of bearings failure, and verified. Finally, design criteria are proposed for LRB for the safety evaluation. Copyright © 2003 John Wiley & Sons, Ltd. [source] Impact of inter-individual differences in drug metabolism and pharmacokinetics on safety evaluationFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004J.L.C.M. Dorne Abstract Safety evaluation aims to assess the dose,response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is ,without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 100.5 (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment. [source] Probabilistic safety analysis of structures under hybrid uncertaintyINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 4 2007Subrata Chakraborty Abstract The probabilistic and the possibilistic methods of safety evaluation of structure under uncertain parameters have been developed independently. When the structural system is defined with some of the input parameters as possibilistic and others are sufficient enough to model as probabilistic, available literatures normally start with either probabilistic or possibilistic description of all the variables. This may pose restriction on necessary flexibility to the designer at early stage of modelling of the structural system. The primary objective of the present work is to critically examine various emerging methods of transformation of the possibilistic variables to equivalent probabilistic variables so that probabilistic safety evaluation approach becomes compatible with the nature and quality of the input data. Relying on the fundamental concept of equivalent transformations, i.e. the entropy based transformation and the scaling of fuzzy membership function, the reliability analysis is proposed in the framework of second moment format. In doing so, the bounds on the reliability indices based on the evidence theory are also obtained encompassing the first-order reliability analysis for consistent comparison among alternative transformations. Finally, the reliability computation under hybrid uncertainty is elucidated numerically with examples for comparative study on the suitability of the transformation alternatives. Copyright © 2006 John Wiley & Sons, Ltd. [source] Detection and characterization of the novel bacteriocin entomocin 9, and safety evaluation of its producer, Bacillus thuringiensis ssp. entomocidus HD9JOURNAL OF APPLIED MICROBIOLOGY, Issue 5 2003A. Cherif Abstract Aims: To identify and characterize new bacteriocins from a collection of 41 strains belonging to 27 subspecies of Bacillus thuringiensis, and to evaluate the safety of the producers. Methods and Results:Bacillus thuringiensis ssp. entomocidus HD9 produced in the culture supernatant an antimicrobial activity against Gram-positive bacteria including Listeria monocytogenes, one of four pathogenic Pseudomonas aeruginosa and several fungi. Production of the antibacterial activity, named entomocin 9, started during mid-logarithmic growth reaching its maximum at the early stationary phase. Entomocin 9 retained more than 72% of activity after incubation for 20 min at 121°C. Activity was lost after proteinase K treatment, it was stable in a pH range between 3 and 9, and resistant to lyophilization. After partial purification with ammonium sulphate precipitation followed by gel-filtration and anion-exchange chromatography, an active protein of ca 12·4 kDa was isolated. The mode of action of entomocin 9 was bactericidal and caused cell lysis of growing cells. Despite the presence of a range of virulence related genes, including haemolysin BL, nonhaemolytic enterotoxin, cytotoxin K and several hydrolytic activities, B. thuringiensis HD9 was not toxic against Vero cells. Conclusions: Entomocin 9 is a novel heat-stable, bacteriocin produced by B. thuringiensis HD9. The absence of toxicity against Vero cells suggests the suitability of strain HD9 for a safe application in antimicrobial treatments. Significance and Impact of the Study: New finding on entomocin 9 would make B. thuringiensis attractive in biotechnological applications as an antimicrobial agent in agriculture and food industry. [source] Pollinex® Quattro Ragweed: safety evaluation of a new allergy vaccine adjuvanted with monophosphoryl lipid A (MPL®) for the treatment of ragweed pollen allergyJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2007Paul Baldrick Abstract A novel allergy vaccine (Pollinex® Quattro Ragweed) has been developed for the prevention or relief of allergic symptoms caused by pollen from Ambrosia spp. (ragweed). An extract from the pollen (chemically modified by glutaraldehyde) is adsorbed onto l -tyrosine with addition of the immunostimulatory adjuvant, monophosphoryl lipid A (MPL®). A specific preclinical safety testing strategy was developed to support clinical use and comprised reference to preclinical data available for the marketed non-MPL® adjuvanted form of the ragweed vaccine (Pollinex® R) and a new repeat dose toxicity study in the rat. Studies with Pollinex® R comprised single dose subcutaneous toxicity studies in mice and rats, repeat dose (10 injections over 20 days) parenteral toxicity studies in rats and dogs, an in vitro gene mutation assay along with single and multiple injection local tolerance studies in rats and dogs. The repeat dose subcutaneous toxicity study with Pollinex® Quattro Ragweed involved seven injections over 3 weeks (which was more aggressive than the four weekly doses used in the clinic) with dose levels of up to 0.5 ml per animal used. Overall, the product showed no toxicological findings of significance at levels greatly in excess of