Sample records for preclinical toxicology studies

  1. Preclinical toxicology studies with acyclovir: genetic toxicity tests.

    PubMed

    Clive, D; Turner, N T; Hozier, J; Batson, A G; Tucker, W E

    1983-01-01

    Acyclovir (ACV), an antiviral drug active in the treatment of oral and genital Herpes infections, has been evaluated for mutagenic and carcinogenic potential in a battery of in vitro and in vivo short-term assays. Negative results were obtained in the following in vitro tests: Ames Salmonella, plate incorporation and preincubation modification assays; E. coli polA+/polA- DNA repair; yeast (S. cerevisiae D4) gene conversion; Chinese hamster ovary cells (HGPRT, APRT loci and ouabain-resistance marker); L5178Y mouse lymphoma cells (HGPRT locus and ouabain-resistance marker); and C3H/10T1/2 mouse fibroblast neoplastic transformation assay. All except the last assay were performed in the presence and absence of an exogenous metabolic activation system. ACV was positive at high concentrations X exposure times in the absence of exogenous metabolic activation in the following in vitro systems and at the indicated concentrations: BALB/c-3T3 neoplastic transformation (50 micrograms/mL, 72 h exposure); human lymphocyte cytogenetics (250-500 micrograms/mL, 48 h exposure); and L5178Y mouse lymphoma cells (TK locus, 400-2400 micrograms/mL, 4 h exposure; predominantly small colony mutants of chromosomal origin produced). No effects were seen in vivo (mouse dominant lethal assay; rat and Chinese hamster bone marrow cytogenetics) at up to maximum tolerated doses (MTD). An unusual clastogenic effect was seen in Chinese hamsters at 5 times the MTD. Overall, positive effects were seen only at either high concentrations (greater than or equal to 250 micrograms/mL in vitro or plasma levels) or prolonged exposure (72 hr in the BALB/c-3T3 neoplastic transformation assay). These studies support the view that ACV is a chromosomal mutagen, i.e., one which causes multi-locus damage but not single gene effects. The significance of these results for the genetic risk of ACV to man is discussed. PMID:6662301

  2. In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies

    PubMed Central

    Broichhausen, Christiane; Riquelme, Paloma; Ahrens, Norbert; Wege, Anja K; Koehl, Gudrun E; Schlitt, Hans J; Banas, Bernhard; Fändrich, Fred; Geissler, Edward K; Hutchinson, James A

    2014-01-01

    A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances. PMID:26015968

  3. Preclinical studies on the pharmacokinetics, safety, and toxicology of oxfendazole: toward first in human studies.

    PubMed

    Codd, Ellen E; Ng, Hanna H; McFarlane, Claire; Riccio, Edward S; Doppalapudi, Rupa; Mirsalis, Jon C; Horton, R John; Gonzalez, Armando E; Garcia, H Hugo; Gilman, Robert H

    2015-01-01

    A 2-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases. PMID:25701764

  4. Phospholipogenic pharmaceuticals are associated with a higher incidence of histological findings than nonphospholipogenic pharmaceuticals in preclinical toxicology studies.

    PubMed

    Barone, Linda R; Boyer, Scott; Damewood, James R; Fikes, James; Ciaccio, Paul J

    2012-01-01

    While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics. PMID:22745636

  5. Phospholipogenic Pharmaceuticals Are Associated with a Higher Incidence of Histological Findings than Nonphospholipogenic Pharmaceuticals in Preclinical Toxicology Studies

    PubMed Central

    Barone, Linda R.; Boyer, Scott; Damewood, James R.; Fikes, James; Ciaccio, Paul J.

    2012-01-01

    While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics. PMID:22745636

  6. Preclinical validation of a vaginal cream containing copaiba oil (reproductive toxicology study)

    Microsoft Academic Search

    C. S. Lima; B. J. L. de Medeiros; H. A. S. Favacho; K. C. dos Santos; B. R. de Oliveira; J. C. Taglialegna; E. V. M. da Costa; K. J. de Campos; J. C. T. Carvalho

    2011-01-01

    The aims of this study was to evaluate the effects of oil-resin of Copaiba (Copaifera duckei Dwyer), aired in vaginal cream on the reproductive performance of female rats (Rattus norvegicus). To determine the components of the C. duckei oleoresin, gas chromatography coupled with mass spectrometry (CG–MS) was used, and considering the trans-caryophyllene sesquiterpene as a phytochemical marker in the oleoresin.

  7. Statistical considerations for preclinical studies.

    PubMed

    Aban, Inmaculada B; George, Brandon

    2015-08-01

    Research studies must always have proper planning, conduct, analysis and reporting in order to preserve scientific integrity. Preclinical studies, the first stage of the drug development process, are no exception to this rule. The decision to advance to clinical trials in humans relies on the results of these studies. Recent observations show that a significant number of preclinical studies lack rigor in their conduct and reporting. This paper discusses statistical aspects, such as design, sample size determination, and methods of analyses, that will help add rigor and improve the quality of preclinical studies. PMID:25725352

  8. [Preclinical study of noopept toxicity].

    PubMed

    Kovalenko, L P; Smol'nikova, N M; Alekseeva, S V; Nemova, E P; Sorokina, A V; Miramedova, M G; Kurapova, S P; Sidorina, E I; Kulakova, A V; Daugel'-Dauge, N O

    2002-01-01

    Within the framework of a preclinical investigation, the new nootrope drug noopept (N-phenyl-acetyl-L-propyl-glycine ethylate) was tested for chronic toxicity upon peroral administration in a dose of 10 or 100 mg/kg over 6 months in both male and female rabbits. The results of observations showed that noopept administered in this dose range induced no irreversible pathologic changes in the organs and systems studied and exhibited no allergenic, immunotoxic, and mutagen activity. The drug affected neither the generative function nor the antenatal or postnatal progeny development. Noopept produced a dose-dependent suppression of inflammation reaction to concanavalin A and stimulated the cellular and humoral immune response in mice. PMID:12025790

  9. Research progress of Hemoporfin--part one: preclinical study.

    PubMed

    Pu, Yu; Chen, Wenhui; Yu, Zhengwei

    2012-06-01

    The second generation photosensitizer Hemoporfin (7(12)-(1-methoxyethyl) -12(7)-(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid) is a porphyrin derivative which processes a stable structure, high singlet oxygen yield, high photoactivity, low dark toxicity and fast clearance rate. Hemoporfin, also known as hematoporphyrin monomethyl ether (HMME) has been studied and used in photodynamic therapy (PDT) in China since 1989. This series of reports will provide an overview on the preclinical and clinical studies of this PDT photosensitizer. The first part of this series will highlight the results of preclinical studies that focused on the compound's optical characteristics, mechanism of the activities, pharmacological and toxicological properties. PMID:22594989

  10. [The actual problems of pre-clinical toxicological expertise of medicaments].

    PubMed

    Verstakova, O L

    2008-01-01

    The development of pre-clinical toxicological expertise of medicaments in Russia is accompanied of improvement in research and expertise methods, inculcation of international standards. The main principles of expertise were development: experts' competency and objectivity; experts' independence in realization their procurations and noninterference of persons who represent interest of the expertise client in experts' actions; abidance by lawfulness in expertise procedures; fullness of expertise, corresponding to state-of-the-art world level of scientific, technical and technological knowledge subject to normative legal documents regulating pharmacotoxicological examinations performance; systematization of expert scientific analysis; abidance by principles of biomedical ethics; uniqueness of each medicament; service to interests of patient and of community health protection. PMID:18589732

  11. Preclinical Studies of Raloxifene and Related Compounds

    Microsoft Academic Search

    Robin Fuchs-Young

    \\u000a The development of raloxifene (also know as keoxifene) for clinical use was based on a series of preclinical studies that\\u000a demonstrated it has a highly desirable tissue-specific activity. Results indicated that the therapeutic effects of raloxifene\\u000a (LY138481 HCl; LY156758) mimicked some of those of estrogen in ovariectomized animals by reducing bone loss and lowering serum\\u000a cholesterol levels. Conversely, in mammary

  12. Preclinical Studies for Cartilage Repair

    PubMed Central

    Hurtig, Mark B.; Buschmann, Michael D.; Fortier, Lisa A.; Hoemann, Caroline D.; Hunziker, Ernst B.; Jurvelin, Jukka S.; Mainil-Varlet, Pierre; McIlwraith, C. Wayne; Sah, Robert L.; Whiteside, Robert A.

    2011-01-01

    Investigational devices for articular cartilage repair or replacement are considered to be significant risk devices by regulatory bodies. Therefore animal models are needed to provide proof of efficacy and safety prior to clinical testing. The financial commitment and regulatory steps needed to bring a new technology to clinical use can be major obstacles, so the implementation of highly predictive animal models is a pressing issue. Until recently, a reductionist approach using acute chondral defects in immature laboratory species, particularly the rabbit, was considered adequate; however, if successful and timely translation from animal models to regulatory approval and clinical use is the goal, a step-wise development using laboratory animals for screening and early development work followed by larger species such as the goat, sheep and horse for late development and pivotal studies is recommended. Such animals must have fully organized and mature cartilage. Both acute and chronic chondral defects can be used but the later are more like the lesions found in patients and may be more predictive. Quantitative and qualitative outcome measures such as macroscopic appearance, histology, biochemistry, functional imaging, and biomechanical testing of cartilage, provide reliable data to support investment decisions and subsequent applications to regulatory bodies for clinical trials. No one model or species can be considered ideal for pivotal studies, but the larger animal species are recommended for pivotal studies. Larger species such as the horse, goat and pig also allow arthroscopic delivery, and press-fit or sutured implant fixation in thick cartilage as well as second look arthroscopies and biopsy procedures.

  13. Endpoints for Prenatal Exposures in Toxicological Studies

    Microsoft Academic Search

    A. Mantovani; F. Maranghi

    The standard approach to developmental toxicology includes, 1) studies targeting the organogenesis\\/pregnancy period, to assess\\u000a birth defects, minor anomalies (that may be a signal of more severe effects at higher dose levels), fetal growth and viability\\u000a (OECD guideline 414); 2) one- and two-generation studies (OECD guidelines 415 and 416) that provide an overall assessment\\u000a of general parameters related to postnatal

  14. Toxicological study of Balacaturbhadrika churna

    PubMed Central

    Nariya, Mukeshkumar B.; Parmar, Parag; Shukla, Vinay J.; Ravishankar, B.

    2011-01-01

    Balacaturbhadrika churna has an important place in pediatric practice in Ayurveda. Millennia of use of this formulation bears testimony to its safety when used for prolonged duration in children. This prompted us to initiate a long-term, acute oral toxicity evaluation of Balacaturbhadrika churna in rats. The study was carried out by administering Balacaturbhadrika churna orally once only in a dose up to 2000 mg/kg. For long-term toxicity, Balacaturbhadrika churna was administered in doses of 450 and 900 mg/kg orally for 45 consecutive days. The effects of the drug on ponderal changes, hematological, biochemical and histological parameters were noted. The acute toxicity experiment showed that the drug did not produce any signs and symptoms of toxicity (or mortality) up to the dose of 2000 mg/kg. Long-term toxicity results showed that, even at higher dose of 900 mg/kg, Balacaturbhadrika churna did not affect the parameters studied, to a significant extent. The doses employed for these toxicity studies were several times higher than normal clinical doses of Balacaturbhadrika churna, hence the observed changes will probably not become apparent at therapeutic dose level. PMID:21760693

  15. Toxicological studies on ratanjyot oil.

    PubMed

    Gandhi, V M; Cherian, K M; Mulky, M J

    1995-01-01

    Ratanjyot (Jatropha curcas) grows wild in many parts of India and Brazil. Experimental studies on the toxicity of its oil are scarce despite its use as a cathartic purgative, for treatment of many ailments in human medicine and in industrial applications. This study aims to provide data on its toxicity. The proximate composition of the kernels and physicochemical characteristics of its oil were determined. The kernels constitute 62% of the seed and contain 52% oil, which is reported to contain phorbol esters. A toxic fraction (2.4%) containing the phorbol esters was isolated from the oil. The acute oral LD50 of the oil was found to be 6 ml/kg body weight in rats. The oil caused severe diarrhoea and gastro-intestinal inflammation. The isolated toxic fraction, when applied to the skin of rabbits and rats, produced a severely irritant reaction followed by necrosis; in mice, this fraction had a dermally toxic and lethal effect. The oil and the toxic fraction at 25 and 1 mg respectively in 10 ml saline showed haemolytic activity, disrupting red blood cells. Detoxification or complete removal of the potent toxins present in ratanjyot oil is essential before its use in industrial applications or in human medicine can be considered. PMID:7821875

  16. Toxicological studies on plant proteins: a review.

    PubMed

    Wu, Wenbiao; Sun, Rong

    2012-06-01

    Nowadays, toxicological studies are contributing to human health more than ever. Reports on the toxicological studies of plant proteins, which are continuously growing in number in the literature, have been reviewed. Two important aspects are discussed: dietary safety evaluation, including toxicity tests and the maximum daily intake allowance, and the appropriate proportion in our daily diets of proteins from traditional foods and of new proteins from plant sources not traditionally employed as foods. Water hyacinth leaf proteins, sweet lupin proteins and canola proteins have not been shown to be toxic, although they are not traditionally employed as food proteins. These findings are very important for exploiting valuable new protein sources that are suitable for human or animal consumption and applicable to the food industry. Acutely toxic proteins, including lectins, ribosome-inactivating proteins, inhibitors of proteolytic enzymes and glycohydro-lases, have been isolated from plant materials and identified. Their toxicities and molecular characteristics have been described. The toxicity of proteins depends upon their specific native structures. Once they are denatured by appropriate treatment, such as heating, their toxicity can be reduced or even eliminated. These findings indicate that raw materials that contain this kind of toxic protein are not edible. However, after proper processing, they may be suitable for human or animal consumption. Although the toxicities of type 2 ribosome-inactivating proteins reported by different authors vary, the maximum dosages are still trace amounts. PMID:22183867

  17. PRECLINICAL STUDY Elevated tissue sodium concentration in malignant breast lesions

    E-print Network

    Ouwerkerk, Ronald

    Magnetic resonance imaging Á 23 Na magnetic resonance Á Sodium Á Quantification Introduction The use errors. Sodium (23 Na) MRI also yields useful information that reflects the physiological and biochemicalPRECLINICAL STUDY Elevated tissue sodium concentration in malignant breast lesions detected

  18. Eribulin—A review of preclinical and clinical studies

    PubMed Central

    Swami, Umang; Chaudhary, Imran; Ghalib, Mohammad H.; Goel, Sanjay

    2013-01-01

    Eribulin mesylate is a non-taxane, structurally simplified, completely synthetic, halichondrin B derivative with an end poisoning, microtubule inhibitory action. Preclinical studies have demonstrated activity in various cancer cell lines and synergistic action with gemcitabine, epirubicin, trastuzumab, cisplatin, docetaxel and vinorelbine. Eribulin has recently been approved by United States Food and Drug Administration as a third line therapy for metastatic breast cancer patients, who have previously been treated with an anthracycline and a taxane. It has also advanced to phase II trials in non-small cell lung cancer, pancreatic, prostate, bladder, head and neck cancers, sarcomas and ovarian and other gynecological tumors. Combination trials with carboplatin, gemcitabine, pemetrexed, cisplatin, and erlotinib are currently ongoing. Eribulin potentially has a low incidence of peripheral neuropathy. The predominant side effects are neutropenia and fatigue, which are manageable. This article reviews the available information on eribulin with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, preclinical studies and clinical trials. PMID:21493087

  19. Pharmacology should be at the centre of all preclinical and clinical studies on new psychoactive substances (recreational drugs).

    PubMed

    Green, A Richard; Nutt, David J

    2014-08-01

    Despite the publication of a substantial body of preclinical and clinical information on recent recreational drugs such as 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and cathinone compounds such as mephedrone there remains a disturbing lack of consensus as to how dangerous these compounds are to the health of the individual and to society in general. This perspective proposes that use of good pharmacological practice should be mandatory in all preclinical and clinical studies. Its use will assist both translation and reverse translation of information produced in animals and clinical subjects. We propose several basic rules to be followed in all future studies. Preclinical studies should employ pharmacokinetic-pharmacodynamic integration thereby exposing animals to known or calculable drug concentrations. This will provide results relevant to pharmacology rather than toxicology and, crucially, data relevant to human drug use. Full experimental detail should be routinely provided, to allow comparison with other similar work. In clinical studies evidence should be provided that the drug under investigation has been ingested by the subjects being examined, and details given of all other drugs being ingested. Drug-drug interactions are an unavoidable confound but studies of a size that allows reliable statistical evaluation and preferably allows sub-group analysis, particularly by using meta-analysis, should help with this problem. This may require greater collaboration between investigative groups, as routinely occurs during pharmaceutical clinical trials. Other proposals include greater integration of preclinical and clinical scientists in both preclinical and clinical studies and changes in the law regarding Good Manufacturing Process (GMP) sourcing of drug for human studies. PMID:24674814

  20. Confidentiality in preclinical Alzheimer disease studies

    PubMed Central

    Arias, Jalayne J.

    2014-01-01

    Clinical trials to advance the diagnosis and treatment of Alzheimer disease (AD) may expose research subjects to discrimination risks. An individual enrolled in a research study that uses positive test results from amyloid PET imaging or CSF measures of ?-amyloid 42 as inclusion criteria has biomarkers indicative of AD pathology. If insurers and employers learn this information, it could expose subjects to discrimination. Unfortunately, current legal and regulatory mechanisms are not sufficient to protect against harms that have significant consequences for subjects. Existing law that prohibits employment and insurance discrimination based on genetic status does not apply to amyloid biomarkers or any other biomarkers for neurodegenerative diseases. Gaps in legal protections fail to protect research subjects from discrimination by long-term care and disability insurers. This risk is particularly concerning because individuals with AD dementia ultimately need long-term care services. To maximize subject protections and advance valuable research, policymakers, investigators, and research institutions must address shortcomings in the design of the electronic medical record, revise laws to limit discrimination, and develop practices that inform research participants of risks associated with loss of confidentiality. PMID:24477112

  1. Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs

    PubMed Central

    2014-01-01

    Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting. PMID:25183392

  2. Drug-Eluting Stents in Preclinical Studies Updated Consensus Recommendations for Preclinical Evaluation

    PubMed Central

    Schwartz, Robert S.; Edelman, Elazer; Virmani, Renu; Carter, Andrew; Granada, Juan F.; Kaluza, Greg L.; Chronos, Nicolas A.F.; Robinson, Keith A.; Waksman, Ron; Weinberger, Judah; Wilson, Gregory J.; Wilensky, Robert L.

    2010-01-01

    Coronary drug-eluting stents are commonplace in clinical practice with acceptable safety and efficacy. Preclinical evaluation of novel drug-eluting stent technologies has great importance for understanding safety and possibly efficacy of these technologies, and well-defined preclinical testing methods clearly benefit multiple communities within the developmental, testing, and clinical evaluation chain. An earlier consensus publication enjoyed widespread adoption but is in need of updating. This publication is an update, presenting an integrated view for testing drug-eluting technologies in preclinical models, including novel devices such as bioabsorbable coatings, totally bioabsorbable stents, bifurcation stents, and stent-free balloon-based drug delivery. This consensus document was produced by preclinical and translational scientists and investigators engaged in interventional technology community. The United States Food and Drug Administration (USFDA) recently issued a Draft Guidance for Industry Document for Drug-Eluting Stents. This expert consensus document is consistent with the Food and Drug Administration guidance. The dynamic nature of this field mandates future modifications and additions that will be added over time. PMID:20031669

  3. Statistical studies in genetic toxicology: a perspective from the U.S. National Toxicology Program.

    PubMed Central

    Margolin, B H

    1985-01-01

    This paper surveys recent, as yet unpublished, statistical studies arising from research in genetic toxicology within the U.S. National Toxicology Program (NTP). These studies all involve analyses of data from Ames Salmonella/microsome mutagenicity tests, but the statistical methodologies are broadly applicable. Three issues are addressed: First, what is a tenable sampling model for Ames test data, and how does one best test the adequacy of the Poisson sampling assumption? Second, given that nonmonotone dose-response curves are fairly common in the Salmonella assay, what new statistical techniques or modifications of existing ones seem appropriate to accommodate to this reality? Finally, an intriguing question: How can the extensive NTP Ames test data base be used to assess the characteristics of any mutagen-nonmutagen decision rule? The last issue is illustrated with the commonly used "two-times background" rule. PMID:4076083

  4. Accumulation of heavy metals by freshwater zooplankton - a toxicological study

    Microsoft Academic Search

    S. K. Baliarsingh; S. Srichandan; T. Padmavati; Subrat Naik; K. C. Sahu

    2010-01-01

    So far many toxicologic studies are made earlier; we studied the acute toxicity estimation related to some specific identified freshwater zooplanktons of Paradip (Harbour City) area of Jagatsingpur District, Orissa, India which is situated on the bank of Mahanadi River. The study area is prone to heavy metal pollution because mineral based industries in relation to zinc, lead and cadmium

  5. Experimental Design and Efficient Parameter Estimation in Preclinical Pharmacokinetic Studies

    Microsoft Academic Search

    Ene I. Ette; Catherine A. Howie; Andrew W. Kelman; Brian Whiting

    1995-01-01

    Monte Carlo simulation technique used to evaluate the effect of the arrangement of concentrations on the efficiency of estimation of population pharmacokinetic parameters in the preclinical setting is described. Although the simulations were restricted to the one compartment model with intravenous bolus input, they provide the basis of discussing some structural aspects involved in designing a destructive (“quantic”) preclinical population

  6. Progressive Impairment on Neuropsychological Tasks in a Longitudinal Study of Preclinical Alzheimer's Disease

    E-print Network

    Wixted, John T.

    Progressive Impairment on Neuropsychological Tasks in a Longitudinal Study of Preclinical Alzheimer. The authors report a detailed neuropsychological evaluation of 11 patients over the course of 3 years up the neuropsychological profile of 11 preclinical patients. These individuals were among a large group of older adult

  7. Preclinical studies of [ 99mTc]DTPA-mannosyl-dextran? ? ? Supported in part by National Cancer Institute Grant CA72751 and University of California Breast Cancer Research Program Grants 2RB0018 and 4IB0051

    Microsoft Academic Search

    Carl K Hoh; Anne M Wallace; David R Vera

    2003-01-01

    We report the preclinical testing of a synthetic receptor-binding macromolecule, [99mTc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, KD = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration,

  8. A toxicological study of gadolinium nitrate

    SciTech Connect

    London, J.E.

    1988-05-01

    The sensitization study in the guinea pig did not show gadolinium nitrate to have potential sensitizing properties. Skin application studies in the rabbit demonstrated that it was cutaneously a severe irritant. This material was considered an irritant in the rabbit eye application studies. 3 refs., 1 tab.

  9. Preliminary toxicological study of Irganox 1010

    Microsoft Academic Search

    G. A. Drake; J. E. London; D. M. Smith; R. G. Thomas

    1979-01-01

    Acute oral LDââââ values for mice and rats receiving Irganox 1010 were found to be greater than 5 g\\/kg. According to classical guidelines, this material would be considered slightly toxic or practically nontoxic in both species. Skin applicaton studies in rabbits showed the material to be nonirritating. Eye irritation studies, also in the rabbit, showed that Irganox 1010 was a

  10. [Felines: an alternative in genetic toxicology studies?].

    PubMed

    Zamora-Perez, Ana; Gómez-Meda, Belinda C; Ramos-Ibarra, Maria L; Batista-González, Cecilia M; Luna-Aguirre, Jaime; González-Rodríguez, Andrés; Rodríguez-Avila, José L; Zúñiga-González, Guillermo M

    2008-06-01

    The micronuclei (MN) test carry out in peripheral blood is fast, simple, economic and it is used to detect genotoxic environmental agents. MN are fragments of chromosomes or complete chromosomes remaining in the cytoplasm after cell division, which increase when organisms are exposed to genotoxic agents. Therefore, species with the highest values of spontaneous micronucleated erythrocytes (MNE) are the most suitable to be potentials biomonitor of micronucleogenic agents, using a drop of blood. Nine species of Felines that present spontaneous MNE in peripheral blood are shown. From these species, the cat has been previously proven, with positive results and also lion (Panthera leo), yaguaroundi (Felis yagoaroundi), lynx (Lynx ruffus), jaguar (Panthera onca), puma (Puma concolor), tiger (Panthera tigris), ocelote (Felis padalis) and leopard (Panthera pardus) display spontaneous MNE, and with this characteristic this Family can be propose like a potential group to be used in toxicogenetic studies. PMID:19256458

  11. Behavioral and pharmaco-toxicological study of Papaver rhoeas L. in mice

    Microsoft Academic Search

    Rachid Soulimani; Chafique Younos; Salah Jarmouni-Idrissi; Dalila Bousta; Farid Khalouki; Amazzale Laila

    2001-01-01

    A lyophilized ethanolic aqueous extract of Papaver rhoeas petals was evaluated for its behavioral and pharmaco-toxicological effects in mice and its chemical composition was studied using thin layer chromatography (TLC). In this study, chemical analysis by TLC showed that the petals contain some anthocyanins, whereas no alkaloids were detected. The toxicological effect of alcoholic and aqueous plant extract administered intraperitoneally

  12. Chick embryo chorioallantoic membrane (CAM): an alternative predictive model in acute toxicological studies for anti-cancer drugs

    PubMed Central

    KUE, Chin Siang; TAN, Kae Yi; LAM, May Lynn; LEE, Hong Boon

    2015-01-01

    The chick embryo chorioallantoic membrane (CAM) is a preclinical model widely used for vascular and anti-vascular effects of therapeutic agents in vivo. In this study, we examine the suitability of CAM as a predictive model for acute toxicology studies of drugs by comparing it to conventional mouse and rat models for 10 FDA-approved anticancer drugs (paclitaxel, carmustine, camptothecin, cyclophosphamide, vincristine, cisplatin, aloin, mitomycin C, actinomycin-D, melphalan). Suitable formulations for intravenous administration were determined before the average of median lethal dose (LD50) and median survival dose (SD50) in the CAM were measured and calculated for these drugs. The resultant ideal LD50 values were correlated to those reported in the literature using Pearson’s correlation test for both intravenous and intraperitoneal routes of injection in rodents. Our results showed moderate correlations (r2=0.42 ? 0.68, P<0.005–0.05) between the ideal LD50 values obtained using the CAM model with LD50 values from mice and rats models for both intravenous and intraperitoneal administrations, suggesting that the chick embryo may be a suitable alternative model for acute drug toxicity screening before embarking on full toxicological investigations in rodents in development of anticancer drugs. PMID:25736707

  13. CHARACTERIZATION OF REFERENCE ARTEMIA III FOR MARINE TOXICOLOGICAL STUDIES

    EPA Science Inventory

    ASTM Practice for Using Brine Shrimp Nauplii as Food for Test Animals in Aquatic Toxicology Tests (E 1203) suggests use of Reference Artemis as a reference standard for evaluating other batches of brine shrimp as food for organisms used in toxicology. in 1988, the U.S. EPA was ab...

  14. Novel therapies for FSGS: preclinical and clinical studies.

    PubMed

    Malaga-Dieguez, Laura; Bouhassira, Diana; Gipson, Debbie; Trachtman, Howard

    2015-03-01

    Focal segmental glomerulosclerosis (FSGS) is a rare but important cause of end-stage kidney disease in children and adults. Current therapy, consisting of corticosteroids and calcineurin inhibitors, fails to achieve a sustained remission in most patients. Therefore, there is a pressing need to develop new treatments for this glomerulopathy. Traditional approaches have focused on agents that modulate the immune system. In this review, we summarize preclinical and clinical data with newer agents that may ameliorate FSGS. We focus on drugs that inhibit immune injury or inflammation, such as abatacept, rituximab, adalimumab, and stem cells. The potential of agents that block the glomerular action of circulating permeability factors such as soluble urokinase receptor is reviewed. Finally, because fibrosis represents the final common pathway of glomerular damage in FSGS, the experience with a wide range of antifibrotic agents is presented. Despite extensive research on the podocyte dysfunction in the pathogenesis of FSGS, there are few agents that directly target podocyte structure or viability. We conclude that FSGS is a heterogeneous disorder and that intensified translational research is vital to improve our understanding of distinct subtypes that have a defined prognosis and predictable response to targeted therapeutic interventions. PMID:25704355

  15. Exploratory Study of Factors Related to Educational Scores of First Preclinical Year Medical Students

    ERIC Educational Resources Information Center

    Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarawut

    2014-01-01

    The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students.…

  16. Ultra-high-resolution imaging of small animals: Implications for preclinical and research studies

    Microsoft Academic Search

    David A. Weber; Marijana Ivanovic

    1999-01-01

    Higher spatial resolution is continuously sought in nuclear medicine to improve the spatial detail and image quality that can be used for preclinical and cfinical imaging studies. The greater tissue specificity and highly selective uptake of many of the new labeled monoclonal antibodies, receptor-specific molecules, peptides, and other new radiopharmaceuticals investigated for use in imaging and therapy often require higher

  17. Clinical chemistry and haematology historical data in control Sprague-Dawley rats from pre-clinical toxicity studies.

    PubMed

    Petterino, Claudio; Argentino-Storino, Alberta

    2006-01-01

    The purpose of this paper is to provide historical data pertaining to clinical chemistry and haematology parameters, obtained from control Sprague-Dawley rats, used in pre-clinical toxicity studies. Mean, standard deviation, minimum and maximum values for haematological and coagulative profiles, haemato-biochemistry and urine analysis data, and the differences per sex and study duration, 4 versus 13 weeks, are presented. The studies were conducted in agreement with the GLP (Good Laboratory Practice) regulations. Statistically significant differences, at the confidence level of 99%, for the red blood cell (RBC) parameters, the white blood cell (WBC) series parameters, plasmatic albumin/globulin (A/G), alanine amino-transferase (ALT), alkaline phosphatase (ALP), creatinine, globulin, glucose, sodium, total protein, tryglycerides, urea and urine volume were observed in males, when 4-week study values were compared with those obtained from 13-week studies. Female rats showed statistically significant variations, at the confidence level of 99% for RBC number and mean corpuscular haemoglobin (MCH), mean red blood cell volume (MCV), WBCs count and lymphocytes percentage, A/G, albumin, ALT, AST, ALP, creatinine, globulin, and sodium, when 4-week study values were compared to 13-week studies. Similar differences were observed comparing the female with male haematological and biochemical data for the two different times of the sample collection. These data could be useful as a reference for evaluation of background pathology in Sprague-Dawley rats, when used in studies performed to evaluate the toxicological profile of a new chemical entity (NCE) in agreement with requirements from international regulatory agencies. PMID:16343876

  18. An overview of the toxicology of HFA134a (1,1,1,2-tetrafluoroethane)

    Microsoft Academic Search

    DJ Alexander; SE Libretto

    1995-01-01

    1 This paper reviews the results of preclinical toxicology studies on HFA-134a carried out by Glaxo Research and Development Ltd.2 A comprehensive range of studies was conducted in ani mal models suitable for the type of investigation.3 The inhalation route of administration was used in all in vivo studies (with the exception of local tolerance and sensitisation studies) as patients

  19. Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons From Preclinical Studies

    SciTech Connect

    Medin, Paul M., E-mail: Paul.medin@utsouthwestern.ed [Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX (United States); Boike, Thomas P. [Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX (United States)

    2011-04-01

    Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

  20. A magnetic resonance (MR) compatible selective brain temperature manipulation system for preclinical study

    PubMed Central

    Liu, Qingwei; Cai, Yu; Lin, Weili; Turner, Gregory H; An, Hongyu

    2012-01-01

    There is overwhelming evidence that hypothermia can improve the outcome of an ischemic stroke. However, the most widely used systemic cooling method could lead to multiple side effects, while the incompatibility with magnetic resonance imaging of the present selective cooling methods highly limit their application in preclinical studies. In this study, we developed a magnetic resonance compatible selective brain temperature manipulation system for small animals, which can regulate brain temperature quickly and accurately for a desired period of time, while maintaining the normal body physiological conditions. This device was utilized to examine the relationship between T1 relaxation, cerebral blood flow, and temperature in brain tissue during magnetic resonance imaging of ischemic stroke. The results showed that this device can be an efficient brain temperature manipulation tool for preclinical studies needing local hypothermic or hyperthermic conditions. PMID:23166453

  1. Application of toxicogenomics in hepatic systems toxicology for risk assessment: Acetaminophen as a case study

    SciTech Connect

    Kienhuis, Anne S., E-mail: anne.kienhuis@rivm.nl [Laboratory for Health Protection Research, National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands); RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Netherlands Toxicogenomics Centre (NTC), Maastricht University, PO Box 616, 6200 MD, Maastricht (Netherlands); Bessems, Jos G.M., E-mail: jos.bessems@rivm.nl [Centre for Substances and Integrated Risk Assessment, National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands); Pennings, Jeroen L.A., E-mail: jeroen.pennings@rivm.nl [Laboratory for Health Protection Research, National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands); Netherlands Toxicogenomics Centre (NTC), Maastricht University, PO Box 616, 6200 MD, Maastricht (Netherlands); Driessen, Marja, E-mail: marja.driessen@rivm.nl [Laboratory for Health Protection Research, National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands); Netherlands Toxicogenomics Centre (NTC), Maastricht University, PO Box 616, 6200 MD, Maastricht (Netherlands); Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, 2300 RA, Leiden (Netherlands); Luijten, Mirjam, E-mail: mirjam.luijten@rivm.nl [Laboratory for Health Protection Research, National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands); Netherlands Toxicogenomics Centre (NTC), Maastricht University, PO Box 616, 6200 MD, Maastricht (Netherlands); Delft, Joost H.M. van, E-mail: j.vandelft@grat.unimaas.nl [Netherlands Toxicogenomics Centre (NTC), Maastricht University, PO Box 616, 6200 MD, Maastricht (Netherlands); Department of Health Risk Analysis and Toxicology, Maastricht University, PO Box 616, 6200 MD, Maastricht (Netherlands)

    2011-01-15

    Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employed toxicogenomic technologies to date have already provided a proof of principle for the value of hepatic systems toxicology in hazard identification. In the present review, acetaminophen is used as a model compound to discuss the application of toxicogenomics in hepatic systems toxicology for its potential role in the risk assessment process, to progress from hazard identification towards hazard characterization. The toxicogenomics-based parallelogram is used to identify current achievements and limitations of acetaminophen toxicogenomic in vivo and in vitro studies for in vitro-to-in vivo and interspecies comparisons, with the ultimate aim to extrapolate animal studies to humans in vivo. This article provides a model for comparison of more species and more in vitro models enhancing the robustness of common toxicogenomic responses and their relevance to human risk assessment. To progress to quantitative dose-response analysis needed for hazard characterization, in hepatic systems toxicology studies, generation of toxicogenomic data of multiple doses/concentrations and time points is required. Newly developed bioinformatics tools for quantitative analysis of toxicogenomic data can aid in the elucidation of dose-responsive effects. The challenge herein is to assess which toxicogenomic responses are relevant for induction of the apical effect and whether perturbations are sufficient for the induction of downstream events, eventually causing toxicity.

  2. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials

    Microsoft Academic Search

    A Pardanani

    2008-01-01

    The recent identification of somatic mutations such as JAK2V617F that deregulate Janus kinase (JAK)–signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy

  3. Beneficial health effects of lupeol triterpene: a review of preclinical studies.

    PubMed

    Siddique, Hifzur Rahman; Saleem, Mohammad

    2011-02-14

    Since ancient times, natural products have been used as remedies to treat human diseases. Lupeol, a phytosterol and triterpene, is widely found in edible fruits, and vegetables. Extensive research over the last three decades has revealed several important pharmacological activities of lupeol. Various in vitro and preclinical animal studies suggest that lupeol has a potential to act as an anti-inflammatory, anti-microbial, anti-protozoal, anti-proliferative, anti-invasive, anti-angiogenic and cholesterol lowering agent. Employing various in vitro and in vivo models, lupeol has also been tested for its therapeutic efficiency against conditions including wound healing, diabetes, cardiovascular disease, kidney disease, and arthritis. Lupeol has been found to be pharmacologically effective in treating various diseases under preclinical settings (in animal models) irrespective of varying routes of administration viz; topical, oral, intra-peritoneal and intravenous. It is noteworthy that lupeol has been reported to selectively target diseased and unhealthy human cells, while sparing normal and healthy cells. Published studies provide evidence that lupeol modulates the expression or activity of several molecules such as cytokines IL-2, IL4, IL5, IL?, proteases, ?-glucosidase, cFLIP, Bcl-2 and NF?B. This minireview discusses in detail the preclinical studies conducted with lupeol and provides an insight into its mechanisms of action. PMID:21118697

  4. PRECLINICAL STUDY Adult human mesenchymal stem cells enhance breast

    E-print Network

    McLachlan, John

    . Keywords Mesenchymal stem cells Á Breast carcinoma Á Progesterone receptor Á Stromal-derived factor 1 ÁPRECLINICAL STUDY Adult human mesenchymal stem cells enhance breast tumorigenesis and promote Adult human mesenchymal stem cells (hMSCs) have been shown to home to sites of breast cancer

  5. A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study

    E-print Network

    Paris-Sud XI, Université de

    A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study W. A of ablative technologies such as HIFU for the treatment of liver tumors in humans has been studied in animal models without tumors or in small animals like rats and rabbits with established tumors. Because

  6. Preclinical studies of indapamide, a new 2-methylindoline antihypertensive diuretic

    SciTech Connect

    Pruss, T.; Wolf, P.S.

    1983-07-01

    Indapamide is a new indoline antihypertensive diuretic agent whose chemical structure differs substantially from those of the thiazides. The hydrophobic indoline moiety of indapamide confers a lipid solubility to the molecule that is 5 to 80 times greater than that of the thiazide diuretics. Thus indapamide accumulates in vascular smooth muscle at a concentration 10 times higher than that of protein-free perfusate. The affinity of indapamide for vascular smooth muscle manifests itself in vitro and in vivo as a decrease in reactivity following various pharmacologic interventions. Moreover, in vitro studies have demonstrated that indapamide decreases the inward calcium current and the transmembrane influx of calcium. The diuretic effect of indapamide is predominantly due to inhibition of sodium reabsorption at the cortical diluting segment of the distal convoluted tubule. In animal studies, intravenous indapamide has no effect on glomerular filtration rate or renal blood flow. Indapamide is well absorbed and extensively metabolized in animals and humans, with biliary excretion being the predominant route of elimination in animals. Most important, repeat administration of indapamide to dogs with both kidneys removed produces no accumulation of intact indapamide or its metabolites. Extensive drug safety studies in animals indicate that indapamide produces no overt toxicity and exhibits a good margin of safety.

  7. Intradermal inactivated poliovirus vaccine: a preclinical dose-finding study.

    PubMed

    Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

    2015-05-01

    Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. PMID:25391313

  8. Preclinical and Clinical Studies for Sodium Tungstate: Application in Humans

    PubMed Central

    Bertinat, Romina; Nualart, Francisco; Li, Xuhang; Yáñez, Alejandro J.; Gomis, Ramón

    2015-01-01

    Diabetes is a complex metabolic disorder triggered by the deficient secretion of insulin by the pancreatic ?-cell or the resistance of peripheral tissues to the action of the hormone. Chronic hyperglycemia is the major consequence of this failure, and also the main cause of diabetic problems. Indeed, several clinical trials have agreed in that tight glycemic control is the best way to stop progression of the disease. Many anti-diabetic drugs for treatment of type 2 diabetes are commercially available, but no ideal normoglycemic agent has been developed yet. Moreover, weight gain is the most common side effect of many oral anti-diabetic agents and insulin, and increased weight has been shown to worsen glycemic control and increase the risk of diabetes progression. In this sense, the inorganic salt sodium tungstate (NaW) has been studied in different animal models of metabolic syndrome and diabetes, proving to have a potent effect on normalizing blood glucose levels and reducing body weight, without any hypoglycemic action. Although the liver has been studied as the main site of NaW action, positive effects have been also addressed in muscle, pancreas, brain, adipose tissue and intestine, explaining the effective anti-diabetic action of this salt. Here, we review NaW research to date in these different target organs. We believe that NaW deserves more attention, since all available anti-diabetic treatments remain suboptimal and new therapeutics are urgently needed. PMID:25995968

  9. Anticancer potential of curcumin: preclinical and clinical studies.

    PubMed

    Aggarwal, Bharat B; Kumar, Anushree; Bharti, Alok C

    2003-01-01

    Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF-kappa B, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. PMID:12680238

  10. Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies.

    PubMed

    Fraczek, J; Bolleyn, J; Vanhaecke, T; Rogiers, V; Vinken, M

    2013-04-01

    Continuously increasing understanding of the molecular triggers responsible for the onset of diseases, paralleled by an equally dynamic evolution of chemical synthesis and screening methods, offers an abundance of pharmacological agents with a potential to become new successful drugs. However, before patients can benefit of newly developed pharmaceuticals, stringent safety filters need to be applied to weed out unfavourable drug candidates. Cost effectiveness and the need to identify compound liabilities, without exposing humans to unnecessary risks, has stimulated the shift of the safety studies to the earliest stages of drug discovery and development. In this regard, in vivo relevant organotypic in vitro models have high potential to revolutionize the preclinical safety testing. They can enable automation of the process, to match the requirements of high-throughput screening approaches, while satisfying ethical considerations. Cultures of primary hepatocytes became already an inherent part of the preclinical pharmaco-toxicological testing battery, yet their routine use, particularly for long-term assays, is limited by the progressive deterioration of liver-specific features. The availability of suitable hepatic and other organ-specific in vitro models is, however, of paramount importance in the light of changing European legal regulations in the field of chemical compounds of different origin, which gradually restrict the use of animal studies for safety assessment, as currently witnessed in cosmetic industry. Fortunately, research groups worldwide spare no effort to establish hepatic in vitro systems. In the present review, both classical and innovative methodologies to stabilize the in vivo-like hepatocyte phenotype in culture of primary hepatocytes are presented and discussed. PMID:23242478

  11. Preclinical studies of opioids and opioid antagonists on gastrointestinal function.

    PubMed

    Greenwood-Van Meerveld, B; Gardner, C J; Little, P J; Hicks, G A; Dehaven-Hudkins, D L

    2004-10-01

    Opioid receptors in the gastrointestinal (GI) tract mediate the effects of endogenous opioid peptides and exogenously administered opioid analgesics, on a variety of physiological functions associated with motility, secretion and visceral pain. The studies reviewed or reported here describe a range of in vivo activities of opioid receptor antagonists upon GI function in rodents, focusing on mu receptors. Naloxone, and the peripherally acting mu-opioid receptor antagonists alvimopan and methylnaltrexone, reverse morphine-induced inhibition of GI transit in mice and rats, and morphine- or loperamide-induced inhibition of castor oil-induced diarrhoea in mice. At doses producing maximal reversal of morphine-induced effects upon GI transit, only the central nervous system (CNS) penetrant antagonist naloxone was able to reverse morphine-induced analgesia. Both central and peripheral opioid antagonists may affect GI function and/or visceromotor sensitivity in the absence of exogenous opioid analgesics, suggesting a constitutive role for endogenous opioid peptides in the control of GI physiology. Furthermore, in contrast to naloxone, alvimopan does not produce hypersensitivity to the visceromotor response induced by nociceptive levels of colorectal distension in a rodent model of post-inflammatory colonic hypersensitivity, suggesting that in the periphery endogenous mu-opioid receptor-mediated mechanisms do not regulate colonic sensitivity. The data support the hypothesis that peripherally acting opioid antagonists may be able to selectively block opioid receptors in the GI tract, thereby preserving normal GI physiology, while not blocking the effects of endogenous opioid peptides or exogenous opioid analgesics in the CNS. These findings suggest that the primary sites of action of mu-opioid agonists with respect to inhibition of GI function are in the periphery, whereas analgesic activity resides primarily in the CNS. PMID:15357851

  12. Analgesic and hypnotic activities of Laghupanchamula: A preclinical study

    PubMed Central

    Ghildiyal, Shivani; Gautam, Manish K.; Joshi, Vinod K.; Goel, Raj K.

    2014-01-01

    Background: In Ayurvedic classics, two types of Laghupanchamula -five plant roots (LP) have been mentioned containing four common plants viz. Kantakari, Brihati, Shalaparni, and Prinshniparni and the fifth plant is either Gokshura (LPG) or Eranda (LPE). LP has been documented to have Shothahara (anti-inflammatory), Shulanashka (analgesic), Jvarahara (antipyretic), and Rasayana (rejuvenator) activities. Aim: To evaluate the acute toxicity (in mice), analgesic and hypnotic activity (in rats) of 50% ethanolic extract of LPG (LPGE) and LPE (LPEE). Materials and Methods: LPEG and LPEE were prepared separately by using 50% ethanol following the standard procedures. A graded dose (250, 500 and 1000 mg/kg) response study for both LPEE and LPGE was carried out for analgesic activity against rat tail flick response which indicated 500 mg/kg as the optimal effective analgesic dose. Hence, 500 mg/kg dose of LPEE and LPGE was used for hot plate test and acetic acid induced writhing model in analgesic activity and for evaluation of hypnotic activity. Results: Both the extracts did not produce any acute toxicity in mice at single oral dose of 2.0 g/kg. Both LPGE and LPEE (250, 500, and 1000 mg/kg) showed dose-dependent elevation in pain threshold and peak analgesic effect at 60 min as evidenced by increased latency period in tail-flick method by 25.1-62.4% and 38.2-79.0% respectively. LPGE and LPEE (500 mg/kg) increased reaction time in hot-plate test at peak 60 min analgesic effect by 63.2 and 85.8% and reduction in the number of acetic acid-induced writhes by 55.9 and 65.8% respectively. Both potentiated pentobarbitone-induced hypnosis as indicated by increased duration of sleep in treated rats. Conclusion: The analgesic and hypnotic effects of LP formulations authenticate their uses in Ayurvedic system of Medicine for painful conditions. PMID:25364205

  13. Preclinical and Clinical Studies on 5-Aza-2?Deoxycytidine, a Potent Inhibitor of DNA Methylation, in Cancer Therapy

    Microsoft Academic Search

    Richard L. Momparler

    The preclinical and clinical investigations by the author on the antineoplastic activity of 5-Aza-2?-deoxycytidine (5AZA),\\u000a a potent inhibitor of DNA methylation are reviewed. These include studies on the molecular, cellular and animal pharmacology\\u000a of 5AZA. These preclinical studies indicated that 5AZA has enormous potential in cancer therapy. This potential is supported\\u000a by reports in the literature indicate that 5AZA can

  14. Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies

    PubMed Central

    2011-01-01

    Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable. PMID:21943025

  15. Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees

    PubMed Central

    2011-01-01

    Background Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA), strategic approach (SA) and surface apathetic or superficial approach (SAA). The aim of this study was to identify factors affecting the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in the pattern of study skills with time and experience. Method Pre-clinical and clinical students of the Faculty of Medicine, University of Colombo and postgraduate trainees in Surgery at the National Hospital of Sri Lanka were invited to complete the Approaches and Study Skills Inventory for Students (ASSIST) questionnaire. Results A total of 187 pre clinical (M: F = 96:91), 124 clinical (M: F = 61:63) and 53 post graduate trainees (M: F = 50:3) participated in the study. Approaches of male and female students were similar. SA was significantly affected by age among the preclinical students (p = 0.01), but not in other groups. Among pre-clinical students, males preferred a teacher who supported understanding (p = 0.04) but females preferred a passive transmission of information (p < 0.001). This, too, was not visible among other groups. A linear regression performed on group (batch), gender, island rank at GCE Advance Level (AL) examination, self appraisal score and the preference scores of type of teacher only managed to explain 35% or less of variance observed for each approach in individual groups. Conclusion Different factors affect the approach to studying in different groups but these explain only a small fraction of the variance observed. PMID:21599886

  16. Nanomaterial synthesis and characterization for toxicological studies: TiO2 case study

    USGS Publications Warehouse

    Valsami-Jones, E.; Berhanu, D.; Dybowska, A.; Misra, S.; Boccaccini, A.R.; Tetley, T.D.; Luoma, S.N.; Plant, J.A.

    2008-01-01

    In recent years it has become apparent that the novel properties of nanomaterials may predispose them to a hitherto unknown potential for toxicity. A number of recent toxicological studies of nanomaterials exist, but these appear to be fragmented and often contradictory. Such discrepancies may be, at least in part, due to poor description of the nanomaterial or incomplete characterization, including failure to recognise impurities, surface modifications or other important physicochemical aspects of the nanomaterial. Here we make a case for the importance of good quality, well-characterized nanomaterials for future toxicological studies, combined with reliable synthesis protocols, and we present our efforts to generate such materials. The model system for which we present results is TiO2 nanoparticles, currently used in a variety of commercial products. ?? 2008 The Mineralogical Society.

  17. Attempted and successful compensation in preclinical and early manifest neurodegeneration - a review of task FMRI studies.

    PubMed

    Scheller, Elisa; Minkova, Lora; Leitner, Mathias; Klöppel, Stefan

    2014-01-01

    Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of "attempted" and "successful" compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington's disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset. PMID:25324786

  18. Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies

    PubMed Central

    Kwon, Youngjoo

    2014-01-01

    Breast cancer is the most common cancer among women worldwide, and many women with breast cancer live more than 5 years after their diagnosis. Breast cancer patients and survivors have a greater interest in taking soy foods and isoflavone supplements. However, the effect of isoflavones on breast cancer remains controversial. Thus, it is critical to determine if and when isoflavones are beneficial or detrimental to breast cancer patients. According to the available preclinical data, high concentrations of isoflavones inhibit the proliferation of breast cancer cells, regardless of their estrogen receptor (ER) status. In comparison, genistein, a major isoflavone, has stimulated tumor growth at low concentrations and mitigated tamoxifen efficacy in ER-positive breast cancer. Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth. However, studies using ovariectomized mice and subcutaneous xenograft models might not truly reflect estrogen concentrations in human breast tumors. Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen. Therefore, the concentrations of isoflavones and estrogen in human breast tumors should be considered better in future preclinical studies and the parameters that can estimate those levels in breast tumors are required in human clinical/epidemiological investigation. In addition, it will be important to identify the molecular mechanisms that either inhibit or promote the growth of breast cancer cells by soy isoflavones, and use those molecules to evaluate the relevance of the preclinical findings to the human disease and to predict the health effects of isoflavones in human breast tumors. PMID:25493176

  19. Toxicological study of plant extracts on termite and laboratory animals.

    PubMed

    Rahman, I; Gogoi, Inee; Dolui, A K; Handique, Ruma

    2005-04-01

    Toxic activity of leaf extracts of Polygonum hydropiper L. and Pogostemon parviflorus Benth. were tested in the laboratory against tea termite, Odontotermes assamensis Holm. Both the tested extracts caused mortality of the termite. The highest toxic activity (100%) was found in the 2.0% chloroform extracts of P. hydropiper. The chloroform extract of P. hydropiper was explored for possible mammalian toxicological effects. The LD50 was 758.58 mg/kg in male albino mice. Subcutaneous injection of sub-lethal dose of extract into male mice once a week for 6 weeks failed to express any significant influence on WBC, RBC count and blood cholesterol. PMID:16161979

  20. Targeting SRC in glioblastoma tumors and brain metastases: rationale and preclinical studies.

    PubMed

    Ahluwalia, Manmeet S; de Groot, John; Liu, Wei Michael; Gladson, Candece L

    2010-12-01

    Glioblastoma (GBM) is an extremely aggressive, infiltrative tumor with a poor prognosis. The regulatory approval of bevacizumab for recurrent GBM has confirmed that molecularly targeted agents have potential for GBM treatment. Preclinical data showing that SRC and SRC-family kinases (SFKs) mediate intracellular signaling pathways controlling key biologic/oncogenic processes provide a strong rationale for investigating SRC/SFK inhibitors, e.g., dasatinib, in GBM and clinical studies are underway. The activity of these agents against solid tumors suggests that they may also be useful in treating brain metastases. This article reviews the potential for using SRC/SFK inhibitors to treat GBM and brain metastases. PMID:20947248

  1. Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.

    PubMed

    Sarris, Jerome; McIntyre, Erica; Camfield, David A

    2013-03-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase or glutamic acid decarboxylase inhibition; a range of monoaminergic effects; and potential cannabinoid receptor modulation. Future research should focus on conducting human clinical trials on the plants reviewed with promising anxiolytic activity. PMID:23436255

  2. Exploratory study of factors related to educational scores of first preclinical year medical students.

    PubMed

    Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarayut

    2014-03-01

    The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P < 0.001 for all) by Pearson's method. Using multiple linear regression analysis, anatomy scores could be predicted by pre-MD GPA, student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R(2) = 0.598, P < 0.001). Physiology scores could be estimated by pre-MD GPA, the percentage of expected reading, monthly earnings, and percentage of those who fell asleep during class and near exam time (R = 0.722, R(2) = 0.521, P < 0.001). Biochemistry scores could be calculated by pre-MD GPA, the percentage of expected reading, motivation to study medicine, student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R(2) = 0.630, P < 0.001). In conclusion, pre-MD GPA and the percentage of expected reading are factors involved in producing good academic results in the first preclinical year. Anatomy and biochemistry, but not physiology, scores are influenced by satisfaction. PMID:24585466

  3. DTP | Toxicology and Pharmacology Branch (TPB)

    Cancer.gov

    Preclinical toxicology and pharmacology are required for decision making throughout drug discovery and development and for IND filing for clinical trials. Toxicological and pharmacological data can inform clinical trial design, such as determination of maximum tolerated dose, dose-limiting toxicities, and starting dose. With appropriate characterization, in most cases, safe operating parameters can be established for human clinical trials.

  4. Food for Thought Look Back in Anger – What Clinical Studies Tell Us About Preclinical Work

    PubMed Central

    Hartung, Thomas

    2013-01-01

    Summary Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies. PMID:23861075

  5. Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors

    PubMed Central

    Schott, Anne F.; Landis, Melissa D.; Dontu, Gabriela; Griffith, Kent A.; Layman, Rachel M.; Krop, Ian; Paskett, Lacey A; Wong, Helen; Dobrolecki, Lacey E.; Froehlich, Amber M.; Paranilam, Jaya; Hayes, Daniel F.; Wicha, Max S.; Chang, Jenny C.

    2013-01-01

    Purpose Accumulating evidence supports the existence of breast cancer stem cells (BCSCs), which are characterized by their capacity to self-renew and divide indefinitely, and resistance to conventional therapies. The Notch pathway is important for stem cell renewal, and is a potential target for BCSC-directed therapy. Experimental Design Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in advanced breast cancer patients, designed to determine the maximally tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results Treatment with GSI reduced BCSCs in MC1 and BMC-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically meaningful doses of both drugs were possible, with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24?, ALDH+, and MSFE were observed in tumors of patients undergoing serial biopsies. Conclusions These preclinical data demonstrate that pharmacological inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial demonstrates feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. PMID:23340294

  6. Chemical and toxicological studies of coal gasification wastewater circulated through a cooling tower

    Microsoft Academic Search

    J. R. Stetter; V. C. Stamoudis; R. D. Flotard; Reilly C. A. Jr; K. E. Wilzbach

    1984-01-01

    Argonne National Laboratory is studying health and environmental issues related to coal gasification, using data and samples from the oxygen-blown slagging fixed-bed gasifier at the University of North Dakota Energy Research Center (UNDERC). The pilot study reported here developed preliminary chemical and toxicological data needed to evaluate the health and environmental, as well as the process, implications of using partially

  7. Extracting Respirable Particles from Lunar Regolith for Toxicology Studies B. L. Cooper1

    E-print Network

    Perfect, Ed

    Extracting Respirable Particles from Lunar Regolith for Toxicology Studies B. L. Cooper1 , .D.S. Mc will be done using the respirable fraction of actual lunar soils (particles with physical size of less than 2 months may cause serious damage, while a short exposure may cause none. WHY RESPIRABLE PARTICLES MUST

  8. Size Distributions and Characterization of Native and Ground Samples for Toxicology Studies

    NASA Technical Reports Server (NTRS)

    McKay, David S.; Cooper, Bonnie L.; Taylor, Larry A.

    2010-01-01

    This slide presentation shows charts and graphs that review the particle size distribution and characterization of natural and ground samples for toxicology studies. There are graphs which show the volume distribution versus the number distribution for natural occurring dust, jet mill ground dust, and ball mill ground dust.

  9. Preclinical studies with platelet-activating factor antagonists in models of septic shock.

    PubMed

    Dejoy, S Q; Oronsky, A L; Wick, M M; Kerwar, S S

    1993-01-01

    Since the isolation and elucidation of the structure of platelet-activating factor (PAF) in the late 1970's, several preclinical studies have suggested that PAF is a key mediator of septic shock induced in animals by either endotoxin or by Gram-negative bacteria. A number of PAF antagonists have been sythesized that protect animals from the lethal effects of endotoxin. Some of these antagonists are in early stages of clinical development. The most advanced cadidate is BN 52021, a ginkgolide, that is in Phase II/III clinical trials in patients with septic shock. Preliminary results with BN 52021 indicate that it is efficacious and significantly reduces mortality associated with Gram-negative sepsis. Pivotal trials with BN 52021 aer ongoing. The present review summarizes the biological effects of PAF and the effect of PAF antagonists in animal models of septic shock. The interrelationship of PAF and tumor necrosis factor (another key mediator of septic shock) is also discussed. PMID:18611559

  10. Integration of preclinical and clinical knowledge to predict intravenous PK in human: bilastine case study.

    PubMed

    Vozmediano, Valvanera; Ortega, Ignacio; Lukas, John C; Gonzalo, Ana; Rodriguez, Monica; Lucero, Maria Luisa

    2014-03-01

    Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes. PMID:23619917

  11. Preclinical toxicological assessment of a phytotherapeutic product--CPV (based on dry extracts of Crataegus oxyacantha L., Passiflora incarnata L., and Valeriana officinalis L.).

    PubMed

    Tabach, Ricardo; Rodrigues, Eliana; Carlini, E A

    2009-01-01

    Associations of plants have been widely used, for centuries, in Ayurveda and in Chinese medicine and have been increasingly acknowledged in Western medicine. The objective of this study is to assess the level of toxicity of an association of three plants: Crataegus oxyacantha, Passiflora incarnata, and Valeriana officinalis (CPV extract). This association was administered to rats, mice, and dogs, both acute and chronically for 180 days. The tests used in the acute experiments were: observational pharmacological screening, LD(50), motor coordination and motor activity. Chronic tests carried out were: weight gain/loss and behavioral parameters in rats and in mice; estrus cycle, effects on fertility, and teratogenic studies in rats and of mutagenic features in mice, in addition to the Ames test. The following parameters were assessed in dogs: weight gain/loss, general physical conditions, water/food consumption and anatomopathological examination of the organs subsequent to the 180 days of treatment. All of the results were negative, showing that CPV administered in high doses and over a long period of time presents no toxicity, suggestive of the fact that this is an association devoid of risk for human beings. PMID:19048610

  12. Nonindustry-sponsored preclinical studies on statins yield greater efficacy estimates than industry-sponsored studies: a meta-analysis.

    PubMed

    Krauth, David; Anglemyer, Andrew; Philipps, Rose; Bero, Lisa

    2014-01-01

    Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966-April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I(2) statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (-1.99; 95% CI -2.68, -1.31) versus studies sponsored by industry (-0.73; 95% CI -1.00, -0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study. PMID:24465178

  13. Experimental designs for detecting synergy and antagonism between two drugs in a pre-clinical study.

    PubMed

    Sperrin, Matthew; Thygesen, Helene; Su, Ting-Li; Harbron, Chris; Whitehead, Anne

    2015-05-01

    The identification of synergistic interactions between combinations of drugs is an important area within drug discovery and development. Pre-clinically, large numbers of screening studies to identify synergistic pairs of compounds can often be ran, necessitating efficient and robust experimental designs. We consider experimental designs for detecting interaction between two drugs in a pre-clinical in vitro assay in the presence of uncertainty of the monotherapy response. The monotherapies are assumed to follow the Hill equation with common lower and upper asymptotes, and a common variance. The optimality criterion used is the variance of the interaction parameter. We focus on ray designs and investigate two algorithms for selecting the optimum set of dose combinations. The first is a forward algorithm in which design points are added sequentially. This is found to give useful solutions in simple cases but can lack robustness when knowledge about the monotherapy parameters is insufficient. The second algorithm is a more pragmatic approach where the design points are constrained to be distributed log-normally along the rays and monotherapy doses. We find that the pragmatic algorithm is more stable than the forward algorithm, and even when the forward algorithm has converged, the pragmatic algorithm can still out-perform it. Practically, we find that good designs for detecting an interaction have equal numbers of points on monotherapies and combination therapies, with those points typically placed in positions where a 50% response is expected. More uncertainty in monotherapy parameters leads to an optimal design with design points that are more spread out. Copyright © 2015?John Wiley & Sons, Ltd. PMID:25810342

  14. Exercise as a Potential Treatment for Drug Abuse: Evidence from Preclinical Studies

    PubMed Central

    Smith, Mark A.; Lynch, Wendy J.

    2012-01-01

    Epidemiological studies reveal that individuals who engage in regular aerobic exercise are less likely to use and abuse illicit drugs. Until recently, very few studies had examined the causal influences that mediate this relationship, and it was not clear whether exercise was effective at reducing substance use and abuse. In the past few years, several preclinical studies have revealed that exercise reduces drug self-administration in laboratory animals. These studies have revealed that exercise produces protective effects in procedures designed to model different transitional phases that occur during the development of, and recover from, a substance use disorder (e.g., acquisition, maintenance, escalation, and relapse/reinstatement of drug use). Moreover, recent studies have revealed several behavioral and neurobiological consequences of exercise that may be responsible for its protective effects in these assays. Collectively, these studies have provided convincing evidence to support the development of exercise-based interventions to reduce compulsive patterns of drug intake in clinical and at-risk populations. PMID:22347866

  15. Computational Toxicology

    EPA Science Inventory

    ?Computational toxicology? is a broad term that encompasses all manner of computer-facilitated informatics, data-mining, and modeling endeavors in relation to toxicology, including exposure modeling, physiologically based pharmacokinetic (PBPK) modeling, dose-response modeling, ...

  16. COMPUTATIONAL TOXICOLOGY

    EPA Science Inventory

    Over the last several years, there has been increased pressure to utilize novel technologies derived from computational chemistry, molecular biology and systems biology in toxicological risk assessment. This new area has been referred to as "Computational Toxicology". Our resear...

  17. CCD-camera-based diffuse optical tomography to study ischemic stroke in preclinical rat models

    NASA Astrophysics Data System (ADS)

    Lin, Zi-Jing; Niu, Haijing; Liu, Yueming; Su, Jianzhong; Liu, Hanli

    2011-02-01

    Stroke, due to ischemia or hemorrhage, is the neurological deficit of cerebrovasculature and is the third leading cause of death in the United States. More than 80 percent of stroke patients are ischemic stroke due to blockage of artery in the brain by thrombosis or arterial embolism. Hence, development of an imaging technique to image or monitor the cerebral ischemia and effect of anti-stoke therapy is more than necessary. Near infrared (NIR) optical tomographic technique has a great potential to be utilized as a non-invasive image tool (due to its low cost and portability) to image the embedded abnormal tissue, such as a dysfunctional area caused by ischemia. Moreover, NIR tomographic techniques have been successively demonstrated in the studies of cerebro-vascular hemodynamics and brain injury. As compared to a fiberbased diffuse optical tomographic system, a CCD-camera-based system is more suitable for pre-clinical animal studies due to its simpler setup and lower cost. In this study, we have utilized the CCD-camera-based technique to image the embedded inclusions based on tissue-phantom experimental data. Then, we are able to obtain good reconstructed images by two recently developed algorithms: (1) depth compensation algorithm (DCA) and (2) globally convergent method (GCM). In this study, we will demonstrate the volumetric tomographic reconstructed results taken from tissuephantom; the latter has a great potential to determine and monitor the effect of anti-stroke therapies.

  18. Behavioral and pharmaco-toxicological study of Papaver rhoeas L. in mice.

    PubMed

    Soulimani, R; Younos, C; Jarmouni-Idrissi, S; Bousta, D; Khallouki, F; Khalouki, F; Laila, A

    2001-03-01

    A lyophilized ethanolic aqueous extract of Papaver rhoeas petals was evaluated for its behavioral and pharmaco-toxicological effects in mice and its chemical composition was studied using thin layer chromatography (TLC). In this study, chemical analysis by TLC showed that the petals contain some anthocyanins, whereas no alkaloids were detected. The toxicological effect of alcoholic and aqueous plant extract administered intraperitoneally was determined in mice. The toxicological results obtained indicated that 2000 mg/kg is LD10 and 4000 mg/kg is LD50. Behavioral and pharmacological studies of ethanolic and aqueous extract showed that the plant extract reduced locomotory, exploratory and postural behavior of mice. This was evaluated through two specific behavioral tests; a non-familiar environment test (the Staircase test) and a familiar environment test (Free exploratory test). These behavioral and pharmacological effects are more pronounced when the solvent used for extraction is 10% ethanol and is not antagonized by benzodiazepines, opioids, dopaminergic and cholinergic compounds (flumazenil, naloxone, sulpuride and atropine). The plant extract did not induce sleep in mice after treatment with an infrahypnotic dose of pentobarbital. This finding shows that the plant extract has a sedative effect at a 400 mg/kg dosage. PMID:11274828

  19. Amorphous solid dispersion successfully improved oral exposure of ADX71943 in support of toxicology studies.

    PubMed

    Ayad, Mohamad H; Bonnet, Beatrice; Quinton, Jacques; Leigh, Matthew; Poli, Sonia M

    2013-09-01

    ADX71943 is a potent and selective GABA(b) receptor positive allosteric modulator (PAM) which exhibits poor aqueous solubility at all physiologically relevant pHs. The aim of this study was to identify an adequate formulation to improve the solubility of ADX71943 to achieve a sufficiently high plasma exposure after oral administration to support the toxicology program. Considering the overall physicochemical properties and the low solubility of ADX71943 in a variety of solvents, solid dispersion, and particle size reduction have been successfully chosen as potential strategies to improve its oral bioavailability. Both technologies have proven useful in improving the in vitro dissolution profile and as a result of the solubility enhancement, higher bioavailability was obtained in vivo. As the solid dispersion gave better bioavailability (30-fold compared with the neat active pharmaceutical ingredient (API)), this formulation was selected for the toxicology study. Changing the crystalline form of ADX71943 into amorphous state by preparing a solid dispersion has greatly improved its oral bioavailability and has allowed achieving the required plasma concentration needed in toxicology studies. PMID:23066824

  20. What level of accuracy is achievable for preclinical dose painting studies on a clinical irradiation platform?

    PubMed

    Trani, Daniela; Reniers, Brigitte; Persoon, Lucas; Podesta, Mark; Nalbantov, Georgi; Leijenaar, Ralph T H; Granzier, Marlies; Yaromina, Ala; Dubois, Ludwig; Verhaegen, Frank; Lambin, Philippe

    2015-05-01

    Advancements made over the past decades in both molecular imaging and radiotherapy planning and delivery have enabled studies that explore the efficacy of heterogeneous radiation treatment ("dose painting") of solid cancers based on biological information provided by different imaging modalities. In addition to clinical trials, preclinical studies may help contribute to identifying promising dose painting strategies. The goal of this current study was twofold: to develop a reproducible positioning and set-up verification protocol for a rat tumor model to be imaged and treated on a clinical platform, and to assess the dosimetric accuracy of dose planning and delivery for both uniform and positron emission tomography-computed tomography (PET-CT) based heterogeneous dose distributions. We employed a syngeneic rat rhabdomyosarcoma model, which was irradiated by volumetric modulated arc therapy (VMAT) with uniform or heterogeneous 6 MV photon dose distributions. Mean dose to the gross tumor volume (GTV) as a whole was kept at 12 Gy for all treatment arms. For the nonuniform plans, the dose was redistributed to treat the 30% of the GTV representing the biological target volume (BTV) with a dose 40% higher than the rest of the GTV (GTV - BTV) (~15 Gy was delivered to the BTV vs. ~10.7 Gy was delivered to the GTV - BTV). Cone beam computed tomography (CBCT) images acquired for each rat prior to irradiation were used to correctly reposition the tumor and calculate the delivered 3D dose. Film quality assurance was performed using a water-equivalent rat phantom. A comparison between CT or CBCT doses and film measurements resulted in passing rates >98% with a gamma criterion of 3%/2 mm using 2D dose images. Moreover, between the CT and CBCT calculated doses for both uniform and heterogeneous plans, we observed maximum differences of <2% for mean dose to the tumor and mean dose to the biological target volumes. In conclusion, we have developed a robust method for dose painting in a rat tumor model on a clinical platform, with a high accuracy achieved in the delivery of complex dose distributions. Our work demonstrates the technical feasibility of this approach and enables future investigations on the therapeutic effect of preclinical dose painting strategies using a state-of-the-art clinical platform. PMID:25897556

  1. Coil optimization for low-field MRI: a dedicated process for small animal preclinical studies.

    PubMed

    Feuillet, T; Seurin, M-J; Leveneur, O; Viguier, E; Beuf, O

    2015-04-01

    We demonstrate a method for the fast in vivo quantification of small volumes, down to 25 µL, using low-field magnetic resonance imaging (MRI) coils. The coils were designed so as to maximize the signal-to-noise ratio (SNR) in the images. For this we developed an analytical model for describing the variations of the SNR with coil design and with size/shape suited to the object under observation. Based on the conclusions drawn from the model, the coil parameters were chosen in order to reach an SNR close to the maximum. For the validation of the model, coils were finally characterized in terms of quality factor using saline phantoms. The coil design procedure is illustrated here with two examples: first, the quantification of about 200 µL of intradermal injected gel on rabbits with a single loop surface coil and second, the imaging of the intervertebral disks in rat tails using a small volume coil to detect possible lesions. Such studies would not have been feasible for the clinical low-field MRI system at our disposal using any of the commercially available medium-sized manufactured coils. As a result of this simple optimization procedure, a wide range of applications is accessible even at low magnetic fields, leading to new opportunities for low-cost, though efficient, preclinical studies. PMID:25359877

  2. A technical feasibility study of surfactant-free drug suspensions using octenyl succinate-modified starches

    Microsoft Academic Search

    Martin Kuentz; Peter Egloff; Dieter Röthlisberger

    2006-01-01

    Many new drugs exhibit poor wetting behaviour and low aqueous solubility. This is particularly an issue for preclinical studies like toxicological trials, in which considerably higher doses and volumes are being administered compared to clinical studies. Preclinical vehicles typically contain high levels of surfactants that can exert biological effects. However, the biological inertness of vehicles is pivotal for the application

  3. Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD

    PubMed Central

    Schindler, Suzanne Elizabeth; Fagan, Anne M.

    2015-01-01

    Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-? peptide (A?) leading to early deposition of A? in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF A?42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD.

  4. The basics of preclinical drug development for neurodegenerative disease indications.

    PubMed

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial. PMID:19534731

  5. TISSUE SLICES IN THE STUDY OF LUNG METABOLISM AND TOXICOLOGY

    EPA Science Inventory

    Lung tissue slices are model systems for the study of pulmonary metabolism. Because of the speed and simplicity of slice preparation, lung slices have been used in studies of oxygen, amino acid, carbohydrate and lipid utilization and adenine nucleotide metabolism. Dose-response c...

  6. IN VITRO STUDIES: WHAT IS THEIR ROLE IN TOXICOLOGY?

    EPA Science Inventory

    Many epidemiology studies have reported associations between inhaled environmental pollutants, especially particles, and mortality or morbidity. Despite these impressive associations, fundamental uncertainties exist as to the underlying pathophysiological mechanisms responsible f...

  7. ISOTOPIC STUDY OF THE INHALATION TOXICOLOGY OF OXIDANTS

    EPA Science Inventory

    The purpose of these studies was to develop novel methods to investigate the biological fate of inhaled ozone and other oxygen-containing pollutants in animal and human tissues using the heavy isotope of oxygen, oxygen-18 (18O). Methods were developed which facilitated the conver...

  8. Pharmacological and toxicological studies of Drimys angustifolia Miers. (Winteraceae)

    Microsoft Academic Search

    A. Witaicenis; E. F. Roldão; L. N. Seito; N. P. Rocha; L. C. Di Stasi

    2007-01-01

    Drimys angustifolia Miers. (Winteraceae) is a Brazilian medicinal plant used as analgesic, antiulcer and anti-inflammatory without studies to assure its efficacy and safety Leaf and stem bark extracts were evaluated to determine the antiulcer, analgesic, antiinflammatory and antioxidant activities. Preliminary toxic effects and qualitative phytochemical profile were also performed. The antiulcer activity was detected in both extracts. Administration of the

  9. Streams of Coal or Streams of Death? A Toxicology Case Study

    NSDL National Science Digital Library

    Linda Niedziela

    2007-01-01

    Mary Beth was raised in Western Pennsylvania, an area where thousands of abandoned coal mines have led to extensive contamination of streams and associated ground waters. Aquatic life has clearly suffered, but the health effects on people living along the waterways have not been so clear. In working through this interrupted case study, students consider the biological consequences for Mary Beth’s family by analyzing selected research articles. Originally developed for an upper level toxicology course, it would also be appropriate for a cancer biology course and could easily be adapted for a course in science and society or environmental studies.

  10. Isomaltulose (Palatinose): a review of biological and toxicological studies.

    PubMed

    Lina, B A R; Jonker, D; Kozianowski, G

    2002-10-01

    Isomaltulose is a natural occurring disaccharide composed of alpha-1,6-linked glucose and fructose. Commercial isomaltulose is produced from sucrose by enzymatic rearrangement and has been used as a sugar in Japan since 1985. It is particularly suitable as a non-cariogenic sucrose replacement and is favorable in products for diabetics and prediabetic dispositions. In vivo studies with rats and pigs indicate that isomaltulose is completely hydrolyzed and absorbed in the small intestine. This is supported by in vitro studies showing that intestinal disaccharidases from various species (including man) can hydrolyze isomaltulose. The rate of hydrolysis, however, is very slow compared with sucrose and maltose. Thus, blood glucose and insulin levels in humans after oral administration rise slower and reach lower maxima than after sucrose administration. After absorption, fructose and glucose are metabolized as typical for these monosaccharides. From intravenous studies it can be assumed that any systemic isomaltulose would be hydrolyzed as well, or excreted in urine. In several subchronic toxicity studies, the administration of large doses (up to 7.0 and 8.1 g/kg body weight/day in male and female rats, respectively) of isomaltulose, did not result in adverse effects. Isomaltulose induced neither embryotoxic or teratogenic effects in rat foetuses, nor maternal toxicity at levels up to 7 g/kg body weight/day. Isomaltulose was non-mutagenic in the Ames test. As hydrolysis in the small intestine is complete, even high levels of isomaltulose are well tolerated in animals and humans. In studies with healthy as well as diabetic subjects high doses up to 50 g were tolerated without signs of intestinal discomfort. On the basis of the data reviewed it is concluded that the use of isomaltulose as an alternative sugar is as safe as the use of other digestible sugars consisting of glucose and fructose. PMID:12387299

  11. Cerebrovascular protection as a possible mechanism for the protective effects of NXY-059 in preclinical models: an in vitro study.

    PubMed

    Culot, Maxime; Mysiorek, Caroline; Renftel, Mila; Roussel, Benoit D; Hommet, Yannick; Vivien, Denis; Cecchelli, Roméo; Fenart, Laurence; Berezowski, Vincent; Dehouck, Marie-Pierre; Lundquist, Stefan

    2009-10-19

    NXY-059, a polar compound with limited transport across the blood-brain barrier, has demonstrated neuroprotection in several animal models of acute ischemic stroke but failed to confirm clinical benefit in the second phase III trial (SAINT-II). To improve the understanding of the mechanisms responsible for its neuroprotective action in preclinical models a series of experiments was carried out in an in vitro blood-brain barrier (BBB) model. A clinically attainable concentration of 250 mumol/L of NXY-059 administered at the onset or up to 4 h after oxygen glucose deprivation (OGD) produced a significant reduction in the increased BBB permeability caused by OGD. Furthermore, OGD produced a huge influx of tissue plasminogen activator across the BBB, which was substantially reduced by NXY-059. This study suggests that the neuroprotective effects of NXY-059 preclinically, may at least in part be attributed to its ability to restore functionality of the brain endothelium. PMID:19631615

  12. A preclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma.

    PubMed

    Biau, Julian; Devun, Flavien; Jdey, Wael; Kotula, Ewa; Quanz, Maria; Chautard, Emmanuel; Sayarath, Mano; Sun, Jian-Sheng; Verrelle, Pierre; Dutreix, Marie

    2014-10-01

    Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of "palliative" RT (10 × 3 Gy) or "radical" RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the "palliative" protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the "radical" protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial). PMID:25379020

  13. Alterations in the rate of binge ethanol consumption: implications for preclinical studies in mice.

    PubMed

    Linsenbardt, David N; Boehm, Stephen L

    2014-09-01

    The rate at which alcohol (ethanol) is consumed has direct impact on its behavioral and subjective effects. For this reason, alterations in the pattern of ethanol consumption as a function of drinking history might be critical to the development and maintenance of alcoholism. Furthermore, because pharmacological interventions aimed at disrupting the motivation to consume ethanol are dependent on the brain/plasma concentrations present when an individual is most likely to engage in consumption of this substance, characterizing temporal drinking patterns might be useful to determine the timing of such treatments. The primary goal of the present study was to evaluate alterations in the timecourse of daily binge (drinking-in-the-dark; DID) ethanol consumption. We gave 14 daily 2 hour DID ethanol or water access sessions to male C57BL/6J (B6) mice using a state of the art volumetric drinking monitoring device. We then, primarily as a proof-of-principle, used the GABAB allosteric modulator GS39783 (GS) to determine how this compound influenced the timecourse of binge-like ethanol intake. The rate of ethanol consumption increased dramatically over sessions with the majority occurring in the first few minutes of the final session. Additionally, ethanol consumption occurring immediately following access was almost completely abolished in mice pre-treated with GS; an effect which was ethanol-specific only at this early time interval. These data characterize progressive alterations in the rate of ethanol intake using the DID model and suggest that careful consideration of prior ethanol history and timing of drug administration are warranted when interpreting results of pre-clinical drug administration studies. PMID:23742054

  14. Toxicological studies on 2,4,6-tribromoanisole

    Microsoft Academic Search

    F. Koschier; M. A. Gallo; X. Feng; G. E. Baxter; R. Preston; K. Stevens; W. Powers

    2011-01-01

    TBA, or 2,4,6-tribromoanisole, is a musty-smelling metabolite of 2,4,6-tribromophenol that is used as a flame retardant and an antifungal agent for wooden pallets and packaging materials. The compound can impart its peculiar, often offensive, odor on product packaging to the concern of consumers for the safety of the package contents. These studies were conducted to evaluate the safety of TBA

  15. The zoapatle IV--toxicological and clinical studies.

    PubMed

    Southam, L; Pedrón, N; Ponce-Monter, H; Girón, H; Estrada, A; Lozoya, X; Enríquez, R G; Bejar, E; Gallegos, A J

    1983-03-01

    The zoapatle aqueous crude extract has been used in Mexico for the last 5 centuries for the induction of labor, treatment of post-partum bleeding problems, and as a menses inducer. Today, it is sold in street markets, and its long documented history of use by humans could be taken as indirect evidence of a lack of toxicity. Rigorous pharmacological and clinical studies described here, fully confirm the empirical observations. PMID:6851559

  16. Toxicological investigations on silicon carbide. 1. Inhalation studies.

    PubMed Central

    Bruch, J; Rehn, B; Song, H; Gono, E; Malkusch, W

    1993-01-01

    The question of lung damage as a result of exposure to silicon carbide (SiC) was investigated by inhalation experiments to obtain information on the qualitative response of lung tissue to the test substance (SiC). For comparison, quartz, kaolinite, and tempered clay dusts were used. The indices for the effects of the dusts studied were organ weights, numbers of bronchoalveolar cells, lung surfactant phospholipid concentrations including subfractions, and lung clearance. Exposure to the test samples was carried out according to the Essen inhalation model in two independent series. The results of the two series were similar: Compared with sham controls, exposure to SiC did not affect the indices studied. Even at a low dose (a quarter of the SiC dose) quartz gave pronounced deviations in all indices. In particular, an increase in granulocytes indicated toxic properties of the dust. The long term elimination of quartz from the lung was worse than that of SiC. The kaolinite and tempered clay dusts were intermediate between SiC and quartz based on several of the indices studied. It is concluded that SiC is deposited practically inert in the lung. PMID:8398873

  17. Subchronic Toxicological Study of Two Artemisinin Derivatives in Dogs

    PubMed Central

    Yin, Ji-ye; Wang, He-mei; Wang, Quan-jun; Dong, Yan-sheng; Han, Gang; Guan, Yong-biao; Zhao, Ke-yong; Qu, Wen-sheng; Yuan, Ye; Gao, Xiao-xin; Jing, Shu-fang; Ding, Ri-gao

    2014-01-01

    The objective of our study was to profile and compare the systematic changes between orally administered artesunate and intramuscularly injected artemether at a low dose over a 3-month period (92 consecutive days) in dogs. Intramuscular administration of 6 mg kg-1 artemether induced a decreased red blood cell (RBC) count (anemia), concurrent extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. We also observed a prolonged QT interval and neuropathic changes in the central nervous system, which demonstrated the cortex and motor neuron vulnerability, but no behavioral changes. Following treatment with artesunate, we observed a decreased heart rate, which was most likely due to cardiac conduction system damage, as well as a deceased RBC count, extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. However, in contrast to treatment with artemether, neurotoxicity was not observed following treatment with artesunate. In addition, ultra-structural examination by transmission electron microscopy showed mitochondrial damage following treatment with artesunate. These findings demonstrated the spectrum of toxic changes that result upon treatment with artesunate and artemether and show that the prolonged administration of low doses of these derivatives result in diverse toxicity profiles. PMID:24739881

  18. Analysis of volatile combustion products and a study of their toxicological effects.

    NASA Technical Reports Server (NTRS)

    Seader, J. D.; Einhorn, I. N.; Drake, W. O.; Mihlfeith, C. M.

    1972-01-01

    An experimental program was conducted to study the thermochemical, flammability and toxicological characteristics of uncoated and coated polyisocyanurate foams. The coatings used were fluorinated copolymer and an intumescent material. Combustion and pyrolysis gases were analyzed by gas chromatography and mass spectrometry. The LD-50 and LD-100 tests were performed on Sprague-Dawley rats housed in an environmental chamber. The isocyanurate foam, fluorinated-copolymer-coated foam, and the intumescent-coated foam were found to have excellent flammability and insulation characteristics, although smoke development was substantial.

  19. Trajectories of memory decline in preclinical Alzheimer's disease: results from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing.

    PubMed

    Pietrzak, Robert H; Lim, Yen Ying; Ames, David; Harrington, Karra; Restrepo, Carolina; Martins, Ralph N; Rembach, Alan; Laws, Simon M; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C; Maruff, Paul

    2015-03-01

    Memory changes in preclinical Alzheimer's disease (AD) are often characterized by heterogenous trajectories. However, data regarding the nature and determinants of predominant trajectories of memory changes in preclinical AD are lacking. We analyzed data from 333 cognitively healthy older adults who participated in a multicenter prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments. Latent growth mixture modeling revealed 3 predominant trajectories of memory change: a below average, subtly declining memory trajectory (30.9%); a below average, rapidly declining memory trajectory (3.6%); and an above average, stable memory trajectory (65.5%). Compared with the stable memory trajectory, high ?? (relative risk ratio [RRR] = 2.1), and lower Mini-Mental State Examination (RRR = 0.6) and full-scale IQ (RRR = 0.9) scores were independently associated with the subtly declining memory trajectory; and high ?? (RRR = 8.3), APOE ?4 carriage (RRR = 6.1), and greater subjective memory impairment (RRR = 1.2) were independently associated with the rapidly declining memory trajectory. Compared with the subtly declining memory trajectory group, APOE ?4 carriage (RRR = 8.4), and subjective memory complaints (RRR = 1.2) were associated with a rapidly declining memory trajectory. These results suggest that the preclinical phase of AD may be characterized by 2 predominant trajectories of memory decline that have common (e.g., high ??) and unique (e.g., APOE ?4 genotype) determinants. PMID:25585532

  20. Future directions--toxicology studies of 1,3-butadiene and isoprene.

    PubMed Central

    Bird, M G

    1990-01-01

    Examination of a profile of data already existing on 1,3-butadiene shows adequate knowledge in many areas of toxicology that are conventionally required in hazard identification. However, while much progress has been made in areas of metabolism and pharmacokinetics, further studies would be worthwhile to improve mechanistic understanding such as the examination of alternate metabolic pathways, the generation of interspecies scaling factors, and an assessment of the relevance of various tumor sites. In this respect, data pertaining to repeated and pulse exposures of rodents and primates would be helpful. Another important aspect is the need to understand any human health implications of the observed 1,3-butadiene-induction of the murine leukemia virus. In this respect, studies have been pursued that include the comparison of leukemogenesis in congenetic strains, the leukemogenicity of viral isolates in rodent carcinogenicity and human cell culture studies, and the mechanisms of activation of ecotropic proviral sequences. Molecular epidemiological and toxicological research is ongoing in rodents and primates to evaluate hemoglobin adduct formation as an index of 1,3-butadiene exposure. Challenges of specificity, sensitivity, and simplification of current procedures need to be overcome. Recent mutagenicity and metabolism data suggest that structurally-related isoprene may have carcinogenic potential. The use of interstrain comparative studies and data in a second species is discussed, as well as proposed metabolism studies. PMID:2205496

  1. Nubac Disc Arthroplasty: Preclinical Studies and Preliminary Safety and Efficacy Evaluations

    PubMed Central

    Songer, Matthew; Pimenta, Luis; Werner, Dieter; Reyes-Sanchez, Alejandro; Balsano, Massimo; Agrillo, Umberto; Coric, Domagoj; Davenport, Kenneth; Yuan, Hansen

    2007-01-01

    Background Disc arthroplasty is gaining popularity for treatment of low-back pain caused by degenerative disc disease (DDD). It can involve total disc replacement or partial disc or nucleus replacement (or augmentation). Compared with total disc replacement, nucleus replacement is less invasive, has less surgical risk, has faster postoperative recovery, and doesn't “burn bridges” should further surgery be required. However, nucleus replacement has a high risk of implant expulsion because the device is not fixed to the vertebrae. Nubac is the first polyetheretherketone (PEEK)-on-PEEK articulated disc arthroplasty device designed to optimally restore the lumbar anatomy and biomechanics. Methods ISO 10993 standards were used to evaluate the biocompatibility of the PEEK material. Chemical and thermal–mechanical tests and in vivo study assessed PEEK's biostability after exposure to high g irradiation and harsh oxidative conditions. Biomechanical tests to evaluate kinematic properties and anatomical restoration of the implanted lumbar motion segments and implant expulsion risk assessments were performed with a human cadaveric model. Because of the novelty of PEEK-on-PEEK as a self-mating articulating material, extensive wear tests were conducted with unidirectional and coupled motions. Static and fatigue strength also were tested. Animal study with a baboon model was conducted with gross, radiographic, biomechanical, and histological evaluations at 6 and 12 months postoperatively. Preliminary clinical data were collected through a prospective multicenter cohort study. Results PEEK demonstrated exceptional biocompatibility and biodurability. Nubac restored disc height and motion segment range of motion. The unique articulating design of the Nubac demonstrated low risk of implant expulsion in a human cadaveric model. Wear tests showed that the Nubac has minimal wear and compares favorably to other disc arthroplasty materials. The Nubac also had excellent static and fatigue properties for the intended application. The animal study showed that the Nubac caused no adverse local or systematic tissue reaction and there was no detectable wear debris. The preliminary clinical data showed no major intraoperative vascular and neurological complications. There was significant Visual Analog Scale and Oswestry Disability Index score improvement. Conclusions The preclinical data supported the design rationale, and the preliminary clinical data (level II evidence) on safety and efficacy were encouraging. Clinical Relevance The Nubac could be a viable first surgical option for patients with back pain caused by DDD. PMID:25802577

  2. Biological basis of sex differences in drug abuse: preclinical and clinical studies

    Microsoft Academic Search

    Wendy J. Lynch; Megan E. Roth; Marilyn E. Carroll

    2002-01-01

    .   The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review,\\u000a we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie\\u000a these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men;

  3. Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

    Microsoft Academic Search

    Sridhar Natesan; Greg E Reckless; Karen B L Barlow; José N Nobrega; Shitij Kapur

    2007-01-01

    There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT2 antagonist and as a partial agonist to dopamine D2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried

  4. DTP | Toxicology and Pharmacology Branch (TPB)

    Cancer.gov

    As a member of a Drug Development team, the individual serves as a primary resource for pharmacology and toxicity information by providing preclinical pharmacology and toxicology data to other NCI staff investigators and managers as well as to toxicologists, pharmacologists, clinicians and other investigators from drug companies, Cancer Centers, universities, etc.

  5. Preclinical and Pilot Clinical Studies of Docetaxel Chemoradiation for Stage III Non-Small-Cell Lung Cancer

    SciTech Connect

    Chen Yuhchyau, E-mail: yuhchyau_chen@urmc.rochester.edu [Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY (United States); Pandya, Kishan J. [Department of Medical Oncology, University of Rochester Medical Center, Rochester, NY (United States); Hyrien, Ollivier [Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY (United States); Keng, Peter C.; Smudzin, Therese; Anderson, Joy [Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY (United States); Qazi, Raman; Smith, Brian [Department of Medical Oncology, University of Rochester Medical Center, Rochester, NY (United States); Watson, Thomas J. [Division of Cardiothoracic Surgery, University of Rochester Medical Center, Rochester, NY (United States); Feins, Richard H. [Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC (United States); Johnstone, David W. [Division of Cardiothoracic Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Lebanon)

    2011-08-01

    Purpose: Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxel's cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT. Methods and Materials: A preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m{sup 2} of docetaxel and 75 mg/m{sup 2} of cisplatin on Day 1 and 150 mg/m{sup 2} of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m{sup 2} and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease. Results: The preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients. Conclusions: One-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation.

  6. Overall Type I Error Rate and Power of Multiple Dunnett's Tests on Rodent Body Weights in Toxicology Studies

    Microsoft Academic Search

    Wherly P. Hoffman; Justin Recknor; Cindy Lee

    2008-01-01

    Body weight data are routinely collected in in vivo general toxicology studies, including 2-year carcinogenicity studies, to help assess the overall health of animals. The effect of the compound on body weight is statistically evaluated for each sex separately using a linear trend test or a many-to-one test by Dunnett. These tests are performed either in the framework of a

  7. Equivalence of concentration-response relationships in aquatic toxicology studies: Testing and implications for potency estimation

    SciTech Connect

    Oris, J.T. [Miami Univ., Oxford, OH (United States). Center for Environmental Toxicology and Statistics

    1997-10-01

    The purpose of this study was to describe statistical procedures to test the equivalence of concentration-response relationships in acute toxicology studies and to illustrate the implications of nonequivalence on potency endpoints such as LC10, LC50, or LC90. A logistic regression model for binary response endpoints such as mortality that allowed for the examination of equivalence of slopes and intercepts of the responses between populations is described. Test statistics were derived from comparing nested regression models. This procedure was used to test the equivalence of concentration versus acute mortality response relationships between two nonpolar, narcotic chemicals in a single population of fish and between two populations of fish with different exposure histories to a polycyclic aromatic hydrocarbon. These case studies illustrate different outcomes in the comparison of concentration-response relationships and demonstrate the need to consider more than a single endpoint (e.g., LC50) in a risk assessment context when nonparallel concentration-responses are observed.

  8. Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.

    PubMed

    Sarris, Jerome; McIntyre, Erica; Camfield, David A

    2013-04-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (?(9)-THC)) Cannabis spp. PMID:23653088

  9. An approach to minimise dog use in regulatory toxicology: production of a best practice guide to study design.

    PubMed

    Phillips, Barry; Smith, David; Combes, Robert; Descotes, Gerard; Jacobsen, Soren Dyring; Hack, Ruediger; Kemkowski, Joerg; Krauser, Klaus; Pfister, Rudolf; Rabemampianina, Yvon; Sparrow, Sue; Stephan-Gueldner, Markus; von Landenberg, Friedrich

    2004-06-01

    The primary non-rodent species used in toxicology is the dog. It is generally agreed that, for ethical reasons, dog use should be reduced to the minimum consistent with maintaining the scientific quality of toxicology studies and ensuring human safety. Dog use in toxicology has been discussed widely, both from a scientific and ethical viewpoint, and there appears to be real potential for achieving significant reductions in the number of dogs used in pharmaceutical safety testing. An industry animal welfare initiative commenced in 2000, with the aim of evaluating and, where possible, putting into practice, scientifically valid approaches to minimise dog use in regulatory toxicology without increasing the use of other non-rodent species, such as non-human primates or minipigs. The study's Steering Group categorised potential reduction approaches into three distinct areas, one of which is the production of a best practice guide on aspects of study design, including: group sizes, use of control animals, single sex studies and design of maximum tolerated dose (MTD) studies. Information on current practice and experience within the pharmaceutical industry is now being analysed, and additional input is invited. PMID:23581116

  10. Creation of a digital slide and tissue microarray resource from a multi-institutional predictive toxicology study in the rat: an initial report from the PredTox group.