those proposed for clinical use. As is a feature with vaccination, some dose site irritation was seen. Copyright © 2007 John Wiley & Sons, Ltd. [source] Controlled trial of cumulative behavioural effects of a common bread preservative,JOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 4 2002S Dengate Objective: Many anecdotes and one scientific report describe cumulative behavioural effects of bread preservative on children. Methodology: Twenty-seven children, whose behaviour improved significantly on the Royal Prince Alfred Hospital diet, which excludes food additives, natural salicylates, amines and glutamates, were challenged with calcium propionate (preservative code 282) or placebo through daily bread in a double-blind placebo-controlled crossover trial. Results: Due to four placebo responders, there was no significant difference by anova of weighted placebo and challenge Rowe Behaviour Rating Inventory means, but a statistically significant difference existed in the proportion of children whose behaviours ,worsened' with challenge (52%), compared to the proportion whose behaviour ,improved' with challenge (19%), relative to placebo (95% confidence intervals 14,60%). Conclusions: Irritability, restlessness, inattention and sleep disturbance in some children may be caused by a preservative in healthy foods consumed daily. Minimizing the concentrations added to processed foods would reduce adverse reactions. Testing for behavioural toxicity should be included in food additive safety evaluation. [source] Cichorium intybus L , cultivation, processing, utility, value addition and biotechnology, with an emphasis on current status and future prospectsJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 5 2001Harsh Pal Bais Abstract Cultivation of chicory plants for various applications, such as utilisation of the root biomass for preparation of a coffee adjuvant, utilisation as a vegetable and, recently, utility of the plants for important phytochemicals, has received global attention. Chicory is widely grown in countries of different geographical locations owing to the economic importance of this crop. This review addresses cultivation, utility, phytochemical studies and pharmacological aspects, with an emphasis on biotechnological developments in recent years and safety evaluation of genetically modified chicory crops. These aspects are dealt with in detail to bring out the current status and future prospects of cultivation and utility of this economically important crop. © 2001 Society of Chemical Industry [source] Evaluation of mutagenic and antimutagenic properties of some bioactive xanthone derivatives using Vibrio harveyi testLETTERS IN APPLIED MICROBIOLOGY, Issue 3 2010Abstract Aims:, Drug safety evaluation plays an important role in the early phase of drug development, especially in the preclinical identification of compounds' biological activity. The Vibrio harveyi assay was used to assess mutagenic and antimutagenic activity of some aminoalkanolic derivatives of xanthone (1,5), which were synthesized and evaluated for their anticonvulsant and hemodynamic activities. Methods and Results:, A novel V. harveyi assay was used to assess mutagenic and antimutagenic activity of derivatives of xanthone 1,5. Two V. harveyi strains were used: BB7 (natural isolate) and BB7M (BB7 derivative containing mucA and mucB genes on a plasmid pAB91273, products of these genes enhance error-prone DNA repair). According to the results obtained, the most beneficial mutagenic and antimutagenic profiles were observed for compounds 2 and 3. A modification of the chemical structure of compound 2 by the replacement of the hydroxy group by a chloride improved considerably the antimutagenic activity of the compound. Thus, antimutagenic potency reached a maximum with the presence of tertiary amine and chloride atom in the side chain. Conclusions:, Among the newly synthesized aminoalkanolic derivatives of xanthone with potential anticonvulsant properties, there are some compounds exhibiting in vitro antimutagenic activity. In addition, it appears that the V. harveyi assay can be applied for primary mutagenicity and antimutagenicity assessment of compounds. Significance and Impact of the Study:, The obtained preliminary mutagenicity and antimutagenicity results encourage further search in the group of amino derivatives of xanthone as the potential antiepileptic drugs also presenting some antimutagenic potential. Furthermore, V. harveyi test may be a useful tool for compounds safety evaluation. [source] The current global status of chinese materia medicaPHYTOTHERAPY RESEARCH, Issue 10 2009Liu Xinmin Abstract The Chinese government has recently established a national project to improve the standards of Chinese Materia Medica (CMM) products, particularly regarding their quality control and safety evaluation, in order to promote modernization and increase international trade. In 2006, the global sales value of Chinese medicinal products increased to 20 billion US$, and the export value of CMM was up to more than 1 billion US$. However, the standard of these products still needs to be improved to meet the more stringent requirements of the international markets. Over the past decade we have witnessed the increasing growth in popularity of health foods and herbal medicinal products, especially Chinese Materia Medica products (CMM). Copyright © 2009 John Wiley & Sons, Ltd. [source] Isolation, structure elucidation and In Vivo hepatoprotective potential of trans -tetracos-15-enoic acid from Indigofera tinctoria Linn.PHYTOTHERAPY RESEARCH, Issue 10 2006B. Singh