    PubMed

    Mulrane, Laoighse; Rexhepaj, Elton; Smart, Valerie; Callanan, John J; Orhan, Diclehan; Eldem, Türkan; Mally, Angela; Schroeder, Susanne; Meyer, Kirstin; Wendt, Maria; O'Shea, Donal; Gallagher, William M

    2008-08-01

    The widespread use of digital slides has only recently come to the fore with the development of high-throughput scanners and high performance viewing software. This development, along with the optimisation of compression standards and image transfer techniques, has allowed the technology to be used in wide reaching applications including integration of images into hospital information systems and histopathological training, as well as the development of automated image analysis algorithms for prediction of histological aberrations and quantification of immunohistochemical stains. Here, the use of this technology in the creation of a comprehensive library of images of preclinical toxicological relevance is demonstrated. The images, acquired using the Aperio ScanScope CS and XT slide acquisition systems, form part of the ongoing EU FP6 Integrated Project, Innovative Medicines for Europe (InnoMed). In more detail, PredTox (abbreviation for Predictive Toxicology) is a subproject of InnoMed and comprises a consortium of 15 industrial (13 large pharma, 1 technology provider and 1 SME) and three academic partners. The primary aim of this consortium is to assess the value of combining data generated from 'omics technologies (proteomics, transcriptomics, metabolomics) with the results from more conventional toxicology methods, to facilitate further informed decision making in preclinical safety evaluation. A library of 1709 scanned images was created of full-face sections of liver and kidney tissue specimens from male Wistar rats treated with 16 proprietary and reference compounds of known toxicity; additional biological materials from these treated animals were separately used to create 'omics data, that will ultimately be used to populate an integrated toxicological database. In respect to assessment of the digital slides, a web-enabled digital slide management system, Digital SlideServer (DSS), was employed to enable integration of the digital slide content into the 'omics database and to facilitate remote viewing by pathologists connected with the project. DSS also facilitated manual annotation of digital slides by the pathologists, specifically in relation to marking particular lesions of interest. Tissue microarrays (TMAs) were constructed from the specimens for the purpose of creating a repository of tissue from animals used in the study with a view to later-stage biomarker assessment. As the PredTox consortium itself aims to identify new biomarkers of toxicity, these TMAs will be a valuable means of validation. In summary, a large repository of histological images was created enabling the subsequent pathological analysis of samples through remote viewing and, along with the utilisation of TMA technology, will allow the validation of biomarkers identified by the PredTox consortium. The population of the PredTox database with these digitised images represents the creation of the first toxicological database integrating 'omics and preclinical data with histological images. PMID:18479893

  11. Preclinical Evaluation of the Immunogenicity and Safety of an Inactivated Enterovirus 71 Candidate Vaccine

    PubMed Central

    Hwa, Shi-Hsia; Lee, Yock Ann; Brewoo, Joseph N.; Partidos, Charalambos D.; Osorio, Jorge E.; Santangelo, Joseph D.

    2013-01-01

    Human enterovirus 71 (EV71) is a significant cause of morbidity and mortality from Hand, Foot and Mouth Disease (HFMD) and neurological complications, particularly in young children in the Asia-Pacific region. There are no vaccines or antiviral therapies currently available for prevention or treatment of HFMD caused by EV71. Therefore, the development of therapeutic and preventive strategies against HFMD is of growing importance. We report the immunogenic and safety profile of inactivated, purified EV71 preparations formulated with aluminum hydroxide adjuvant in preclinical studies in mice and rabbits. In mice, the candidate vaccine formulations elicited high neutralizing antibody responses. A toxicology study of the vaccine formulations planned for human use performed in rabbits showed no vaccine-related pathological changes and all animals remained healthy. Based on these preclinical studies, Phase 1 clinical testing of the EV71 inactivated vaccine was initiated. PMID:24244774

  12. Genetic susceptibility to environmental toxicants: the interface between human and experimental studies in the development of new toxicological concepts

    Microsoft Academic Search

    Ricarda Thier; Klaus Golka; Thomas Brüning; Yon Ko; Hermann M. Bolt

    2002-01-01

    The growing knowledge of the genetic polymorphisms of enzymes metabolising xenobiotics in humans and their connections with individual susceptibility towards toxicants has created new and important interfaces between human epidemiology and experimental toxicology. The results of molecular epidemiological studies may provide new hypotheses and concepts, which call for experimental verification, and experimental concepts may obtain further proof by molecular epidemiological

  13. THE ROLE OF TOXICOLOGY AND RELATED STUDIES IN EVALUATING THE RISK OF MYCOTOXINS: FUMONISIN B1 AS AN EXAMPLE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisins are mycotoxins that are found worldwide in corn and in corn-based foods. They are suspected human carcinogens and are the subject of ongoing risk assessments. Rodent feeding studies of fumonisin B1 (FB1) have been important for characterizing the toxicological effects of these mycotoxins...

  14. UNUSUAL FINDINGS IN ZEBRAFISH, DANIO RERIO, FROM TOXICOLOGICAL STUDIES AND THE ZEBRAFISH INTERNATIONAL RESOURCE CENTER DIAGNOSTIC SERVICE

    EPA Science Inventory

    A number of interesting and unusual lesions have been diagnosed in zebrafish that have been evaluated from toxicological studies or submitted as cases to the Diagnostic Service at Oregon State University. Lesions were observed in various wild-type and mutant lines of zebrafish an...

  15. Toxicological and epidemiological studies on effects of airborne fibers: coherence and public [corrected] health implications.

    PubMed

    Lippmann, Morton

    2014-09-01

    Airborne fibers, when sufficiently biopersistent, can cause chronic pleural diseases, as well as excess pulmonary fibrosis and lung cancers. Mesothelioma and pleural plaques are caused by biopersistent fibers thinner than ?0.1 ?m and longer than ?5 ?m. Excess lung cancer and pulmonary fibrosis are caused by biopersistent fibers that are longer than ?20 ?m. While biopersistence varies with fiber type, all amphibole and erionite fibers are sufficiently biopersistent to cause pathogenic effects, while the greater in vivo solubility of chrysotile fibers makes them somewhat less causal for the lung diseases, and much less causal for the pleural diseases. Most synthetic vitreous fibers are more soluble in vivo than chrysotile, and pose little, if any, health pulmonary or pleural health risk, but some specialty SVFs were sufficiently biopersistent to cause pathogenic effects in animal studies. My conclusions are based on the following: 1) epidemiologic studies that specified the origin of the fibers by type, and especially those that identified their fiber length and diameter distributions; 2) laboratory-based toxicologic studies involving fiber size characterization and/or dissolution rates and long-term observation of biological responses; and 3) the largely coherent findings of the epidemiology and the toxicology. The strong dependence of effects on fiber diameter, length, and biopersistence makes reliable routine quantitative exposure and risk assessment impractical in some cases, since it would require transmission electronic microscopic examination, of representative membrane filter samples, for determining statistically sufficient numbers of fibers longer than 5 and 20 ?m, and those thinner than 0.1 ?m, based on the fiber types. PMID:25168068

  16. Spaceflight Toxicology

    NASA Technical Reports Server (NTRS)

    Meyers, Valerie

    2008-01-01

    This viewgraph presentation provides a review of NASA Johnson Space Center's Toxicology program. The mission of this program is to protect crews from toxic exposures during spaceflight. The presentation reviews some of the health hazards. A toxicological hazard level chart is presented that reviews the rating of hazard level, irritancy, systemic effects and containability. The program also participates in the Lunar Airborne Dust Toxicity Advisory Group.

  17. Evaluation of toxicological properties and photodynamic activity of Photolon ointment: an experimental study

    NASA Astrophysics Data System (ADS)

    Shliakhtsin, Siarhei V.; Trukhachova, Tatsiana V.; Istomin, Yuriy P.; Dunetz, Ludmila N.; Kuvshinov, Andrey V.; Naumovich, Semen A.

    2009-06-01

    The purpose of the present study was to evaluate toxicological properties and photodynamic activity of a new ready form of the photosensitizer Photolon (Fotolon) - an ointment for topical use. The data obtained show the use of topicaly applied photosensitizer provides sufficient penetration and accumulation of the active compound in tumor tissue as well as in affected periodontal tissues for the effective PDT. There are several advantages of PDT with topical application of the photosensitizer such as absence of systemic toxic and photosensitive reactions, relatively low cost of the treatment and etc. We have shown that PDT of affected periodontal tissues with local application of Photolon/Fotolon ointment provides an ability of local destruction of microbial cell, located as on the gum surface as in the spatium intercellulare what is extremely important for successful treatment of acute and chronic periodontitis.

  18. Pre-clinical and clinical walking kinematics in female breeding pigs with lameness: A nested case-control cohort study.

    PubMed

    Stavrakakis, S; Guy, J H; Syranidis, I; Johnson, G R; Edwards, S A

    2015-07-01

    Gait profiles were investigated in a cohort of female pigs experiencing a lameness period prevalence of 29% over 17 months. Gait alterations before and during visually diagnosed lameness were evaluated to identify the best quantitative clinical lameness indicators and early predictors for lameness. Pre-breeding gilts (n=?84) were recruited to the study over a period of 6 months, underwent motion capture every 5 weeks and, depending on their age at entry to the study, were followed for up to three successive gestations. Animals were subject to motion capture in each parity at 8 weeks of gestation and on the day of weaning (28 days postpartum). During kinematic motion capture, the pigs walked on the same concrete walkway and an array of infra-red cameras was used to collect three dimensional coordinate data of reflective skin markers attached to the head, trunk and limb anatomical landmarks. Of 24 pigs diagnosed with lameness, 19 had preclinical gait records, whilst 18 had a motion capture while lame. Depending on availability, data from one or two preclinical motion capture 1-11 months prior to lameness and on the day of lameness were analysed. Lameness was best detected and evaluated using relative spatiotemporal gait parameters, especially vertical head displacement and asymmetric stride phase timing. Irregularity in the step-to-stride length ratio was elevated (deviation??0.03) in young pigs which presented lameness in later life (odds ratio 7.2-10.8). PMID:25986130

  19. Dicycloplatin, a novel platinum analog in chemotherapy: synthesis of chinese pre-clinical and clinical profile and emerging mechanistic studies.

    PubMed

    Yu, Jing Jie; Yang, Xuqing; Song, Qinhua; Mueller, Michael D; Remick, Scot C

    2014-01-01

    Dicycloplatin (DCP) has better solubility and stability than both cisplatin and carboplatin. Pre-clinical and phase I studies demonstrated significant antitumor activity and fewer adverse events than carboplatin. Phase II clinical trials in advanced non-small cell lung cancer found efficacy and safety of DCP-plus-paclitaxel comparable to carboplatin-plus-paclitaxel but better tolerability. This article summarizes and reviews pre-clinical and clinical data for dicycloplatin from the Chinese medical literature. We also report on new mechanistic findings in our laboratory in West Virginia, USA. Patient blood samples were collected for DCP-prototype determination by liquid chromatography mass spectrometry (LC-MS/MS). Molecular studies of ovarian cancer cells treated with DCP or cisplatin were carried out for gene-signature profiling using immunoblotting. Pharmacokinetic mass-spectrometry showed different spectrum profiles of DCP and carboplatin in plasma. Plasma concentration of DCP prototype was 17.1 ?g/ml 2h after administration, with a peak concentration of 26.9 ?g/ml at 0.5 h. Immunoblotting showed DCP-induced activation of DNA damage pathways, including double-phosphorylated checkpoint kinase 2 (CHK2) and breast cancer 1 (BRCA1) and triple-phosphorylated p53, compared to controls. Cisplatin produced a similar profile, with increased p53 protein. DCP and cisplatin activate DNA-damage response through similar pathways. DCP may be more soluble and stable, and better-tolerated. PMID:24403501

  20. Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

    PubMed Central

    Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

    2013-01-01

    The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment. PMID:23527068

  1. Translational reciprocity: bridging the gap between preclinical studies and clinical treatment of stress effects on the adolescent brain.

    PubMed

    Neigh, G N; Ritschel, L A; Kilpela, L S; Harrell, C S; Bourke, C H

    2013-09-26

    The genetic, biological, and environmental backgrounds of an organism fundamentally influence the balance between risk and resilience to stress. Sex, age, and environment transact with responses to trauma in ways that can mitigate or exacerbate the likelihood that post-traumatic stress disorder will develop. Translational approaches to modeling affective disorders in animals will ultimately provide novel treatments and a better understanding of the neurobiological underpinnings behind these debilitating disorders. The extant literature on trauma/stress has focused predominately on limbic and cortical structures that innervate the hypothalamic-pituitary-adrenal axis and influence glucocorticoid-mediated negative feedback. It is through these neuroendocrine pathways that a self-perpetuating fear memory can propagate the long-term effects of early life trauma. Recent work incorporating translational approaches has provided novel pathways that can be influenced by early life stress, such as the glucocorticoid receptor chaperones, including FKBP51. Animal models of stress have differing effects on behavior and endocrine pathways; however, complete models replicating clinical characteristics of risk and resilience have not been rigorously studied. This review discusses a four-factor model that considers the importance of studying both risk and resilience in understanding the developmental response to trauma/stress. Consideration of the multifactorial nature of clinical populations in the design of preclinical models and the application of preclinical findings to clinical treatment approaches comprise the core of translational reciprocity, which is discussed in the context of the four-factor model. PMID:23069751

  2. Latent Structure and Factorial Invariance of a Neuropsychological Test Battery for the Study of Preclinical Alzheimer’s Disease

    PubMed Central

    Dowling, N. Maritza; Hermann, Bruce; La Rue, Asenath; Sager, Mark A.

    2010-01-01

    Objective To examine the latent structure of a test battery currently being used in a longitudinal study of asymptomatic middle-aged adults with a parental history of Alzheimer’s disease (AD) and test the invariance of the factor solution across subgroups defined by selected demographic variables and known genetic risk factors for AD. Method An exploratory factor analysis (EFA) and a sequence of confirmatory factor analyses (CFA) were conducted on 24 neuropsychological measures selected to provide a comprehensive estimate of cognitive abilities most likely to be affected in preclinical AD. Once the underlying latent model was defined and the structural validity established through model comparisons, a multi-group confirmatory factor analysis model was used to test for factorial invariance across groups. Results The EFA solution revealed a factor structure consisting of 5 constructs: verbal ability, visuo-spatial ability, speed & executive function, working memory, and verbal learning & memory. The CFA models provided support for the hypothesized 5-factor structure. Results indicated factorial invariance of the model across all groups examined. Conclusions Collectively, the results suggested a relatively strong psychometric basis for using the factor structure in clinical samples that match the characteristics of this cohort. This confirmed an invariant factor structure should prove useful in research aimed to detect the earliest cognitive signature of preclinical AD in similar middle aged cohorts. PMID:21038965

  3. Preclinical anti-arthritic study and pharmacokinetic properties of a potent histone deacetylase inhibitor MPT0G009.

    PubMed

    Hsieh, I-N; Liou, J-P; Lee, H-Y; Lai, M-J; Li, Y-H; Yang, C-R

    2014-01-01

    The pathology of rheumatoid arthritis includes synoviocyte proliferation and inflammatory mediator expression, which may result from dysregulated epigenetic control by histone deacetylase (HDAC). Thus, HDAC inhibitors may be useful for treating inflammatory disease. This was a preclinical study of the HDAC inhibitor, MPT0G009. The IC50 values of MPT0G009 for HDAC1, 2, 3, 6 and 8 enzymatic activities were significantly lower than those for the currently marketed HDAC inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat). In addition, MPT0G009 markedly inhibited cytokine secretion and macrophage colony-stimulating factor/receptor activator of nuclear factor kappa B ligand-induced osteoclastogenesis by macrophages (50 ng/ml each). These MPT0G009 effects on cytokine secretion and osteoclast formation were reduced by the overexpression of HDAC 1 (class I HDAC) and 6 (class II HDAC) in cells, suggesting that these effects were due to the inhibition of its activity. In an in vivo rat model, oral administration of MPT0G009 (25 mg/kg) significantly inhibited paw swelling and bone destruction. Furthermore, compared with SAHA, MPT0G009 exhibited longer half-life (9.53 h for oral administration) and higher oral bioavailability (13%) in rats. These results established the preclinical anti-arthritic efficacy and pharmacokinetic parameters of MPT0G009, which may provide a new therapeutic approach for treating inflammatory arthritis. PMID:24722291

  4. A QSAR, pharmacokinetic and toxicological study of new artemisinin compounds with anticancer activity.

    PubMed

    Vieira, Josinete B; Braga, Francinaldo S; Lobato, Cleison C; Santos, César F; Costa, Josivan S; Bittencourt, José Adolfo H M; Brasil, Davi S B; Silva, Jocivânia O; Hage-Melim, Lorane I S; Macêdo, Williams Jorge C; Carvalho, José Carlos T; Santos, Cleydson Breno R

    2014-01-01

    The Density Functional Theory (DFT) method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with different degrees of cytotoxicity against the human hepatocellular carcinoma HepG2 line. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to select the most important descriptors related to anticancer activity. The significant molecular descriptors related to the compounds with anticancer activity were the ALOGPS_log, Mor29m, IC5 and GAP energy. The Pearson correlation between activity and most important descriptors were used for the regression partial least squares (PLS) and principal component regression (PCR) models built. The regression PLS and PCR were very close, with variation between PLS and PCR of R(2) = ± 0.0106, R(2)(ajust) = ± 0.0125, s = ± 0.0234, F(4,11) = ± 12.7802, Q(2) = ± 0.0088, SEV = ± 0.0132, PRESS = ± 0.4808 and SPRESS = ± 0.0057. These models were used to predict the anticancer activity of eight new artemisinin compounds (test set) with unknown activity, and for these new compounds were predicted pharmacokinetic properties: human intestinal absorption (HIA), cellular permeability (PCaCO2), cell permeability Maden Darby Canine Kidney (PMDCK), skin permeability (P(Skin)), plasma protein binding (PPB) and penetration of the blood-brain barrier (C(Brain/Blood)), and toxicological: mutagenicity and carcinogenicity. The test set showed for two new artemisinin compounds satisfactory results for anticancer activity and pharmacokinetic and toxicological properties. Consequently, further studies need be done to evaluate the different proposals as well as their actions, toxicity, and potential use for treatment of cancers. PMID:25061720

  5. Academic Warning Preclinical Y

    E-print Network

    Leistikow, Bruce N.

    Academic Warning 1st Clinical Y 3rd Preclinical Y 2nd Preclinical Y 1st Preclinical Y 1st USMLE fail Student meets with ADSA & DOSLER ---------------------- 2 Y's left Student retakes exam Pass = off --------------------- 1 Y left Student retakes exams Pass = off warning/continue ---------------------- Fail = probation

  6. Taking Journal Clubs off Autopilot: A Case Study of Teaching Literature Evaluation Skills to Preclinical MD/PhD Students

    PubMed Central

    Currier, Rebecca L.; Schneider, Marguerite Reid; Heubi, James E.

    2014-01-01

    Researchers designed learner-directed journal clubs to develop literature evaluation skills in preclinical students. Sessions balanced student-led discussion with structured objectives and faculty support. During the pilot with preclinical MD/PhD students, self-rated mastery improved over all 17 measured objectives. Six exercises have since been incorporated into the full medical school curriculum. PMID:24634798

  7. Evaluation of N-desmethylclozapine as a potential antipsychotic--preclinical studies.

    PubMed

    Natesan, Sridhar; Reckless, Greg E; Barlow, Karen B L; Nobrega, José N; Kapur, Shitij

    2007-07-01

    There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT(2) antagonist and as a partial agonist to dopamine D(2) and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D(2) and 5-HT(2) receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT(2) (64-79%), but minimal D(2) occupancy (<15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens. PMID:17164815

  8. Therapeutic vaccination and immunomodulation in the treatment of chronic hepatitis B: preclinical studies in the woodchuck.

    PubMed

    Kosinska, Anna D; Liu, Jia; Lu, Mengji; Roggendorf, Michael

    2015-02-01

    Infection with hepatitis B virus (HBV) may lead to subclinical, acute or chronic hepatitis. In the prevaccination era, HBV infections were endemic due to frequent mother to child transmission in large regions of the world. However, there are still estimated 240 million chronic HBV carriers today and ca. 620,000 patients die per year due to HBV-related liver diseases. Recommended treatment of chronic hepatitis B with interferon-? and/or nucleos(t)ide analogues does not lead to satisfactory results. Induction of HBV-specific T cells by therapeutic vaccination or immunomodulation may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients with or without therapeutic reduction of viral load did not result in effective immune control of HBV infection, suggesting that combination of antiviral treatment with new formulations of therapeutic vaccines is needed. The woodchuck (Marmota monax) and its HBV-like woodchuck hepatitis virus are a useful preclinical animal model for developing new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments using nucleos(t)ide analogues, with prime-boost vaccination using DNA vaccines, new hepadnaviral antigens or recombinant adenoviral vectors were tested in the woodchuck model. In this review, we summarize these encouraging results obtained with these therapeutic vaccines. In addition, we present potential innovations in immunostimulatory strategies by blocking the interaction of the inhibitory programmed death receptor 1 with its ligand in this animal model. PMID:25535101

  9. The Optimal Partnership of Radiation and Immunotherapy: from Preclinical Studies to Clinical Translation

    PubMed Central

    Demaria, Sandra; Pilones, Karsten A.; Vanpouille-Box, Claire; Golden, Encouse B.; Formenti, Silvia C.

    2014-01-01

    The main role of the immune system is to restore tissue homeostasis when altered by pathogenic processes, including neoplastic transformation. Immune-mediated tumor rejection has been recognized as an extrinsic tumor suppressor mechanism that tumors need to overcome to progress. By the time a tumor becomes clinically apparent it has successfully escaped immune control by establishing an immunosuppressive microenvironment. Ionizing radiation applied locally to a tumor alters these tumor-host interactions. Accumulating evidence indicates that standard therapeutic doses of radiation have the potential to recover tumor immunogenicity and convert the tumor into an in situ personalized vaccine. Radiotherapy induces an immunogenic tumor cell death promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. In addition, radiotherapy stimulates chemokine-mediated recruitment of effector T cells to the tumor, and cellular recognition and killing by T cells that is facilitated by upregulation of major histocompatibility antigens, NKG2D ligands, adhesion molecules and death receptors. Despite these effects, radiotherapy alone is only rarely capable of generating enough proinflammatory signals to sufficiently overcome suppression, as it can also activate immunosuppressive factors. However, our group and others have shown that when combined with targeted immunotherapy agents radiotherapy significantly contributes to a therapeutically effective anti-tumor immune response. To illustrate this partnership between radiation and immunotherapy we will discuss as an example our experience in preclinical models and the molecular mechanisms identified. Additionally, the clinical translation of these combinations will be discussed. PMID:24937779

  10. Advances in reproductive toxicology

    SciTech Connect

    Scialli, A.R. (Department of Obstetrics and Gynecology, Georgetown University Medical Center, Washington, DC (United States))

    1992-06-01

    Research in reproductive toxicology has relied on several animal models as well as on the more difficult-to-perform human studies. In animals, ovarian toxicity is being investigated in more detail, with investigation of characteristics of reversibility. Epidemiology studies using time-to-pregnancy techniques have been useful in identifying potential at-risk populations for further study. Male toxicology research has concentrated on defining normal sperm parameters in experimental animals and in men, particularly when those parameters are evaluated by computer-assisted techniques.37 references.

  11. (99m)Tc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study.

    PubMed

    Essa, B M; Sakr, T M; Khedr, Mohammed A; El-Essawy, F A; El-Mohty, A A

    2015-08-30

    Lactoperoxidase (LPO) inhibitors are very selective for solid tumor due to their high binding affinity to the LPO enzyme. A computational study was used to select top-ranked LPO inhibitor (alone and in complex with (99m)Tc) with high in silico affinity. The novel prepared (99m)Tc-amitrole complex demonstrated both in silico and in vivo high affinity toward solid tumors.(99m)Tc-amitrole was radio-synthesized with a high radiochemical yield (89.7±3.25). It showed in vitro stability for up to 6h. Its preclinical evaluation in solid tumor-bearing mice showed high retention and biological accumulation in solid tumor cells with a high Target/Non-Target (T/NT) ratio equal to 4.9 at 60min post-injection. The data described previously could recommend (99m)Tc-amitrole as potential targeting scintigraphic probe for solid tumor imaging. PMID:25956074

  12. Physical and chemical characterization of mn phosphate/sulfate mixture used in an inhalation toxicology study.

    PubMed

    Beaupré, Linda A; Salehi, Fariba; Zayed, Joseph; Plamondon, Philippe; L'Espérance, Gilles

    2004-04-01

    The use of methylcyclopentadienyl manganese tricarbonyl (MMT) in unleaded gasoline has given rise to numerous debates on the potential public health risk associated with manganese emissions. In fact, combustion products are mainly Mn phosphate, Mn sulfate, and Mn phosphate/sulfate mixture. Our research group did several inhalation studies in order to assess the toxicity of each Mn species. The objective of this study is to determine the physical and the chemical characteristics of a mixture of Mn phosphate/sulfate used in one of these inhalation toxicology studies. First, the mixture was analyzed by X-ray diffraction in order to obtain the specific peak of Mn phosphate and Mn sulfate. These peaks were used as reference. Second, samples of the mixture were collected on filters in the inhalation chamber at a concentration level of 3000 microg/m(3). They were analyzed by scanning electron microscopy (SEM), analytical transmission electron microscopy (ATEM), and x-ray energy-dispersive spectrometry (EDS) to show their size, morphology, and chemical composition. Results indicate that 33% of the particles were found to be agglomerated, while free particles accounted for 44% for Mn phosphate and 23% for Mn sulfate. PMID:15204770

  13. Occupational Toxicology

    Microsoft Academic Search

    J. T. Carter

    1988-01-01

    1 Toxicology plays an important part in the prevention of work related disease.2 The toxic effects of substances used at work are similar to those of other types of chemical, hence similar methods of investigation are used.3 A very wide range of substances is used at work. The conditions of use determine the degree of exposure and the likelihood of

  14. Preclinical Diastolic Dysfunction

    PubMed Central

    Wan, Siu-Hin; Vogel, Mark W.; Chen, Horng H

    2014-01-01

    Preclinical Diastolic Dysfunction (PDD) has been broadly defined as subjects with left ventricular diastolic dysfunction, without the diagnosis of congestive heart failure (HF), and with normal systolic function. PDD is an entity which remains poorly understood, yet has definite clinical significance. Although few original studies have focused on PDD, it has been shown that PDD is prevalent, and that there is a clear progression from PDD to symptomatic heart failure including dyspnea, edema, and fatigue. In diabetic patients and patients with coronary artery disease or hypertension, it has been shown that patients with PDD have a significantly higher risk of progression to heart failure and death compared to patients without PDD. Because of these findings and the increasing prevalence of the heart failure epidemic, it is clear that an understanding of PDD is essential to decreasing patients’ morbidity and mortality. This review will focus on what is known concerning preclinical diastolic dysfunction, including definitions, staging, epidemiology, pathophysiology, and the natural history of the disease. In addition, given the paucity of trials focused on PDD treatment, studies targeting risk factors associated with the development of PDD and therapeutic trials for heart failure with preserved ejection fraction will be reviewed. PMID:24291270

  15. A review of inhalation toxicology studies with para-aramid fibrils.

    PubMed

    Warheit, D B

    1995-10-01

    The paper summarizes the results of inhalation toxicology studies associated with para-aramid (p-aramid) fibrils. The review is subdivided into two categories: the results of inhalation toxicity studies and mechanistic inhalation studies. Keratin-associated lesions were observed in the lungs of female rats following chronic exposure to high concentrations of p-aramid. These lesions were originally interpreted as cystic keratinizing squamous cell carcinomas (CKSCC). In recent years, this keratinizing lesion has been observed in the lungs of rats with greater regularity in numerous chronic inhalation studies following exposures to a variety of dusts. In an attempt to reach a consensus on an appropriate diagnosis for this lesion, an international panel of pathologists was convened to evaluate the morphological aspects of this lesion. The panel considered that the most appropriate diagnosis for this lesion was 'proliferative keratin cyst' (PKC), the biological potential of the PKC remains controversial, but it appears to be unique to the rat species and has little relevance for humans. Mechanistic studies with p-aramid have demonstrated that acute inhalation of high concentrations of fibrils produces a potent but transient pulmonary inflammatory and cell labelling response. The inhaled fibrils have low durability in the lungs of rats as evidenced by a progressive decrease in median fibre lengths with increasing residence time in the lung. In contrast, in a comparative study, size-separated chrysotile asbestos produced a sustained increase over controls in cellular proliferation responses of terminal airways, parenchyma, subpleural and mesothelial regions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8526399

  16. Osteogenic Potential of Dental Mesenchymal Stem Cells in Preclinical Studies: A Systematic Review Using Modified ARRIVE and CONSORT Guidelines

    PubMed Central

    Ramamoorthi, Murali; Bakkar, Mohammed; Jordan, Jack; Tran, Simon D.

    2015-01-01

    Background and Objective. Dental stem cell-based tissue engineered constructs are emerging as a promising alternative to autologous bone transfer for treating bone defects. The purpose of this review is to systematically assess the preclinical in vivo and in vitro studies which have evaluated the efficacy of dental stem cells on bone regeneration. Methods. A literature search was conducted in Ovid Medline, Embase, PubMed, and Web of Science up to October 2014. Implantation of dental stem cells in animal models for evaluating bone regeneration and/or in vitro studies demonstrating osteogenic potential of dental stem cells were included. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to ensure the quality of the search. Modified ARRIVE (Animal research: reporting in invivo experiments) and CONSORT (Consolidated reporting of trials) were used to critically analyze the selected studies. Results. From 1914 citations, 207 full-text articles were screened and 137 studies were included in this review. Because of the heterogeneity observed in the studies selected, meta-analysis was not possible. Conclusion. Both in vivo and in vitro studies indicate the potential use of dental stem cells in bone regeneration. However well-designed randomized animal trials are needed before moving into clinical trials.

  17. In vitro release--in vivo microbiological and toxicological studies on ketoconazole lipid granules.

    PubMed

    Ozyazici, Mine; Gokce, Evren Homan; Ozer, Ozgen; Ay, Zeynep; Guneri, Tamer; Ertan, Gokhan; Gokce, Goksel; Metin, Dilek Yesim; Hilmioglu, Suleyha; Durmaz, Guliz; Yalcin, Ayfer; Pekcetin, Cetin; Ozyurt, Dogan

    2007-01-01

    In some multidrug therapy programs, ketoconazole (KTZ) may be administered with some antacids that could modify its dissolution rate and reduce its absorption, thus leading to therapeutic failures. The primary aim of this study was to evaluate the influence of Compritol HD5 ATO and Compritol 888 ATO on this interaction in comparison with commercial KTZ tablets. The second aim was to prepare lipid granules of KTZ that could be an alternative to the commercial formulation. Therefore, six KTZ sustained-release granules were prepared with different lipid concentrations, because they were found to be more suitable than tablets that are dissolved only in gastric medium. The results confirmed that the dissolution rate of KTZ granules was significantly reduced in the presence of antacids. The ideal formulation was selected as granules including 5% of Compritol lipids in relation to the suitability of the target profile. Therapeutic effects of orally administered, ideal KTZ granule formulations, and commercial tablets were evaluated in vivo by the experimental model of murine vulvo-vaginal candidiasis (VVC) with and without antacids. It was found that formulations were very effective on VVC, and the therapeutic effect decreased significantly in the presence of antacids. Histopathological studies were carried out for vagina, stomach, and liver tissues and hepatoxicity was also examined. The levels of reduced glutathione (GSH) were measured to assess the oxidative stress induced by KTZ and function of the liver. It was observed that orally administered formulations of KTZ were successful in treating candidiasis in mice without irritancy in stomach. However, liver tissues were damaged. The decreased GSH levels indicated toxicity in our study. This study suggested that in vitro release and in vivo microbiological-toxicological properties of KTZ were affected by antacids and drug-excipient interactions. Lipid granules of KTZ prepared with Compritol 888 ATO could be proposed as a new KTZ solid dosage form with optimum dissolution and therapeutic characteristics. PMID:18161631

  18. Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics

    PubMed Central

    Newell, D R; Burtles, S S; Fox, B W; Jodrell, D I; Connors, T A

    1999-01-01

    Preclinical toxicology studies are performed prior to phase I trials with novel cancer therapeutics to identify a safe clinical starting dose and potential human toxicities. The primary aim of this study was to evaluate the ability of rodent-only toxicology studies to identify a safe phase I trial starting dose. In addition, the ability of murine studies to predict the quantitative and qualitative human toxicology of cancer therapeutics was studied. Data for 25 cancer drugs were collated for which the preclinical and clinical routes and schedules of administration were either the same (22/25), or closely matched. The maximum tolerated dose/dose lethal to 10% of mice (MTD/LD10) was identified for 24 drugs, and in patients the maximum administered dose (MAD) was associated with dose-limiting toxicity (DLT) in initial clinical trials with 20 compounds. In addition, for 13 agents, the toxicity of the drug at one-tenth the mouse MTD/LD10 was also investigated in rats, following repeated administration (20 doses). A phase I trial starting dose of one-tenth the mouse MTD/LD10 (mg m–2) was, or would have been, safe for all 25 compounds. With the exception of nausea and vomiting, which cannot be assessed in rodents, other common DLTs were accurately predicted by the murine studies (i.e. 7/7 haematological and 3/3 neurological DLTs). For two of the 13 drugs studied in rats, repeated administration of one-tenth the mouse MTD/LD10 was toxic, leading to a reduction in the phase I trial starting dose; however, one-tenth the mouse MTD/LD10 was subsequently tolerated in patients. For the 20 drugs where clinical DLT was reached, the median ratio of the human MAD to the mouse MTD/LD10 was 2.6 (range 0.2–16) and the median ratio of the clinical starting dose to the MAD was 35 (range 2.3–160). In contrast, in 13 subsequent phase I trials with 11 of the initial 25 drugs, the median ratio of the clinical starting dose to the MAD was 2.8 (range 1.6–56), emphasizing the value of early clinical data in rapidly defining the dose range for therapeutic studies. For all 25 drugs studied, rodent-only toxicology provided a safe and rapid means of identifying the phase I trial starting dose and predicting commonly encountered DLTs. This study has shown that the routine use of a non-rodent species in preclinical toxicology studies prior to initial clinical trials with cancer therapeutics is not necessary. © 1999 Cancer Research Campaign PMID:10555743

  19. The contribution of regional gray/white matter volume in preclinical depression assessed by the Automatic Thoughts Questionnaire: a voxel-based morphometry study.

    PubMed

    Cun, Lingli; Wang, Yanqiu; Zhang, Songyan; Wei, Dongtao; Qiu, Jiang

    2014-09-10

    Negative automatic thought is a characteristic of depression that contributes toward the risk for episodes of depression. Evidence suggests that gray and white matter abnormalities are linked with depression, but little is known about the association between the negative cognitive experience and brain structure in preclinical depression. We examined the correlation between negative thought and gray (GMV)/white matter volume (WMV) in healthy individuals with preclinical depression. The participants were 309 university students with preclinical depression, as measured by their Automatic Thoughts Questionnaire (ATQ) scores. We collected brain MRIs and used voxel-based morphometry to analyze the correlation of regional GMV/WMV with the ATQ scores. The voxel-based morphometry results showed that the GMV of the right parahippocampal gyrus and fusiform gyrus and the WMV of the right superior temporal pole increased with the severity of depression. Furthermore, the corpus callosum volume decreased with the ATQ scores. This study implied that GMV increase and corpus callosum volume reduction may be associated with negative thought in nonclinical individuals, even at a preclinical depressed level. PMID:24999908

  20. The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides.

    PubMed

    Holt, Jonathon D S; Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

    2015-07-01

    When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. PMID:25845860

  1. INTEGRATED TECHNOLOGY-BASED TOXICOLOGY STUDIES ON DRINKING WATER DISINFECTION BYPRODUCTS (DBPS)

    EPA Science Inventory

    DBPs are formed by reactions of chemical disinfectants with natural organic matter in the source water. Although more than 300 DBPs are known, many remain unidentified; for chlorination, known DBPs account for ~50% of the mass of total organic halide. Toxicological evaluation o...

  2. Estimation and hypothesis testing of treatment effects in animal reproductive toxicology studies

    Microsoft Academic Search

    Kao-Tai Tsai; Jiann-Ping Hsu

    1994-01-01

    Healy (1) and Dempster et al. (8) proposed statistical methods to evaluate the treatment effects in animal reproductive toxicology research. Both methods assume homogeneous variance for the dams and the pups, respectively, in all the treatment groups. In this paper, via mixed effect modeling, we propose a method to estimate the treatment effects allowing heterogeneous variances for the dams and

  3. Chemical and toxicological studies of coal gasification wastewater circulated through a cooling tower

    SciTech Connect

    Stetter, J.R.; Stamoudis, V.C.; Flotard, R.D.; Reilly, C.A., Jr.; Wilzbach, K.E.

    1984-08-01

    Argonne National Laboratory is studying health and environmental issues related to coal gasification, using data and samples from the oxygen-blown slagging fixed-bed gasifier at the University of North Dakota Energy Research Center (UNDERC). The pilot study reported here developed preliminary chemical and toxicological data needed to evaluate the health and environmental, as well as the process, implications of using partially treated gasifier wastewater in cooling towers. This minimal-treatment process removes organic compounds by solvent extraction and removes ammonia and acid gas by steam stripping; then, without intermediate biological treatment, the wastewater is reused in a cooling tower. Samples were collected of both the influent wastewater to the cooling tower and the effluent in the tower's blowdown pipeline. These samples were analyzed for the presence of organic chemicals and trace metals and tested for mutagenic and teratologic activity. Results indicate that the UNDERC solvent-extracted and steam-stripped coal gasification wastewaters doe not contain any easily observed mutagenic or cytotoxic activity. The blowdown water sampled was not cytotoxic or mutagenic after phenol removal and ten-fold concentration. Initial indications are that UNDEREC cooling tower blowdown water may contain teratogenically active compounds. Phenolic material is volatilized in the cooling tower and 85 to 90% is lost as a vapor effluent. Probably less than 10% oxidative degradation of phenols occurs in the UNDERC cooling tower. Hydantoins and most inorganic elements are concentrated in the blowdown water approximately ten-fold, as expected. Trace element distributions of zinc and lead in the blowdown water are not as predicted and are unexplained. The aerodynamic size of the drift aerosol may be 12 ..mu..m or greater, depending on the characteristics of the cooling tower's eliminators. 26 references, 2 figures, 13 tables.

  4. The underlying toxicological mechanism of chemical mixtures: A case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum

    SciTech Connect

    Tian, Dayong [State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China); Department of Chemical and Environmental Engineering, Anyang Institute of Technology, Anyang 455000 (China); Lin, Zhifen, E-mail: lzhifen@tongji.edu.cn [State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China); Zhou, Xianghong [Department of Public Management, Tongji University, Shanghai 200092 (China); Yin, Daqiang [Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China)

    2013-10-15

    Intracellular chemical reaction of chemical mixtures is one of the main reasons that cause synergistic or antagonistic effects. However, it still remains unclear what the influencing factors on the intracellular chemical reaction are, and how they influence on the toxicological mechanism of chemical mixtures. To reveal this underlying toxicological mechanism of chemical mixtures, a case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum was employed, and both their joint effects and mixture toxicity were observed. Then series of two-step linear regressions were performed to describe the relationships between joint effects, the expected additive toxicities and descriptors of individual chemicals (including concentrations, binding affinity to receptors, octanol/water partition coefficients). Based on the quantitative relationships, the underlying joint toxicological mechanisms were revealed. The result shows that, for mixtures with their joint effects resulting from intracellular chemical reaction, their underlying toxicological mechanism depends on not only their interaction with target proteins, but also their transmembrane actions and their concentrations. In addition, two generic points of toxicological mechanism were proposed including the influencing factors on intracellular chemical reaction and the difference of the toxicological mechanism between single reactive chemicals and their mixtures. This study provided an insight into the understanding of the underlying toxicological mechanism for chemical mixtures with intracellular chemical reaction. - Highlights: • Joint effects of nitriles and aldehydes at non-equitoxic ratios were determined. • A novel descriptor, ligand–receptor interaction energy (E{sub binding}), was employed. • Quantitative relationships for mixtures were developed based on a novel descriptor. • The underlying toxic mechanism was revealed based on quantitative relationships. • Two generic points of toxicological mechanism were elucidated.

  5. Toxicology 1: Toxicology and Living Systems

    NSDL National Science Digital Library

    American Association for the Advancement of Science (; )

    2005-06-13

    In the first lesson, Toxicology 1: Toxicology and Living Systems, students are introduced to the basic concepts and terminology of the science. Toxicology 2: Finding the Toxic Dose allows students the opportunity to conduct a toxicology experiment on a plant. Specifically, students determine the toxic dose of a chemical that will inhibit seed germination in Brassica rapa, a relative to cabbages and mustards. In the third lesson, Toxicology 3: Toxicology and Human Health, students investigate the effect of environmental tobacco smoke on human lung development. These lessons can be done in a series or they can stand alone.

  6. Preclinical Studies of the Chinese Herbal Medicine formulation PHY906 as a Potential Adjunct to Radiation Therapy

    PubMed Central

    Rockwell, Sara; Grove, Tina A.; Liu, Yanfeng; Cheng, Yung-Chi; Higgins, Susan A; Booth, Carmen J

    2013-01-01

    Purpose/Objectives Abdominal and pelvic radiotherapy is limited by the radiosensitivity of the small and large intestine. PHY906, a state-of-the-art adaptation of a traditional Chinese medicine, decreased intestinal injury from chemotherapy in preclinical studies and is in clinical trials with chemotherapy. This project assessed whether PHY906 would also reduce intestinal injury from whole-abdomen irradiation in mice. Materials/Methods BALB/c mice received whole-abdomen irradiation (2 Gy/day) ± PHY906 by oral gavage twice daily for 4 days. Intestinal injury was assayed by physiological observations and histological studies. Effects of PHY906 on tumor radiation response were assayed in tumor growth studies. Results PHY906 decreased the toxicity of fractionated abdominal irradiation. Radiation alone produced marked blunting and loss of villi, crypt loss, crypt hyperplasia and irregular crypt morphology, which were reduced by PHY906. The radiation-induced reduction in viable crypt counts was also mitigated by PHY906. PHY906 did not alter radiation-induced weight loss, but resulted in more rapid recovery. PHY906 did not alter growth, local invasion or metastatic spread of EMT6 mouse mammary tumors or protect tumors from growth delays produced by single-dose and fractionated irradiation. Conclusion In this mouse model system, PHY906 decreased the toxicity of abdominal irradiation, without protecting tumors, thereby increasing the therapeutic ratio. PMID:22856538

  7. Comparative plasma exposure and lung distribution of two human use commercial azithromycin formulations assessed in murine model: a preclinical study.

    PubMed

    Rivulgo, Virginia; Sparo, Mónica; Ceci, Mónica; Fumuso, Elida; Confalonieri, Alejandra; Delpech, Gastón; Bruni, Sergio F Sánchez

    2013-01-01

    Azithromycin (AZM) therapeutic failure and relapses of patients treated with generic formulations have been observed in clinical practice. The main goal of this research was to compare in a preclinical study the serum exposure and lung tissue concentration of two commercial formulations AZM-based in murine model. The current study involved 264 healthy Balb-C. Mice were divided into two groups (n = 44): animals of Group A (reference formulation -R-) were orally treated with AZM suspension at 10 mg/kg of b.w. Experimental animals of Group B (generic formulation -G-) received identical treatment than Group A with a generic formulation AZM-based. The study was repeated twice as Phase II and III. Serum and lung tissue samples were taken 24 h post treatment. Validated microbiological assay was used to determine the serum pharmacokinetic and lung distribution of AZM. After the pharmacokinetic analysis was observed, a similar serum exposure for both formulations of AZM assayed. In contrast, statistical differences (P < 0.001) were obtained after comparing the concentrations of both formulations in lung tissue, being the values obtained for AUC and Cmax (AZM-R-) +1586 and 122%, respectively, than those obtained for AZM-G- in lung. These differences may indicate large differences on the distribution process of both formulations, which may explain the lack of efficacy/therapeutic failure observed on clinical practice. PMID:24073402

  8. Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

    PubMed Central

    Consalvi, Silvia; Mozzetta, Chiara; Bettica, Paolo; Germani, Massimiliano; Fiorentini, Francesco; Del Bene, Francesca; Rocchetti, Maurizio; Leoni, Flavio; Monzani, Valmen; Mascagni, Paolo; Puri, Pier Lorenzo; Saccone, Valentina

    2013-01-01

    Previous work has established the existence of dystrophin–nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice—the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients. PMID:23552722

  9. MR imaging-detectable metabolic alterations in attention deficit/hyperactivity disorder: from preclinical to clinical studies.

    PubMed

    Altabella, L; Zoratto, F; Adriani, W; Canese, R

    2014-06-01

    MR spectroscopy represents one of the most suitable in vivo tool to assess neurochemical dysfunction in several brain disorders, including attention deficit/hyperactivity disorder. This is the most common neuropsychiatric disorder in childhood and adolescence, which persists into adulthood (in approximately 30%-50% of cases). In past years, many studies have applied different MR spectroscopy techniques to investigate the pathogenesis and effect of conventional treatments. In this article, we review the most recent clinical and preclinical MR spectroscopy results on subjects with attention deficit/hyperactivity disorder and animal models, from childhood to adulthood. We found that the most investigated brain regions were the (pre)frontal lobes and striatum, both involved in the frontostriatal circuits and networks that are known to be impaired in this pathology. Neurometabolite alterations were detected in several regions: the NAA, choline, and glutamatergic compounds. The creatine pool was also altered when an absolute quantitative protocol was adopted. In particular, glutamate was increased in children with attention deficit/hyperactivity disorder, and this can apparently be reversed by methylphenidate treatment. The main difficulties in reviewing MR spectroscopy studies were in the nonhomogeneity of the analyzed subjects, the variety of the investigated brain regions, and also the use of different MR spectroscopy techniques. As for possible improvements in future studies, we recommend the use of standardized protocols and the analysis of other brain regions of particular interest for attention deficit hyperactivity disorder, like the hippocampus, limbic structures, thalamus, and cerebellum. PMID:24481327

  10. A comparative study of the toxicological aspects of vanadium pentoxide and vanadium oxide nanoparticles.

    PubMed

    Kulkarni, Apoorva; Kumar, Goru Santosh; Kaur, Jasmine; Tikoo, Kulbhushan

    2014-11-01

    Indiscriminate use of vanadium oxide nanoparticles (NPs) in steel industries and their release during combustion of fossil fuels makes it essential to study their toxic potential. Herein, we assessed the toxicological effects of two types of in-house synthesized vanadium oxide NPs in Wistar rats exposed to NPs through inhalation route. V2O5 and VO2 NPs exhibited rod and spherical symmetry, respectively with a mean diameter of 50±20 and 30±10?nm. Assessment of bronchoalveolar lavage fluid parameters demonstrated that VO2 NP-exposed animals had higher levels of lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase as compared to V2O5 NP-exposed animals. The levels of oxidative stress markers malondialdehyde and reduced glutathione also indicated higher toxic potential of VO2 NPs. Moreover, after 7-day recovery, the levels of the above parameters were closer to normal levels only in V2O5-exposed animals. Interestingly, histopathological and immune-histopathology analysis (TNF-?) of lung tissue showed higher damage and inflammatory response in VO2 NP-exposed animals, which persisted even after 7 days of recovery period. Surprisingly, the carcinogenic potential of vanadium oxide NPs came into light which was indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay as well as the decreased levels of p53 and Bax, in lung tissue of NP-exposed animals. Notably, the physiochemical characterization of NPs, especially the shape and the size, play a central role in shaping the toxicity of these NPs and thus should be extensively evaluated for outlining the regulatory guidelines. PMID:25296879

  11. Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment.

    PubMed

    Naksuriya, Ornchuma; Okonogi, Siriporn; Schiffelers, Raymond M; Hennink, Wim E

    2014-03-01

    Curcumin, a natural yellow phenolic compound, is present in many kinds of herbs, particularly in Curcuma longa Linn. (turmeric). It is a natural antioxidant and has shown many pharmacological activities such as anti-inflammatory, anti-microbial, anti-cancer, and anti-Alzheimer in both preclinical and clinical studies. Moreover, curcumin has hepatoprotective, nephroprotective, cardioprotective, neuroprotective, hypoglycemic, antirheumatic, and antidiabetic activities and it also suppresses thrombosis and protects against myocardial infarction. Particularly, curcumin has demonstrated efficacy as an anticancer agent, but a limiting factor is its extremely low aqueous solubility which hampers its use as therapeutic agent. Therefore, many technologies have been developed and applied to overcome this limitation. In this review, we summarize the recent works on the design and development of nano-sized delivery systems for curcumin, including liposomes, polymeric nanoparticles and micelles, conjugates, peptide carriers, cyclodextrins, solid dispersions, lipid nanoparticles and emulsions. Efficacy studies of curcumin nanoformulations using cancer cell lines and in vivo models as well as up-to-date human clinical trials are also discussed. PMID:24439402

  12. Common Handling Procedures Conducted in Preclinical Safety Studies Result in Minimal Hepatic Gene Expression Changes in Sprague-Dawley Rats

    PubMed Central

    Werner, Jon; Everds, Nancy; Di Palma, Chris; Chen, Yuan; Higgins-Garn, Marnie; Tran, Sandra; Afshari, Cynthia A.; Hamadeh, Hisham K.

    2014-01-01

    Gene expression profiling is a tool to gain mechanistic understanding of adverse effects in response to compound exposure. However, little is known about how the common handling procedures of experimental animals during a preclinical study alter baseline gene expression. We report gene expression changes in the livers of female Sprague-Dawley rats following common handling procedures. Baseline gene expression changes identified in this study provide insight on how these changes may affect interpretation of gene expression profiles following compound exposure. Rats were divided into three groups. One group was not subjected to handling procedures and served as controls for both handled groups. Animals in the other two groups were weighed, subjected to restraint in Broome restrainers, and administered water via oral gavage daily for 1 or 4 days with tail vein blood collections at 1, 2, 4, and 8 hours postdose on days 1 and 4. Significantly altered genes were identified in livers of animals following 1 or 4 days of handling when compared to the unhandled animals. Gene changes in animals handled for 4 days were similar to those handled for 1 day, suggesting a lack of habituation. The altered genes were primarily immune function related genes. These findings, along with a correlating increase in corticosterone levels suggest that common handling procedures may cause a minor immune system perturbance. PMID:24551150

  13. [Preclinical study of AV0012 early stage inhibitor of hepatitis C virus infection: I. In vitro ADME and pharmacokinetics].

    PubMed

    Ivashchenko, A V; Iamanushkin, P M; Mit'kin, O D; Ezhova, E V; Korzinov, O M; Shevkun, N A; Koriakova, A G; Karapetian, R N; Bychko, V V; Ivashchenko, A A; Agrba, V Z; Lapin, B A; Orlov, S V

    2014-01-01

    In vitro immunohistochemical investigations on the human hepatoma cell line (Huh7) infected with hepatitis C virus (HCV) strain JFH-1 showed that AV0012 compound blocks the early stages of viral infection. AV0012 also blocked viral infection spread in tissue culture through the secreted virus and through tight cell-to-cell contact. AV0012 is a specific inhibitor of HCV but not of related pestivirus, flaviviruses and other RNA-containing viruses such as bovine diarrhea (BVDV), Venezuelan equine encephalitis (strain TC-83), dengue type 2 (New Guinea), yellow fever (strain 17D), west Nile fever, parainfluenza (type 3) virus, RSV (strain A2), and Rhinovirus (type 2 strain HGP). It is established that human serum does not significantly affect the antiviral activity of AV0012 in vitro. The drug combination studies with AV0012 and interferon alpha 2a in vitro showed that the two inhibitors act additively, which makes possible the use of this combination in clinical tests. AV0012 is highly soluble and stable in aqueous solutions and murine blood plasma, has limited metabolic stability, low binding to human plasma proteins, high permeability through biological membranes, and only interacts with isoenzymes 2D6 and 3A4 of human cytochrome P450. In animal pharmacokinetic studies, AV0012 was rapidly absorbed into the blood stream upon oral administration, showed sufficiently long half-elimination times, and had high oral bioavailability that reached 92% in monkeys. Further preclinical development of AV0012 is in progress. PMID:25076758

  14. [Preclinical study of immunocorrection action of the sum of active substances of Coluria geoides (Pall.) Ledeb. (Rosaceae)].

    PubMed

    Dutova, S V; Karpova, M R; Myadelets, M A; Myasnaya, N V; Sherstoboev, E Yu

    2015-01-01

    A preclinical study of the immunocorrection action of the sum of active substances isolated from ethereal-oil plants Coluria geoides (Pall.) Ledeb. (Rosaceae family) with respect to experimental immunodeficiency showed that preparations relieve symptoms of immunodeficiency caused by the administration of cyclophosphan: suppressed synthesis of anti-erythrocyte antibodies (agglutinine) and proliferative processes in the spleen. Under the influence of C. geoides preparations, the absolute numbers of cariocytes and antibody forming cells in spleen significantly increased (compared to the group of animals with experimental immunodeficiency) and in some cases reached the background level. The drugs studied produced a more pronounced stimulating effect on the synthesis of specific immunoglobulins and proliferation of antibody forming cells of spleen as compared to the effect of Echinacea tincture. Preparation C-2 (extract from underground organs and grass of C. geoides obtained by percolation method with 70% ethanol) is most promising for in-depth research and the development of new effective drugs with immunocorrecting properties. PMID:26036007

  15. PHARMACOLOGY AND TOXICOLOGY GRADUATE GROUP BY-LAWS Administrative Home: Department of Environmental Toxicology

    E-print Network

    Ullrich, Paul

    PHARMACOLOGY AND TOXICOLOGY GRADUATE GROUP BY-LAWS Administrative Home: Department of Environmental in Pharmacology and Toxicology (hereafter referred to as the Group) is organized primarily to establish in Pharmacology and Toxicology, in conformance with the rules of the Office of Graduate Studies of the Davis

  16. Toxicology of Biodiesel Combustion products

    EPA Science Inventory

    1. Introduction The toxicology of combusted biodiesel is an emerging field. Much of the current knowledge about biological responses and health effects stems from studies of exposures to other fuel sources (typically petroleum diesel, gasoline, and wood) incompletely combusted. ...

  17. Analytical toxicology.

    PubMed

    Maurer, Hans H

    2010-01-01

    This paper reviews procedures for screening, identification and quantification of drugs, poisons and their metabolites in biosamples, and the corresponding work-up procedures. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry are mostly used today in analytical toxicology. Selection of the most appropriate biosample, e.g., ante/postmortem blood, urine, or tissues or alternative matrices like hair, sweat and oral fluid, nails or meconium, is discussed. The importance of quality control and possibilities and limitations of interpretation of the analytical result are also discussed. PMID:20358688

  18. Timely toxicology.

    PubMed Central

    Medlin, J F

    1999-01-01

    The ToxChip, a DNA microarray chip, allows the monitoring of the expression levels of thousands of different genes at a time, thereby condensing months of painstaking laboratory tasks into a day's work. For toxicology researchers in particular, this tool is important because it promises a more effective way to identify environmental hazards and their effects on DNA. The ToxChip, developed by NIEHS scientists J. Carl Barrett, Cynthia Afshari, and Emile F. Nuwaysir, could transform the way toxicologists approach environmental problems. PMID:10210703

  19. The Relationship between Risk of Bias Criteria, Research Outcomes, and Study Sponsorship in a Cohort of Preclinical Thiazolidinedione Animal Studies: A Meta-Analysis

    PubMed Central

    Abdel-Sattar, Maher; Krauth, David; Anglemyer, Andrew; Bero, Lisa

    2015-01-01

    Introduction There is little evidence regarding the influence of conflicts of interest on preclinical research. This study examines whether industry sponsorship is associated with increased risks of bias and/or effect sizes of outcomes in published preclinical thiazolidinedione (TZD) studies. Methods We identified preclinical TZD studies published between January 1, 1965 and November 14, 2012. Coders independently extracted information on study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties from the 112 studies meeting the inclusion criteria. The average standardized mean difference (SMD) across studies was calculated for plasma glucose (efficacy outcome) and weight gain (harm outcome). In subgroup analyses, TZD outcomes were assessed by sponsorship source and risk of bias criteria. Results Seven studies were funded by industry alone, 17 studies funded by both industry and non-industry, 49 studies funded by non-industry alone, and 39 studies had no disclosures. None of the studies used sample size calculations, intention-to-treat analyses, blinding of investigators, or concealment of allocation. Most studies reported favorable results (88 of 112) and conclusions (95 of 112) supporting TZD use. Efficacy estimates were significantly larger in 6 studies sponsored by industry alone (?3.41; 95% CI ?5.21, ?1.53; I2 = 93%) versus 42 studies sponsored by non-industry sources (?0.97; 95% CI ?1.37, ?0.56; I2 = 81%) (p value = 0.01). Harms estimates were significantly larger in 4 studies sponsored by industry alone (5.00; 95% CI 1.22, 8.77; I2 = 93%) versus 38 studies sponsored by non-industry sources (0.30; 95% CI ?0.08, 0.68; I2 = 79%) (p value = 0.02). TZD efficacy and harms did not differ by disclosure of financial COIs or risks of bias. Conclusions Industry-sponsored TZD animal studies have exaggerated efficacy and harms outcomes compared to studies funded by non-industry sources. There was poor reporting of COIs. PMID:25642330

  20. Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees

    Microsoft Academic Search

    Dakshitha P Wickramasinghe; Dharmabandu N Samarasekera

    2011-01-01

    Background  Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA), strategic\\u000a approach (SA) and surface apathetic or superficial approach (SAA). The aim of this study was to identify factors affecting\\u000a the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in\\u000a the pattern of study

  1. Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment.

    PubMed

    Johnson, G E; Soeteman-Hernández, L G; Gollapudi, B B; Bodger, O G; Dearfield, K L; Heflich, R H; Hixon, J G; Lovell, D P; MacGregor, J T; Pottenger, L H; Thompson, C M; Abraham, L; Thybaud, V; Tanir, J Y; Zeiger, E; van Benthem, J; White, P A

    2014-10-01

    Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose-response data (Gollapudi et al., 2013), here we present analyses of 1-ethyl-1-nitrosourea (ENU) and 1-methyl-1-nitrosourea (MNU) dose-response data and additional approaches for the determination of genetic toxicity point-of-departure (PoD) metrics. We previously described methods to determine the no-observed-genotoxic-effect-level (NOGEL), the breakpoint-dose (BPD; previously named Td), and the benchmark dose (BMD10 ) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non-linear slope-transition-dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL10 and BMDL1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL10 values were often lower than the other PoDs, and the distribution of BMDL10 values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. PMID:24801602

  2. Boswellic acids and glucosamine show synergistic effect in preclinical anti-inflammatory study in rats

    Microsoft Academic Search

    Surjeet Singh; Anamika Khajuria; Subhash Chandra Taneja; Ravi Kant Khajuria; Jaswant Singh; Ghulam Nabi Qazi

    2007-01-01

    The present study revealed the synergistic effect of boswellic acid mixture (BA) and glucosamine for anti-inflammatory and anti-arthritic activities in rats. Two studies were conducted, that is, acute anti-inflammatory by carrageenan edema and chronic anti-arthritic by Mycobacterium-induced developing arthritis. Five groups of animals were included in each of the study: the vehicle control, positive control (ibuprofen 100mg\\/kg), boswellic acids (250mg\\/kg),

  3. Improved bioavailability of aceclofenac from spherical agglomerates: development, in vitro and preclinical studies.

    PubMed

    Muatlik, S; Usha, A N; Reddy, M S; Ranjith, A K; Pandey, S

    2007-07-01

    The objective of present study was to improve the solubility, dissolution rate, micromeritic properties and bioavailability of aceclofenac (NSAID) by formulating its spherical agglomerates. They were prepared with different water soluble polymers (polyvinylpyrrolidone-K30, polyvinylpyrrolidone-K90 and sodium alginate) by using acetone-water-dichloromethane solvent system. The agglomerates were subjected to various physicochemical properties, DSC, IR spectroscopy, scanning electron microscopy (SEM), micromeritic properties and dissolution studies. The in vivo studies (anti-inflammatory, analgesic and pharmacokinetic studies) were conducted in Wistar rats and Swiss albino mice. SEM studies showed that agglomerates were spherical in structure and formed by cluster of small crystals. The agglomerates prepared with polyvinylpyrrolidone-K90 exhibited improved solubility, dissolution rate and micromeritic properties compared to those prepared with other polymers and pure drug. These optimized agglomerates showed rapid analgesic and anti-inflammatory activity besides exhibiting improved bioavailability of drug when compared to pure drug. PMID:17545107

  4. Apoptosis as a determinant of tumor sensitivity to topotecan in human ovarian tumors: preclinical in vitro/in vivo studies.

    PubMed

    Caserini, C; Pratesi, G; Tortoreto, M; Bedogné, B; Carenini, N; Supino, R; Perego, P; Righetti, S C; Zunino, F

    1997-06-01

    Preclinical and clinical studies have documented the pharmacological interest in camptothecin derivatives in the treatment of resistant tumors. In particular, topotecan, a water-soluble derivative, exhibited promising activity in pretreated ovarian carcinoma. The present study investigated the pattern of tumor response in two human ovarian carcinoma xenografts and in their cisplatin-resistant sublines characterized by different mechanisms of drug resistance. In IGROV-1/Pt1 cells, cisplatin resistance has been ascribed to a reduced susceptibility to apoptosis as a consequence of p53 mutation and inactivation of its function. In the A2780 cisplatin-resistant subline, which retained the wild-type p53 gene status, the development of resistance has been possibly related to increased cell ability to repair drug-induced DNA damage. The in vivo results of the present study showed that topotecan could overcome the resistance in A2780/CP but not in IGROV-1/Pt1 tumor xenografts. The pattern of tumor response following in vivo topotecan treatment correlated with drug ability to induce apoptosis but not with its in vitro antiproliferative activity. The antitumor efficacy of topotecan in the four tumors reflected a different cell response to drug-induced DNA damage, as suggested by different perturbations of cell cycle progression. Indeed, only in the subline refractory to topotecan in vivo, IGROV-1/Pt1, did we observe a persistent arrest of the cells in the S-phase, resulting in a cytostatic and not a cytotoxic effect, since a low level of apoptosis was induced by the drug. In conclusion, the current results support that determination of drug-induced apoptosis is a useful predictor of tumor response to topotecan in ovarian carcinomas and suggest that p53 gene status may be a critical determinant of cell response to topoisomerase inhibitors. PMID:9815771

  5. An evaluation of hERG current assay performance: Translating preclinical safety studies to clinical QT prolongation.

    PubMed

    Gintant, Gary

    2011-02-01

    Block of delayed rectifier current (I(Kr), Kv11.1 encoding the hERG gene) is associated with delayed cardiac repolarization (QTc prolongation), a surrogate marker of proarrhythmia. Despite its recognized role in assessing QTc prolongation risk, a quantitative analysis of the utility and limitations of the hERG current assay has not been reported. To benchmark hERG assay performance, this retrospective study compared hERG block potency with drug-induced QTc prolongation assessed during rigorous thorough QT (TQT) clinical studies for 39 drugs from multiple classes. To place block in context, hERG safety margins (IC(50) values for block/mean maximal plasma drug concentrations during TQT studies) were compared to QTc prolongation (QTc increase?5ms). Most (9/10) drugs eliciting essentially no hERG block at maximal concentrations demonstrate no QTc prolongation despite representing a wide hERG safety margin range. Based on receiver-operator characteristics, a hERG safety margin of 45 provided optimal overall performance linking safety margins to QTc prolongation (sensitivity (true positive rate)=0.64, specificity (true negative rate)=0.88); the area under the receiver-operator curve (0.72) is indicative of moderate overall concordance. Likelihood ratios calculated from multitier contingency tables suggest that QTc prolonging drugs are only 5-7 times as likely to demonstrate low safety margins (1-30 range) compared to drugs that do not prolong QTc. Paradoxically, higher safety margins demonstrate lesser confidence predicting prolongation. The overall limitations of hERG safety margins shown using these quantitative, evidence-based approaches highlight the need for additional preclinical assays and adaptive strategies throughout drug discovery to reliably mitigate QTc prolongation risk. PMID:20807552

  6. The Importance of Non-Human Primate Models for Preclinical Studies in Hematopoiesis

    Microsoft Academic Search

    Erzsebet Szilagyi; Nadim Mahmud; Amelia Bartholomew

    \\u000a Of all living experimental models, murine studies of hematopoiesis represent the greatest number. Such models can be undeniably\\u000a elegant reflecting the extensive technological tools available. While mice can be used to study specific genetic pedigrees,\\u000a specific physiologic, and gene pathways using knockouts, and a variety of immune responses using immunologically deficient\\u000a mice, murine models are limited in their applicability for

  7. Preclinical Studies Identify Non-Apoptotic Low-Level Caspase-3 as Therapeutic Target in Pemphigus Vulgaris

    PubMed Central

    Luyet, Camille; Schulze, Katja; Sayar, Beyza S.; Howald, Denise; Müller, Eliane J.; Galichet, Arnaud

    2015-01-01

    The majority of pemphigus vulgaris (PV) patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis). The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg) 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG), PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice) as well as PV patients’ biopsies (n=6). A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP) and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation including c-Myc induction, p38MAPK activation and acantholysis. Together, these data identify low-level caspase-3 activation downstream of disrupted Dsg3 trans- or cis-adhesion as a major event in PV pathogenesis that is non-synonymous with apoptosis and represents, unlike apoptotic components, a promising target for clinical therapy. At a broader level, these results posit that an impairment of adhesive functions in concert with low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other diseases including cancer. PMID:25748204

  8. Metabolic phenotyping applied to pre-clinical and clinical studies of acetaminophen metabolism and hepatotoxicity.

    PubMed

    Coen, Muireann

    2015-02-01

    Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF) following overdose. APAP-induced hepatotoxicity is related to the formation of an electrophilic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). One method that has been applied to study APAP metabolism and hepatotoxicity is that of metabolic phenotyping, which involves the study of the small molecule complement of complex biological samples. This approach involves the use of high-resolution analytical platforms such as NMR spectroscopy and mass spectrometry to generate information-rich metabolic profiles that reflect both genetic and environmental influences and capture both endogenous and xenobiotic metabolites. Data modeling and mining and the subsequent identification of panels of candidate biomarkers are typically approached with multivariate statistical tools. We review the application of multi-platform metabolic profiling for the study of APAP metabolism in both in vivo models and humans. We also review the application of metabolic profiling for the study of endogenous metabolic pathway perturbations in response to APAP hepatotoxicity, with a particular focus on metabolites involved in the biosynthesis of GSH and those that reflect mitochondrial function such as long-chain acylcarnitines. Taken together, this body of work sheds much light on the mechanism of APAP-induced hepatotoxicity and provides candidate biomarkers that may prove of translational relevance for improved stratification of APAP-induced ALF. PMID:25533740

  9. Choosing preclinical study models of diabetic retinopathy: key problems for consideration

    PubMed Central

    Mi, Xue-Song; Yuan, Ti-Fei; Ding, Yong; Zhong, Jing-Xiang; So, Kwok-Fai

    2014-01-01

    Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. PMID:25429204

  10. IL-2 plasmid electroporation: from preclinical studies to phase I clinical trial.

    PubMed

    Horton, Holly M; Lalor, Peggy A; Rolland, Alain P

    2008-01-01

    Electroporation (EP)-assisted intralesional delivery of Interleukin-2 (IL-2) plasmid (pDNA) has the potential to increase the local concentration of the expressed cytokine for an extended time in the injected tumors while minimizing its systemic concentration, in comparison with systemic delivery of the recombinant cytokine. Nonclinical Investigational New Drug application-enabling studies were performed in mice to evaluate the effect of intratumoral administration of murine IL-2 pDNA on local expression and systemic distribution of IL-2 transgene as well as the inhibition of established tumor growth. The safety of repeated administrations of a human IL-2 pDNA product candidate with EP was evaluated in rats. Following the nonclinical safety and efficacy studies, a human IL-2 pDNA product candidate intralesionally administered with EP to metastatic melanoma patients is currently being investigated in a phase I clinical trial. PMID:18370214

  11. Revising the high-density lipoprotein targeting strategies - insights from human and preclinical studies.

    PubMed

    Nesan, Dinushan; Ng, Dominic S

    2014-12-01

    In recent years, the high-density lipoprotein (HDL) hypothesis has been challenged. Several completed randomized clinical trials continue to fall short in demonstrating HDL, or at least HDL-cholesterol (HDL-C) levels, as being a consistent target in the prevention of cardiovascular diseases. However, population studies and findings in lipid modifying trials continue to strongly support HDL-C as a superb risk predictor. It is increasingly evident that the complexity of HDL metabolism confounds the use of HDL-C concentration as a unified target. However, important insights continue to emerge from the post hoc analyses of recently completed (i) fibrate-based FIELD and ACCORD trials, including the unexpected beneficial effect of fibrates in microvascular diseases, (ii) the niacin-based AIM-HIGH and HPS2-THRIVE studies, (iii) recombinant HDL-based as well as (iv) the completed CETP inhibitor-based trials. These together with on-going mechanistic studies on novel pathways, which include the unique roles of microRNAs, post-translational remodeling of HDL and novel pathways related to HDL modulators will provide valuable insights to guide how best to refocus and redesign the conceptual framework for selecting HDL-based targets. PMID:25115413

  12. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle.

    PubMed

    Eliasof, Scott; Lazarus, Douglas; Peters, Christian G; Case, Roy I; Cole, Roderic O; Hwang, Jungyeon; Schluep, Thomas; Chao, Joseph; Lin, James; Yen, Yun; Han, Han; Wiley, Devin T; Zuckerman, Jonathan E; Davis, Mark E

    2013-09-10

    Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans. PMID:23980155

  13. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

    PubMed Central

    Eliasof, Scott; Lazarus, Douglas; Peters, Christian G.; Case, Roy I.; Cole, Roderic O.; Hwang, Jungyeon; Schluep, Thomas; Chao, Joseph; Lin, James; Yen, Yun; Han, Han; Wiley, Devin T.; Zuckerman, Jonathan E.; Davis, Mark E.

    2013-01-01

    Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans. PMID:23980155

  14. Neural Stem Cell-Mediated Enzyme-Prodrug Therapy for Glioma: Preclinical Studies

    PubMed Central

    Aboody, Karen S.; Najbauer, Joseph; Metz, Marianne Z.; D’Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J.; Synold, Timothy W.; Couture, Larry A.; Blanchard, Suzette; Moats, Rex A.; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V.; Frank, Richard T.; Barish, Michael E.; Brown, Christine E.; Kim, Seung U.; Badie, Behnam; Portnow, Jana

    2013-01-01

    High-grade gliomas are extremely difficult to treat because they are invasive and therefore are not curable by surgical resection; the toxicity of currently chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles that can target enzyme/prodrug therapy selectively to tumors. We have used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the tumor-localized prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, indicating that these cells are genetically and functionally stable. In vivo biodistribution studies demonstrated that these NSCs retained tumor tropism, even in mice pre-treated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor bearing, and in orthotopic glioma-bearing, immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was approximately one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, non-toxic and effective in mice. These data have led to approval of a first-inhuman study of an allogeneic NSC-mediated enzyme/prodrug targeted cancer therapy in patients with recurrent high-grade glioma. PMID:23658244

  15. Novel sugar esters proniosomes for transdermal delivery of vinpocetine: preclinical and clinical studies.

    PubMed

    El-Laithy, Hanan M; Shoukry, Omar; Mahran, Laila G

    2011-01-01

    Vinpocetine (Vin) existing oral formulations suffer poor bioavailability (?7%) since Vin undergoes a marked first-pass effect (?75%) and its absorption is dissolution rate-limited. In this study, a novel sustained release proniosomal system was designed using sugar esters (SEs) as non-ionic surfactants in which proniosomes were converted to niosomes upon skin water hydration following topical application under occlusive conditions. Different in vitro aspects (encapsulation efficiency, vesicle size and shape, effect of occlusion, in vitro release, skin permeation and stability) were studied leading to an optimized formula that was assessed clinically for transdermal pharmacokinetics and skin irritation. All formulae exhibited high entrapment efficiencies, regardless of the surfactant HLB. Vesicle size analysis showed that all vesicles were in the range from 0.63 ?m to 2.52 ?m which favored efficient transdermal delivery. The extent of drug permeation through the skin from the optimized formula--containing laurate SE with shorter fatty acid chain length and high HLB--was quite high (91%) after 48 h under occlusive conditions. The extent of absorption of Vin from proniosomes was larger when compared to the oral tablet with a relative bioavailability (F(rel)) of 206%. Histopathological evaluation revealed only moderate skin irritation when using SEs compared to skin inflammation when using Tween 80. Sugar esters proniosomes may be a promising carrier for vinpocetine, especially due to their simple scaling up and their ability to control drug release. PMID:21056658

  16. A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies.

    PubMed

    Althoff, K; Beckers, A; Bell, E; Nortmeyer, M; Thor, T; Sprüssel, A; Lindner, S; De Preter, K; Florin, A; Heukamp, L C; Klein-Hitpass, L; Astrahantseff, K; Kumps, C; Speleman, F; Eggert, A; Westermann, F; Schramm, A; Schulte, J H

    2015-06-01

    Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine ?-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of >75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies. PMID:25174395

  17. A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies

    PubMed Central

    Althoff, K; Beckers, A; Bell, E; Nortmeyer, M; Thor, T; Sprüssel, A; Lindner, S; De Preter, K; Florin, A; Heukamp, L C; Klein-Hitpass, L; Astrahantseff, K; Kumps, C; Speleman, F; Eggert, A; Westermann, F; Schramm, A; Schulte, J H

    2015-01-01

    Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20–25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine ?-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of >75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17–92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies. PMID:25174395

  18. A transplantable TH-MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma.

    PubMed

    Kroesen, Michiel; Nierkens, Stefan; Ansems, Marleen; Wassink, Melissa; Orentas, Rimas J; Boon, Louis; den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

    2014-03-15

    Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild-type and Rag1(-/-) mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients. PMID:24038106

  19. Space Toxicology

    NASA Technical Reports Server (NTRS)

    James, John T.

    2011-01-01

    Safe breathing air for space faring crews is essential whether they are inside an Extravehicular Mobility Suit (EMU), a small capsule such as Soyuz, or the expansive International Space Station (ISS). Sources of air pollution can include entry of propellants, excess offgassing from polymeric materials, leakage of systems compounds, escape of payload compounds, over-use of utility compounds, microbial metabolism, and human metabolism. The toxicological risk posed by a compound is comprised of the probability of escaping to cause air pollution and the magnitude of adverse effects on human health if escape occurs. The risk from highly toxic compounds is controlled by requiring multiple levels of containment to greatly reduce the probability of escape; whereas compounds that are virtually non-toxic may require little or no containment. The potential for toxicity is determined by the inherent toxicity of the compound and the amount that could potentially escape into the breathing air.

  20. Preclinical studies of [61Cu]ATSM as a PET radiopharmaceutical for fibrosarcoma imaging.

    PubMed

    Jalilian, Amir R; Rostampour, Nima; Rowshanfarzad, Pejman; Shafaii, Kamaleddin; Kamali-Dehghan, Mohsen; Akhlaghi, Mehdi

    2009-03-01

    [61Cu]diacetyl-bis(N4-methylthiosemicarbazone) ([61Cu] ATSM) was prepared using in house-made diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) ligand and [61Cu]CuCl2 produced via the natZn(p, x)61Cu (180 muA proton irradiation, 22 MeV, 3.2 h) and purified by a ion chromatography method. [61Cu]ATSM radiochemical purity was >98 %, as shown by HPLC and RTLC methods. [61Cu]ATSM was administered into normal and tumor bearing rodents for up to 210 minutes, followed by biodistribution and co-incidence imaging studies. Significant tumor/non-tumor accumulation was observed either by animal sacrification or imaging. [61Cu]ATSM is a positron emission tomography (PET) radiotracer for tumor hypoxia imaging. PMID:19304557

  1. Preclinical studies on histone deacetylase inhibitors as therapeutic reagents for endometrial and ovarian cancers

    PubMed Central

    Singh, Brahma N; Zhou, Hongyuan; Li, Jinping; Tipton, Tracy; Wang, Bin; Shao, Guo; Gilbert, E Nickolas; Li, Qiang; Jiang, Shi-Wen

    2012-01-01

    Histone deacetylases (HDACs) remove acetyl groups from lysine residues of histones and the deacetylation allows for tighter electrostatic interactions between DNA and histones, leading to a more compact chromatin conformation with limited access for transactivators and the suppression of transcription. HDAC mRNA and protein overexpression was observed in endometrial and ovarian cancers. Numerous in vitro studies have shown that HDAC inhibitors, through their actions on histone and nonhistone proteins, are able to reactivate the tumor suppressor genes, inhibit cell cycle progression and induce cell apoptosis in endometrial and ovarian cancer cell cultures. Results from mou se xenograft models also demonstrated the potency of HDAC inhibitors as anticancer reagents when used as single agent or in combination with classical chemotherapy drugs. PMID:22112317

  2. Treating the Developing versus Developed Brain: Translating Preclinical Mouse and Human Studies.

    PubMed

    Casey, B J; Glatt, Charles E; Lee, Francis S

    2015-06-17

    Behaviors and underlying brain circuits show characteristic changes across the lifespan that produce sensitive windows of vulnerability and resilience to psychopathology. Understanding the developmental course of these changes may inform which treatments are best at what ages. Focusing on behavioral domains and neurobiological substrates conserved from mouse to human supports reciprocal hypothesis generation and testing that leverages the strengths of each system in understanding their development. Introducing human genetic variants into mice can further define effects of individual variation on normative development, how they contribute to risk and resilience for mental illness, and inform personalized treatment opportunities. This article emphasizes the period of adolescence, when there is a peak in the emergence of mental illness, anxiety disorders in particular. We present cross-species studies relating fear learning to anxiety across development and discuss how clinical treatments can be optimized for individuals and targeted to the biological states of the developing brain. PMID:26087163

  3. Physiology and Endocrinology Symposium: FGF21: Insights into mechanism of action from preclinical studies.

    PubMed

    Antonellis, P J; Kharitonenkov, A; Adams, A C

    2014-02-01

    Fibroblast growth factor 21 (FGF21) is a multifaceted metabolic regulator which has several potential applications in the treatment of metabolic disease. When administered in vivo, FGF21 exhibits a plethora of actions, modulating metabolic homeostasis in a diverse manner. However, the mechanism and site of action underlying these effects were, until recently, entirely uncertain. Using mouse models lacking either FGF receptor isoform 1 (FGFR1) or ?Klotho (KLB), a transmembrane co-factor critical for FGF21 action, our group and others sought to determine the tissue on which FGF21 acts and the receptor complex responsible for mediating its in vivo efficacy. Importantly, when KLB was ablated from all tissues mice were completely refractory to FGF21 action. Therefore, to determine the precise tissue of action we utilized mice with tissue specific deletion of FGFR1 in either adipose tissue or neurons, respectively. Surprisingly, in animals with neuronal FGFR1 loss there was no change in the metabolic activity of FGF21, suggesting a lack of central FGF21 action in the pharmacologic setting. In contrast, we found dramatic attenuation of metabolic efficacy in mice with adipose-specific FGFR1 ablation following either acute or chronic dosing with recombinant FGF21. Furthermore, several recent studies have suggested that the metabolic effects of FGF21 may occur via modulation of adipokines such as adiponectin and leptin. Importantly, the action of FGF21 via adipose tissue results in alterations in both secretion as well as systemic sensitivity to these factors. Therefore, while FGF21 itself does not seem to directly act on the CNS, leptin and other endocrine mediators may serve as intermediary facilitators of FGF21's secondary central effects downstream of an initial and direct engagement of FGF21 receptor complex in adipose tissue. Further studies are required to delineate the precise mechanistic basis underlying the interplay between peripheral and central FGF21 modes of action in both the physiological and pharmacological settings. PMID:24398833

  4. Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)

    PubMed Central

    Summerfield, NJ; Boswood, A; O'Grady, MR; Gordon, SG; Dukes-McEwan, J; Oyama, MA; Smith, S; Patteson, M; French, AT; Culshaw, GJ; Braz-Ruivo, L; Estrada, A; O'Sullivan, ML; Loureiro, J; Willis, R; Watson, P

    2012-01-01

    Background The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. Hypothesis That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Animals Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. Methods The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. Results The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034). Conclusion and Clinical Importance The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome. PMID:23078651

  5. The Usefulness of Systematic Reviews of Animal Experiments for the Design of Preclinical and Clinical Studies

    PubMed Central

    de Vries, Rob B. M.; Wever, Kimberley E.; Avey, Marc T.; Stephens, Martin L.; Sena, Emily S.; Leenaars, Marlies

    2014-01-01

    The question of how animal studies should be designed, conducted, and analyzed remains underexposed in societal debates on animal experimentation. This is not only a scientific but also a moral question. After all, if animal experiments are not appropriately designed, conducted, and analyzed, the results produced are unlikely to be reliable and the animals have in effect been wasted. In this article, we focus on one particular method to address this moral question, namely systematic reviews of previously performed animal experiments. We discuss how the design, conduct, and analysis of future (animal and human) experiments may be optimized through such systematic reviews. In particular, we illustrate how these reviews can help improve the methodological quality of animal experiments, make the choice of an animal model and the translation of animal data to the clinic more evidence-based, and implement the 3Rs. Moreover, we discuss which measures are being taken and which need to be taken in the future to ensure that systematic reviews will actually contribute to optimizing experimental design and thereby to meeting a necessary condition for making the use of animals in these experiments justified. PMID:25541545

  6. High-throughput monitoring of integration site clonality in preclinical and clinical gene therapy studies

    PubMed Central

    Giordano, Frank A; Appelt, Jens-Uwe; Link, Barbara; Gerdes, Sebastian; Lehrer, Christina; Scholz, Simone; Paruzynski, Anna; Roeder, Ingo; Wenz, Frederik; Glimm, Hanno; von Kalle, Christof; Grez, Manuel; Schmidt, Manfred; Laufs, Stephanie

    2015-01-01

    Gene transfer to hematopoietic stem cells with integrating vectors not only allows sustained correction of monogenic diseases but also tracking of individual clones in vivo. Quantitative real-time PCR (qPCR) has been shown to be an accurate method to quantify individual stem cell clones, yet due to frequently limited amounts of target material (especially in clinical studies), it is not useful for large-scale analyses. To explore whether vector integration site (IS) recovery techniques may be suitable to describe clonal contributions if combined with next-generation sequencing techniques, we designed artificial ISs of different sizes which were mixed to simulate defined clonal situations in clinical settings. We subjected all mixes to either linear amplification–mediated PCR (LAM-PCR) or nonrestrictive LAM-PCR (nrLAM-PCR), both combined with 454 sequencing. We showed that nrLAM-PCR/454-detected clonality allows estimating qPCR-detected clonality in vitro. We then followed the kinetics of two clones detected in a patient enrolled in a clinical gene therapy trial using both, nrLAM-PCR/454 and qPCR and also saw nrLAM-PCR/454 to correlate to qPCR-measured clonal contributions. The method presented here displays a feasible high-throughput strategy to monitor clonality in clinical gene therapy trials is at hand. PMID:26052530

  7. Comparative toxicology of borates

    Microsoft Academic Search

    Susan A. Hubbard

    1998-01-01

    Inorganic borates, including boric acid, Na, ammonium, K, and Zn borates generally display low acute toxicity orally, dermally,\\u000a and by inhalation. They are either not irritant or mild skin and eye irritants. Exceptions owing to physiochemical properties\\u000a do occur.\\u000a \\u000a Longer-term toxicological studies have been reported mainly on boric acid or borax where the properties are generally similar\\u000a on an equivalent

  8. Confocal Raman microspectroscopy of stratum corneum: a pre-clinical validation study.

    PubMed

    Wu, J; Polefka, T G

    2008-02-01

    Skin moisturization is not only important for maintaining skin functional properties but also has great impact on the skin's aesthetic properties. The top layer of the skin, the stratum corneum (SC), plays a key role in protecting and preventing against external aggressions as well as in regulating water flux in and out. Confocal Raman microspectroscopy is the first commercially available technique that provides a non-invasive, in vivo method to determine depth profiles of water concentration in the skin, however, in this case it was applied in an in vitro setting. As the first phase of validating the usefulness of confocal Raman microspectroscopy, we used porcine skin as a surrogate for human skin. Water concentration profiles were obtained using confocal Raman microspectroscopy from isolated pigskin SC and compared with that using the Karl Fischer titration method. The two methods correlated very well with a regression coefficient of 1.07 as well as a correlation coefficient, R(2) = 0.989, which demonstrated the consistency and accuracy of confocal Raman microspectroscopy for water concentration determination. To evaluate the instrument's response to different skin care/cleansing products, a wide range of products were tested to compare their skin moisturization ability. Among those tested were a lotion, commercial soap bar, syndet bar, traditional non-emollient shower gel (water, Sodium Laureth Ether Sulfate (SLES), cocamidopropyl betaine system) and emollient containing shower gel (water, sunflower oil, SLES, cocamidopropyl betaine, glycerin, petrolatum). The results were consistent with what was expected. The water content on skin treated with (A) lotion was significantly higher than the non-treated control; (B) syndet bar-treated skin had a significantly higher water content than soap-based bar-treated sites; (C) non-emollient shower gel washed sites were more moisturized than soap-based bar-treated samples; and (D) emollient shower gel-treated skin was significantly more hydrated than non-emollient shower gel washed skin. The unique and direct quantitative water content information provided by confocal Raman microspectroscopy offers a whole new perspective for fundamental skin moisturization studies and will play an important role in evaluating moisturizing profiles and the hydration potential of products designed for personal care in the cosmetic industry. PMID:18377630

  9. Preclinical immunogenicity study of trivalent meningococcal AWX-OMV vaccines for the African meningitis belt.

    PubMed

    Tunheim, G; Naess, L M; Acevedo, R; Fjeldheim, Å K; Bolstad, K; García, L; Cardoso, D; Aase, A; Zayas, C; González, H; Rosenqvist, E; Norheim, G

    2014-11-20

    In the recent decade, epidemic meningitis in the African meningitis belt has mostly been caused by Neisseria meningitidis of serogroups A, W and X (MenA, MenW and MenX, respectively). There is at present no licensed vaccine available to prevent MenX meningococcal disease. To explore a trivalent MenAWX vaccine concept, we have studied the immunogenicity in mice of MenX outer membrane vesicles (X-OMV) or MenX polysaccharide (X-PS) when combined with a bivalent A-OMV and W-OMV (AW-OMV) vaccine previously shown to be highly immunogenic in mice. The vaccine antigens were produced from three representative wild type strains of MenA (ST-7), MenW (ST-11) and MenX (ST-751) isolated from patients in the African meningitis belt. Groups of mice were immunized with two doses of X-OMV or X-PS combined with the AW-OMV vaccine or as individual components. All vaccine preparations were adsorbed to Al(OH)3. Sera from immunized mice were tested by ELISA and immunoblotting. Functional antibody responses were measured as serum bactericidal activity (SBA) and opsonophagocytic activity (OPA). Immunization of mice with X-OMV, alone or in combination with AW-OMV induced high levels of anti-X OMV IgG. Moreover, X-OMV alone or in combination with the AW-OMV vaccine induced high SBA and OPA titers against the MenX target strain. X-PS alone was not immunogenic in mice; however, addition of the AW-OMV vaccine to X-PS increased the immunogenicity of X-PS. Both AWX vaccine formulations induced high levels of IgG against A- and W-OMV and high SBA titers against the MenA and MenW vaccine strains. These results suggest that a trivalent AWX vaccine, either as a combination of OMV or OMV with X-PS, could potentially prevent the majority of meningococcal disease in the meningitis belt. PMID:25305564

  10. Occupational toxicology in Mexico: current status and the potential use of molecular studies to evaluate chemical exposure.

    PubMed

    Muñoz, Balam; Albores, Arnulfo

    2011-11-01

    Occupational toxicology is of considerable concern for several world organizations including the International Labour Organization, the World Health Organization and the International Commission for Occupational Health and, in Latin America, the Pan American Health Organization. The countries of this Region, including Mexico, own manufacturing, chemical, and petrochemical industries that employ thousands workers who are continually exposed to hazardous chemicals such as solvents, particles and exhaust fumes, many of which are very complex mixtures. Traditionally, physicians have used biochemical analyses to assess the damage caused by chronic chemical exposure. Presently, recent advances in molecular biology may offer tools to perform more thorough and precise evaluations on worker health damage, risk and current health status. In this review, we present a perspective of occupational toxicology in Mexico, as an example for Latin America and developing countries. Moreover, we summarize current reports about occupational disease associated with chemical exposure, and we present an array of molecular studies proposed for the analysis and diagnosis of workers related with industry and the relevance of including molecular biology testing to complement traditional occupational medical assays in order to improve occupational health. We conclude that developing countries, e.g., Mexico, should improve work environment standards by using new technical approaches that will result in more reliable and precise data to design better health policy strategies. PMID:22003922

  11. Toxicological approaches to complex mixtures.

    PubMed Central

    Mauderly, J L

    1993-01-01

    This paper reviews the role of toxicological studies in understanding the health effects of environmental exposures to mixtures. The approach taken is to review mixtures that have received the greatest emphasis from toxicology; major mixtures research programs; the toxicologist's view of mixtures and approaches to their study; and the complementary roles of toxicological, clinical, and epidemiological studies. Studies of tobacco smoke, engine exhaust, combustion products, and air pollutants comprise most of the past research on mixtures. Because of their great experimental control over subjects, exposures, and endpoints, toxicologists tend to consider a wider range of toxic interactions among mixture components and sequential exposures than is practical for human studies. The three fundamental experimental approaches used by toxicologists are integrative (studying the mixture as a whole), dissective (dissecting a mixture to determine causative constituents), and synthetic (studying interactions between agents in simple combinations). Toxicology provides information on potential hazards, mechanisms by which mixture constituents interact to cause effects, and exposure dose-effect relationships; but extrapolation from laboratory data to quantitative human health risks is problematic. Toxicological, clinical, and epidemiological approaches are complementary but are seldom coordinated. Fostering synergistic interactions among the disciplines in studying the risks from mixtures could be advantageous. PMID:7515806

  12. NTP Toxicology and Carcinogeneis Studies of Sodium Azide (CAS: 26628-22-8) in F344 Rats (Gavage Studies).

    PubMed

    1991-09-01

    Sodium azide is a white crystalline solid used in the manufacture of the explosive lead azide. It is the principal chemical used to generate nitrogen gas in automobile safety airbags and airplane escape chutes and is a broad-spectrum biocide used in both research and agriculture. Toxicology and carcinogenicity studies were conducted by administering sodium azide (greater than 99% pure) in distilled water by gavage to groups of male and female F344/N rats once daily, 5 days per week for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Rats received 0, 5, 10, 20, 40, or 80 mg/kg sodium azide. All male and female rats receiving 40 or 80 mg/kg and two of five female rats receiving 20 mg/kg died during the first week of the studies. Clinical findings of toxicity included lethargy and inactivity. No grossly observable lesions were present in any of the dose groups. 13-Week Studies: Rats received 0, 1.25, 2.5, 5, 10, or 20 mg/kg sodium azide. Seven of 9 males and all 10 females receiving 20 mg/kg died before the end of the studies. Final mean body weights of treated rats were within 10% of those of the controls. Compound-related clinical findings of toxicity in the 20 mg/kg dose groups included lethargy and labored breathing. Histopathologic lesions induced by sodium azide were limited to the brain (necrosis of the cerebrum and thalamus) and lung (congestion, hemorrhage, and edema), and were observed in rats receiving 20 mg/kg that died during the studies. Body Weights, Feed Consumption, and Survival in the 2-Year Studies: Because compound-related deaths were observed in the groups receiving 20 mg/kg in the 13-week studies, lower dose levels were used in the 2-year studies. Two-year studies were conducted by administering 0, 5, or 10 mg/kg sodium azide to groups of 60 male and 60 female rats. Dose-related depression in mean body weight was observed throughout the study period. Mean feed consumption values in low- and high-dose groups were lower than control values. Survival of high-dose rats of each sex was significantly (P<0.05) lower than controls (males-control, 24/60; low-dose, 27/60; high-dose, 9/60; females-37/60; 43/60; 21/59). The reduced survival was attributed to brain necrosis and cardiovascular collapse induced by sodium azide. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: There were no compound-related increases in incidences of neoplasms in rats. Significantly decreased incidences were observed for certain neoplasms, including mononuclear cell leukemia in male rats (control, 33/60; low-dose, 28/60; high-dose, 14/60), adrenal gland pheochromocytoma in male rats (26/55; 16/56; 6/54), mammary gland fibroadenoma in female rats (20/60; 11/60; 8/59), and pituitary gland neoplasms in female rats (37/60; 28/60; 17/59). These decreases reflected to some extent, but could not be attributed solely to, the reduced survival of the high-dose groups. Compound-related nonneoplastic brain lesions (necrosis of the cerebrum and thalamus) were observed at significantly (P<0.001) increased incidences in high-dose male and female rats. The increased incidence of lung congestion observed in this dose group was considered due to cardiovascular collapse secondary to brain necrosis. Genetic Toxicology: Sodium azide was mutagenic in Salmonella typhimurium strains TA100 and TA1535, with or without exogenous metabolic activation (S9); it was not mutagenic in strain TA1537 or TA98. In cytogenetic tests with Chinese hamster ovary cells, sodium azide induced sister chromatid exchanges, but not chromosomal aberrations, in the presence and the absence of S9. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of sodium azide in male or female F344/N rats administered 5 or 10 mg/kg. Sodium azide induced necrosis in the cerebrum and the thalamus of the brain in both male and female rats. Synonyms: Azide, Azium, Smite PMID:12637970

  13. Characterisation of an in vivo Pig-a gene mutation assay for use in regulatory toxicology studies.

    PubMed

    Godin-Ethier, Jessica; Leroux, Francis; Wang, Nan; Thébaud, Sybil; Merah, Farida; Nelson, Andrew

    2015-05-01

    Integration of in vivo genotoxicity testing into standard toxicology studies presents multiple advantages as it reduces animal use and costs, accelerates data generation and provides concurrent data that are useful for interpreting results. The in vivo Pig-a assay is a mammalian gene mutation assay that utilises peripheral blood and thus has a high integration potential. Although inter-laboratory reproducibility has been well demonstrated, further characterisation is required for this assay. In this study, we evaluated intra-laboratory reproducibility of the in vivo Pig-a gene mutation assay (MutaFlow® kit) in rats through the conduct of an assay characterisation prior to subsequent use in Good Laboratory Practices (GLP) toxicology studies. To evaluate intra-laboratory reproducibility, intra-assay and inter-assay variability, ruggedness, robustness and blood storage stability were assessed. These assessments were performed using blood obtained from male Sprague-Dawley rats exposed to 0, 20 or 40mg/kg/day N-ethyl-N-nitrosourea via oral gavage for three consecutive days. Blood was collected from these rats on multiple occasions from Day 29 to Day 71 and samples were analysed for Pig-a mutation using the rat MutaFlow kit. Frequencies of reticulocytes (RET), mutant phenotype erythrocytes (RBC(CD59-)) and mutant phenotype RET (RET(CD59-)) were determined. Overall, the proportion of RET and frequencies of RBC(CD59-) and of RET(CD59-) were consistent throughout the different assessments. The assay demonstrated acceptable intra-run and inter-run variability with coefficients of variation of ?4.8 and 20.6%, respectively. The method was shown to be independent of the analyst performing the assay and unaffected by small changes in assay conditions. Comparable results were obtained from freshly collected samples and samples refrigerated for up to 4 days. Although technically challenging, the rat Pig-a gene mutation assay using a high-throughput automated method was shown to be reliable. The different assay parameters evaluated during the conduct of this study yielded acceptable results. Thus, the method was considered suitable for use in GLP toxicology studies. PMID:25680869

  14. Studies on the metabolism and the toxicological analysis of the nootropic drug fipexide in rat urine using gas chromatography–mass spectrometry

    Microsoft Academic Search

    Roland F. Staack; Hans H. Maurer

    2004-01-01

    Qualitative studies are described on the metabolism and the toxicological analysis of the nootropic fipexide (FIP) in rat urine using gas chromatography–mass spectrometry (GC–MS). FIP was extensively metabolized to 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), 4-chlorophenoxyacetic acid, 1-[2-(4-chlorophenoxy)acetyl]piperazine, N-(4-hydroxy-3-methoxy-benzyl)piperazine, piperazine, N-(3,4-methylenedioxybenzyl)ethylenediamine, and N-[2-(4-chlorophenoxy)acetyl]ethylenediamine. The authors’ systematic toxicological analysis (STA) procedure using full-scan GC–MS after acid hydrolysis of one urine aliquot, liquid-liquid extraction and acetylation

  15. Liquid chromatography–mass spectrometry in occupational toxicology: A novel approach to the study of biotransformation of industrial chemicals

    Microsoft Academic Search

    Paola Manini; Roberta Andreoli; Wilfried M. A. Niessen

    2004-01-01

    Biological monitoring and biomarkers are used in occupational toxicology for a more accurate risk assessment of occupationally exposed people. Appropriate and validated biomarkers of internal dose, like urinary metabolites, besides to be positively correlated with external exposure, have a predictive value to the risk of adverse effects. The application of liquid chromatography–mass spectrometry (LC–MS) in occupational and environmental toxicology, although

  16. TOXLINE (TOXICOLOGY INFORMATION ONLINE)

    EPA Science Inventory

    TOXLINE? (TOXicology information onLINE) are the National Library of Medicines extensive collection of online bibliographic information covering the pharmacological, biochemical, physiological, and toxicological effects of drugs and other chemicals. TOXLINE and TOXLINE65 together...