Abstract The bioassay guided fractionation of the dried aerial part of Indigofera tinctoria Linn. led to the identification of an active fraction labelled as indigotin. On further chemical analysis, a compound isolated from indigotin was identified and characterized as trans- tetracos -15-enoic acid (TCA). The chemical structure of this compound was established on the basis of physical properties and spectral data, including NMR. It afforded significant hepatoprotection against carbon tetrachloride and paracetamol induced hepatotoxicity in experimental models. Silymarin, a well known plant based hepatoprotective agent, and N -acetylcysteine, which has proven efficacy as a replenisher of sulfhydryls, were used for relative efficacy. TCA was found to reverse the altered hepatic parameters in experimental liver damage. In the safety evaluation study the oral LD50 was found to be more than 2000 mg/kg, with no signs of abnormalities or any mortality for the 15 day period of observation after administration of a single dose of drug in mice. The studies revealed significant and concentration dependent hepatoprotective potential of TCA as it reversed the majority of the altered hepatic parameters in experimental liver damage in rats and mice and may be useful in the management of liver disorders. Copyright © 2006 John Wiley & Sons, Ltd. [source] The journey of Indian GLP programme,looking back and forwardQUALITY ASSURANCE JOURNAL, Issue 1 2009V. Amalan Stanley Abstract The Indian GLP (Good Laboratory Practice) compliance monitoring programme has successfully brought the task of implementing the programme to the foreground where full OECD (Organization for Economic Cooperation and Development) membership is about to happen. It has been a long journey, more than five years for the programme to arrive at this juncture, succeeding through sheer commitment and will of the Science and Technology initiatives under which the programme has been implemented. Considering the spontaneous and natural challenges that are bound to make the effort of implementing the GLP compliance programme tougher for any country, the progress made by the Indian GLP programme can be considered very rapid. Though the dawn of full OECD membership for the Indian GLP programme is imminent the paper deals with the details of the journey it has traveled so far and the challenges ahead, commending the commitment of the efforts of the GLP MA (Monitoring Authority) as well as the preparedness of the test facilities. This paper discusses the GLP policy aspects that favoured the growth of the programme among non-member adherents, such as the allowance for getting GLP certification by GLP MA abroad. It also deals with the challenge of harmonizing the policies of the internal agencies that have direct influence on the implementation of the GLP programme, other than legalizing the GLP aspects as there are various government departments in India dealing with the regulatory aspects of specific drug products for human use or that are of chemical in origin. There are data requirements made mandatory by these institutions on pre-clinical or non-clinical safety evaluation of those products, which invariably necessitate studies conducted in compliance with the principles of GLP. The paper concludes with the emphasis that there is a primary need for harmony as well as legal or judicial underpinnings under the umbrella of a national GLP Monitoring Authority, a gray area to be essentially tackled with foresight, to earn credibility on the international front. Copyright © 2009 John Wiley & Sons, Ltd. [source] Magnitude of Error Introduced by Application of Heart Rate Correction Formulas to the Canine QT IntervalANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2006Andrew King B.V.M.S. Background: Accurate detection of drug-induced QT interval changes is often confounded by concurrent heart rate changes. Application of heart rate correction formulas has been the traditional approach to account for heart rate,induced QT interval changes, and thereby identify the direct effect of the test article on cardiac repolarization. Despite numerous recent studies identifying the imprecision of these formulas they continue to be applied. Methods: Using a chronic atrioventricular dissociated His-paced canine model, heart rate correction methods were evaluated for their ability to generate a corrected QT interval independent of original heart rate. Additionally, His bundle pacing at a heart rate of 60 beats/min allowed calculation of the magnitude of error introduced by application of heart rate correction formulas. Results: Of the fixed parameter heart rate correction formulas, only Van de Water was able to predict corrected QT values independent of the original heart rate. The magnitude of error discovered by application of heart rate correction formulas varied, but in many cases was very large. Bazett's formula was associated with a mean overcorrection of 67.9 ms; Fridericia's 28.7 ms. Van de Water was the best fixed parameter formula with a mean error of 10.8 ms. As expected, group and individual corrections derived from linear regression of the HR-QT data offered improvement over the traditional formulas. Both were able to predict QTc values independent of the heart rate. However, errors of the magnitude of 10 and 6 ms, respectively, were still introduced. Conclusion: Van de Water and linear regression correction methods were superior to others in this study, but all methods generated QTc errors equal to or much greater than the magnitude of interest for drug safety evaluation. [source] | |||||||||||||||||||