  17. THE BENEFITS OF A QUALITY ASSURANCE REVIEW OF A RESEARCH STUDY ON THE PHYSICOCHEMISTRY AND PULMONARY TOXICOLOGICAL PROPERTIES OF ORIMULSION FLY ASH

    EPA Science Inventory

    THE BENEFITS OF A QUALITY ASSURANCE REVIEW OF A RESEARCH STUDY ON THE PHYSICOCHEMISTRY AND PULMONARY TOXICOLOGICAL PROPERTIES OF ORIMULSION FLY ASH. K Dreher', J. Richards', J. McGee', J. Lehmann', T. Hughes', A. Miller, W. Linak2, and A. Mallett3.'National Health and Environment...

  18. Toxicological Study of Ocimum sanctum Linn Leaves: Hematological, Biochemical, and Histopathological Studies.

    PubMed

    Gautam, M K; Goel, R K

    2014-01-01

    The present study was aimed to study the acute and subacute toxicity studies with orally administered 50% ethanolic leaves extract of Ocimum sanctum Linn (OSE). In acute toxicity tests, four groups of mice (n = 6/group/sex) were orally treated with doses of 200, 600, and 2000?mg/kg, and general behavior, adverse effects, and mortality were recorded for up to 14 days. In subacute toxicity study, rats received OSE by gavage at the doses of 200, 400, and 800?mg/kg/day (n = 6/group/sex) for 28 days, and biochemical, hematological, and histopathological changes in tissues (liver, kidney, spleen, heart, and testis/ovary) were determined. OSE did not produce any hazardous symptoms or death and CNS and ANS toxicities in the acute toxicity test. Subacute treatment with OSE did not show any change in body weight, food and water consumption, and hematological and biochemical profiles. In addition, no change was observed both in macroscopic and microscopic aspects of vital organs in rats. Our result showed that Ocimum sanctum extract could be safe for human use. PMID:24616736

  19. Toxicological Study of Ocimum sanctum Linn Leaves: Hematological, Biochemical, and Histopathological Studies

    PubMed Central

    Gautam, M. K.; Goel, R. K.

    2014-01-01

    The present study was aimed to study the acute and subacute toxicity studies with orally administered 50% ethanolic leaves extract of Ocimum sanctum Linn (OSE). In acute toxicity tests, four groups of mice (n = 6/group/sex) were orally treated with doses of 200, 600, and 2000?mg/kg, and general behavior, adverse effects, and mortality were recorded for up to 14 days. In subacute toxicity study, rats received OSE by gavage at the doses of 200, 400, and 800?mg/kg/day (n = 6/group/sex) for 28 days, and biochemical, hematological, and histopathological changes in tissues (liver, kidney, spleen, heart, and testis/ovary) were determined. OSE did not produce any hazardous symptoms or death and CNS and ANS toxicities in the acute toxicity test. Subacute treatment with OSE did not show any change in body weight, food and water consumption, and hematological and biochemical profiles. In addition, no change was observed both in macroscopic and microscopic aspects of vital organs in rats. Our result showed that Ocimum sanctum extract could be safe for human use. PMID:24616736

  20. Forensic toxicology.

    PubMed

    Drummer, Olaf H

    2010-01-01

    Forensic toxicology has developed as a forensic science in recent years and is now widely used to assist in death investigations, in civil and criminal matters involving drug use, in drugs of abuse testing in correctional settings and custodial medicine, in road and workplace safety, in matters involving environmental pollution, as well as in sports doping. Drugs most commonly targeted include amphetamines, benzodiazepines, cannabis, cocaine and the opiates, but can be any other illicit substance or almost any over-the-counter or prescribed drug, as well as poisons available to the community. The discipline requires high level skills in analytical techniques with a solid knowledge of pharmacology and pharmacokinetics. Modern techniques rely heavily on immunoassay screening analyses and mass spectrometry (MS) for confirmatory analyses using either high-performance liquid chromatography or gas chromatography as the separation technique. Tandem MS has become more and more popular compared to single-stage MS. It is essential that analytical systems are fully validated and fit for the purpose and the assay batches are monitored with quality controls. External proficiency programs monitor both the assay and the personnel performing the work. For a laboratory to perform optimally, it is vital that the circumstances and context of the case are known and the laboratory understands the limitations of the analytical systems used, including drug stability. Drugs and poisons can change concentration postmortem due to poor or unequal quality of blood and other specimens, anaerobic metabolism and redistribution. The latter provides the largest handicap in the interpretation of postmortem results. PMID:20358697

  1. Recent Advances in Particulate Matter and Nanoparticle Toxicology: A Review of the In Vivo and In Vitro Studies

    PubMed Central

    Nemmar, Abderrahim; Holme, Jørn A.; Rosas, Irma; Schwarze, Per E.

    2013-01-01

    Epidemiological and clinical studies have linked exposure to particulate matter (PM) to adverse health effects, which may be registered as increased mortality and morbidity from various cardiopulmonary diseases. Despite the evidence relating PM to health effects, the physiological, cellular, and molecular mechanisms causing such effects are still not fully characterized. Two main approaches are used to elucidate the mechanisms of toxicity. One is the use of in vivo experimental models, where various effects of PM on respiratory, cardiovascular, and nervous systems can be evaluated. To more closely examine the molecular and cellular mechanisms behind the different physiological effects, the use of various in vitro models has proven to be valuable. In the present review, we discuss the current advances on the toxicology of particulate matter and nanoparticles based on these techniques. PMID:23865044

  2. From DNA to Protein: a study of genomic instability candidate genes during zebrafish development

    Microsoft Academic Search

    Kristine Griffett

    2011-01-01

    The zebrafish, Danio rerio, is a type of freshwater minnow often used to model human diseases including cancer, anxiety and aging diseases. The overall biology of zebrafish is strikingly similar to that of humans, allowing these fish to be used for drug discovery and toxicology studies for preclinical trials. In this study, zebrafish embryos were used to identify and characterize

  3. TOXNET (TOXICOLOGY DATA NETWORK)

    EPA Science Inventory

    TOXNET (Toxicology Data Network) is a computerized system of files oriented to toxicology and related areas. It is managed by the National Library of Medicines Toxicology and Environmental Health Information Program (TEHIP) and runs on a series of microcomputers in a networked cl...

  4. Optimization of the Hamilton-Thorn computerized sperm motility analysis system for use with rat spermatozoa in toxicological studies.

    PubMed

    Slott, V L; Suarez, J D; Poss, P M; Linder, R E; Strader, L F; Perreault, S D

    1993-10-01

    To optimize the Hamilton-Thorn Motility Analyzer (HTM; Hamilton-Thorn Research, Beverly, MA) for use in reproductive toxicology studies with rat spermatozoa, the accuracy and precision of the instrument were assessed under a variety of instrument settings. Videotapes of both fast- and slow-swimming sperm were analyzed repeatedly to obtain data across a range of sperm velocities as might be encountered as a consequence of exposure to reproductive toxicants. Acquisition rates were varied across the HTM menu choices (30, 19, 10, or 7 frames/sec) as were the number of frames analyzed (5 to 20) at each framing rate. For fast-swimming samples (mean straight-line velocity (VSL) approximately 130 microns/sec) generally good agreement between computer-assisted sperm analysis (CASA) and manually obtained data was found for percentage of motile sperm and straight-line velocity; i.e., CASA values were within 10% of manual values for most frame/rate combinations. The accuracy of these measures held true over a wide range of sperm concentrations and percentage motilities. However, CASA measures were less accurate for sperm samples of lower velocities (mean VSL approximately 50 microns/sec and mean VSL approximately 30 microns/sec) in that the velocity of very slow sperm was overestimated (particularly at 30 frames/sec). A soft-ware change (6.5R) and performing analyses at 19 instead of 30 frames/sec improved straight-line accuracy for the slow sperm and enhanced the discrimination between fast (presumably control) and slow (presumably treated) sperm samples. These data show that this motility analyzer could be successfully configured to evaluate rodent sperm samples. The use of such CASA systems in toxicology studies will provide valuable information that may improve human reproductive risk assessment. PMID:8258383

  5. Inhalation developmental toxicology studies: Teratology study of n-hexane in rats: Final report

    SciTech Connect

    Mast, T.J.

    1987-12-01

    The straight chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent used in industrial, academic, and smaller commercial environments. The significant opportunity for women of child-bearing age to be exposed to this chemical prompted the undertaking of a study to assess the developmental toxicity of n-hexane in an animal model. Timed-pregnant (30 animals per group) and virgin (10 animals per group) Sprague-Dawley rats were exposed to 0 (filtered air), 200, 1000, and 5000 ppM n-hexane (99.9% purity) vapor in inhalation chambers for 20 h/day for a period of 14 consecutive days. Sperm-positive females were exposed for 6 to 19 days of gestation (dg) and virgins were exposed concurrently for 14 consecutive days. The day of sperm detection was designated as 0 dg for mated females. Adult female body weights were monitored prior to, throughout the exposure period, and at sacrifice. Uterine, placental, and fetal body weights were obtained for gravid females at sacrifice. Implants were enumerated and their status recorded as live fetus, early or late resorption, or dead. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 16 refs., 3 figs., 7 tabs.

  6. Identification of Prenatal Amphetamines Exposure by Maternal Interview and Meconium Toxicology in the Infant Development, Environment and Lifestyle (IDEAL) Study

    PubMed Central

    Gray, Teresa R.; LaGasse, Linda L.; Smith, Lynne M.; Derauf, Chris; Grant, Penny; Shah, Rizwan; Arria, Amelia M.; Della Grotta, Sheri A.; Strauss, Arthur; Haning, William F.; Lester, Barry M.; Huestis, Marilyn A.

    2009-01-01

    The Infant Development Environment and Lifestyle (IDEAL) study is investigating the effects of prenatal methamphetamine (MAMP) exposure on infant and child development; potential concurrent exposure to cannabis and tobacco also are evaluated. Maternal self-reported drug use and/or meconium toxicology results defined drug exposure status. It is unclear how the frequency, duration and magnitude of maternal MAMP exposure affect qualitative and quantitative meconium results. Materials and Methods Interviews regarding maternal drug use were collected shortly after birth; meconium specimens were screened for amphetamines, cannabis and cotinine by immunoassay and confirmed by gas chromatography mass spectrometry (GCMS). Results The majority of MAMP- and cannabis-exposed infants were identified by maternal interview alone. Meconium tests were more likely to be positive if the mother reported MAMP and cannabis use, particularly in the third trimester. Less than half of immunoassay-positive amphetamines (31.0%) and cannabis (17.9%) meconium results were confirmed by GCMS. Tobacco exposure was equally detected by immunoassay cotinine screen and maternal report. Meconium concentrations did not correlate with maternal self-report status or trimester of use, frequency or route of MAMP use. Discussion Maternal self-report was more sensitive than meconium testing for identifying MAMP and cannabis-exposed neonates; however, the timing of drug exposure may influence meconium toxicology results. Most women ceased MAMP and cannabis use before the third trimester. In the first trimester, meconium has not yet formed, and based on our recent results for opiates and cocaine, drug use in the second trimester appears to be poorly reflected in meconium. Conclusion Low confirmation rates in meconium reinforce the need for confirmatory testing following positive screening results and additional research to identify alternative biomarkers. PMID:19935364

  7. Regionally contaminated aquifers--toxicological relevance and remediation options (Bitterfeld case study).

    PubMed

    Heidrich, Susanne; Schirmer, Mario; Weiss, Holger; Wycisk, Peter; Grossmann, Jochen; Kaschl, Arno

    2004-12-15

    Large-scale contaminated megasites like Bitterfeld in eastern Germany are characterized by a regional contamination of soil, surface water and groundwater as a result of a long and varied history of chemical production. While the contaminants in soils and sediments mostly represent a localized problem, pollutants in groundwater may spread to uncontaminated areas and endanger receptors like surface water and drinking water wells according to the site-specific hydrologic regime. From the toxicological point of view, the contaminants at the Bitterfeld megasite represent a dangerous cocktail of various harmful substances coming from a multitude of sources. Appropriate remediation techniques must be able to remedy the specific problems arising from hot spot areas within the megasite in addition to preventing a further extension of the contaminated zone towards uncontaminated compartments. Therefore, a combination of specifically designed remediation technologies based on the pump and treat-principle with in situ technologies, such as reactive walls and monitored/enhanced natural attenuation, is necessary to efficiently address the miscellaneous challenges at this megasite. In this paper, the currently known contaminant distribution, the associated problems for human health and the environment and possible remediation strategies are presented for the Bitterfeld megasite. PMID:15464625

  8. Development of novel combined anticalcification protocols including immunologic modification for prolonged durability of cardiac xenograft: preclinical study using large-animal long-term circulatory models.

    PubMed

    Lim, Hong-Gook; Jeong, Saeromi; Shin, Jun-Seop; Park, Chung-Gyu; Kim, Yong Jin

    2015-01-01

    Cardiac xenografts are conventionally cross-linked with glutaraldehyde (GA) to impart tissue stability, reduce antigenicity, and maintain tissue sterility. However, GA-fixed xenografts are prone to calcification after long-term implantation in humans, because of phospholipids, free aldehyde groups, and residual antigenicity. We evaluated preclinical safety and efficacy using large-animal long-term circulatory models for our novel combined anticalcification protocol including immunological modification, which had been proven effective in small animal experiments. Bovine/porcine xenografts were treated with decellularization, immunological modification with ?-galactosidase, GA fixation with organic solvent, and detoxification with glycine. Valve conduits made of these xenografts were transplanted into the pulmonary root of goats, and hemodynamic, radiological, immunohistopathological, and biochemical results were obtained for 12 months after implantation. Evaluation of echocardiography and cardiac catheterization demonstrated good hemodynamic status and function of the pulmonary xenograft valves. Durability of the xenografts was well preserved without calcification by specimen radiography and immunohistopathological examination. The calcium concentrations of the explanted xenografts were lower than the control xenografts. This preclinical study using large-animal long-term circulatory models demonstrated that our synergistic and simultaneous employment of multiple anticalcification therapies and novel tissue treatments, including immunological modifications, have promising safety and efficacy and should be examined further in future clinical studies. PMID:25303800

  9. Timing of Decompressive Surgery of Spinal Cord after Traumatic Spinal Cord Injury: An Evidence-Based Examination of Pre-Clinical and Clinical Studies

    PubMed Central

    Furlan, Julio C.; Noonan, Vanessa; Cadotte, David W.

    2011-01-01

    Abstract While the recommendations for spine surgery in specific cases of acute traumatic spinal cord injury (SCI) are well recognized, there is considerable uncertainty regarding the role of the timing of surgical decompression of the spinal cord in the management of patients with SCI. Given this, we sought to critically review the literature regarding the pre-clinical and clinical evidence on the potential impact of timing of surgical decompression of the spinal cord on outcomes after traumatic SCI. The primary literature search was performed using MEDLINE, CINAHL, EMBASE, and Cochrane databases. A secondary search strategy incorporated articles referenced in prior meta-analyses and systematic and nonsystematic review articles. Two reviewers independently assessed every study with regard to eligibility, level of evidence, and study quality. Of 198 abstracts of pre-clinical studies, 19 experimental studies using animal SCI models fulfilled our inclusion and exclusion criteria. Despite some discrepancies in the results of those pre-clinical studies, there is evidence for a biological rationale to support early decompression of the spinal cord. Of 153 abstracts of clinical studies, 22 fulfilled the inclusion and exclusion criteria. While the vast majority of the clinical studies were level-4 evidence, there were two studies of level-2b evidence. The quality assessment scores varied from 7 to 25 with a mean value of 12.41. While 2 of 22 clinical studies assessed feasibility and safety, 20 clinical studies examined efficacy of early surgical intervention to stabilize and align the spine and to decompress the spinal cord; the most common definitions of early operation used 24 and 72?h after SCI as timelines. A number of studies indicated that patients who undergo early surgical decompression can have similar outcomes to patients who received a delayed decompressive operation. However, there is evidence to suggest that early surgical intervention is safe and feasible and that it can improve clinical and neurological outcomes and reduce health care costs. Based on the current clinical evidence using a Delphi process, an expert panel recommended that early surgical intervention should be considered in all patients from 8 to 24?h following acute traumatic SCI. PMID:20001726

  10. UNCOVERING THE DESIGN PRINCIPLES OF POLYAMINE REGULATION IN YEAST: AN INTEGRATED MODELLING AND EXPERIMENTAL STUDY

    E-print Network

    Ward, Karen

    are potential targets for cancer therapeutics. Unregulated polyamine synthesis can trigger uncontrolled cell AND EXPERIMENTAL STUDY Dr Svetlana Amirova Visiting scientist at University of Texas at El Paso A new complete applications are in the areas of pharmacology; toxicology, preclinical drug development for cancer

  11. Nanomedicines for cancer therapy: state-of-the-art and limitations to pre-clinical studies that hinder future developments

    NASA Astrophysics Data System (ADS)

    Dawidczyk, Charlene; Russell, Luisa; Searson, Peter

    2014-08-01

    The ability to efficiently deliver a drug or gene to a tumor site is dependent on a wide range of factors including circulation time, interactions with the mononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics and tumor accumulation. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokinetics of FDA-approved nanomedicines. Next we review nanomedicines under development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics. We show how the lack of uniformity in preclinical trials prevents systematic comparison and hence limits advances in the field.

  12. [Actual problems of genetic toxicology].

    PubMed

    Sycheva, L P; Zhurkov, V S; Rakhmanin, Iu A

    2013-03-01

    The review deals with current issues of genetic toxicology and aims to develop this science at the contemporary stage. We study general approaches to assessing the genotoxic and mutagenic activity of environmental factors; to constructing a regulatory system of chemical compounds that considers the mutagenic effect in Russia and abroad; and to determining modem methods for assessing the organ specificity of mutagens, alternative methods of genetic toxicology, the mutagenic action of various factors in the survey of population, and the abilities of toxicogenomics to identify the mutagenic properties of the environment. PMID:23755529

  13. Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma.

    PubMed

    Laursen, Maria Bach; Falgreen, Steffen; Bødker, Julie Støve; Schmitz, Alexander; Kjeldsen, Malene Krag; Sørensen, Suzette; Madsen, Jakob; El-Galaly, Tarec Christoffer; Bøgsted, Martin; Dybkær, Karen; Johnsen, Hans Erik

    2014-11-01

    Drug resistance in cancer refers to recurrent or primary refractory disease following drug therapy. At the cellular level, it is a consequence of molecular functions that ultimately enable the cell to resist cell death-one of the classical hallmarks of cancer. Thus, drug resistance is a fundamental aspect of the cancer cell phenotype, in parallel with sustained proliferation, immortality, angiogenesis, invasion, and metastasis. Here we present a preclinical model of human B-cell cancer cell lines used to identify genes involved in specific drug resistance. This process includes a standardized technical setup for specific drug screening, analysis of global gene expression, and the statistical considerations required to develop resistance gene signatures. The state of the art is illustrated by the first-step classical drug screen (including the CD20 antibody rituximab, the DNA intercalating topoisomerase II inhibitor doxorubicin, the mitotic inhibitor vincristine, and the alkylating agents cyclophosphamide and melphalan) along with the generation of gene lists predicting the chemotherapeutic outcome as validated retrospectively in clinical trial datasets. This B-cell lineage-specific preclinical model will allow us to initiate a range of laboratory studies, with focus on specific gene functions involved in molecular resistance mechanisms. PMID:25072621

  14. Comparative preclinical pharmacokinetics study of 3,3?-diindolylmethane formulations: is personalized treatment and targeted chemoprevention in the horizon?

    PubMed Central

    2013-01-01

    Background 3,3?-Diindolylmethane (DIM) is known as an agent of natural origin that provides protection against different cancers due to the broad spectrum of its biological activities in vivo. However, this substance has a very poor biodistribution and absorption in animal tissues. This preclinical trial was conducted to evaluate the pharmacokinetics and bioavailability of various DIM formulations in animal model. Materials and methods The pharmacokinetic parameters of one crystalline DIM formulation and one liquid DIM formulation (oil solution) compared to non-formulated crystalline DIM (control) were tested in 200 rats. The formulations were orally administered to animals by gavage at doses of 200 mg/kg per DIM (crystalline DIM formulation and non-formulated crystalline DIM) and 0.1 mg/kg per DIM (DIM in oil solution). DIM plasma elimination was measured using HPLC method; after that, the area under the curve (AUC), relative bioavailability, and absolute bioavailability were estimated for two formulations in relation to non-formulated crystalline DIM. Results and conclusion The highest bioavailability was achieved by administering liquid DIM (oil solution), containing cod liver oil and polysorbate. The level of DIM in rat blood plasma was about fivefold higher, though the 2,000-fold lower dose was administered compared to crystalline DIM forms. The novel pharmacological DIM substance with high bioavailability may be considered as a promising targeted antitumor chemopreventive agent. It could be used to prevent breast and ovarian cancer development in patients with heterozygous inherited and sporadic BRCA1 gene mutations. Further preclinical and clinical trials are needed to prove this concept. PMID:24325835

  15. The application of ICH S6 to the preclinical safety evaluation of plasma derivative therapeutic products.

    PubMed

    Lewis, Richard M; Cavagnaro, Joy

    2010-07-01

    The ICH S6 guidance was developed to describe a rational science-based flexible approach to the preclinical evaluation for biotechnology-derived pharmaceutical products. It also suggested that some of the principles described may be suitable for plasma-derived therapeutics. Some of the specific concerns unique to protein-based therapeutics include complexity in structure and potential immunogenicity. S6 has been interpreted by some industry and regulatory authorities, often due to lack of experience with these types of products, as encouraging a broader or more conventional toxicology program similar to that normally conducted for small molecules. The guidance does encourage important and necessary preclinical evaluations but also recognizes the limitations of studies in non-relevant animal species because they are without pharmacological interaction with the biologic. In addition, studies of human proteins are often limited in useful chronic, reproductive and carcinogenic toxicity evaluations by the immunological response in animals. Thus the safety evaluation of biopharmaceuticals and plasma derivatives in animals has limitations that cannot be adequately addressed by the use of testing paradigms used for small molecule pharmaceuticals. S6 focuses evaluations on well-designed studies in relevant species for reasonable time periods to make the best use of available resources and enable clinical trials. PMID:20359910

  16. Preclinical Rheumatoid Arthritis (Autoantibodies): An Updated Review

    PubMed Central

    Deane, Kevin D.

    2014-01-01

    Multiple studies demonstrate that there is a period of development of rheumatoid arthritis (RA) during which there are elevations of disease-related biomarkers, including autoantibodies, in the absence of and prior to the development of RA; this period can be termed ‘preclinical RA’. These ‘preclinical’ autoantibodies including rheumatoid factor and antibodies to citrullinated protein antigens, and more recent studies have also identified a wider variety of autoantibodies and a wide range of inflammatory biomarkers. These findings in conjunction with established and emerging data about genetic and environmental risk factors for RA support a model of disease development where certain factors lead to an initial triggering of RA-related autoimmunity that expands over time to the point where symptomatic arthritis classifiable as RA develops. Herein will be reviewed updates in the field, as well as a discussion of current limitations of our understanding of preclinical RA, and potential future directions for study. PMID:24643396

  17. Adaptation of the ToxRTool to assess the reliability of toxicology studies conducted with genetically modified crops and implications for future safety testing.

    PubMed

    Koch, Michael S; DeSesso, John M; Williams, Amy Lavin; Michalek, Suzanne; Hammond, Bruce

    2014-09-10

    Abstract To determine the reliability of food safety studies carried out in rodents with genetically modified (GM) crops, a Food Safety Study Reliability Tool (FSSRTool) was adapted from the European Centre for the Validation of Alternative Methods' ToxRTool. Reliability was defined as the inherent quality of the study with regard to use of standardized testing methodology, full documentation of experimental procedures and results, and the plausibility of the findings. Codex guidelines for GM crop safety evaluations indicate toxicology studies are not needed when comparability of the GM crop to its conventional counterpart has been demonstrated. This guidance notwithstanding, animal feeding studies have routinely been conducted with GM crops, but their conclusions on safety are not always consistent. To accurately evaluate potential risks from GM crops, risk assessors need clearly interpretable results from reliable studies. The development of the FSSRTool, which provides the user with a means of assessing the reliability of a toxicology study to inform risk assessment, is discussed. Its application to the body of literature on GM crop food safety studies demonstrates that reliable studies report no toxicologically relevant differences between rodents fed GM crops or their non-GM comparators. PMID:25208336

  18. Toxicological Assessment of Inhaled Nanoparticles: Role of in Vivo, ex Vivo, in Vitro, and in Silico Studies

    PubMed Central

    Fröhlich, Eleonore; Salar-Behzadi, Sharareh

    2014-01-01

    The alveolar epithelium of the lung is by far the most permeable epithelial barrier of the human body. The risk for adverse effects by inhaled nanoparticles (NPs) depends on their hazard (negative action on cells and organism) and on exposure (concentration in the inhaled air and pattern of deposition in the lung). With the development of advanced in vitro models, not only in vivo, but also cellular studies can be used for toxicological testing. Advanced in vitro studies use combinations of cells cultured in the air-liquid interface. These cultures are useful for particle uptake and mechanistic studies. Whole-body, nose-only, and lung-only exposures of animals could help to determine retention of NPs in the body. Both approaches also have their limitations; cellular studies cannot mimic the entire organism and data obtained by inhalation exposure of rodents have limitations due to differences in the respiratory system from that of humans. Simulation programs for lung deposition in humans could help to determine the relevance of the biological findings. Combination of biological data generated in different biological models and in silico modeling appears suitable for a realistic estimation of potential risks by inhalation exposure to NPs. PMID:24646916

  19. [Studies of biologic activation associated with molecular receptor increase and tumor response in ChL6/L6 protocol patients; Studies in phantoms; Quantitative SPECT; Preclinical studies; and Clinical studies]. DOE annual report, 1994--95

    SciTech Connect

    DeNardo, S.J.

    1995-12-31

    The authors describe results which have not yet been published from their associated studies listed in the title. For the first, they discuss Lym-1 single chain genetically engineered molecules, analysis of molecular genetic coded messages to enhance tumor response, and human dosimetry and therapeutic human use radiopharmaceuticals. Studies in phantoms includes a discussion of planar image quantitation, counts coincidence correction, organ studies, tumor studies, and {sup 90}Y quantitation with Bremsstrahlung imaging. The study on SPECT discusses attenuation correction and scatter correction. Preclinical studies investigated uptake of {sup 90}Y-BrE-3 in mice using autoradiography. Clinical studies discuss image quantitation verses counts from biopsy samples, S factors for radiation dose calculation, {sup 67}Cu imaging studies for lymphoma cancer, and {sup 111}In MoAb imaging studies for breast cancer to predict {sup 90}Y MoAb therapy.

  20. Determination of GDC-0980 (apitolisib), a small molecule dual phosphatidylinositide 3-kinase/mammalian target of rapamycin inhibitor in dog plasma by LC-MS/MS to support a GLP toxicology study.

    PubMed

    Ding, Xiao; Salphati, Laurent; Kim, Amy; Morinello, Eric; Wong, Lisa; Pang, Jodie; Percey, Shaundel; Meng, Min; Reuschel, Scott; Dean, Brian

    2015-08-01

    An LC-MS/MS method for the determination of GDC-0980 (apitolisib) concentrations in dog plasma has been developed and validated for the first time to support pre-clinical drug development. Following protein precipitation with acetonitrile, the resulting samples were analyzed using reverse-phase chromatography on a Metasil AQ column. The mass analysis was performed on a triple quadruple mass spectrometer coupled with an electrospray interface in positive ionization mode. The selected reaction monitoring transitions monitored were m/z 499.3???341.1 for GDC-0980 and m/z 507.3???341.1 for IS. The method was validated over the calibration curve range 0.250-250?ng/mL with linear regression and 1/x(2) weighting. Relative standard deviation (RSD) ranged from 0.0 to 10.9% and accuracy ranged from 93.4 to 113.6% of nominal. Stable-labeled internal standard GDC-0980-d8 was used to minimize matrix effects. This assay was used for the measurement of GDC-0980 dog plasma concentrations to determine toxicokinetic parameters after oral administration of GDC-0980 (0.03, 0.1 and 0.3?mg/kg) to beagle dogs in a GLP toxicology study. Peak concentration ranged from 3.23 to 84.9?ng/mL. GDC-0980 was rapidly absorbed with a mean time to peak concentration ranging from 1.3 to 2.4?h. Mean area under the concentration-time curve from 0 to 24?hours ranged from 54.4 to 542?ng?h/mL. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25677784

  1. NATIONAL TOXICOLOGY PROGRAM (NTP) DATA

    EPA Science Inventory

    The National Toxicology Program (NTP) was established in 1978 by the Department of Health and Human Services (DHHS) to coordinate toxicological testing programs within the department, strengthen the science base in toxicology; develop and validate improved testing methods; and pr...

  2. Toxicological evaluation of New Zealand deer velvet powder. Part I: acute and subchronic oral toxicity studies in rats.

    PubMed

    Zhang, H; Wanwimolruk, S; Coville, P F; Schofield, J C; Williams, G; Haines, S R; Suttie, J M

    2000-11-01

    Potential toxic effects of acute and subchronic dosage regimens of deer velvet powder have been assessed in rats following OECD guidelines. In the acute study, rats of both sexes were exposed to a single dose of 2 g/kg body weight. There was no mortality or other signs of toxicity during 14 days' observation. Furthermore, no significant alteration either in relative organ weights or their histology was discernible at terminal autopsy. In the 90-day subchronic study, deer velvet was administered in 1 g/kg daily doses by gavage to rats. A control group of rats received water only. There was no effect on body weight, food consumption, clinical signs, haematology and most parameters of blood chemistry including carbohydrate metabolism, liver and kidney function. No significant differences were seen between the mean organ weights of the adrenal, kidney and brain in rats treated with deer velvet and control rats. However, there was a significant difference (P<0.05) in the group mean relative liver weight (3.52 +/- 0.30 vs 3.81 +/- 0.26 g/100 g body weight) of deer velvet-treated and control male rats. The gross necropsy and pathological examination of rats treated with deer velvet did not reveal any abnormalities in tissue morphology. Based on these results, it may be concluded that rats had no deer velvet treatment-related toxicological and histopathological abnormalities at the doses administered, despite the observed minor changes in liver weight. PMID:11038235

  3. A New Stochastic Kriging Method for Modeling Multi-Source Exposure-Response Data in Toxicology Studies.

    PubMed

    Wang, Kai; Chen, Xi; Yang, Feng; Porter, Dale W; Wu, Nianqiang

    2014-07-01

    One of the most fundamental steps in risk assessment is to quantify the exposure-response relationship for the material/chemical of interest. This work develops a new statistical method, referred to as SKQ (stochastic kriging with qualitative factors), to synergistically model exposure-response data, which often arise from multiple sources (e.g., laboratories, animal providers, and shapes of nanomaterials) in toxicology studies. Compared to the existing methods, SKQ has several distinct features. First, SKQ integrates data across multiple sources and allows for the derivation of more accurate information from limited data. Second, SKQ is highly flexible and able to model practically any continuous response surfaces (e.g., dose-time-response surface). Third, SKQ is able to accommodate variance heterogeneity across experimental conditions and to provide valid statistical inference (i.e., quantify uncertainties of the model estimates). Through empirical studies, we have demonstrated SKQ's ability to efficiently model exposure-response surfaces by pooling information across multiple data sources. SKQ fits into the mosaic of efficient decision-making methods for assessing the risk of a tremendously large variety of nanomaterials and helps to alleviate safety concerns regarding the enormous amount of new nanomaterials. PMID:25068094

  4. A New Stochastic Kriging Method for Modeling Multi-Source Exposure–Response Data in Toxicology Studies

    PubMed Central

    2015-01-01

    One of the most fundamental steps in risk assessment is to quantify the exposure–response relationship for the material/chemical of interest. This work develops a new statistical method, referred to as SKQ (stochastic kriging with qualitative factors), to synergistically model exposure–response data, which often arise from multiple sources (e.g., laboratories, animal providers, and shapes of nanomaterials) in toxicology studies. Compared to the existing methods, SKQ has several distinct features. First, SKQ integrates data across multiple sources and allows for the derivation of more accurate information from limited data. Second, SKQ is highly flexible and able to model practically any continuous response surfaces (e.g., dose–time–response surface). Third, SKQ is able to accommodate variance heterogeneity across experimental conditions and to provide valid statistical inference (i.e., quantify uncertainties of the model estimates). Through empirical studies, we have demonstrated SKQ’s ability to efficiently model exposure–response surfaces by pooling information across multiple data sources. SKQ fits into the mosaic of efficient decision-making methods for assessing the risk of a tremendously large variety of nanomaterials and helps to alleviate safety concerns regarding the enormous amount of new nanomaterials. PMID:25068094

  5. Genetic toxicology studies comparing the activity of sidestream smoke from cigarettes which burn or only heat tobacco.

    PubMed

    Doolittle, D J; Lee, C K; Ivett, J L; Mirsalis, J C; Riccio, E; Rudd, C J; Burger, G T; Hayes, A W

    1990-02-01

    The results of in vitro genetic toxicology studies of sidestream cigarette smoke (SSCS) from cigarettes which heat but do not burn tobacco were compared to those of sidestream smoke from cigarettes which burn tobacco. SSCSs from 5 cigarettes were compared. Three of the cigarettes, the Kentucky reference research cigarette (1R4F), a commercially available ultra-low-tar brand (ULT) and a commercially available ultra-low-tar menthol brand (ULT-menthol) burn tobacco while two of the cigarettes, a regular (TEST) and a menthol (TEST-menthol) heat tobacco. SSCSs from all cigarettes were prepared by identical techniques, which involved collecting sidestream smoke particulate matter on Cambridge filter pads and combining the particulate matter with the vapor-phase materials collected by bubbling the smoke exiting the Cambridge pad through DMSO. The SSCSs obtained (equivalent to 0.4 cigarettes/ml DMSO) were evaluated at identical concentrations in an in vitro genetic toxicology test battery. SSCS from 1R4F, ULT and ULT-menthol cigarettes produced positive results in Ames bacterial strains TA98, TA100, TA1537 and TA1538 in the presence of metabolic activation (S9 from Aroclor-induced rat liver) but negative results in strain TA1535. In the absence of metabolic activation, 1R4F, ULT and ULT-menthol SSCSs were not significantly mutagenic. TEST and TEST-menthol SSCSs produced negative results in all 5 bacterial strains, both with and without metabolic activation. SSCS from 1R4F, ULT and ULT-menthol cigarettes produced positive results in the CHO chromosomal aberration assay and in the CHO sister-chromatid exchange assay both with and without metabolic activation while TEST and TEST-menthol SSCSs produced negative results in both assays, either with or without metabolic activation. The SSCSs from 1R4F, ULT and ULT-menthol cigarettes were weakly positive in inducing DNA repair in cultured rat hepatocytes while TEST and TEST-menthol SSCSs were negative in this assay. All 5 SSCSs were nonmutagenic in the CHO-HGPRT assay both with and without metabolic activation. SSCSs from the 1R4F, ULT and ULT-menthol cigarettes were cytotoxic in the CHO-HGPRT assay, both with and without metabolic activation, while TEST and TEST-menthol SSCSs were not cytotoxic under either condition. These results demonstrate that sidestream smoke from cigarettes which heat but do not burn tobacco (TEST and TEST-menthol) was neither genotoxic nor cytotoxic under conditions where sidestream smoke from cigarettes which burn tobacco (1R4F, ULT and ULT-menthol) was genotoxic and/or cytotoxic in a concentration-dependent manner. PMID:2300076

  6. Preclinical evaluation of gene transfer products: safety and immunological aspects

    Microsoft Academic Search

    Marielle Christ

    2002-01-01

    As any new drug in development, gene transfer products have to be tested for their potential toxicity in preclinical studies. Strategies for preclinical safety evaluation of gene transfer compounds are similar to those undertaken for biotechnology-derived pharmaceuticals with the added complexity of having to test additional components, such as the vector and genetic material. Some recommendations have been issued by

  7. The Economics of Reproducibility in Preclinical Research

    PubMed Central

    Freedman, Leonard P.; Cockburn, Iain M.; Simcoe, Timothy S.

    2015-01-01

    Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total) prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B)/year spent on preclinical research that is not reproducible—in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures. PMID:26057340

  8. The Economics of Reproducibility in Preclinical Research.

    PubMed

    Freedman, Leonard P; Cockburn, Iain M; Simcoe, Timothy S

    2015-06-01

    Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total) prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B)/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures. PMID:26057340

  9. Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming

    SciTech Connect

    Hmila, Issam [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Cosyns, Bernard [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Tounsi, Hayfa [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Roosens, Bram; Caveliers, Vicky [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Abderrazek, Rahma Ben [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Boubaker, Samir [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Muyldermans, Serge [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium) [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium); Department of Structural Biology, VIB, Brussels (Belgium); El Ayeb, Mohamed [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Bouhaouala-Zahar, Balkiss, E-mail: balkiss.bouhaouala@pasteur.rns.tn [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia) [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Faculté de Médecine de Tunis, Université de Tunis-El Manar (Tunisia); Lahoutte, Tony [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)

    2012-10-15

    Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab?{sub 2} based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of {sup 99m}Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab?{sub 2} product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab?{sub 2} based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10. -- Highlights: ? Nanobody therapy prevents the hemodynamic disturbances induced by a lethal dose. ? Late injection of Nanobody restores hemodynamic parameters to baseline values. ? Nanobody therapy prevents lung and heart lesions of treated mice after envenoming. ? Labeled Nanobody and Fab’2 pharmacokinetics curves reach plateau in favour of Nanobody.

  10. The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies.

    PubMed

    Terbeck, Sylvia; Akkus, Funda; Chesterman, Laurence P; Hasler, Gregor

    2015-01-01

    In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches-from basic neurobiological approaches to human studies-might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5's important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC's arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems. PMID:25852460

  11. Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

    NASA Astrophysics Data System (ADS)

    Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

    2014-02-01

    Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

  12. Occupational medicine and toxicology

    Microsoft Academic Search

    David A Groneberg; Axel Fischer

    2006-01-01

    This editorial is to announce the Journal of Occupational Medicine and Toxicology, a new Open Access, peer-reviewed, online journal published by BioMed Central. Occupational medicine and toxicology belong to the most wide ranging disciplines of all medical specialties. The field is devoted to the diagnosis, prevention, management and scientific analysis of diseases from the fields of occupational and environmental medicine

  13. Toxicology ontology perspectives.

    PubMed

    Hardy, Barry; Apic, Gordana; Carthew, Philip; Clark, Dominic; Cook, David; Dix, Ian; Escher, Sylvia; Hastings, Janna; Heard, David J; Jeliazkova, Nina; Judson, Philip; Matis-Mitchell, Sherri; Mitic, Dragana; Myatt, Glenn; Shah, Imran; Spjuth, Ola; Tcheremenskaia, Olga; Toldo, Luca; Watson, David; White, Andrew; Yang, Chihae

    2012-01-01

    The field of predictive toxicology requires the development of open, public, computable, standardized toxicology vocabularies and ontologies to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. In this article we review ontology developments based on a set of perspectives showing how ontologies are being used in predictive toxicology initiatives and applications. Perspectives on resources and initiatives reviewed include OpenTox, eTOX, Pistoia Alliance, ToxWiz, Virtual Liver, EU-ADR, BEL, ToxML, and Bioclipse. We also review existing ontology developments in neighboring fields that can contribute to establishing an ontological framework for predictive toxicology. A significant set of resources is already available to provide a foundation for an ontological framework for 21st century mechanistic-based toxicology research. Ontologies such as ToxWiz provide a basis for application to toxicology investigations, whereas other ontologies under development in the biological, chemical, and biomedical communities could be incorporated in an extended future framework. OpenTox has provided a semantic web framework for the implementation of such ontologies into software applications and linked data resources. Bioclipse developers have shown the benefit of interoperability obtained through ontology by being able to link their workbench application with remote OpenTox web services. Although these developments are promising, an increased international coordination of efforts is greatly needed to develop a more unified, standardized, and open toxicology ontology framework. PMID:22562487

  14. Studies of various elements of nutritional and toxicological interest associated with different molecular weight fractions in Brazil nuts.

    PubMed

    Kannamkumarath, Sasi S; Wuilloud, Rodolfo G; Caruso, Joseph A

    2004-09-22

    On-line hyphenation of size exclusion chromatography (SEC), UV, and inductively coupled plasma mass spectrometry (ICP-MS) was used to study the molecular weight distribution patterns of several elements in Brazil nuts (Bertholletia excelsa). This technique was used for the elemental speciation of different elements of nutritional and toxicological interests such as Mg, Fe, Co, Mo, Ag, Hg, and Pb. Elemental fractionation in Brazil nuts was studied using a Superdex peptide column with resolving capacity in the range of 14 to 0.18 kDa. Three different mobile phases, Tris buffer solution (pH 8.0), phosphate buffer (pH 7.5), and CAPS buffer solution (pH 10.0), were tried for the SEC fractionation. Size exclusion fractionation of all the extracted solutions was performed using a 50 mmol L(-)(1) Tris buffer (pH 8) as the mobile phase at a flow rate of 0.6 mL min(-)(1). Three different extractions, 0.05 mol L(-)(1) NaOH, 0.05 mol L(-)(1) HCl, and hot water at 60 degrees C, were performed, and the association of elements with various molecular weight fractions was evaluated. Total elemental concentrations in the extracted samples were determined and compared with the values obtained after total digestion to calculate the recovery values. Generally, high extraction efficiency was obtained with the NaOH solution as compared with HCl and hot water except in the case of magnesium, for which HCl was found to be a good extractant. Chromatographic elution profiles for these extractions were quite distinct from each other in most cases. Most of the elemental species were found to be associated with high molecular weight fractions. To study the differences obtained during the sample-processing step, the results obtained for nuts with shell were treated differently from those obtained for nuts purchased without shell and were compared. PMID:15366819

  15. Optimization of Preclinical Animal Models

    E-print Network

    Optimization of Preclinical Animal Models Steven Perrin, PhD CEO, CSO ALS Therapy Development Institute #12;Historical Issue with Pre-clinical Animal Model Development and Validation Optimized Copy Animals · Variable #3: Gender · Variable #4: Litter Effect of increasing 'n' on Noise for Each

  16. Toxicological evaluation of pH-sensitive nanoparticles of curcumin: Acute, sub-acute and genotoxicity studies

    Microsoft Academic Search

    Prajakta Dandekar; Rohit Dhumal; Ratnesh Jain; Dinesh Tiwari; Geeta Vanage; Vandana Patravale

    2010-01-01

    Research in nanotoxicology is still in nascent stages. This hampers the design of appropriate regulatory policies for these beneficial nano-drug delivery systems thus affecting their routine employment as therapeutics. Establishing the entire toxicological profile is thus indispensable for proving the human safety of nanocarriers, which was the primary objective of the current investigation. The developed curcumin loaded polymeric nanoparticles of

  17. Cannabinoids in postmortem toxicology.

    PubMed

    Lemos, Nikolas P; Ingle, Eric A

    2011-09-01

    Cannabinoids are often excluded from postmortem toxicology screens due to their ubiquitous nature, interpretative difficulties and unanswered questions regarding their postmortem redistribution. In this study, we review 30 postmortem cases where a drug screen gave a positive cannabinoids result and a confirmation identified ??-tetrahydrocannabinol (THC), 11-hydroxy-??-tetrahydrocannabinol (11-OH-THC), and/or 11-nor-9-carboxy-??-tetrahydrocannabinol (THC-COOH) in peripheral (BL-P) or cardiac/central blood (BL-C) and/or urine (UR). Had cannabinoids not been included in these toxicologic evaluations, incomplete or erroneous inferences would have been drawn in a substantial number of cases regarding cause/manner of death. THC was detected in 28 BL-C and in all 30 BL-P. THC and THC-COOH were confirmed present in 2 and 23 UR, respectively. 11-OH-THC was detected in 4 BL-C, 6 BL-P, and 0 UR. The mean THC concentrations in BL-C and BL-P were 8.0 and 15.8 ng/mL, respectively. The mean THC-COOH concentrations in BL-C and BL-P were 55.2 and 60.6 ng/mL, respectively. The mean 11-OH-THC concentrations in BL-C and BL-P were 17.0 and 12.5 ng/mL, respectively. Postmortem interval (PMI) for each case was determined and evaluated in relation to BL-C/BL-P concentration ratios with THC-COOH exhibiting a possible trend. This study is the first of its kind and demonstrates the usefulness of cannabinoid analyses as part of death investigations. Furthermore, it provides distribution data that will improve the ability of toxicologists and pathologists to evaluate cannabinoid concentrations in human postmortem specimens. PMID:21871147

  18. [Toxicology in legal medicine].

    PubMed

    Kojima, T

    1992-12-01

    The purpose of toxicology in legal medicine is to determine the presence of chemicals effecting the human body in biological samples and to interpret the concentrations of chemicals. Analytical methods and medico-legal interpretations of the results of poisoning cases were discussed. 1. "Yusho," PCB poisoning "Yusho" was determined to be PCB poisoning by the detection of PCB in Rice-oil used by a "Yusho" family. My toxicological works were based on the study of "Yusho," which taught me the importance of the collaboration between faculties, the moral of the co-worker, and the PCB contamination in the laboratory. 2. Drugs In order to interpret the concentration of bromvalerylurea in blood, a very sensitive method was developed using a Florisil mini-column for cleaning up, and ECD-GC for analysis. GC/MS is used to determine the concentrations of other drugs in biological samples as well. 3. Pesticides In the first case of fatal ethyl parathion poisoning, only ethyl parathion in the stomach contents was analyzed by ECD-GC, and the cause of death was determined to be ethyl parathion poisoning. In the second case, parathion in the blood, brain, and stomach contents was analyzed. Both cases, however, were not reported in detail in the journal. Joint study on pesticides with the Division of Emergency Medicine is carrying on now. 4. Thinner Male rats were exposed to toluene vapor in pure oxygen, air, and 10%-O2 air. Anesthetic death from thinner vapor was confirmed. It seems that inhalation of toluene in a hypoxic atmosphere, such as from a plastic bag, is very dangerous.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1303426

  19. The preclinical stage of spinocerebellar ataxias.

    PubMed

    Maas, Roderick P P W M; van Gaalen, Judith; Klockgether, Thomas; van de Warrenburg, Bart P C

    2015-07-01

    The autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of degenerative diseases of the cerebellum and connected regions. The discovery of various SCA genes and the subsequent possibility of predictive testing currently allow a genetic diagnosis to be established years or even decades before the actual appearance of ataxia symptoms. A growing body of evidence, however, indicates that this preclinical stage is subject to the earliest pathophysiologic changes. This review article comprehensively summarizes the studies conducted in preclinical carriers of a mutation in one of the SCA genes. From these data, it can indeed be concluded that the preclinical phase in SCA is already characterized by detectable central and peripheral nervous system changes, which are reflected by subtle abnormalities during a careful clinical examination, changes in structural and functional brain imaging, abnormal neurophysiologic measurements, and/or altered motor learning paradigms. As these may be compensated for a long time, ataxia symptoms probably only appear after a certain threshold of dysfunction or degeneration has been exceeded. Detailed knowledge of this disease stage is of particular relevance for a better understanding of the pathogenesis of SCAs, will allow us to determine the optimal point in time for interventions in future therapeutic trials, and points to objective, valid biomarkers to assess disease progression. Further studies will benefit from a consensus-based definition of the preclinical stage, from using one and the same validated ataxia rating scale with one fixed cutoff value, and from applying similar mathematical models to calculate time to predicted disease onset. PMID:26062625

  20. Metabolic profiling studies on the toxicological effects of realgar in rats by {sup 1}H NMR spectroscopy

    SciTech Connect

    Wei Lai; Liao Peiqiu; Wu Huifeng [Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China); Li Xiaojing [Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China)], E-mail: xjli@ciac.jl.cn; Pei Fengkui [Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China)], E-mail: peifk@ciac.jl.cn; Li Weisheng; Wu Yijie [Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China)

    2009-02-01

    The toxicological effects of realgar after intragastrical administration (1 g/kg body weight) were investigated over a 21 day period in male Wistar rats using metabonomic analysis of {sup 1}H NMR spectra of urine, serum and liver tissue aqueous extracts. Liver and kidney histopathology examination and serum clinical chemistry analyses were also performed. {sup 1}H NMR spectra and pattern recognition analyses from realgar treated animals showed increased excretion of urinary Kreb's cycle intermediates, increased levels of ketone bodies in urine and serum, and decreased levels of hepatic glucose and glycogen, as well as hypoglycemia and hyperlipoidemia, suggesting the perturbation of energy metabolism. Elevated levels of choline containing metabolites and betaine in serum and liver tissue aqueous extracts and increased serum creatine indicated altered transmethylation. Decreased urinary levels of trimethylamine-N-oxide, phenylacetylglycine and hippurate suggested the effects on the gut microflora environment by realgar. Signs of impairment of amino acid metabolism were supported by increased hepatic glutamate levels, increased methionine and decreased alanine levels in serum, and hypertaurinuria. The observed increase in glutathione in liver tissue aqueous extracts could be a biomarker of realgar induced oxidative injury. Serum clinical chemistry analyses showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. The time-dependent biochemical variations induced by realgar were achieved using pattern recognition methods. This work illustrated the high reliability of NMR-based metabonomic approach on the study of the biochemical effects induced by traditional Chinese medicine.

  1. Use of genetic toxicology data in U.S. EPA risk assessment: the mercury study report as an example.

    PubMed Central

    Schoeny, R

    1996-01-01

    Assessment of human health risks of environmental agents has often been limited to consideration of the potential for the agent to cause cancer or general systemic toxicity after long-term exposure. The U.S. Environmental Protection Agency (U.S. EPA) is increasingly moving toward the development of integrated assessments, which consider all potential health end points including developmental toxicity, neurotoxicity, immunotoxicity, reproductive effects, and germ cell mutagenicity. The U.S. EPA has a responsibility to assess risks to nonhuman species or ecosystems when appropriate data are available. An example of a recent integrated human health and ecological risk assessment can be found in the U.S. EPA Mercury Study Report to Congress. This report covers the following topics in separate volumes: an inventory of anthropogenic mercury emissions in the United States; an exposure assessment using measured and predicted values and including indirect dietary exposure; an evaluation of human health risks; an assessment of ecologic risk wherein water criteria are presented for several wildlife species; an overall integrated characterization of human and nonhuman risk; and a discussion of risk management considerations. In the evaluation of human health risk, genetic toxicology data were considered for three forms of mercury: elemental, inorganic (divalent), and methylmercury. These data were used in judgments of two types of potential health effects (carcinogenicity and germ cell mutagenicity). In assessment of potential carcinogenicity of inorganic and methylmercury, genetic toxicity data were key. Data for clastogenicity in the absence of mutagenicity supported the characterization of inorganic and methylmercury as materials that produce carcinogenic effects only at high, toxic doses. The evidence for clastogenicity, coupled with information on metabolism and distribution, resulted in a judgment of a moderate degree of concern (or weight of evidence) that inorganic mercury can act as a human germ cell mutagen. For methylmercury, the degree of concern for germ cell mutagenicity is high. PMID:8781402

  2. Preclinical Molecular Imaging of Tumor Angiogenesis

    PubMed Central

    Zhu, Lei; Niu, Gang; Fang, Xuexun; Chen, Xiaoyuan

    2010-01-01

    Angiogenesis, a course that new blood vessels grow from the existing vasculature, plays important roles both physiologically and pathologically. Angiogenesis can be switched on by growth factors secreted by tumor cells, and in turn supplies more oxygen and nutrition to the tumor. More and more preclinical studies and clinical trials have shown that inhibition of angiogenesis is an effective way to inhibit tumor growth, substantiating the development of anti-angiogenesis therapeutics. Imaging technologies accelerate the translation of preclinical research to the clinic. In oncology, various imaging modalities are widely applied to drug development, tumor early detection and therapy response monitoring. So far, several angiogenesis related imaging agents are promising in cancer diagnosis. However, more effective imaging agents with less side-effect still need to be pursued to visualize angiogenesis process non-invasively. The main purpose of this review is to summarize the recent progresses in preclinical molecular imaging of angiogenesis and to discuss the potential of the current preclinical probes specific to various angiogenesis targets including vascular endothelial growth factor and its receptors (VEGF/VEGFRs), integrin ?v?3 and matrix metalloproteinases (MMPs). It is predicable that related investigations in the field will benefit cancer research and quicken the anti-angiogenic drug development. PMID:20639815

  3. A pharmacokinetic study of ethyl glucuronide in blood and urine: Applications to forensic toxicology

    Microsoft Academic Search

    Gudrun Høiseth; Jean Paul Bernard; Ritva Karinen; Lene Johnsen; Anders Helander; Asbjørg S. Christophersen; Jørg Mørland

    2007-01-01

    This pharmacokinetic study investigated the kinetics of ethanol and its metabolite ethyl glucuronide (EtG) in blood and urine during the whole time course of absorption and elimination. There are few previous studies on the kinetics of EtG in blood, and we wanted to evaluate whether such knowledge could yield valuable information regarding the time of ethanol ingestion in forensic cases,

  4. Toxicology and Carcinogenesis Studies of Microencapsulated Citral in Rats and Mice

    Microsoft Academic Search

    N. B. Ress; J. R. Hailey; R. R. Maronpot; J. R. Bucher; G. S. Travlos; J. K. Haseman; D. P. Orzech; J. D. Johnson; M. R. Hejtmancik

    2003-01-01

    Citral, a widely used natural ingredient, is added to foods and cosmetics as a flavoring and fragrance agent. Male and female F344\\/N rats and B6C3F1 mice were exposed to microencapsulated citral in the feed for 14 weeks or two years. All studies included untreated and vehicle control groups. In the 14-week studies, rats and mice were given diets containing 3900,

  5. Toxicological significance of dihydrodiol metabolites

    SciTech Connect

    Hsia, M.T.

    1982-01-01

    Dihydrodiols are often found as the major organic-extractable metabolites of various olefinic or aromatic xenobiotics in many biological samples. Studies on the chemistry of dihydrodiol metabolites have provided insight into the pharmacokinetic behavior and the mode of action of the parent compound. The toxicology of dihydrodiol is more complex than what can be deduced solely on the basis of diminished bioavailability of the epoxide precursor, and the increased hydrophilicity associated with the dihydrodiol moiety. Dihydrodiols can be intrinsically toxic and may even represent metabolically activated species. Some of the dihydrodiol metabolites may still retain sufficient lipophilic character to serve again as substrates for microsomal oxygenases. Because of the tremendous chemical and biological diversity that existed among the various dihydrodiols, more mechanistic studies are needed to examine the toxicological properties of these compounds. It may be premature to conclude dihydrodiol formation as purely a detoxification route for xenobioties.

  6. Toxicological studies and antimicrobial properties of some Iron(III) complexes of Ciprofloxacin

    Microsoft Academic Search

    J. A. Obaleye; C. A. Akinremi; E. A. Balogun; J. O. Adebayo

    Two iron(III) complexes of Ciprofloxacin were synthesized by reaction of the ligand with iron(III) chloride hexahydrate in different solutions. The nature of bonding of the ligands and the structure of the isolated metal complexes were elucidated on the basis of their physical and spectroscopic studies. The infrared spectra suggest that two classes of compounds were obtained: molecular complex in which

  7. The rodent estrous cycle: Characterization of vaginal cytology and its utility in toxicological studies

    EPA Science Inventory

    An evaluation of the estrous cycle in laboratory rodents can be a useful measure of the integrity of the hypothalamic-pituitary-ovarian reproductive axis. It can also serve as a way of insuring that animals exhibiting abnormal cycling patterns are disincluded from a study prior t...

  8. APPLICATION OF CDNA MICROARRAY TO THE STUDY OF ARSENIC TOXICOLOGY AND CARCINOGENESIS

    EPA Science Inventory

    Arsenic (As) is a common environmental toxicant and known human carcinogen. Epidemiological studies link As exposure to various disorders and cancers. However, the molecular mechanisms for As toxicity and carcinogenicity are not completely known. The cDNA microarray, a high-th...

  9. HEART RATE VARIABILITY IN RODENTS ? USES AND CAVEATS IN TOXICOLOGICAL STUDIES

    EPA Science Inventory

    Heart rate variability (HRV) is a measure of cardiac pacing dynamics that has recently garnered a great deal of interest in environmental health studies. While the use of these measures has become popular, much uncertainty remains in the interpretation of results, both in terms ...

  10. Effects of pyridoxal 5'-phosphate on plasma alanine aminotransferase determinations in toxicological studies.

    PubMed

    Evans, G O; Whitehorn, L C

    1995-10-01

    Alanine aminotransferase activities (ALT) were measured in rat plasma samples with three different reagent formulations. The inclusion of pyridoxal 5'-phosphate in the reagent produced higher ALT values, and altered the statistical relationships between control and treatment groups in three studies where plasma ALT values were reduced by xenobiotics. PMID:7482589

  11. Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer

    NASA Astrophysics Data System (ADS)

    Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric

    2014-05-01

    Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets.

  12. Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer

    SciTech Connect

    Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric, E-mail: frederic.lesage@polymtl.ca [Institute of Biomedical Engineering, École Polytechnique de Montréal, Montreal, Quebec H3C 3A7 (Canada) [Institute of Biomedical Engineering, École Polytechnique de Montréal, Montreal, Quebec H3C 3A7 (Canada); Montreal Heart Institute, Montreal, Quebec H1T 1C8 (Canada)

    2014-05-15

    Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets.

  13. Toxicological studies of the false morel (Gyromitra esculenta): Embryotoxicity of monomethylhydrazine in the rat

    Microsoft Academic Search

    Premysl Slanina; Eva Cekan; Barbro Halen; Kerstin Bergman; Robert Samuelsson

    1993-01-01

    The embryotoxic and teratogenic potential of monomethylhydrazine (MMH), a toxic component of the widely consumed false morel (Gyromitra esculenta), was studied in rat. Groups of pregnant Sprague?Dawley rats received MMH as a constant i.v. infusion via implanted osmotic minipumps (1.2, 3.0, 4.2, 6.0, 9.0 or 13.2 mg MMH \\/kg bw\\/day) on days 6–13 of pregnancy, or as a single intragastric

  14. Biochemical and toxicological studies of aqueous extract of Syzigium aromaticum (L.) Merr. & Perry (Myrtaceae) in rodents.

    PubMed

    Agbaje, E O; Adeneye, A A; Daramola, A O

    2009-01-01

    The effects of long-term administration of boiled aqueous extract of Syzigium aromaticum (SYZ), commonly known as clove (which has been locally employed for treating gastrointestinal tract diseases and also used as food spices), on some biochemical indices, such as body weight, liver functions and blood parameters were studied in adult albino rats of both sexes. Selected doses of 300 and 700 mg kg(-1) were given orally through cannular to groups of animals for a period of 90 days, while the control group received distilled water throughout the duration of study via the same route. Blood samples collected after therapy and assayed for activities of some liver enzymes recorded a significant (p<0.05) and prominent effect on ALP and AST. Measurement of haematological parameters also revealed significant effects (p<0.05; p<0.001) on Hb, RBC (p<0.05), PCV (p<0.001), platelets (p<0.001) and granulocytes (p<0.001). An insignificant reduction was recorded for total WBC. The histopathological study conducted was in consonance with the results of the biochemical investigations that the aqueous extract of SYZ even at moderate doses, significantly affects body organs, their enzymes as well as the various functions. LD(50) for both intraperitoneal and oral routes of SYZ were 263 and 2500 mg kg(-1) respectively. The present work has revealed the toxicity of sub chronic administration of SYZ, which suggests that its prolonged usage must be avoided. PMID:20448849

  15. Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA)—Power plant studies: assessment of breathing pattern

    PubMed Central

    Diaz, Edgar A.; Lemos, Miriam; Coull, Brent; Long, Mark S.; Rohr, Annette C.; Ruiz, Pablo; Gupta, Tarun; Kang, Choong-Min; Godleski, John J.

    2013-01-01

    Our approach to study multi-pollutant aerosols isolates a single emissions source, evaluates the toxicity of primary and secondary particles derived from this source, and simulates chemical reactions that occur in the atmosphere after emission. Three U.S. coal-fired power plants utilizing different coals and with different emission controls were evaluated. Secondary organic aerosol (SOA) derived from ?-pinene and/or ammonia was added in some experiments. Male Sprague-Dawley rats were exposed for 6 h to filtered air or different atmospheric mixtures. Scenarios studied at each plant included the following: primary particles (P); secondary (oxidized) particles (PO); oxidized particles + SOA (POS); and oxidized and neutralized particles + SOA (PONS); additional control scenarios were also studied. Continuous respiratory data were obtained during exposures using whole body plethysmography chambers. Of the 12 respiratory outcomes assessed, each had statistically significant changes at some plant and with some of the 4 scenarios. The most robust outcomes were found with exposure to the PO scenario (increased respiratory frequency with decreases in inspiratory and expiratory time); and the PONS scenario (decreased peak expiratory flow and expiratory flow at 50%). PONS findings were most strongly associated with ammonium, neutralized sulfate, and elemental carbon (EC) in univariate analyses, but only with EC in multivariate analyses. Control scenario O (oxidized without primary particles) had similar changes to PO. Adjusted R2 analyses showed that scenario was a better predictor of respiratory responses than individual components, suggesting that the complex atmospheric mixture was responsible for respiratory effects. PMID:21639693

  16. Toxicological and cytogenetic assessment of a Salacia oblonga extract in a rat subchronic study.

    PubMed

    Flammang, A M; Erexson, G L; Mirwald, J M; Henwood, S M

    2007-10-01

    Salacia oblonga holds potential as a natural method to mitigate the blood glucose response for people with diabetes by inhibiting the activity of intestinal alpha-glucosidases. As part of a safety evaluation of novel ingredients for use in blood glucose control, the toxicity of a S. oblonga root extract (SOE) was evaluated in a subchronic 90-day feeding study in rats. An in vivo-in vitro rat peripheral blood lymphocyte chromosomal aberrations assay was added at termination of the subchronic rat study to examine cultured lymphocytes for possible chromosomal aberration induction. This was conducted due to a previous weak; although reproducible, positive chromosomal aberrations response in cultured peripheral blood human lymphocytes after acute in vitro treatment with SOE. The present study results indicate that SOE was negative for the induction of chromosomal aberrations in cultured rat peripheral blood lymphocytes after 90 consecutive days of treatment with SOE. The no observable adverse effect level (NOAEL) was determined to be 2,500 mg/kg/day following daily subchronic oral gavage administrations to rats. PMID:17566623

  17. National Toxicology Program

    MedlinePLUS

    ... collaboration among federal agencies to characterize the potential toxicity of chemicals using cells and isolated molecular targets ... is to develop and apply tools of modern toxicology and molecular biology to identify substances in the ...

  18. DISEASE REGISTRY TOXICOLOGICAL PROFILES

    EPA Science Inventory

    By Congressional mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) produces "toxicological profiles" for hazardous substances found at National Priorities List (NPL) sites. These hazardous substances are ranked based on frequency of occurrence at NPL sites, to...

  19. Computational Toxicology (S)

    EPA Science Inventory

    The emerging field of computational toxicology applies mathematical and computer models and molecular biological and chemical approaches to explore both qualitative and quantitative relationships between sources of environmental pollutant exposure and adverse health outcomes. Th...

  20. Toxicological studies of the false morel (Gyromitra esculenta): embryotoxicity of monomethylhydrazine in the rat.

    PubMed

    Slanina, P; Cekan, E; Halen, B; Bergman, K; Samuelsson, R

    1993-01-01

    The embryotoxic and teratogenic potential of monomethylhydrazine (MMH), a toxic component of the widely consumed false morel (Gyromitra esculenta), was studied in rat. Groups of pregnant Sprague-Dawley rats received MMH as a constant i.v. infusion via implanted osmotic minipumps (1.2, 3.0, 4.2, 6.0, 9.0 or 13.2 mg MMH/kg bw/day) on days 6-13 of pregnancy, or as a single intragastric bolus (1 mg MMH/kg/bw or 5 mg MMH/kg/bw) on day 6 of pregnancy. Controls received corresponding amounts of saline. The average maternal serum concentrations, measured during the infusion treatment with a sensitive HPLC method, ranged from 0.072 micrograms MMH/ml (lowest dose) to 0.60 microgram MMH/ml (highest dose). The average serum levels measured 45 min after the intragastric application (peak levels) were 0.28 microgram MMH/ml and 1.6 microgram MMH/ml, respectively. Serum concentrations of MMH corresponding to those measured in the lower dose groups in this study were seen in pilot studies after a single mushroom meal in human volunteers. A dose-dependent, statistically significant increase in the number of resorptions was seen in all but the lowest dose group after the infusion of MMH. In addition, except for the two lowest doses, there was a dramatic, dose-dependent decrease in the pregnancy rate as compared to controls, with no pregnancies occurring at the two highest dose level groups. The decreased pregnancy rate was probably due to preimplantation loss which was shown to occur after a single intragastric bolus dose of MMH (5 mg/kg bw).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8405578

  1. Establishment of an in vitro brain barrier epithelial transport system for pharmacological and toxicological study

    PubMed Central

    Shi, Lewis Zhichang; Zheng, Wei

    2014-01-01

    An immortalized Z310 murine choroidal epithelial cell line was recently established in this laboratory. The purposes of this study were (1) to investigate the presence of tight junction (TJ) proteins in Z310 cells and (2) to develop a Z310 cell-based in vitro brain barrier transport model. Real-time RT-PCR studies revealed that Z310 cells possess mRNAs encoding ZO-1, ?2, and ?3, claudin?1, ?2, ?4, and ?8, occludin, and connexin-32. Confocal microscopic analyses confirmed the presence of claudin-1 and ZO-1 in Z310 cells at cell–cell contact sites. When Z310 cells were grown on a two-chamber Transwell device, the [14C]sucrose permeability coefficient and transepithelial electrical resistance (TEER) across the cell monolayer were 6 × 10–4 cm/min and 61 ?-cm2, respectively. To improve the tightness of Z310 barrier, the cells were cultured in astrocyte-conditioned medium (ACM), or in the presence of eicosapentaenoic acids (EPA, 10 ?M), epidermal growth factor (EGF, 100 ng/mL), or dexamethasone (1 ?M) in the growth medium. Treatment with ACM, EPA, EGF and dexamethasone significantly increased the TEER by 33%, 38%, 40%, and 50% above controls, respectively. However, only dexamethasone significantly reduced [14C]sucrose paracellular permeability (–231% of controls). These data suggest that Z310 cells possess the TJ proteins. The presence of dexamethasone in the growth medium improves the tightness of Z310 cell monolayer to the level better than that of the primary culture of choroidal epithelial cells. The Z310 cell-based in vitro model appears to be suitable for transepithelial transport study of drugs and toxicants. PMID:16126179

  2. A pharmacokinetic study of ethyl glucuronide in blood and urine: applications to forensic toxicology.

    PubMed

    Høiseth, Gudrun; Bernard, Jean Paul; Karinen, Ritva; Johnsen, Lene; Helander, Anders; Christophersen, Asbjørg S; Mørland, Jørg

    2007-10-25

    This pharmacokinetic study investigated the kinetics of ethanol and its metabolite ethyl glucuronide (EtG) in blood and urine during the whole time course of absorption and elimination. There are few previous studies on the kinetics of EtG in blood, and we wanted to evaluate whether such knowledge could yield valuable information regarding the time of ethanol ingestion in forensic cases, such as, for instance, drunk driving. Ten male volunteers consumed ethanol at a fixed dose of 0.5 g/kg body weight in a fasted state. Blood samples were collected for 14 h and urine samples were collected for 45-50 h after the start of drinking. EtG reached its maximum concentration (C(max)) in blood after a median of 4 h (range 3.5-5), a median of 3 h (range 2-4.5) after C(max) for ethanol. The ethanol-to-EtG ratios in blood (ethanol in g/L, EtG in mg/L) were >1 only for the first median 3.5 h (range 2.5-3.5) after drinking. EtG elimination occurred with a median half-life of 2.2 h (range 1.7-3.1 h), and the renal clearance was 8.32 L/h (median, range 5.25-20.86). The concentrations of EtG were always much higher in urine than in blood. The total amount of EtG excreted in the urine was median 30 mg (range 21.5-39.7), representing 0.017% (median, range 0.013-0.022) of the ethanol given, on a molar basis. The information from the present study may be a valuable supplement to determine the time of ethanol ingestion. For this purpose, two subsequent increasing EtG values and a high ethanol-to-EtG ratio in blood would support information of recent drinking. PMID:17306943

  3. Novel biological recycling water purification system for use in fish toxicology studies

    SciTech Connect

    Veriangieri, A.J.; Lewis, R.M.; Bannon, A.W.; Wilson, M.C.

    1988-02-01

    A major problem with fish toxicity testing has been maintaining an adequate supply of healthy, acclimated fish in the laboratory setting from which test populations can be obtained. The build-up of metabolic waste (ammonia) in holding tank environments leads to a stressful situation for the fish, resulting in mortality or erroneous toxicity data. Ammonia is the principal nitrogenous waste product of catfish and is excreted primarily as the toxic unionized ammonia from the gills. The purpose of this study was to develop a novel biological filter system which facilitates the nitrification process, thereby removing or controlling the build-up of toxic metabolic waste products in holding tanks in the laboratory. This system would provide a healthy, non-stressful environment for blue channel catfish (Ictalurus Punctatus) fingerlings prior to their use in LC50 determinations of various insecticides, herbicides, and fungicides currently employed in the vicinity of catfish ponds or farms.

  4. Toxicological studies of shale oils, some of their components, and commercial products.

    PubMed

    Veldre, I A; Jänes, H J

    1979-06-01

    Estonian shale oil contains about 25--30% phenols, and their action determines the toxicity of shale oils. The clinical symptoms of intoxication are rather similar, regardless of route of administration. Due to neurotropic action, the coordination of movements is impaired, and clonic and tetanic convulsions, paresis and paralysis of extremities, and narcosis are observed. In subacute and chronic toxicity tests, dysfunction of the central nervous system was found. In long-term (4--6 month) experiments, changes in liver and kidney function were found. Shale oil has gonadotropic activity and causes changes in the sexual cycle as well as diminution of the number of primordial folicles in the ovaries or a decrease in the quantity of normal spermatogonia in testicular germinal epithelium. Shale oils produce local irritation of skin and mucous membranes. Shale oil can induce sensitization of the organism after repeated administration. The results of acute intoxication tests have proved that volatile and nonvolatile phenol fractions, isomeric dimethylphenols, and 5-methylresorcinol, must be characterized as moderately toxic substances; the LD50 ranges from 501 to 1500 mg/kg. The clinical symptoms of acute toxication are similar for all studied phenols (restlessness, unsteadiness, clonic tremor, paresis and paralysis of extremities, and death). In spite of the moderate toxicity of phenols in acute experiments, repeated administration of small doses can cause different changes in the nervous system and internal organs of experimental animals. For all the phenols studied, the maximum allowable concentration in water was limited by their effect on the organoleptic properties of water. The nonactive dose for warm-blooded animals is from 100 to 3000 times the threshold limit value of phenols on the basis of their organoleptic properties. The effect of commercial products of oil shale industry is generally determined by the toxicity of the main components: water-soluble oil shale phenols. PMID:571802

  5. Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss

    PubMed Central

    Andrade-Vieira, Rafaela; Goguen, Donna; Bentley, Heidi A.; Bowen, Chris V.; Marignani, Paola A.

    2014-01-01

    Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1?/?NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1?/?NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers. PMID:25436981

  6. Rapid and sensitive ultra-high-pressure liquid chromatography method for quantification of antichagasic benznidazole in plasma: application in a preclinical pharmacokinetic study.

    PubMed

    Davanço, Marcelo Gomes; de Campos, Michel Leandro; Peccinini, Rosângela Gonçalves

    2014-11-26

    Benznidazole (BNZ) and nifurtimox are the only drugs available for treating Chagas disease. In this work, we validated a bioanalytical method for the quantification of BNZ in plasma aimed at improving sensitivity and time of analysis compared with the assays already published. Furthermore, we demonstrated the application of the method in a preclinical pharmacokinetic study after administration of a single oral dose of BNZ in Wistar rats. A Waters® Acquity UHPLC system equipped with a UV-vis detector was employed. The method was established using an Acquity® UHPLC HSS SB C18 protected by an Acquity® UHPLC HSS SB C18 VanGuard guard column and detection at 324 nm. The mobile phase consisted of ultrapure water-acetonitrile (65:35), and elution was isocratic. The mobile phase flow rate was 0.55 mL/min, the volume of injection was 1 ?L, and the run time was just 2 min. The samples were kept at 25°C until injection and the column at 45°C for the chromatographic separation. The sample preparation was performed by a rapid protein precipitation with acetonitrile. The linear concentration range was 0.15-20 µg/mL. The pharmacokinetic parameters of BNZ in rats were determined and the method was considered sensitive, fast and suitable for application in pharmacokinetic studies. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25424984

  7. Toxicology as a nanoscience? – Disciplinary identities reconsidered

    PubMed Central

    Kurath, Monika; Maasen, Sabine

    2006-01-01

    Toxicology is about to establish itself as a leading scientific discipline in addressing potential health effects of materials on the nanosize level. Entering into a cutting-edge field, has an impact on identity-building processes within the involved academic fields. In our study, we analyzed the ways in which the entry into the field of nanosciences impacts on the formation of disciplinary identities. Using the methods of qualitative interviews with particle toxicologists in Germany, Holland, Switzerland and the USA, we could demonstrate that currently, toxicology finds itself in a transitional phase. The development of its disciplinary identity is not yet clear. Nearly all of our interview partners stressed the necessity of repositioning toxicology. However, they each suggested different approaches. While one part is already propagandizing the establishment of a new discipline – 'nanotoxicology'- others are more reserved and are demanding a clear separation of traditional and new research areas. In phases of disciplinary new-orientation, research communities do not act consistently. Rather, they establish diverse options. By expanding its disciplinary boundaries, participating in new research fields, while continuing its previous research, and only vaguely defining its topics, toxicology is feeling its way into the new fields without giving up its present self-conception. However, the toxicological research community is also discussing a new disciplinary identity. Within this, toxicology could develop from an auxiliary into a constitutive position, and take over a basic role in the cognitive, institutional and social framing of the nanosciences. PMID:16646961

  8. Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy of the prostate: a preclinical study with radiological and pathological correlation using customised MRI-based moulds

    PubMed Central

    Partanen, Ari; Yerram, Nitin K.; Trivedi, Hari; Dreher, Matthew R.; Oila, Juha; Hoang, Anthony N.; Volkin, Dmitry; Nix, Jeffrey; Turkbey, Baris; Bernardo, Marcelino; Haines, Diana C.; Benjamin, Compton J.; Linehan, W. Marston; Choyke, Peter; Wood, Bradford J.; Ehnholm, Gösta J.; Venkatesan, Aradhana M.; Pinto, Peter A.

    2013-01-01

    Objective To characterise the feasibility and safety of a novel transurethral ultrasound (US)-therapy device combined with real-time multi-plane magnetic resonance imaging (MRI)-based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model. To correlate ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. Materials and methods Three dogs were treated with three targeted ablations each, using a prototype MRI-guided transurethral US-therapy system (Philips Healthcare, Vantaa, Finland). MRI provided images for treatment planning, guidance, real-time multi-planar thermometry, as well as post-treatment evaluation of efficacy. After treatment, specimens underwent histopathological analysis to determine the extent of necrosis and cell viability. Statistical analyses (Pearson’s correlation, Student’s t-test) were used to evaluate the correlation between ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. Results MRI combined with a transurethral US-therapy device enabled multi-planar temperature monitoring at the target as well as in surrounding tissues, allowing for safe, targeted, and controlled ablations of prescribed lesions. Ablated volumes measured by cumulative thermal dose positively correlated with volumes determined by histopathological analysis (r2 0.83, P < 0.001). Post-procedural contrast-enhanced and diffusion-weighted MRI showed a positive correlation with non-viable areas on histopathological analysis (r2 0.89, P < 0.001, and r20.91, P = 0.003, respectively). Additionally, there was a positive correlation between ablated volumes according to cumulative thermal dose and volumes identified on post-procedural contrast-enhanced MRI (r2 0.77, P < 0.01). There was no difference in mean ablation volumes assessed with the various analysis methods (P > 0.05, Student’s t-test). Conclusions MRI-guided transurethral US therapy enabled safe and targeted ablations of prescribed lesions in a preclinical canine prostate model. Ablation volumes were reliably predicted by intra- and post-procedural imaging. Clinical studies are needed to confirm the feasibility, safety, oncological control, and functional outcomes of this therapy in patients in whom focal therapy is indicated. PMID:23746198

  9. The identification of complex interactions in epidemiology and toxicology: a simulation study of boosted regression trees

    PubMed Central

    2014-01-01

    Background There is a need to evaluate complex interaction effects on human health, such as those induced by mixtures of environmental contaminants. The usual approach is to formulate an additive statistical model and check for departures using product terms between the variables of interest. In this paper, we present an approach to search for interaction effects among several variables using boosted regression trees. Methods We simulate a continuous outcome from real data on 27 environmental contaminants, some of which are correlated, and test the method’s ability to uncover the simulated interactions. The simulated outcome contains one four-way interaction, one non-linear effect and one interaction between a continuous variable and a binary variable. Four scenarios reflecting different strengths of association are simulated. We illustrate the method using real data. Results The method succeeded in identifying the true interactions in all scenarios except where the association was weakest. Some spurious interactions were also found, however. The method was also capable to identify interactions in the real data set. Conclusions We conclude that boosted regression trees can be used to uncover complex interaction effects in epidemiological studies. PMID:24993424

  10. Toxicological studies of Karlodinium micrum (Dinophyceae) isolated from East China Sea.

    PubMed

    Zhou, Chengxu; Fernández, Nuria; Chen, Haiming; You, Yurong; Yan, Xiaojun

    2011-01-01

    Karlodinium micrum (Strain NMBjah047) was isolated from the water samples of East China Sea (ECS). The hemolytic, ichthyotoxic, and cytotoxic activities of the algae was characterized. Embryotoxicity of both intra and extracellular extracts were also tested on a local sea urchin species. The algal intracellular hemolytic toxicity averaged about 87.5% at different algal growth phases. However, extracellular hemolytic activity depended on the population growth phase. The toxicity increased with the increase in the population size, reaching the highest hemolytic activity during the stationary phase, and maintained a relatively high activity even when the population declined. Time and density dependent ichthyotoxicity to Lateolabrax maculates juveniles was also detected. The LD(50) in 24 h was 1.1 × 10(5) cells/mL. Inhibition of the fertilized egg hatching was also observed and estimated the IC(50) in 40 h with 3.5 × 10(4) cells/mL. Extracellular extracts of K. micrum dense culture also showed significant cytotoxic activity on HUVEC (IC(50) = 70.8 ?g/mL). A dose dependent acute toxicity to embryos of sea urchin was also determined. The algal intracellular and extracellular extracts delayed or even restricted the embryological development of the sea urchin, illustrating the potential toxicity of K. micrum not only to vertebrates, but also to marine invertebrates. The hemolytic compounds in the ECS strain were extracted and analyzed. At least two fractions had significant hemolytic activities. A lipid-like compound, named Digalactosyldiacylglycerol (DGDG), was suggested to be responsible for the hemolytic activity in one of these fractions. From the results of the present studies, this strain of K. micrum isolated from the East China Sea might be considered a toxic strain with hemolytic activity, ichthyotoxicity, cytotoxicity and embryotoxicity. PMID:20858509

  11. [Toxicological studies on dibekacin for intravenous injection use. II. Chronic toxicity in rats (author's transl)].

    PubMed

    Koeda, T; Odaki, M; Sasaki, H; Yokota, M; Niizato, T; Watanabe, H; Kawaoto, H; Hirano, F; Ishiwatari, N; Watanuki, T; Senoo, A

    1980-05-01

    The toxic effects of dibekacin sulfate (DKB) in male and female rats were examined in chronic toxicity test (intraperitoneal injection), and the following results were obtained. 1) No death was noted in both male and female. 2) In general conditions, the excretion of soft or diarrheal stool was noted in groups of more than 20 mg/kg of either sex. The mean body weight was less than the control during a certain period in the male group of 40 mg/kg and in the female group of 20 mg/kg. But, in the food intakes, no particular change was noted in each group of either sex. 3) In the auricle reflex, no abnormality was noted in each group of either sex. 4) In the hematological test, the findings such as an increase of BUN, anemia, etc. were noted in the groups more than 10 mg/kg of male and more than 20 mg/kg of female. 5) In the histopathological study, evident degenerative changes of renal tubular epithelia were noted in the groups which were administered more than 20 mg/kg of DKB in both male and female, but no evident pathological findings due to the renal failure were noted in the groups of less than 10 mg/kg. Several slight changes of the thyroid gland noted in a few rats of DKB administration group of both male and female seemed to be artifact, and inflammatory changes owing to intraperitoneal injection were occasionally noted in the peritoneum of DKB injected animals. 6) Considering the above results, "the maximal non effective dose" was estimated to be 10 mg/kg in both male and female. PMID:7431660

  12. Preclinical Evaluation of HIV Eradication Strategies in the Simian Immunodeficiency Virus-Infected Rhesus Macaque: A Pilot Study Testing Inhibition of Indoleamine 2,3-Dioxygenase

    PubMed Central

    Dunham, Richard M.; Gordon, Shari N.; Vaccari, Monica; Piatak, Michael; Huang, Yong; Deeks, Steven G.; Lifson, Jeffrey; Franchini, Genoveffa

    2013-01-01

    Abstract Even in the setting of maximally suppressive antiretroviral therapy (ART), HIV persists indefinitely. Several mechanisms might contribute to this persistence, including chronic inflammation and immune dysfunction. In this study, we have explored a preclinical model for the evaluation of potential interventions that might serve to eradicate or to minimize the level of persistent virus. Given data that metabolic products of the inducible enzyme indoleamine 2,3-dioxygeanse (IDO) might foster inflammation and viral persistence, chronically simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques were treated with the IDO inhibitor 1-methyl tryptophan (1mT). Orally administered 1mT achieved targeted plasma levels, but did not impact tryptophan metabolism or decrease viral RNA or DNA in plasma or in intestinal tissues beyond levels achieved by ART alone. Animals treated with 1mT showed no difference in the levels of T cell activation or differentiation, or in the kinetics or magnitude of viral rebound following cessation of ART. Notwithstanding these negative results, our observations suggest that the chronically SIV-infected rhesus macaque on suppressive ART can serve as a tractable model in which to test and to prioritize the selection of other potential interventions designed to eradicate HIV in vivo. In addition, this model might be used to optimize the route and dose by which such interventions are administered and the methods by which their effects are monitored. PMID:22924680

  13. Autofluorescence imaging device for real-time detection and tracking of pathogenic bacteria in a mouse skin wound model: preclinical feasibility studies

    NASA Astrophysics Data System (ADS)

    Wu, Yichao Charlie; Kulbatski, Iris; Medeiros, Philip J.; Maeda, Azusa; Bu, Jiachuan; Xu, Lizhen; Chen, Yonghong; DaCosta, Ralph S.

    2014-08-01

    Bacterial infection significantly impedes wound healing. Clinical diagnosis of wound infections is subjective and suboptimal, in part because bacteria are invisible to the naked eye during clinical examination. Moreover, bacterial infection can be present in asymptomatic patients, leading to missed opportunities for diagnosis and treatment. We developed a prototype handheld autofluorescence (AF) imaging device (Portable Real-time Optical Detection, Identification and Guidance for Intervention-PRODIGI) to noninvasively visualize and measure bacterial load in wounds in real time. We conducted preclinical pilot studies in an established nude mouse skin wound model inoculated with bioluminescent Staphylococcus aureus bacteria. We tested the feasibility of longitudinal AF imaging for in vivo visualization of bacterial load in skin wounds, validated by bioluminescence imaging. We showed that bacteria (S. aureus), occult to standard examination, can be visualized in wounds using PRODIGI. We also detected quantitative changes in wound bacterial load over time based on the antibiotic treatment and the correlation of bacterial AF intensity with bacterial load. AF imaging of wounds offers a safe, noninvasive method for visualizing the presence, location, and extent of bacteria as well as measuring relative changes in bacterial load in wounds in real time.

  14. Universal hand-held three-dimensional optoacoustic imaging probe for deep tissue human angiography and functional preclinical studies in real time.

    PubMed

    Deán-Ben, Xosé; Fehm, Thomas Felix; Razansky, Daniel

    2014-01-01

    The exclusive combination of high optical contrast and excellent spatial resolution makes optoacoustics (photoacoustics) ideal for simultaneously attaining anatomical, functional and molecular contrast in deep optically opaque tissues. While enormous potential has been recently demonstrated in the application of optoacoustics for small animal research, vast efforts have also been undertaken in translating this imaging technology into clinical practice. We present here a newly developed optoacoustic tomography approach capable of delivering high resolution and spectrally enriched volumetric images of tissue morphology and function in real time. A detailed description of the experimental protocol for operating with the imaging system in both hand-held and stationary modes is provided and showcased for different potential scenarios involving functional and molecular studies in murine models and humans. The possibility for real time visualization in three dimensions along with the versatile handheld design of the imaging probe make the newly developed approach unique among the pantheon of imaging modalities used in today's preclinical research and clinical practice. PMID:25408083

  15. 78 FR 58548 - Request for Information: The National Toxicology Program Requests Information on Use, Human...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-24

    ...of Health Request for Information: The National Toxicology Program Requests Information on Use, Human Exposure, and Toxicity of Vinpocetine SUMMARY: To facilitate the design of toxicological studies for vinpocetine (CAS RN:...

  16. Discovery and preliminary confirmation of novel early detection biomarkers for triple-negative breast cancer using preclinical plasma samples from the Women’s Health Initiative observational study

    PubMed Central

    Li, Christopher I.; Mirus, Justin E.; Zhang, Yuzheng; Ramirez, Arturo B.; Ladd, Jon J.; Prentice, Ross L.; McIntosh, Martin; Hanash, Samir M.; Lampe, Paul D.

    2012-01-01

    Triple-negative breast cancer is a particularly aggressive and lethal breast cancer subtype that is more likely to be interval-detected rather than screen-detected. The purpose of this study is to discover and initially validate novel early detection biomarkers for triple-negative breast cancer using preclinical samples. Plasma samples collected up to 17 months prior to diagnosis from 28 triple-negative cases and 28 matched controls from the Women’s Health Initiative Observational Study were equally divided into a training set and a test set and interrogated using a customized antibody array. Data were available on 889 antibodies, and in the training set statistically significant differences in case vs. control signals were observed for 93 (10.5%) antibodies at p<0.05. Of these 93 candidates, 29 were confirmed in the test set at p<0.05. Areas under the curve for these candidates ranged from 0.58 to 0.79. With specificity set at 98%, sensitivity ranged from 4% to 68% with ?20 candidates having a sensitivity 20% and 6 having a sensitivity ?40%. In an analysis of KEGG gene sets, the pyrimidine metabolism gene set was upregulated in cases compared to controls (p=0.004 in the testing set) and the JAK/Stat signaling pathway gene set was downregulated (p=0.003 in the testing set). Numerous potential early detection biomarkers specific to triple-negative breast cancer in multiple pathways were identified. Further research is required to follow-up on promising candidates in larger sample sizes and to better understand their potential biological importance as our understanding of the etiology of triple-negative breast cancer continues to grow. PMID:22903690

  17. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies

    Microsoft Academic Search

    Christine Heim; Charles B. Nemeroff

    2001-01-01

    Epidemiologic studies indicate that children exposed to early adverse experiences are at increased risk for the development of depression, anxiety disorders, or both. Persistent sensitization of central nervous system (CNS) circuits as a consequence of early life stress, which are integrally involved in the regulation of stress and emotion, may represent the underlying biological substrate of an increased vulnerability to

  18. Abstract--A small, hermetic, wirelessly-controlled retinal prosthesis was developed for pre-clinical studies in Yucatan

    E-print Network

    Kelly, Shawn K.

    -clinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, Santa Barbara, CA 93106; J. Chen and J. F. Rizzo are with the Massachusetts Eye and Ear Infirmary inserted into the subjects' eyes, resting on or just above the epi-retinal surface. An external stimulator

  19. Advanced urine toxicology testing.

    PubMed

    Tenore, Peter L

    2010-10-01

    Urine toxicology screening testing is an important standard of care in the addiction and pain treatment setting, offering a reproducible, unbiased, and accurate laboratory test to monitor patients and provide objective support for clinical observations. It has been shown that physicians do not have proficiency in the ordering or interpretation of these tests. This article is an attempt to respond to that need. Current antibody-based enzymatic immunoassays (EIAs) used for urine toxicology screening are useful to detect classes of drugs (ex., opiate) but cannot determine which specific drug (ex., morphine) is present. Gas chromatography and mass spectroscopy can determine exactly which drugs are present, allowing prescribed (or illicit) opiates and benzodiazepines to be identified. This article will discuss principles and details of opiate and benzodiazepine EIA and gas chromatography and mass spectroscopy urine toxicology testing. The approach to detecting patients attributing positive opiate EIAs to prescription opiates who are using heroin or other opioids will be reviewed. Cases of controlled prescription drugs that do not produce the expected positive urine tests (ex., oxycodone producing negative opiate screening tests) will be discussed. How to differentiate codeine from heroin and the role of poppy seeds in toxicology will be examined. The case of an anti-depressant drug that produces false-positive benzodiazepine results and antibiotics that cause positive opiate urine toxicology results will be reviewed. Common benzodiazepines (ex., clonazepam and lorazepam) that do not reliably produce positive benzodiazepine EIAs will be discussed. The approach to detection and management of all these types of toxicology cases will be reviewed, and it is hoped that the analyses presented will impart an adequate information base to medical providers and staff members of drug treatment and pain centers, enabling them to order and interpret these tests in the clinic more effectively as an integrated part of whole patient care. PMID:20924879

  20. Preclinical Safety Pharmacology Study of a Novel Protein-Based Cancer Vaccine CHP-NY-ESO-1

    Microsoft Academic Search

    NAOZUMI HARADA; KIYOTAKA HOSHIAI; YOSHIYASU TAKAHASHI; YASUE SAKAGUCHI; TAKAYOSHI KUNO; TADASHI HISHIDA; HIROSHI SHIKU

    2008-01-01

    CHP-NY-ESO-1 is a novel therapeutic cancer vaccine consisting of a recombinant protein of cancer antigen NY-ESO-1 and a polysaccharide-based delivery system, cholesteryl pullulan. A pilot clinical study of CHP-NY-ESO-1 in cancer patients was previously conducted, and the adverse events related to this drug were observed to be limited to skin reactions at injection sites. To further establish the safety of

  1. Shuttle Lesson Learned - Toxicology

    NASA Technical Reports Server (NTRS)

    James, John T.

    2010-01-01

    This is a script for a video about toxicology and the space shuttle. The first segment is deals with dust in the space vehicle. The next segment will be about archival samples. Then we'll look at real time on-board analyzers that give us a lot of capability in terms of monitoring for combustion products and the ability to monitor volatile organics on the station. Finally we will look at other issues that are about setting limits and dealing with ground based lessons that pertain to toxicology.

  2. Preclinical Study of Treatment Response in HCT-116 Cells and Xenografts with 1H-decoupled 31P MRS

    PubMed Central

    Darpolor, Moses M.; Kennealey, Peter T.; Carl Le, H; Zakian, Kristen L.; Ackerstaff, Ellen; Rizwan, Asif; Chen, Jin-Hong; Sambol, Elliot B.; Schwartz, Gary K.; Singer, Samuel; Koutcher, Jason A.

    2011-01-01

    The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G2/M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G2/M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton (1H)-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p = 0.0004) and inorganic phosphate (p = 0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83±5% G2/M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5±1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39±10% apoptosis. In vivo 1H-decoupled 31P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies. PMID:21994185

  3. Bone-marrow biopsy needle incorporating a snare-coil specimen-capturing device: description and preclinical studies.

    PubMed

    Goldenberg, A S; Rishton, M

    1999-01-01

    A tissue biopsy needle maximizes adequate specimen retrieval and minimizes patient pain and tissue disruption. The proposed biopsy needle incorporates an internal snare-coil for capturing specimens. The snare-coil device is described along with needle durability and performance testing. Sharply cut, nonfragmented, cored specimens were retrieved from a resin-based foam. In clinical practice, the snare-coil technology may minimize post-insertion needle manipulations and patient pain. Further studies are required to determine the impact of snare-coil needles on the retrieval of adequate specimens from patients. PMID:10626043

  4. Preclinical pharmacodynamic and pharmacokinetic studies of investigational new drugs. Annual report, 1 November 1993-31 October 1994

    SciTech Connect

    Noker, P.E.

    1994-11-11

    During the past year of this contract pharmacokinetic, pharmacodynamic, bioavailability and metabolism studies have been conducted on two anti-cyanotic agents (WR242511 and p-aminohetanophenone (PAHP)) and one nerve agent antidote (HI-6) which are under consideration for clinical development by the U.S. Army. Radiolabeled formulations of WR242511, PAHP and HI-6 were used in these investigations. Information has been obtained on the half-lives of absorption and elimination of both radioactivity and the parent compound following oral and i.v. administration of these three compounds to dogs and, for PAHP, also to rats. In addition, the rates and extent of urinary and fecal elimination of the agents has been characterized; the pharmacodynamics, as assessed by the production of methemoglobin, of two compounds (WR242511 and PAHP) has been studied; and the metabolism of each compound has been investigated. Data obtained to date indicate that: WR242511 does not directly produce methemoglobinemia but a metabolite sequestered in red cells is the responsible agent; dogs appear to metabolize PAHP differently than do rats; the major urinary metabolite of HI-6 is 2-pyridine aldoxime. Further efforts to isolate and identify the metabolites of all three compounds are in progress.

  5. A Preclinical Study of the Safety and Efficacy of Occlusin Trade-Mark-Sign 500 Artificial Embolization Device in Sheep

    SciTech Connect

    Owen, Richard J., E-mail: drrichardowen@tbwifi.ca [University of Alberta, Radiology and Diagnostic Imaging, Walter C. Mackenzie Health Sciences Centre (Canada); Nation, Patrick N. [University of Alberta, Laboratory Medicine and Pathology, Walter C. Mackenzie Health Sciences Centre (Canada); Polakowski, Robert [BioLipids Inc (Canada); Biliske, Jennifer A. [University of Alberta, Biological Sciences, CW405, Biological Sciences Building (Canada); Tiege, Paul B. [University of Alberta, Lipid Products Research Alberta (LiPRA), 410 Agriculture/Forestry Centre (Canada); Griffith, Irwin J. [IMBiotechnologies Ltd (Canada)

    2012-06-15

    Introduction: This study evaluated the safety, effectiveness, and biodegradation of a new embolic agent, Occlusin Trade-Mark-Sign 503 Artificial Embolization Device (OCL 503). The agent consists of biodegradable poly-lactic-co-glycolic acid microspheres (150-212 {mu}m) coated with type I bovine collagen and was compared with Embosphere{sup Registered-Sign} Microspheres (300-500 {mu}m) in this controlled study of uterine artery embolization (UAE) in sheep. Methods: Unilateral UAE was performed in 32 adult ewes randomly assigned. Vessels were embolized to effective stasis. The cohort was divided into four groups, which were sacrificed at 1, 3, 6, and 12 months. Results: Both agents were 100% effective in achieving stasis. At 6 months, all OCL 503-treated arteries were occluded, the microspheres degraded with time, and at 12 months all four animals examined demonstrated recanalization. OCL 503 was found in the untreated uterine artery in one animal with no other evidence of non target embolization. In the Embosphere-treated group, all vessels remained occluded and microspheres were detected in the contralateral uterine artery in 6 of 15 examined vessels and in 10 vaginal, 2 ovarian, and 1 vesical artery. No procedural-related complications were seen in either group. Conclusions: OCL 503 is as effective an embolic agent as Embosphere{sup Registered-Sign} Microspheres when embolizing ovine uterine arteries and resorbs with time, allowing recanalization of the treated arteries. No device-related issues or adverse events were observed.

  6. Fluorine-18-fluorodeoxygglucose-guided breast cancer surgery with a positron-sensitive probe: Validation in preclinical studies

    SciTech Connect

    Raylman, R.R.; Fisher, S.J.; Brown, R.S.; Ethier, S.P.; Wahl, R.L. [Univ. of Michigan Medical Center, Ann Arbor, MI (United States)

    1995-10-01

    In this study, the feasibility of utilizing 2-deoxy-2-fluoro-d-glucose (FDG) in conjunction with a positron-sensitive intraoperative probe to guide breast tumor excision was investigated. The probe was constructed with a plastic scintillator tip coupled to a photomultiplier tube with fiber optic cable. Anticipated resolution degradation was evaluated by measurement of line spread functions in the presence of background radiation. Realistic photon background distributions were simulated with a human torso phantom and a cardiac insert. The relationship between resolution and energy threshold was measured to find the optimal discriminator settings. In addition, probe sensitivity as a function of energy threshold was determined for various size-simulated tumors. Finally, the ability to localize breast cancers in vivo was tested in a rodent model. Mammary rat tumors implanted in Lewis rats were examined after injection with FDG; these results were correlated with those of histologic analyses. Measurements of line spread functions indicated that resolution could be maximized in a realistic background photon environment by increasing the energy threshold to levels at or above the Compton continuum edge (340 keV). At this setting, the probe`s sensitivity was determined to be 58 and 11 cps/{mu}Ci for 3.18- and 6.35-mm diameter simulated tumors, respectively. Probe readings correlated well with histologic results; the probe was generally able to discriminate between tumor and normal tissue. This study indicates that breast cancer surgery guided by a positron-sensitive probe warrants future evaluation in breast-conserving surgery of patients with breast cancer. 23 refs., 5 figs.

  7. Preclinical Safety Evaluation of ASCs Engineered by FLPo/Frt-Based Hybrid Baculovirus: In Vitro and Large Animal Studies.

    PubMed

    Li, Kuei-Chang; Chang, Yu-Han; Lin, Chin-Yu; Hwang, Shiaw-Min; Wang, Tzu-Hao; Hu, Yu-Chen

    2015-05-01

    We recently developed hybrid baculovirus (BV) vectors that exploited FLPo/Frt-mediated DNA minicircle formation. Engineering of adipose-derived stem cells (ASCs) with the FLPo/Frt-based BV vectors enabled prolonged transgene expression and, after cell implantation into rabbits, ameliorated cartilage regeneration and bone repair. To translate the hybrid BV one step further toward clinical applications, here we assessed the biosafety profiles of the hybrid BV-engineered human ASCs (hASCs) in vitro and evaluated the immune responses elicited by the engineered porcine ASCs (pASCs) in large animals. We confirmed that the hybrid BV did not compromise the hASCs viability, immunosuppressive capacity, and surface characteristics. Neither did the hybrid BV cause chromosomal abnormality/transgene integration in vitro nor did it induce tumorigenicity in vivo. In the large animal study, pASCs were engineered with the hybrid BV expressing bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF) and implanted into femoral bone defects in mini pigs. The hybrid BV-engineered pASCs enabled prolonged BMP2/VEGF expression and triggered the healing of massive segmental bone defects, while only eliciting transient antibody, cytokine, and local cellular immune responses stemming from the implantation procedure itself. These data altogether demonstrated the safety of the hybrid BV vectors for ASCs engineering and bone healing in large animals, hence implicating the potential in clinical applications. PMID:25602313

  8. Inhibitory Effects of Platelet-Rich Plasma on Intervertebral Disc Degeneration: A Preclinical Study in a Rabbit Model

    PubMed Central

    Gui, Keke; Ren, Weimin; Yu, Yonglin; Li, Xin; Dong, Jiachun; Yin, Wangping

    2015-01-01

    Background Platelet-rich plasma (PRP) contains multiple growth hormones that may stimulate tissue repair. This study aimed to assess the effects of PRP in a rabbit model of IDD (annulus fibrosus puncture). Material/Methods Thirty-six adult New Zealand white rabbits were randomly divided into 3 groups: 0.1 mL PRP (group A), 0.1 mL phosphate-buffered saline (group B), and control (group C) (n=12/group). Annulus fibrosus puncture was performed to establish L4/5 and L5/6 IDD models. Two and 4 weeks later, 6 rabbits from each group were given an IVD injection at L4/5 and L5/6. Two or 4 weeks after injection, rabbits were scanned with X-ray and MRI before being sacrificed. IVDs were collected for hematoxylin and eosin, Masson’s trichrome, and Safranin O staining, and type II collagen immunohistochemistry. Results Over time, IVD height and disc imaging signal intensity decreased gradually in groups B and C, but only slightly in group A (baseline: 100% for all groups; A: 95.9±4.2% at 4 weeks, 90.1±8.4 at 6 weeks; B: 75.3±5.7% at 4 weeks, 70.8±6.4% at 6 weeks; C: 74.7±5.5% at 4 weeks, 69.9±6.2% at 6 weeks; all P<0.001, P<0.01 between A vs. B and C). Degenerative histological changes in IVDs in groups B and C were more severe compared with group A. Conclusions Platelet-rich plasma interventions can effectively attenuate the IDD process in rabbits. PMID:25965093

  9. Toxicology of chlorofluorocarbon replacements.

    PubMed Central

    Dekant, W

    1996-01-01

    Chlorofluorocarbons (CFCs) are stable in the atmosphere and may reach the stratosphere. They are cleaved by UV-radiation in the stratosphere to yield chlorine radicals, which are thought to interfere with the catalytic cycle of ozone formation and destruction and deplete stratospheric ozone concentrations. Due to potential adverse health effects of ozone depletion, chlorofluorocarbon replacements with much lower or absent ozone depleting potential are developed. The toxicology of these compounds that represent chlorofluorohydrocarbons (HCFCs) or fluorohydrocarbons (HFCs) has been intensively studied. All compounds investigated (1, 1-dichloro-1-fluoroethane [HCFC-141b], 1,1,1,2-tetrafluoroethane [HFC-134a], pentafluoroethane [HFC-125], 1-chloro- 1,2,2,2-tetrafluoroethane [HCFC-124], and 1,1-dichloro-2,2,2-trifluoroethane [HCFC-123]) show only a low potential for skin and eye irritation. Chronic adverse effects on the liver (HCFC-123) and the testes (HCFC-141b and HCFC-134a), including tumor formation, were observed in long-term inhalation studies in rodents using very high concentrations of these CFC replacements. All CFC replacements are, to varying extents, biotransformed in the organism, mainly by cytochrome P450-catalyzed oxidation of C-H bonds. The formed acyl halides are hydrolyzed to give excretable carboxylic acids; halogenated aldehydes that are formed may be further oxidized to halogenated carboxylic acids or reduced to halogenated alcohols, which are excretory metabolites in urine from rodents exposed experimentally to CFC replacements. The chronic toxicity of the CFC replacements studied is unlikely to be of relevance for humans exposed during production and application of CFC replacements. PMID:8722112

  10. Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease

    PubMed Central

    Irwin, Ronald W.; Solinsky, Christine M.; Loya, Carlos M.; Salituro, Francesco G.; Rodgers, Kathleen E.; Bauer, Gerhard; Rogawski, Michael A.; Brinton, Roberta Diaz

    2015-01-01

    To develop allopregnanolone as a therapeutic for Alzheimer’s disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ?40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer’s disease. These findings have translational relevance to multiple neurodegenerative conditions. PMID:26039057

  11. Synovial fluid: an alternative toxicologic specimen?

    PubMed

    Deking, Janine; Hargrove, Veronica M; Molina, D Kimberley

    2014-06-01

    Although blood is the most commonly used specimen in forensic toxicology, it is not always available. In those cases, alternative samples are sought on which to perform toxicology testing. The current study assessed the usefulness of synovial fluid for postmortem cocaine and opiate/opioid testing. One hundred four cases were sampled, with 98 cases being tested representing 24 negative controls and 74 cases positive for cocaine, benzoylecgonine, morphine, 6-monoacetylmorphine, hydrocodone, and/or oxycodone. Synovium demonstrated excellent correlation and predictability when compared with blood, although it was not as sensitive for 6-monoacetylmorphine as either vitreous or urine. The authors recommend further study to assess the usefulness of synovial fluid in postmortem toxicology to include the evaluation of its utilize for more drugs and the development of further assays to use its potential even in limited quantities. PMID:24781403

  12. Advanced Urine Toxicology Testing

    Microsoft Academic Search

    Peter L. Tenore

    2010-01-01

    Urine toxicology screening testing is an important standard of care in the addiction and pain treatment setting, offering a reproducible, unbiased, and accurate laboratory test to monitor patients and provide objective support for clinical observations. It has been shown that physicians do not have proficiency in the ordering or interpretation of these tests. This article is an attempt to respond

  13. SALMONID PHARMACOLOGY AND TOXICOLOGY

    EPA Science Inventory

    Pharmacology and toxicology of Salmonids are described. Authors also document territorial behavior of salmonids and their response to effects of drugs, chemicals or pollutants. Current literature is cited as the best source of information regarding the use of drugs and chemicals ...

  14. NTP Toxicology and Carcinogenesis Studies of C.I. Direct Blue 15 (CAS No. 2429-74-5) in F344 Rats (Drinking Water Studies).

    PubMed

    1992-08-01

    C.I. Direct Blue 15 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. The dye, industrial grade C.I. Direct Blue 15, was chosen for study as a product to which workers are potentially exposed. Because of the high salt content, the dye was desalted prior to use. The purity was determined to be approximately 50%, with high-performance liquid chromatography indicating one major peak and approximately 35 impurities. Toxicology and carcinogenesis studies were conducted by administering the dye, C.I. Direct Blue 15, in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 22 months. Planned as 24-month studies, the 22-month studies were terminated early because of rapidly declining animal survival, which was due primarily to neoplasia. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Rats were given C.I. Direct Blue 15 in drinking water at doses of 1,250, 2,500, 5,000, 10,000, or 30,000 ppm. All control and treated rats survived. Body weight gain in high-dose females was less than that in controls. Water consumption declined as the dose increased. Male and female rats receiving 30,000 ppm had slight degeneration and necrosis of individual hepatocytes in the liver, and females also had mild to moderate renal tubule degeneration and thymic lymphoid depletion. 13-Week Studies: C.I. Direct Blue 15 was administered in drinking water at doses of 0, 1,250, 2,500, 5,000, 10,000, or 30,000 ppm to male rats, and at doses of 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm to female rats. Seven of 10 male rats receiving 30,000 ppm died; all rats in the other groups survived until the end of the studies. Mean final body weights of males receiving 10,000 or 30,000 ppm were 92% and 69% of those of controls, and mean final body weights of females receiving 5,000 or 10,000 ppm were 97% and 94% of those of controls. Tissues from treated animals were stained blue. Compound-related lesions were seen in the kidney and liver of male rats given 30,000 ppm and in the kidney of males and females given 10,000 ppm. The renal lesions included necrosis, degeneration, pigmentation and regeneration of the tubule epithelium, and tubule mineralization. Liver lesions included centrilobular hepatocellular degeneration, fatty metamorphosis, and individual cell necrosis with slight periportal hepatocellular hypertrophy. Lymphoid depletion in the thymus was also seen in the high-dose males. Based on the results of the 14-day and 13-week studies, the high dose chosen for the 22-month studies was 2,500 ppm. 22-Month Studies: At study initiation, 70 rats of each sex were given 0 or 2,500 ppm C.I. Direct Blue 15, 45 rats of each sex were given 630 ppm, and 75 rats of each sex were given 1,250 ppm. Interim evaluations were made at 9 and 15 months. The average amounts of compound consumed per day by the six dose groups after week 52 of the studies were estimated to be 45, 90, and 215 mg/kg for male rats and 50, 100, and 200 mg/kg for female rats. Survival and Body Weights: The studies were terminated at 22 months due to extensive mortality associated with chemical-related neoplasia. Survival of control, 630, 1,250, and 2,500 ppm males at 22 months was 37/50, 8/35, 11/65, and 2/50; survival of females was 40/50, 13/35, 22/65, and 4/50. At 22 months, the mean final body weights of the 630, 1,250, and 2,500 ppm groups were 95%, 91%, and 81% of those of the control for male rats and 91% of those of the control for all female dose groups. Histopathologic Effects in the 22-Month Studies: At the 9-month interim evaluations, one adenoma of the Zymbal's gland was seen in a high-dose male rat, and three carcinm

  15. Subsite Awareness in Neuropathology Evaluation of National Toxicology Program (NTP) Studies: A Review of Select Neuroanatomical Structures with their Functional Significance in Rodents

    PubMed Central

    Rao, Deepa B.; Little, Peter B.; Sills, Robert

    2013-01-01

    This review manuscript is designed to serve as an introductory guide in neuroanatomy for toxicologic pathologists evaluating general toxicity studies. The manuscript provides an overview of approximately 50 neuroanatomical subsites and their functional significance across seven coronal sections of the brain. Also reviewed are three sections of the spinal cord, cranial and peripheral nerves (trigeminal and sciatic respectively), and intestinal autonomic ganglia. The review is limited to the evaluation of hematoxylin and eosin (H&E) stained tissue sections, as light microscopic evaluation of these sections is an integral part of the first-tier toxicity screening of environmental chemicals, drugs, and other agents. Prominent neuroanatomical sites associated with major neurological disorders are noted. This guide, when used in conjunction with detailed neuroanatomic atlases may aid in an understanding of the significance of functional neuroanatomy, thereby improving the characterization of neurotoxicity in general toxicity and safety evaluation studies. PMID:24135464

  16. NTP Toxicology and Carcinogenesis Studies of Boric Acid (CAS No. 10043-35-3) in B6C3F1 Mice (Feed Studies).

    PubMed

    1987-10-01

    Boric acid is a component of cosmetics and pharmaceuticals and is also used in numerous industrial processes. Earlier long-term studies did not demonstrate a carcinogenic effect in Sprague-Dawley rats. Because of potential widespread human exposure, corroborative evidence was sought in a second species. Toxicology and carcinogenesis studies were conducted by feeding technical-grade boric acid (99.7% pure) to groups of male and female B6C3F1 mice for 14 days, 13 weeks, and 2 years. In the 14-day studies (five mice per group), mortality occurred in mice fed 25,000 ppm, 50,000 ppm, or 100,000 ppm boric acid; hyperplasia and/or dysplasia of the forestomach was also seen in these dose groups. No compound-related gross pathologic or histopathologic effects were seen in male or female mice exposed at concentrations up to 12,500 ppm in feed. In the 13-week studies, groups of 10 male and 10 female mice were fed boric acid at concentrations up to 20,000 ppm; 8 male mice and 1 female mouse receiving 20,000 ppm and 1 male receiving 10,000 ppm boric acid died before the end of the studies. Male and female mice receiving 20,000 ppm boric acid weighed 23% and 18% less, respectively, than did the controls at the end of the studies. Testicular atrophy in 8/10 male mice, hyperkeratosis and acanthosis of the stomach in 8/10 male and female mice, and extramedullary hematopoiesis of the spleen in all male and female mice receiving 20,000 ppm boric acid indicated that the testis, stomach, and spleen were potential target organs in the 2-year studies. Based on these results, 2-year toxicology and carcinogenesis studies were conducted by feeding diets containing boric acid at concentrations of 0, 2,500, or 5,000 ppm to groups of 50 male and 50 female mice. Survival of high dose male mice after week 63 and of low dose mice after week 84 was lower than that of the controls (final survival: control, 41; low dose, 30; high dose, 22), which may have reduced the sensitivity of the carcinogenicity study; the numbers of female mice (33; 33; 37) that survived to the end of the studies were considered adequate for toxicologic evaluation. Body weight gain was reduced in each sex after week 30; mean final body weights were 7% and 13% below control values for exposed male mice and 7% and 20% below those of controls for exposed female mice. No chemically related clinical signs were reported. At the top dose, boric acid caused an increased incidence of testicular atrophy (control, 3/49; low dose, 6/50; high dose, 27/47) and interstitial cell hyperplasia (0/49; 0/50; 7/47) inmale mice. The testicular atrophy was characterized by variable loss of spermatogonia, primary and secondary spermatocytes, spermatids, and spermatozoa from the seminiferous tubules. The seminiferous tubules contained primarily Sertoli cells and variable numbers of spermatogonia. In some mice, there were accumulations of interstitial cells, indicating hyperplasia. In low dose male mice, there were increased incidences of hepatocellular carcinomas (5/50; 12/50; 8/49) and hepatocellular adenomas or carcinomas (combined) (14/50; 19/50; 15/49) and an increased incidence of subcutaneous tissue fibromas, sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) (2/50; 10/50; 2/50). No increased incidence of subcutaneous tissue neoplasms was seen in male mice receiving 5,000 ppm. Because the incidence of subcutaneous tissue tumors is variable in historical controls, because there was no corresponding increase in the high dose male mice, and because the incidence of hepatocellular tumors was not significant by the incidental tumor test and was within the historical control range, neither of these tumors was considered to be related to the administration of boric acid. Boric acid was not mutagenic in the Salmonella/microsome assay with Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. Boric acid was negative in the mouse lymphoma L5178Y/TK+/- assay and did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells. All assays were preformed with anh

  17. Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson’s disease

    PubMed Central

    Yue, Xu; Hariri, Dana J.; Caballero, Beatrice; Zhang, Shiling; Bartlett, Mitchell J.; Kaut, Oliver; Mount, David W.; Wüllner, Ullrich; Sherman, Scott J.; Falk, Torsten

    2014-01-01

    Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson’s disease (PD) by testing an expanded dose range of VEGF-B (1 ?g and 10 ?g) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 ?g), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 ?g VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p = 1.9 e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p = 0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and Parkinson’s disease patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated. PMID:24291725

  18. TOXICOLOGICAL EVALUATION OF SELECTED CHLORINATED PHENOLS

    EPA Science Inventory

    Toxicology studies were conducted with the mono-, di-, and pentachlorophenols (CP). Chlorophenols (except PC) demonstrate a relatively low order of toxicity. The order of toxicity in mice and rats (most to least) is: PCP > tetra CPs > mono CPs > tri CPs > di CPs. Short-term (14 d...

  19. Transgenic Fish as Models in Environmental Toxicology

    Microsoft Academic Search

    Richard N. Winn

    Historically, fish have played significant roles in assessing potential risks associated with exposure to chemical con- tamination in aquatic environments. Considering the contri- butions of transgenic rodent models to biomedicine, it is reasoned that the development of transgenic fish could enhance the role of fish in environmental toxicology. Application of transgenic fish in environmental studies remains at an early stage,

  20. Use of transgenic animals in toxicology

    Microsoft Academic Search

    David J Kirkland

    1998-01-01

    Transgenic and genetically engineered animals are being increasingly used in the study of diseases and for safety assessments for new products. There are four main areas in which they influence pharmaceutical development; two of these, new disease models and `humanized' animals for the assessment of biopharmaceuticals, have not yet made their impact upon toxicology and so will only be briefly

  1. Toxicological Profile Information Sheet

    NSDL National Science Digital Library

    The Agency for Toxic Substances and Disease Registry (ATSDR) is continually assembling toxicological profiles for hazardous substances. This site contains 256 online profiles listed alphabetically by chemical name. Each profile begins with a non-technical public health statement discussing the chemical, its environmental and health effects, and risk of human exposure. A more technical version of this information can also be downloaded in Adobe Acrobat (.pdf) format.

  2. Inhalation reproductive toxicology studies: Male dominant lethal study of n-hexane in Swiss (CD-1) mice: Final report

    SciTech Connect

    Mast, T.J.; Rommereim, R.L.; Evanoff, J.J.; Sasser, L.B.; Decker, J.R.; Stoney, K.H.; Weigel, R.J.; Westerberg, R.B.

    1988-08-01

    The straight-chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent routinely used in industrial environments; consequently, the opportunity for industrial, environmental or accidental exposure to hexane vapors is significant. Although myelinated nerve tissue is the primary target organ of hexane, the testes have also been identified as being sensitive to hexacarbon exposure. The objective of this study was to evaluate male dominant lethal effects in Swiss (CD-1) mice after exposure to 0, 200, 1000, or 5000 ppM n-hexane, 20 h/day for 5 consecutive days. Each exposure concentration consisted of 30 randomly selected, proven male breeders; 4 groups. The mice were weighed just prior to the first day of exposure and at weekly intervals until sacrifice. Ten males in each dose group were sacrificed one day after the cessation of exposure, and their testes and epididymides were removed for evaluation of the germinal epithelium. The remaining male mice, 20 per group, were individually housed in hanging wire-mesh breeding cages where they were mated with unexposed, virgin females for eight weekly intervals; new females were provided each week. The mated females were sacrificed 12 days after the last day of cohabitation and their reproductive status and the number and viability of the implants were recorded. The appearance and behavior of the male mice were unremarkable throughout the study period and no evidence of n-hexane toxicity was observed. 18 refs., 3 figs., 11 tabs.

  3. Africa's present and future needs in toxicology education: Southern African perspective

    SciTech Connect

    Gulumian, Mary [National Institute for Occupational Health (NIOH), University of the Witwatersrand, Johannesburg (South Africa) and Department of Haematology and Molecular Medicine, School of Health Sciences, University of the Witwatersrand, Johannesburg (South Africa)]. E-mail: mary.gulumian@nioh.nhls.co.za; Ginsburg, Carren [Centre for Health Science Education (CHSE), University of the Witwatersrand, Johannesburg (South Africa); Stewart, Michael J. [Centre for Health Science Education (CHSE), University of the Witwatersrand, Johannesburg (South Africa)

    2005-09-01

    Degrees and diplomas as well as certificates that are granted by universities and technikons in South Africa in scientific disciplines, such as forensic medicine, pharmacology, marine and veterinary sciences, environmental health, and occupational hygiene, include toxicology as one of the subjects in their overall syllabus. However, aspects of toxicology included in each of these courses are biased towards that particular subdiscipline and basic level of toxicology may be taught. Educational needs in toxicology in South Africa can be summarized as follows: (a) recognition of toxicology as a discipline in its own right at these tertiary education institutions and (b) creation of opportunities to study and obtain higher degrees in one or more of the many subdisciplines of toxicology. The results from a survey conducted on the toxicology syllabi offered at these tertiary education institutions are used to substantiate these needs.

  4. NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1990-03-01

    Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--male: vehicle control, 16/50; low dose, 0/50; high dose, 0/50; female: 28/50; 4/50; 0/50). Survival of vehicle control male rats was lower than that usually observed; however, specific causes of deaths could not be determined. The survival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that res

  5. Historical perspectives on cadmium toxicology

    SciTech Connect

    Nordberg, Gunnar F. [Environmental Medicine, Department of Public Health and Clinical Medicine, Umea University, SE-90187 Umea (Sweden)], E-mail: gunnar.nordberg@envmed.umu.se

    2009-08-01

    The first health effects of cadmium (Cd) were reported already in 1858. Respiratory and gastrointestinal symptoms occurred among persons using Cd-containing polishing agent. The first experimental toxicological studies are from 1919. Bone effects and proteinuria in humans were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from Cd-pollution were issued in the 1970's. Reproductive and carcinogenic effects were studied at an early stage, but a quantitative assessment of these effects in humans is still subject to considerable uncertainty. The World Health Organization in its International Program on Chemical Safety, WHO/IPCS (1992) (Cadmium. Environmental Health Criteria Document 134, IPCS. WHO, Geneva, 1-280.) identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's and 2000 several epidemiological studies have reported adverse health effects, sometimes at low environmental exposures to Cd, in population groups in Japan, China, Europe and USA (reviewed in other contributions to the present volume). The early identification of an important role of metallothionein in cadmium toxicology formed the basis for recent studies using biomarkers of susceptibility to development of Cd-related renal dysfunction such as gene expression of metallothionein in peripheral lymphocytes and autoantibodies against metallothionein in blood plasma. Findings in these studies indicate that very low exposure levels to cadmium may give rise to renal dysfunction among sensitive subgroups of human populations such as persons with diabetes.

  6. Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants Part II: Importance of physicochemical properties and dose in animal and in vitro studies as a basis for risk assessment.

    PubMed

    Madl, Amy K; Kovochich, Michael; Liong, Monty; Finley, Brent L; Paustenbach, Dennis J; Oberdörster, Günter

    2015-07-01

    The objective of the Part II analysis was to evaluate animal and in vitro toxicology studies of CoCr particles with respect to their physicochemistry and dose relevance to metal-on-metal (MoM) implant patients as derived from Part I. In the various toxicology studies, physicochemical characteristics were infrequently considered and administered doses were orders of magnitude higher than what occurs in patients. Co was consistently shown to rapidly release from CoCr particles for distribution and elimination from the body. CoCr micron sized particles appear more biopersistent in vivo resulting in inflammatory responses that are not seen with similar mass concentrations of nanoparticles. We conclude, that in an attempt to obtain data for a complete risk assessment, future studies need to focus on physicochemical characteristics of nano and micron sized particles and on doses and dose metrics relevant to those generated in patients or in properly conducted hip simulator studies. PMID:25735266

  7. NEW PUBLIC DATA AND INTERNET RESOURCES IMPACTING PREDICTIVE TOXICOLOGY.

    EPA Science Inventory

    High-throughput screening (HTS) technologies, along with efforts to improve public access to chemical toxicity information resources and to systematize older toxicity studies, have the potential to significantly improve predictive capabilities in toxicology....

  8. 78 FR 38982 - Availability of Draft Toxicological Profiles

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-28

    ...OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [Docket...Toxicological Profiles AGENCY: Agency for Toxic Substances and Disease Registry (ATSDR...and studies on the health effects of toxic substances'' under CERCLA Section...

  9. TOXICO-CHEMINFORMATICS IN SUPPORT OF PREDICTIVE TOXICOLOGY.

    EPA Science Inventory

    Efforts to improve public access to chemical toxicity information resources, coupled with new high-throughput screening (HTS) data and efforts to systematize legacy toxicity studies, have the potential to significantly improve predictive capabilities in toxicology....

  10. Ramucirumab: preclinical research and clinical development

    PubMed Central

    Aprile, Giuseppe; Rijavec, Erika; Fontanella, Caterina; Rihawi, Karim; Grossi, Francesco

    2014-01-01

    Ramucirumab (IMC-1121B, LY3009806), a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramucirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer. PMID:25378934

  11. The toxicological testing of metabolites.

    PubMed

    Burnam, W L

    1982-08-01

    The 1978 Office of Pesticide Programs Guidelines gave guidance to the registrant as to the type and nature of the toxicological studies required to register a pesticide in the United States (Federal Register, Aug. 22, 1978, Part II). The most rigorous data requirements are for pesticides used on food or feed. Usually for major studies such as oncogenicity, chronic feeding and multigeneration reproduction, the test substance is the technical material. The highest dose in these tests is one which is either the maximum tolerated dose or one which induces some toxic effects. Presently the Agency is attempting to harmonize Pesticide Guidelines with those acceptable to the Organization for Economic Cooperation and Development (OECD). When significant pesticide metabolites are found in food residues and these differ from animal metabolites then toxicity testing is needed for these products. The type and duration of testing is determined on an individual basis. PMID:7161852

  12. Cancer Research UK procedures in manufacture and toxicology of radiotracers intended for Pre-phase I positron emission tomography studies in cancer patients

    PubMed Central

    Aboagye, E O; Luthra, S K; Brady, F; Poole, K; Anderson, H; Jones, T; Boobis, A; Burtles, S S; Price, P

    2002-01-01

    Radiolabelled compounds formulated for injection (radiopharmaceuticals), are increasingly being employed in drug development studies. These can be used in tracer amounts for either pharmacokinetic or pharmacodynamic studies. Such radiotracer studies can also be carried out early in man, even prior to conventional Phase I clinical testing. The aim of this document is to describe procedures for production and safety testing of oncology radiotracers developed for imaging by positron emission tomography in cancer patients. We propose strategies for overcoming the inability to produce compounds in sufficient quantities via the radiosynthetic routes for full chemical characterisation and toxicology testing including (i) independent confirmation as far as possible that the stable compound associated with the radiopharmaceutical is identical to the non-labelled compound, (ii) animal toxicity studies with ?10 times (typically 100 times) the intended tracer dose in humans scaled by body surface area, and (iii) patient monitoring during the radiotracer positron emission tomography clinical trial. British Journal of Cancer (2002) 86, 1052–1056. DOI: 10.1038/sj/bjc/6600212 www.bjcancer.com © 2002 Cancer Research UK PMID:11953847

  13. Translational toxicology: a developmental focus for integrated research strategies

    PubMed Central

    2013-01-01

    Background Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of "translational toxicology" be taken to mean? Discussion Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures. The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan 2) Defining modes of action and relevance of data from animal models 3) Use of mathematical models to develop plausible predictions as the basis for 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development. Summary Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics. PMID:24079609

  14. Micro-ultrasound for preclinical imaging.

    PubMed

    Foster, F Stuart; Hossack, John; Adamson, S Lee

    2011-08-01

    Over the past decade, non-invasive preclinical imaging has emerged as an important tool to facilitate biomedical discovery. Not only have the markets for these tools accelerated, but the numbers of peer-reviewed papers in which imaging end points and biomarkers have been used have grown dramatically. High frequency 'micro-ultrasound' has steadily evolved in the post-genomic era as a rapid, comparatively inexpensive imaging tool for studying normal development and models of human disease in small animals. One of the fundamental barriers to this development was the technological hurdle associated with high-frequency array transducers. Recently, new approaches have enabled the upper limits of linear and phased arrays to be pushed from about 20 to over 50 MHz enabling a broad range of new applications. The innovations leading to the new transducer technology and scanner architecture are reviewed. Applications of preclinical micro-ultrasound are explored for developmental biology, cancer, and cardiovascular disease. With respect to the future, the latest developments in high-frequency ultrasound imaging are described. PMID:22866232

  15. Micro-ultrasound for preclinical imaging

    PubMed Central

    Foster, F. Stuart; Hossack, John; Adamson, S. Lee

    2011-01-01

    Over the past decade, non-invasive preclinical imaging has emerged as an important tool to facilitate biomedical discovery. Not only have the markets for these tools accelerated, but the numbers of peer-reviewed papers in which imaging end points and biomarkers have been used have grown dramatically. High frequency ‘micro-ultrasound’ has steadily evolved in the post-genomic era as a rapid, comparatively inexpensive imaging tool for studying normal development and models of human disease in small animals. One of the fundamental barriers to this development was the technological hurdle associated with high-frequency array transducers. Recently, new approaches have enabled the upper limits of linear and phased arrays to be pushed from about 20 to over 50 MHz enabling a broad range of new applications. The innovations leading to the new transducer technology and scanner architecture are reviewed. Applications of preclinical micro-ultrasound are explored for developmental biology, cancer, and cardiovascular disease. With respect to the future, the latest developments in high-frequency ultrasound imaging are described. PMID:22866232

  16. Mitigating risk in academic preclinical drug discovery.

    PubMed

    Dahlin, Jayme L; Inglese, James; Walters, Michael A

    2015-04-01

    The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID:25829283

  17. A CHRONIC INHALATION STUDY OF METHYL BROMIDE TOXICITY IN B6C3F1 MICE. (FINAL REPORT TO THE NATIONAL TOXICOLOGY PROGRAM)

    SciTech Connect

    HABER, S.B.

    1987-06-26

    This report provides a detailed account of a two year chronic inhalation study of methyl bromide toxicity in B6C3Fl mice conducted for the National Toxicology Program. Mice were randomized into three dose groups (10, 33 and 100 ppm methyl bromide) and one control group (0 ppm) per sex and exposed 5 days/week, 6 hours/day, for a total of 103 weeks. Endpoints included body weight; clinical signs and mortality, and at 6, 15 and 24 months of exposure, animals were sacrificed for organ weights, hematology and histopathology. In addition, a subgroup of animals in each dosage group was monitored for neurobehavioral and neuropathological changes. After only 20 weeks of exposure, 48% of the males and 12% of the females in the 100 ppm group had died. Exposures were terminated in that group and the surviving mice were observed for the duration of the study. Exposure of B6C3Fl mice to methyl bromide, even for only 20 weeks, produced significant changes in growth rate, mortality, organ weights and neurobehavioral functioning. These changes occurred in both males and females, but were more pronounced in males.

  18. Acute and 28-day repeated dose toxicology studies in mice with aryloxyalkanoate dioxygenase (AAD-1) protein expressed in 2,4-D tolerant DAS-40278-9 maize.

    PubMed

    Stagg, Nicola J; Thomas, Johnson; Herman, Rod A; Juberg, Daland R

    2012-03-01

    DAS-40278-9 maize (corn) plants have been genetically modified by the insertion of the aad-1 gene (aryloxyalkanoate dioxygenase), which confers tolerance to 2,4-dichlorophenoxyacetic acid (2,4-D) and aryloxyphenoxypropionate (AOPP) acetyl coenzyme A carboxylase (ACCase) inhibitors ("fop" herbicides) to enable the effective use of these herbicides on maize. The aad-1 gene, derived from Sphingobium herbicidovorans, encodes the aryloxyalkanoate dioxygenase (AAD-1) enzyme. As part of the safety assessment of the AAD-1 protein expressed in maize, acute and repeated dose mammalian toxicology studies were conducted. AAD-1 protein (heterologously produced) was orally administered to mice at a dose of 2000mg/kg, and no acute lethality or adverse effects were observed. Similarly, no adverse effects were observed in mice in a 28-day repeated-dose dietary toxicity study that incorporated the AAD-1 protein into diets at concentrations up to 1000-fold greater than the highest estimate of human exposure to maize. These results support the conclusion that the AAD-1 protein, as expressed in biotechnology derived DAS-40278-9 maize, represents a negligible risk to human health. PMID:22100718

  19. Toxicological evaluation of expanded shredded tobacco stems.

    PubMed

    Theophilus, Eugenia H; Pence, Deborah H; Meckley, Daniel R; Higuchi, Mark A; Bombick, Betsy R; Borgerding, Michael F; Ayres, Paul H; Swauger, James E

    2004-04-01

    A tiered testing strategy has been developed to evaluate the potential of tobacco processes, ingredients, or technological developments to change the biological activity resulting from burning tobacco. The strategy is based on comparative chemical and biological testing. Expanded shredded tobacco stems (ESS) constitute an example of a common tobacco components expansion process currently used in the manufacture of cigarettes to increase the tobacco blend filling capacity. As part of the toxicological evaluation of ESS, test cigarettes containing 9.5%, 18.5%, and 25% ESS were compared to control cigarettes containing 0% ESS. Testing included mainstream cigarette smoke chemistry studies, genotoxicity studies (Ames and sister chromatid exchange), a 13-week inhalation study in Sprague-Dawley rats, and a 30-week dermal tumor promotion study in SENCAR mice. Collectively, data indicated that cigarettes with and without ESS had a similar toxicological profile in this test battery. PMID:15019188

  20. The toxicology of chemokine inhibition.

    PubMed

    Schroff, Robert W; Touvay, Caroline; Culler, Michael D; Dong, Jesse Z; Taylor, John E; Thurieau, Christophe; McKilligin, Elaine

    2005-09-01

    The dividing line between essential physiological inflammatory processes and excessive pathological inflammation is often very thin - in some circumstances, indeed, it may be non-existent. Devising anti-inflammatory medications that effectively target only the pathological component therefore remains a central challenge for the pharmaceutical industry. At present, the general rule is that the more powerful the anti-inflammatory effect of a drug, the greater the side-effects that accompany it. Steroids, for example, are potent anti-inflammatory medications, but they have a diverse array of side effects that substantially limit their use. Since chemokines play a central role in regulating the immune system, and in particular, the trafficking of leukocytes, inhibiting their action may represent a powerful new therapeutic strategy for treating diseases with an inflammatory component. However, this potential will only be realized if it is possible to interfere with chemokine signaling networks, without inducing unacceptable side effects. Although very little, direct human toxicology has been carried out using chemokine inhibitors, there is now a sufficient body of indirect and circumstantial evidence (for example, from genetically modified mice and from animal model studies using chemokine inhibitors) to allow a tentative assessment of the biological impact of chemokine inhibition. The purpose of this review is to outline the available data and to speculate on the likely toxicological profile resulting from chemokine inhibition. The tentative conclusion is that anti-inflammatory therapy achieved through chemokine inhibition may have fewer side effects than originally expected, even when the actions of multiple chemokines are inhibited simultaneously. PMID:16178726

  1. Complex effects of two presumably antagonistic endocrine disrupting compounds on the goldfish Carassius aumtus: a comprehensive study with multiple toxicological endpoints.

    PubMed

    Wu, Fengxia; Lin, Li; Qiu, Jian-Wen; Chen, Hao; Weng, Shaoping; Luan, Tiangang

    2014-10-01

    We studied the effects of endocrine disrupting compounds nonylphenol (NP) and letrozole (LE) on the male goldfish Carassius aumtus. Exposure to NP (20 ?g l(-1)) alone caused a significant up-regulation in the expression of aromatase, estrogen receptors and vitellogenin (VTG) genes, an increase in hepatic and plasma VTG concentration, but no obvious testicular impairment. Exposure to LE (1 mg kg(-1)) alone resulted in a significant decline in aromatase activity, reduced levels of plasma 17?-estradiol (E2), and enhanced sperm maturation. Co-exposure with LE (1 mg kg(-1)) could only partially affect some of the estrogenic effects caused by NP (20 ?g l(-1)) (i.e. expression of hepatic and brain estrogen receptor genes, hepatic VTG concentration), but inhibit other estrogenic effects (i.e. brain and testicular aromatase activity, plasma E2). In addition, co-exposure resulted in impairment of liver mitochondria (i.e. detachment of ridges from the membrane, and uneven distribution of the cytoplasm with clusters of glycogen granules), but did not cause significant damage to the testes (i.e. the morphology, the spermatogonia and spermatozoa densities). Our results clearly showed that nonylphenol and letrozole co-exposure could induce profound effects on fish, and highlighted the importance of adopting multiple toxicological endpoints when evaluating the combined effects of endocrine disrupting compounds. PMID:24974122

  2. Systems toxicology: applications of toxicogenomics, transcriptomics, proteomics and metabolomics in toxicology

    Microsoft Academic Search

    Wilbert HM Heijne; Anne S Kienhuis; Ben van Ommen; Rob H Stierum; John P Groten

    2005-01-01

    Toxicogenomics can facilitate the identification and characterization of toxicity, as illustrated in this review. Toxicogenomics, the application of the functional genomics technologies (transcriptomics, proteomics and metabolomics) in toxicology enables the study of adverse effects of xenobiotic substances in relation to structure and activity of the genome. The advantages and limitations of the different technologies are evaluated, and the prospects for

  3. Caenorhabditis elegans: An Emerging Model in Biomedical and Environmental Toxicology

    PubMed Central

    Leung, Maxwell C. K.; Williams, Phillip L.; Benedetto, Alexandre; Au, Catherine; Helmcke, Kirsten J.; Aschner, Michael; Meyer, Joel N.

    2008-01-01

    The nematode Caenorhabditis elegans has emerged as an important animal model in various fields including neurobiology, developmental biology, and genetics. Characteristics of this animal model that have contributed to its success include its genetic manipulability, invariant and fully described developmental program, well-characterized genome, ease of maintenance, short and prolific life cycle, and small body size. These same features have led to an increasing use of C. elegans in toxicology, both for mechanistic studies and high-throughput screening approaches. We describe some of the research that has been carried out in the areas of neurotoxicology, genetic toxicology, and environmental toxicology, as well as high-throughput experiments with C. elegans including genome-wide screening for molecular targets of toxicity and rapid toxicity assessment for new chemicals. We argue for an increased role for C. elegans in complementing other model systems in toxicological research. PMID:18566021

  4. Application of the combination index integrated with confidence intervals to study the toxicological interactions of antibiotics and pesticides in Vibrio qinghaiensis sp.-Q67.

    PubMed

    Liu, Ling; Liu, Shu-Shen; Yu, Mo; Chen, Fu

    2015-01-01

    It is necessary to explore the effect of confidence intervals on the combination index (CI) so that rationally evaluate the toxicological interaction (synergism or antagonism) which is dependent on the concentration ratio, the mixture concentration and the exposure time. To effectively detect the toxicological interaction taking place in mixtures, we combined the CI with the observation-based confidence intervals (OCI) which can characterize the uncertainty in toxicity test and in data fitting. In time scale, the short-term (15min) and long-term (12h) toxicities of three chemicals (imidacloprid (IMI), pirimicarb (PIR) and streptomycin sulfate (STR)) and their binary mixtures on Vibrio qinghaiensis sp.-Q67 were determined by the microplate toxicity analysis (MTA). The mixtures of IMI, PIR and STR have additive actions all but four IMI-PIR rays (R2-R5) at the effect levels above about 30-40% whose long-term toxicological interaction are synergism. PMID:25589171

  5. Use of toxicological information in drug design.

    PubMed

    Matthews, E J; Benz, R D; Contrera, J F

    2000-12-01

    This paper is an extension of the keynote address and another talk at the Symposium on the Use of Toxiciological Information in Drug Design. The symposium was organized by American Chemical Society's Chemical Information Division at the 220th National Meeting of the American Chemical Society in Washington, DC, August 20-24, 2000. We outline an approach for meeting the scientific information needs of the U.S. Food and Drug Administration (FDA). Ready access to scientific information is critical to support safety-related regulatory decisions and is especially valuable in situations where available experimental information from in vivo/in vitro studies are inadequate or unavailable. This approach also has applications for lead selection in drug discovery. A pilot electronic toxicology/safety knowledge base and computational toxicology initiative is underway in the FDA Center for Drug Evaluation and Research (CDER) that may be a prototype for an FDA knowledge base. The objectives of this effort are: (i) to strengthen and broaden the scientific basis of regulatory decisions, (ii) to provide the Agency with an electronic scientific institutional memory, (iii) to create a scientific resource for regulatory and applied research, and (iv) to establish an internal Web-based support service that can provide decision support information for regulators that will facilitate the review process and improve consistency and uniformity. An essential component of this scientific knowledge base is the creation of a comprehensive electronic inventory of CDER-regulated substances that permit identification of clusters of substances having similar chemical, pharmacological or toxicological activities, and molecular structure/substructures. Furthermore, the inventory acts as a pointer and link to other databases and critical non-clinical and clinical pharmacology/toxicology studies and reviews in FDA archives. Clusters of related substances are identified through the use of: (i) an extensive index of alternative names for each substance, (ii) a molecular structure key field consisting of a rudimentary or core structure represented as an ISIS.mol-file, (iii) global search terms (molecular group, chemical class, clinical indication, or pharmacologic activity), and (iv) molecular clustering using structure/sub-structure similarity indices. The information contained in a toxicology knowledge database has limited value unless means are available to extract information, identify relationships, and create and test hypotheses. One such means is computational toxicology, also called in silico toxicology, ComTox, or e-TOX. Computational toxicology is the application of computer technology and information processing (informatics) to analyze, model, and estimate chemical toxicity based upon structure activity relationships (SAR). A computational toxicology software package, MCASE, has been evaluated and successfully improved by CDER through the incorporation of data from FDA archives and concomitant alterations of the logic used in the interpretation of the results to reflect the data analysis and hazard identification practices and priorities of the Center. Our modifications and uses of the MCASE program are discussed in detail. PMID:11155316

  6. Toxicology and military anaesthesia.

    PubMed

    Nicholson-Roberts, T C

    2010-12-01

    The combination of trauma and poisoning is a situation likely to be faced by a deployed force at some point. This article provides practical advice on how to deal with poisoned patients without deviating from the concept of damage control resuscitation. The constraints of limited diagnostics, both at the scene and clinically, and lack of antidotal therapy are fundamental to the practice of clinical toxicology. Some of the specific therapies such as atropine and oximes were not evaluated prior to their introduction and there are few randomised controlled trials of poisoned patients. Most of the diagnoses will be made on clinical grounds and most of the therapy will be supportive; this article aims to reassure military anaesthetists in the process of dealing with the poisoned trauma patient. PMID:21302652

  7. NTP Toxicology and Carcinogenesis Studies of Nitrofurantoin (CAS No. 67-20-9) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    PubMed

    1989-09-01

    Nitrofurantoin was studied and evaluated because of its widespread use as a drug for treating urinary tract infections in humans, its structural relationship to known carcinogenic 5-nitrofuran compounds, and the lack of adequate studies to assess its carcinogenicity. Toxicology and carcinogenesis studies of nitrofurantoin were conducted by administering nitrofurantoin (greater than 99% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: None of the rats (at dietary concentrations up to 20,000 ppm) died before the end of the 14-day studies. Rats that received 5,000, 10,000, or 20,000 ppm lost weight. Four of five male and 4/5 female mice that received 10,000 ppm and 1/5 females that received 5,000 ppm nitrofurantoin died before the end of the studies. Mice that received 5,000 ppm and male mice that received 10,000 ppm lost weight. In the 13-week studies, final mean body weights of rats that received 2,500, 5,000, or 10,000 ppm were 10%, 34%, or 47% lower than that of the controls for males and 15%, 31%, or 41% lower for females. Feed consumption by dosed and control rats was generally similar. Degeneration of the germinal epithelium of the seminiferous tubules of the testis was observed in male rats that received 2,500 to 10,000 ppm nitrofurantoin. Necrosis of the ovarian follicles was observed in 8/10 female rats that received 10,000 ppm, in 3/10 females that received 5,000 ppm, and in 1/10 that received 2,500 ppm. For mice, final mean body weights of the 5,000-ppm groups were 13% lower than that of the controls for males and 15% lower for females. Two of 10 male mice that received 5,000 ppm and 1/10 males that received 300 ppm died before the end of the 13-week studies. Estimated feed consumption was similar for dosed and control groups. Degeneration of the germinal epithelium of the testis was observed in males that received 1,300 to 5,000 ppm; necrosis of the ovarian follicles was observed in females that received 5,000 ppm but not in the lower dose groups. Necrosis of the renal tubular epithelium was observed in 2/9 males that received 5,000 ppm. Based on these results, 2-year studies of nitrofurantoin were conducted by feeding diets containing 0, 1,300, or 2,500 ppm nitrofurantoin to groups of 50 male F344/N rats and to groups of 50 male and female B6C3F1 mice for 103 weeks. Groups of 50 female F344/N rats were fed diets containing 0, 600, or 1,300 ppm nitrofurantoin on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weight and average daily feed consumption of dosed male and female rats were similar to those of the controls throughout the studies. The average amount of nitrofurantoin consumed per day was estimated to be 60 and 110 mg/kg for low and high dose male rats and 30 and 60 mg/kg for low and high dose female rats. No significant differences in the number of rats surviving to the end of the studies were observed between any groups of rats of either sex (male: control, 24/50; low dose, 27/50; high dose, 26/50; female: 25/50; 26/50; 31/50). Mean body weights of high dose male and female mice were up to 12% lower than those of the controls throughout most of the studies. The average daily feed consumption by dosed mice ranged from 93% to 100% that by controls. The average amount of nitrofurantoin consumed per day was estimated to be 280-300 mg/kg and 570-580 mg/kg for low and high dose mice. The survival of the control group of female mice was lower than that of the dosed groups (control, 19/50; low dose, 37/50; high dose, 37/50). The decrease in survival was most likely related to the increase in microbial infection in the reproductive tract observed in the controls. Groups of male mice had similar survival (28/50; 29/50; 34/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Organs showing toxicity from nitrofurantoin exposure identified in the short-term studies were the testis in male rats and mice, the ovary in female rats and mice, and the kidney in male mice. Lesions oba

  8. History of the Journal of the American College of Toxicology.

    PubMed

    Christian, Mildred S

    2004-01-01

    This companion article to the History of the American College of Toxicology also is written in celebration of the 25th Anniversary of the American College of Toxicology (ACT). It relates how the official journal of the College evolved from a privately owned publication, the Journal of Environmental Pathology and Toxicology (JEPT), into publications owned and managed by the College and its Board, for the first 17 years as the Journal of the American College of Toxicology (JACT) and currently as The International Journal of Toxicology (IJT). It relates how the first journal focused on toxicological studies, potential cancer causes and concerns associated with environmental contamination and chemical exposure safety issues. It tells how this journal was replaced by one more broadly based that addressed multiple industries and regulatory approaches, accepted previously unpublishable "no-effect" studies, so important in eliminating unwarranted animal use, and provided review articles, rather than only original research. It also described how the JACT evolved into an international journal finally recognized for its quality reviews and peer-reviewed research. Each of the three journals that represented the College is described, as well as interesting events associated with their development and publication, including the activities and contributions of the first four editors in chief, Drs. Myron A. Mehlman, Mildred S. Christian, Robert M. Diener and Harihara Mehendale. PMID:15513829

  9. BEHAVIORAL TOXICOLOGY: AN EMERGING DISCIPLINE

    EPA Science Inventory

    The book contains the proceedings of a symposium entitled Behavioral Toxicology: An Emerging Discipline, held in conjunction with the Southwest Psychological Association meetings, April 30, 1976 in Albuquerque, New Mexico. Authors of formal presentations later reviewed and enlarg...

  10. Pre-clinical and preliminary dose-finding and safety studies to identify candidate antivenoms for treatment of envenoming by saw-scaled or carpet vipers (Echis ocellatus) in northern Nigeria.

    PubMed

    Abubakar, S B; Abubakar, I S; Habib, A G; Nasidi, A; Durfa, N; Yusuf, P O; Larnyang, S; Garnvwa, J; Sokomba, E; Salako, L; Laing, G D; Theakston, R D G; Juszczak, E; Alder, N; Warrell, D A

    2010-04-01

    The aim of this study was to identify candidate antivenoms with specific activity against the venom of the saw-scaled or carpet viper (Echis ocellatus) in northern Nigeria, where bites by this species cause great morbidity and mortality but where effective antivenoms have become scarce and unaffordable. Selected antivenoms were destined to be compared by randomised controlled clinical trials (RCTs). Standard pre-clinical neutralisation assays were carried out in rodents. We included two licensed antivenoms of established clinical efficacy and 6 candidate antivenoms. Although 6 of the tested antivenoms showed promising efficacy, all but 3 were excluded from further study because of inadequate pre-clinical efficacy or because they were unavailable or unaffordable for the anticipated RCTs. Median effective doses (ED(50)) of the remaining three candidate antivenoms suggested that the following doses might neutralise the maximum observed venom yield of 24.8 mg (dry weight) of venom milked from captive E. ocellatus: 10 ml of MicroPharm "EchiTAb G" (ET-G) antivenom; 30 ml of Instituto Clodomiro Picado "EchiTAb-Plus-ICP" (ET-Plus) antivenom; 50 ml of VacSera, Cairo "EgyVac" antivenom. A preliminary clinical dose-finding and safety study of these three antivenoms was carried out in 24 patients with incoagulable blood after E. ocellatus bites who were not severely envenomed. A 3+3 dose escalation design was employed. Initial doses of 10 ml ET-G and 30 ml ET-Plus restored blood coagulability in groups of 6 patients with early mild reactions (pruritus only) in not more than one third of them. EgyVac antivenom did not fulfil efficacy or safety criteria in 12 patients. On the basis of these results, ET-G and ET-Plus were selected for comparison in a RCT. PMID:19874841

  11. Toxicology and carcinogenesis studies of pulegone (CAS No. 89-82-7) in F344/N rats and B6C3F1 mice (gavage studies).

    PubMed

    2011-08-01

    Several essential oils contain pulegone and are used for flavoring foods, drinks, and dental products, as fragrance agents, and in herbal medicines. Pulegone was nominated for study by the National Institute of Environmental Health Sciences based on the potential for human exposure and the absence of carcinogenicity data. Male and female F344/N rats and B6C3F1 mice received pulegone (approximately 96% pure) by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were administered 0, 37.5, 75, 150, 300, or 600 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 16 days. All male rats and nearly all female rats in the 300 and 600 mg/kg groups died prior to the end of the study. All moribund sacrifices and early deaths were attributed to liver toxicity. Mean body weight gains of males administered 37.5 or 150 mg/kg were significantly less than that of the vehicle controls. Clinical findings in 300 and 600 mg/kg rats included nasal/eye discharge, thinness, lethargy, and ruffled fur. Liver and kidney weights of dosed groups of females were generally significantly greater than those of the vehicle control group. The incidences of necrosis and cytoplasmic vacuolization of the liver in 300 and 600 mg/kg males and females were significantly greater than those in the vehicle control groups. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered 0, 18.75, 37.5, 75, 150, or 300 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 16 days. Four females and one male in the 300 mg/kg groups died by study day 5. All early deaths were attributed to liver toxicity. Mean body weights of the dosed groups were similar to those of the vehicle controls. Clinical findings were observed only in 300 mg/kg mice and included thinness, lethargy, and ruffled fur. Liver weights of 300 mg/kg males were significantly greater than those of the vehicle controls. The incidences of cytoplasmic vacuolization and diffuse fatty change in 300 mg/kg females and necrosis in 300 mg/kg males were significantly greater than those in the vehicle controls. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 9.375, 18.75, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All rats survived until the end of the study except for one female in the 150 mg/kg group that died on day 9. Mean body weights of 75 and 150 mg/kg males and 150 mg/kg females were significantly less than those of the vehicle controls. At the end of the study, there was a small dose-related decrease in the erythron, evidenced by decreases in the hematocrit and hemoglobin values and the erythrocyte counts. An apparent erythroid response to the decreased erythron was evidenced by increased reticulocyte counts. Reduced and oxidized glutathione levels were generally increased in 75 and 150 mg/kg males and in 37.5 mg/kg or greater females. Absolute and relative liver weights of 75 and 150 mg/kg females and relative liver weights of males administered 18.75 mg/kg or greater were significantly greater than those of the vehicle controls. The absolute kidney weight of 150 mg/kg females and the relative kidney weights of all dosed groups, except 9.375 mg/kg males, were significantly greater than those of the vehicle controls. Absolute and relative thymus weights of 150 mg/kg males and females and the absolute thymus weight of 75 mg/kg males were significantly less than those of the vehicle controls. In the kidney, there was hyaline glomerulopathy in 75 mg/kg males and 150 mg/kg males and females. The incidence of renal tubule protein casts was significantly increased in the 150 mg/kg females. In the liver, incidences of bile duct hyperplasia and hepatocyte hypertrophy in 75 and 150 mg/kg males and 150 mg/kg females, hepatocyte focal necrosis in 150 mg/kg males, and oval cell hyperplasia and periportal

  12. EXTOXNET: The Extension Toxicology Network

    NSDL National Science Digital Library

    1999-01-01

    A cooperative effort of University of California-Davis, Oregon State University, Michigan State University, Cornell University, and the University of Idaho, EXTOXNET (the Extension Toxicology Network) is an online resource providing "objective, science-based information about pesticides" and other toxic chemicals. First-time viewers will find useful information in the FAQ section, which covers health effects and risks, diet and cancer, food safety, drinking water, garden chemicals, and other topics. Also available at the site is the University of California at Davis's Environmental Toxicology Newsletter. The heart of the site, however, is the searchable database, which provides extensive profiles of pesticides, toxicology information briefs, toxicology issues of concern, and fact sheets. Although still under construction, the database of pesticide profiles includes trade name(s), regulatory status, chemical class, formulation, toxicological effects, ecological effects (on birds, aquatic organisms, etc.), environmental fate, physical properties, exposure guidelines, basic manufacturer, and references. For toxicology students, researchers, or the general public, this is a well-written and useful resource.

  13. Toxicological assessment of Ashitaba Chalcone.

    PubMed

    Maronpot, Robert R

    2015-03-01

    The plant Angelica keiskei contains two main physiologically active flavonoid chalcones, 4-hydroxyderricin and xanthoangelol. Known as ashitaba in Japan, powder from the sap is widely consumed for its medicinal properties in Asia as a dietary supplement. Limited previously reported mammalian studies were without evidence of toxicity. GLP studies reported here, including a bacterial reverse mutation assay, a chromosome aberration assay, and an in vivo micronucleus assay are negative for genotoxicity. A GLP- compliant 90-day repeated oral gavage study of ashitaba yellow sap powder containing 8.45% chalcones in Sprague Dawley rats resulted in expected known physiological effects on coagulation parameters and plasma lipids at 300 and 1000?mg/kg/day. Ashitaba-related pathology included a dose-related male rat-specific alpha 2-urinary globulin nephropathy at 100, 300, and 1000?mg/kg/day and jejunal lymphangiectasia in both sexes at 1000?mg/kg/day. All other study parameters and histopathological changes were incidental or not of toxicological concern. Based on these studies ashitaba chalcone powder is not genotoxic with a NOAEL of 300?mg/kg in male and female rats. PMID:25576957

  14. Toxicology-based cancer causation analysis of CoCr-containing hip implants: a quantitative assessment of genotoxicity and tumorigenicity studies.

    PubMed

    Christian, Whitney V; Oliver, Lindsay D; Paustenbach, Dennis J; Kreider, Marisa L; Finley, Brent L

    2014-09-01

    In this paper, quantitative methods were used to evaluate the weight of evidence regarding a causative relationship between cobalt-chromium (CoCr)-containing hip implants and increased cancer risk. We reviewed approximately 80 published papers and identified no-observed-adverse-effect level (NOAEL) and/or lowest-observed-adverse-effect level (LOAEL) values for specific endpoints of interest: genotoxic effects from in vitro studies with human cell lines as well as genotoxicity and tumor formation in animal bioassays. Test articles included Co particles and ions, Cr particles and ions, and CoCr alloy particles as well as CoCr alloy implants. The NOAEL/LOAEL values were compared with body burdens of Co/Cr particles and ions we calculated to exist in systemic tissues of hip implant patients under normal and excessive wear conditions. We found that approximately 40 tumor bioassays have been conducted with CoCr alloy implants or Co/Cr particles and ions at levels hundreds to thousands of times higher than those present in hip implant patients, and none reported a statistically significant increased incidence of systemic tumors. Results from in vitro and in vivo genotoxicity assays, which are relatively less informative owing to false positives and other factors, also indicated that DNA effects would be highly unlikely to occur as a result of wear debris from a CoCr implant. Hence, the toxicological weight of evidence suggests that CoCr-containing hip implants are unlikely to be associated with an increased risk of systemic cancers, which is consistent with published and ongoing cancer epidemiology studies involving patients with CoCr hip implants. PMID:25080401

  15. Toxicology and carcinogenesis studies of 1-bromopropane (CAS No. 106-94-5) in F344/N rats and B6C3F1 mice (inhalation studies).

    PubMed

    2011-08-01

    In the early to mid 1990s, 1-bromopropane was used primarily as an intermediate in the production of pesticides, quaternary ammonium compounds, flavors and fragrances, pharmaceuticals, and other chemicals in well-controlled, closed processes. In the mid to late 1990s, it was introduced as a less toxic replacement for methylene chloride in emissive applications such as vapor and immersion degreasing operations and critical cleaning of electronics and metals. 1-Bromopropane was also introduced as a nonflammable, nontoxic, fast-drying, and inexpensive solvent for adhesive resins, and has been marketed as a replacement for ozone depleting refrigerants. 1-Bromopropane was nominated for study by the Occupational Safety and Health Administration based on the potential for widespread occupational and environmental exposure and a lack of toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1 mice were exposed to 1-bromopropane (99% or greater pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to 1-bromopropane vapor at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 days. All rats survived to the end of the study except one 500 ppm male. Mean body weights of 2,000 ppm rats were significantly less than those of the chamber controls. The absolute kidney weight of 1,000 ppm males, relative kidney weights of all exposed groups of males, and absolute and relative kidney weights of all exposed groups of females were significantly increased. The absolute and relative liver weights of 1,000 ppm males, relative liver weights of 500 and 2,000 ppm males, and absolute and relative liver weights of 500 ppm or greater females were significantly increased. Nasal lesions included suppurative inflammation in males exposed to 500 ppm or greater, respiratory epithelial necrosis in 1,000 and 2,000 ppm males, and respiratory epithelial regeneration in 1,000 and 2,000 ppm females. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to 1-bromopropane vapor at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 17 days. All 2,000 ppm males, two 2,000 ppm females, four 500 ppm males, one 1,000 ppm male, and one 1,000 ppm female died early. The mean body weight gain of 1,000 ppm males was significantly less than that of the chamber controls. Abnormal breathing, lethargy, and eye discharge were observed primarily during week 1 in groups exposed to 500 ppm or greater. Liver weights of 1,000 ppm males and of females exposed to 500 ppm or greater were significantly increased. Kidney weights of 1,000 and 2,000 ppm females were significantly increased. Microscopic lesions related to 1-bromopropane exposure occurred in the lung, liver, and nose of males and females and were primarily seen in mice exposed to 500 ppm or greater. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 1-bromopropane vapor at concentrations of 0, 62.5, 125, 250, 500, or 1,000 ppm, 6 hours plus T90 (10 minutes) per day, 5 days per week for 14 weeks. Additional clinical pathology groups of 10 male and 10 female rats were exposed to the same concentrations for 23 days. All rats survived to the end of the study. Mean body weights of 1,000 ppm males were significantly less than those of the chamber controls. The increases in sorbitol dehydrogenase activities in 500 ppm males and 1,000 ppm males and females were consistent with the histopathologic evidence of mild hepatotoxicity caused by 1-bromopropane. Liver weights of males exposed to 250 ppm or greater and of females exposed to 125 ppm or greater were significantly increased. Spleen and kidney weights of 1,000 ppm females were significantly increased. Exposure concentration-related decreases of 28% in sperm motility and 37% in sperm counts were se

  16. Practical Applications of in Vivo and ex Vivo MRI in Toxicologic Pathology Using a Novel High-performance Compact MRI System.

    PubMed

    Tempel-Brami, Catherine; Schiffenbauer, Yael S; Nyska, Abraham; Ezov, Nati; Spector, Itai; Abramovitch, Rinat; Maronpot, Robert R

    2015-07-01

    Magnetic resonance imaging (MRI) is widely used in preclinical research and drug development and is a powerful noninvasive method for assessment of phenotypes and therapeutic efficacy in murine models of disease. In vivo MRI provides an opportunity for longitudinal evaluation of tissue changes and phenotypic expression in experimental animal models. Ex vivo MRI of fixed samples permits a thorough examination of multiple digital slices while leaving the specimen intact for subsequent conventional hematoxylin and eosin (H&E) histology. With the advent of new compact MRI systems that are designed to operate in most conventional labs without the cost, complexity, and infrastructure needs of conventional MRI systems, the possibility of MRI becoming a practical modality is now viable. The purpose of this study was to investigate the capabilities of a new compact, high-performance MRI platform (M2™; Aspect Imaging, Israel) as it relates to preclinical toxicology studies. This overview will provide examples of major organ system pathologies with an emphasis on how compact MRI can serve as an important adjunct to conventional pathology by nondestructively providing 3-dimensional (3-D) digital data sets, detailed morphological insights, and quantitative information. Comparative data using compact MRI for both in vivo and ex vivo are provided as well as validation using conventional H&E. PMID:25694086

  17. Evaluation of submarine atmospheres: effects of carbon monoxide, carbon dioxide and oxygen on general toxicology, neurobehavioral performance, reproduction and development in rats. II. Ninety-day study.

    PubMed

    Hardt, Daniel J; James, R Arden; Gut, Chester P; McInturf, Shawn M; Sweeney, Lisa M; Erickson, Richard P; Gargas, Michael L

    2015-02-01

    Carbon monoxide (CO), carbon dioxide (CO2) and low-level oxygen (O2) (hypoxia) are submarine atmosphere components of highest concern because of a lack of toxicological data available to address the potential effects from long-duration, combined exposures on female reproductive and developmental health. In this study, subchronic toxicity of mixed atmospheres of these three submarine air components was evaluated in rats. Male and female rats were exposed via inhalation to clean air (0.4?ppm CO; 0.13% CO2; 20.6% O2) (control), a low-dose (5.0?ppm CO; 0.41% CO2; 17.1% O2), a mid-dose (13.9?ppm CO; 1.19 or 1.20% CO2; 16.1% O2) and a high-dose (89.9?ppm CO; 2.5% CO2; 15.0% O2) gas mixture for 23?h per day for 70?d premating and a 14-d mating period. Impregnated dams continued exposure to gestation day 19. Adverse reproductive effects were not identified in exposed parents (P0) or first (F1) and second generation (F2) offspring during mating, gestation or parturition. No adverse changes to the estrous cycle or in reproductive hormone concentrations were identified. The exposure-related effects were reduced weight gains and adaptive up-regulation of erythropoiesis in male rats from the high-dose group. No adverse, dose-related health effects on clinical data or physiological data were observed. Neurobehavioral tests identified no apparent developmental deficits at the tested levels of exposure. In summary, subchronic exposures to the submarine atmosphere gases did not affect the ability of the exposed rats or their offspring to reproduce and did not appear to have any significant adverse health effects. PMID:25687554

  18. Predictive toxicology of cobalt nanoparticles and ions: comparative in vitro study of different cellular models using methods of knowledge discovery from data.

    PubMed

    Horev-Azaria, Limor; Kirkpatrick, Charles James; Korenstein, Rafi; Marche, Patrice N; Maimon, Oded; Ponti, Jessica; Romano, Roni; Rossi, Francois; Golla-Schindler, Ute; Sommer, Dieter; Uboldi, Chiara; Unger, Ronald E; Villiers, Christian

    2011-08-01

    The toxicological effects of cobalt nanoparticles (Co-NPs) aggregates were examined and compared with those of cobalt ions (Co-ions) using six different cell lines representing lung, liver, kidney, intestine, and the immune system. Dose-response curves were studied in the concentration range of 0.05-1.0 mM, employing 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide test, neutral red, and Alamar blue as end point assays following exposures for 48 and 72 h. Data analysis and predictive modeling of the obtained data sets were executed by employing a decision tree model (J48), where training and validation were carried out by an iterative process. It was established, as expected, that concentration is the highest rank parameter. This is because concentration parameter provides the highest information gain with respect to toxicity. The second-rank parameter emerged to be either the compound type (Co-ions or Co-NPs) or the cell model, depending on the concentration range. The third and the lowest rank in the model was exposure duration. The hierarchy of cell sensitivity toward cobalt ions was found to obey the following sequence of cell lines: A549 > MDCK > NCIH441 > Caco-2 > HepG2 > dendritic cells (DCs), with A549 being the most sensitive cell line and primary DCs were the least sensitive ones. However, a different hierarchy pattern emerged for Co-NPs: A549 = MDCK = NCIH441 = Caco-2 > DCs > HepG2. The overall findings are in line with the hypothesis that the toxic effects of aggregated cobalt NPs are mainly due to cobalt ion dissolution from the aggregated NPs. PMID:21602188

  19. Society of toxicologic pathology position paper: review series: assessment of circulating hormones in nonclinical toxicity studies: general concepts and considerations.

    PubMed

    Stanislaus, Dinesh; Andersson, Håkan; Chapin, Robert; Creasy, Dianne; Ferguson, Duncan; Gilbert, Mary; Rosol, Thomas J; Boyce, Rogely Waite; Wood, Charles E

    2012-08-01

    This is an introductory paper to a series of papers intended to provide the basis for understanding the contribution of endocrine axis disruption or dysfunction to the pathogenesis of morphological findings and to aid in the interpretation of study outcomes. This is the first in this series of guidance papers prepared by the Working Group and outlines general concepts of study design and assay conduct and validation for hormone studies in general. PMID:22569585

  20. The toxicology of HMG-CoA reductase inhibitors: prediction of human risk.

    PubMed

    MacDonald, James S; Halleck, Margaretann M

    2004-01-01

    The discovery that 3-hydroxy-3-methyglutaryl coenzyme A reductase was a rate-determining step in the biosynthesis of cholesterol led to the discovery of inhibitors of this enzyme. To support the development of these agents (statins) as potential hypocholesterolemic drugs, a variety of preclinical studies were conducted in several animal species. Not unexpectedly due to the central role played by mevalonic acid and its products including cholesterol in development and maintenance of cellular homeostasis, administration of high dosage levels of these agents led to the expression of a broad variety of adverse effects in many different tissues. Using the tools of toxicologic pathology and classical risk assessment, these varied toxicities were evaluated by many groups relative to the conditions of use in human therapy and a perspective was developed on potential human risk. These approaches of mechanism-based risk assessment predicted that most of the adverse effects observed in animals would not be seen under conditions of human use and supported the successful introduction of one of the most important classes of human medicines. PMID:15503662

  1. Arsenic Exposure and Toxicology: A Historical Perspective

    PubMed Central

    Hughes, Michael F.; Beck, Barbara D.; Chen, Yu; Lewis, Ari S.; Thomas, David J.

    2011-01-01

    The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve. PMID:21750349

  2. The toxicology of chemosterilants

    PubMed Central

    Hayes, Wayland J.

    1964-01-01

    Sterilization of males can in certain circumstances be more efficient than killing as a method for control of insects and perhaps other pests. A number of chemicals (chemosterilants) show promise of producing sexual sterility in insects without some of the practical limitations of radiation. The most important compounds are alkylating agents. These have little immediate pharmacological action, but are notable for their selective action against haematopoietic and some other proliferating tissues. A number of alkylating agents have been shown to be mutagens in insects, bacteria, fungi, and higher plants; carcinogens in mammals; and teratogens in insects, birds, and mammals. Some produce sexual sterility, possibly in mammals as well as in insects, at doses too low to produce the other effects. Some have an established reputation as drugs for palliative treatment of leukaemia and other neoplasms. The development of insect sterilization as a vector control technique has been handicapped in part by lack of scientific information on the acute and long-term hazards that might be associated with the use of chemosterilants. In this paper the author brings together the available knowledge on the toxicology of the alkylating agents. PMID:14278008

  3. Multiscale Toxicology - Building the Next Generation Tools for Toxicology

    SciTech Connect

    Thrall, Brian D.; Minard, Kevin R.; Teeguarden, Justin G.; Waters, Katrina M.

    2012-09-01

    A Cooperative Research and Development Agreement (CRADA) was sponsored by Battelle Memorial Institute (Battelle, Columbus), to initiate a collaborative research program across multiple Department of Energy (DOE) National Laboratories aimed at developing a suite of new capabilities for predictive toxicology. Predicting the potential toxicity of emerging classes of engineered nanomaterials was chosen as one of two focusing problems for this program. PNNL’s focus toward this broader goal was to refine and apply experimental and computational tools needed to provide quantitative understanding of nanoparticle dosimetry for in vitro cell culture systems, which is necessary for comparative risk estimates for different nanomaterials or biological systems. Research conducted using lung epithelial and macrophage cell models successfully adapted magnetic particle detection and fluorescent microscopy technologies to quantify uptake of various forms of engineered nanoparticles, and provided experimental constraints and test datasets for benchmark comparison against results obtained using an in vitro computational dosimetry model, termed the ISSD model. The experimental and computational approaches developed were used to demonstrate how cell dosimetry is applied to aid in interpretation of genomic studies of nanoparticle-mediated biological responses in model cell culture systems. The combined experimental and theoretical approach provides a highly quantitative framework for evaluating relationships between biocompatibility of nanoparticles and their physical form in a controlled manner.

  4. NTP technical report on the toxicology and carcinogenesis studies of benzethonium chloride (Cas No. 121-54-0) in F344/N rats and B6C3F1 mice (dermal studies). Technical report series

    SciTech Connect

    NONE

    1995-07-01

    Toxicology and carcinogenicity studies were conducted by dermal administration of benzethonium chloride to groups of 60 F344/N rats and 60 B6C3F1 mice of each sex at doses of 0, 0.15, 0.5, or 1.5 mg/kg body weight. Benzethonium chloride was administered to rats in ethanol 5 days per week and doses were adjusted weekly according to the average body weights of the groups. Under the conditions of these 2 year dermal studies, there was no evidence of carcinogenic activity of benzethonium chloride in male or female F344/N rats or in male or female B6C3F1 mice. Exposure of rats and mice to benzethonium chloride by dermal application in ethanol for 2 years resulted in epithelial hyperplasia in male and female rats and mice and sebaceous gland hyperplasia and ulcers in female rats at the site of application.

  5. [Toxicological evaluation in the childhood].

    PubMed

    Arroyo, Amparo; Rodrigo, Carlos; Marrón, M Teresa

    2014-03-01

    Intoxications in infancy require urgent medical treatment within national health systems. In our country they represent 0.3% of paediatric urgencies. Most of them are accidental intoxications but is not infrequent to find some related to child abuse or to suicidal intentions, especially in adolescence. The objectives of the study are to evaluate both clinical health care and medical legal aspects in intoxications in infancy. Medical assistance is described and it includes clinical diagnosis, typology of the more common toxics, percentages and referral to social work and emergency care equipment units of the Ministry of Social Welfare and the Department of Health or, where appropriate, directly to prosecutors and courts for their intervention. In cases of detection of alcohol, drugs or medication in infants, the importance of the correct interpretation of the results of toxicological findings is discussed. Several studies for the interpretation of results concerning the detection of these toxics are reported. Both legal aspects and the forensic medical opinion are assessed. The findings will be analysed by the judicial authority in order to circumscribe responsibilities or to take appropriate decisions concerning the protection of infants' interests. In conclusion intoxication in infancy can lead to legal proceedings requiring specific actions for their protection. Both physicians and hospitals must comply with the legal requirement of the submission to the court of judicial parties. On the other hand, this information is an interesting step toward reinforcing public health surveillance. PMID:24913753

  6. Toxicological evaluation of New Zealand deer velvet powder. Part I: acute and subchronic oral toxicity studies in rats

    Microsoft Academic Search

    H Zhang; S Wanwimolruk; P. F Coville; J. C Schofield; G Williams; S. R Haines; J. M Suttie

    2000-01-01

    Potential toxic effects of acute and subchronic dosage regimens of deer velvet powder have been assessed in rats following OECD guidelines. In the acute study, rats of both sexes were exposed to a single dose of 2 g\\/kg body weight. There was no mortality or other signs of toxicity during 14 days' observation. Furthermore, no significant alteration either in relative

  7. Combining Mass Spectrometry and Toxicology for a Multi-Country European Epidemiologic Study on Drinking Water Disinfection By-Products.

    EPA Science Inventory

    The HiWATE (Health Impacts of long-term exposure to disinfection by-products in drinking WATEr) project is the first systematic analysis that combines the epidemiology on adverse pregnancy outcomes with analytical chemistry and analytical biology in the European Union. This study...

  8. Combining Mass Spectrometry and Toxicology for a Multi-Country European Epidemiologic Study on Drinking Water Disinfection By-Products

    EPA Science Inventory

    The HiWATE (Health Impacts of long-term exposure to disinfection by-products in drinking WATEr) project is the first systematic analysis that combines the epidemiology on adverse pregnancy outcomes with analytical chemistry and analytical biology in the European Union. This study...

  9. Evaluation of potential health effects of 10 kHz magnetic fields: A short-term mouse toxicology study

    SciTech Connect

    Robertson, I.G.C.; Wilson, W.R.; Dawson, B.V.; Zwi, L.J.; Green, A.W.; Boys, J.T. [Univ. of Auckland (New Zealand)] [Univ. of Auckland (New Zealand)

    1996-05-01

    A high-frequency inductive power distribution (HID) technology has been developed that generates sinusoidal magnetic fields at a frequency of 10 kHz. In typical industrial applications, field intensities in the order of 0.2 mT can be expected between the current-carrying coils. Because the possible health effects of 10 kHz sinusoidal magnetic fields of this type had never been investigated, a broad evaluation of possible effects on animal health was made in a preliminary 14 day acute study and in a 90 day subchromic study using male and female B6C3F1 mice. Exposures were at 0.08, 0.28, and 1.0 mT vs a background exposure of 3.7 {micro}T and were essentially continuous. These studies failed to demonstrate any health effects that can be clearly related to the magnetic field exposure. No changes in animal behavior or indications of morbidity were detected during the initial exposure to the fields. There were no significant differences in body weight between exposed and unexposed (control) mice at any time int h study, and the clinical chemistry and hematology parameters were essentially unchanged. Although minor differences in some clinical chemistry and hematology parameters were seen between control and exposure groups, the lack of exposure dependence, the lack of consistency between sexes, and the lack of correspondence with the results of the two studies all suggest that these were chance associations. Even if the changes were real, the magnitude of the changes was very small and does not indicate serious biological effects. Finally, all organs were macroscopically and microscopically normal except for isolated, generally mild, histological lesions and lesions that were ascribed to fighting among males. There was no obvious association with field intensity.

  10. Latin America's present and future challenges in toxicology education.

    PubMed

    Rojas, M

    2005-09-01

    Industrialization that Latin America has experienced during the past 50 years, the increase of population and the growth of chemical-related industries has generated a variety of environmental problems that must be addressed. After assessing these profound changes, greater emphasis should be placed on the study of environmental health and toxicology. Latin American countries face many problems that are common to other developing nations. Therefore, there is a demand for safety assessment and regulatory control of chemicals that create a need for increasing numbers of toxicologists. To meet this demand, educational programs in toxicology have to be designed. This paper utilizes a consultation questionnaire that includes toxicology-network members, scientists and educational institutions where toxicology is taught. An analysis of the information collected is made, with an emphasis on what we currently lack and on future challenges for toxicology professionals. Although the response from the study institutions was 65% (13 countries out of 20), the paper aims to assess the present situation of toxicology. The convenience for a certification/recognition for toxicologists is also evaluated. Action needs to be taken to promote scientific development based on regional specific needs that require increasing at the number of toxicology programs, and promoting of cooperation between academics and researchers. Among the limitations we have are the variability of curricula, objectives and priorities. The increasing globalization of markets and regulations requires the harmonization of graduate/postgraduate programs to ensure that risk assessment and management are dealt with uniformly. Cooperation among our countries and international assistance should play a more prominent role in the promotion of regional integration and the more efficient utilization of international experience in defining educational policies. PMID:15982696

  11. Latin America's present and future challenges in toxicology education

    SciTech Connect

    Rojas, M. [Center for Toxicological Investigations of the University of Carabobo (CITUC), Calle 144 No. RIO-211, La Ceiba, Valencia (Venezuela)]. E-mail: martini@telcel.net.ve

    2005-09-01

    Industrialization that Latin America has experienced during the past 50 years, the increase of population and the growth of chemical-related industries has generated a variety of environmental problems that must be addressed. After assessing these profound changes, greater emphasis should be placed on the study of environmental health and toxicology. Latin American countries face many problems that are common to other developing nations. Therefore, there is a demand for safety assessment and regulatory control of chemicals that create a need for increasing numbers of toxicologists. To meet this demand, educational programs in toxicology have to be designed. This paper utilizes a consultation questionnaire that includes toxicology-network members, scientists and educational institutions where toxicology is taught. An analysis of the information collected is made, with an emphasis on what we currently lack and on future challenges for toxicology professionals. Although the response from the study institutions was 65% (13 countries out of 20), the paper aims to assess the present situation of toxicology. The convenience for a certification/recognition for toxicologists is also evaluated. Action needs to be taken to promote scientific development based on regional specific needs that require increasing at the number of toxicology programs, and promoting of cooperation between academics and researchers. Among the limitations we have are the variability of curricula, objectives and priorities. The increasing globalization of markets and regulations requires the harmonization of graduate/postgraduate programs to ensure that risk assessment and management are dealt with uniformly. Cooperation among our countries and international assistance should play a more prominent role in the promotion of regional integration and the more efficient utilization of international experience in defining educational policies.

  12. The New Toxicology of Sophisticated Materials: Nanotoxicology and Beyond

    PubMed Central

    Maynard, Andrew D.; Warheit, David B.; Philbert, Martin A.

    2011-01-01

    It has long been recognized that the physical form of materials can mediate their toxicity—the health impacts of asbestiform materials, industrial aerosols, and ambient particulate matter are prime examples. Yet over the past 20 years, toxicology research has suggested complex and previously unrecognized associations between material physicochemistry at the nanoscale and biological interactions. With the rapid rise of the field of nanotechnology and the design and production of increasingly complex nanoscale materials, it has become ever more important to understand how the physical form and chemical composition of these materials interact synergistically to determine toxicity. As a result, a new field of research has emerged—nanotoxicology. Research within this field is highlighting the importance of material physicochemical properties in how dose is understood, how materials are characterized in a manner that enables quantitative data interpretation and comparison, and how materials move within, interact with, and are transformed by biological systems. Yet many of the substances that are the focus of current nanotoxicology studies are relatively simple materials that are at the vanguard of a new era of complex materials. Over the next 50 years, there will be a need to understand the toxicology of increasingly sophisticated materials that exhibit novel, dynamic and multifaceted functionality. If the toxicology community is to meet the challenge of ensuring the safe use of this new generation of substances, it will need to move beyond “nano” toxicology and toward a new toxicology of sophisticated materials. Here, we present a brief overview of the current state of the science on the toxicology of nanoscale materials and focus on three emerging toxicology-based challenges presented by sophisticated materials that will become increasingly important over the next 50 years: identifying relevant materials for study, physicochemical characterization, and biointeractions. PMID:21177774

  13. Toxicological study of a glucose-added acetic acid maintenance infusion solution (VEEN 3G Inj.) local irritation test.

    PubMed

    Onodera, K; Kawaguch, M; Shibata, M; Kagawa, M; Kojima, J; Shimizu, K; Yoneko, M; Wachi, M

    2002-01-01

    The local irritating effect of Veen 3G Inj. (glucose-added acetic acid maintenance infusion solution) was examined in male rabbits. We studied the local irritating effect of the infusion solution compared with that of Ringer's solution, 5% sulfobromophthalein sodium injection, distilled water for injection or glucose-added Ringer's solution. In the vascular irritation test, macroscopical and histopathological changes induced by the infusion solution were not observed in the vessels. Moreover, in the hemolytic test, hemolysis of rabbit erythrocyte was not observed in the mixture with the infusion solution. In the present study, no change suggesting irritation by the infusion solution was observed in the in vivo vascular irritation test using the auricular vein of rabbits or in the in vitro hemolytic test using rabbit erythrocyte. In conclusion, in clinical use the infusion solution produces extremely slight adverse effects, such as vessel pain and phlebitis on the injection site. PMID:12073764

  14. Toxicological evaluation of potassium perfluorobutanesulfonate in a 90-day oral gavage study with Sprague–Dawley rats

    Microsoft Academic Search

    Paul H. Lieder; Shu-Ching Chang; Raymond G. York; John L. Butenhoff

    2009-01-01

    Perfluorobutanesulfonate (PFBS) is a surfactant and degradation product of substances synthesized using perfluorobutanesulfonyl fluoride. A 90-day rat oral gavage study has been conducted with potassium PFBS (K+PFBS). Rats were dosed with K+PFBS at doses of 60, 200, and 600mg\\/kg-day body weight. The following endpoints were evaluated: clinical observations, food consumption, body weight, gross and microscopic pathology, clinical chemistry, and hematology.

  15. Basic toxicology and metabolism studies of 1,5-anhydro- d-fructose using bacteria, cultured mammalian cells, and rodents

    Microsoft Academic Search

    Shukun Yu; Jie Mei; Bo Ahrén

    2004-01-01

    1,5-Anhydro-d-fructose (AF) is a monosaccharide occurring in edible morels, red seaweeds and certain mammalian tissues. It can be formed directly from starch and glycogen in vivo by ?-1,4-glucan lyase (EC 4.2.2.13). In this study, the toxicity, absorption and metabolism of AF using bacteria, mammalian cells, rat and mouse models were examined. In Ames test, AF showed no genotoxicity using five

  16. Acute toxicological studies of the main organosulfur compound derived from Allium sp. intended to be used in active food packaging.

    PubMed

    Llana-Ruiz-Cabello, María; Gutiérrez-Praena, Daniel; Puerto, María; Pichardo, Silvia; Moreno, F Javier; Baños, Alberto; Nuñez, Cristina; Guillamón, Enrique; Cameán, Ana María

    2015-08-01

    Some plant extracts have been proposed as potential alternative to the use of synthetic preservatives in the food industry. Among those, extracts from Allium species exhibit interesting antimicrobial and antioxidant properties for the food packaging industry. The present work aims to assess the usefulness and potential safety of the major organosulfur compound present in a commercial Allium sp. extract (PROALLIUM AP®), namely propyl thiosulfinate oxide (PTSO). For this purpose, its antimicrobial activity was studied in a wide range of microorganisms. Moreover, cytotoxicity and ultrastructural cellular damages caused by PTSO were studied in two human cell lines, Caco-2 and HepG2, being the colonic cells more sensitive to this compound. Finally, the protective role of PTSO against an induced oxidative situation was evaluated in the human intestinal Caco-2 cells. The results revealed damage at high concentration, although no significant adverse effects were recorded for the concentration to be used in food packaging. Moreover, the in vivo study also revealed the potential safety use at the established concentrations. In addition, the antimicrobial properties and the antioxidant role of PTSO were confirmed. Therefore, this compound could be considered as a good natural alternative to synthetic preservatives used in the food packaging industry. PMID:25957743

  17. Recovery of contaminated wetland soils at the Savannah River Site by natural rainfall: An experimental, toxicological study

    SciTech Connect

    Loehle, C.

    1990-08-01

    This study was conducted at the Department of Energy Savannah River Site in South Carolina. Seepage basins at the SRS F-Area received liquid effluent from the 1950s to 1988. This effluent was typically acidic, containing high amounts of total dissolved ions, low levels of tritium and other radioactive elements, and trace levels of various heavy metals. Sodium (from NaOH), and aluminum (from soil matrix reduction due to acid leachate) were at particularly high levels in the outcropping water. The effluent gradually seeped down to the water table and subsequently outcropped along the edge of a forested wetland bordering Four Mile Creek. A laboratory study was conducted to evaluate the potential for natural remediation of contaminated wetland soils by rainfall. Contaminated soils were collected and leached repeatedly with rainwater. After 6 leachings the leachate was observed to be non-toxic to lettuce seedlings, whereas the initial leachate was very toxic. These results suggest that more detailed studies on leaching as a remediation technique would be beneficial. 6 refs., 2 figs., 3 tabs.

  18. Toxicological and biochemical studies on Schinus terebinthifolius concerning its curative and hepatoprotective effects against carbon tetrachloride-induced liver injury

    PubMed Central

    Abdou, Rania H.; Saleh, Sherif Y.; Khalil, Waleed F.

    2015-01-01

    Background: Recently, many efforts have been made to discover new products of natural origin which can limit the xenobiotic-induced hepatic injury. Carbon tetrachloride (CCl4) is a highly toxic chemical that is widely used to study hepatotoxicity in animal models. Objective: The present study was conducted to investigate the curative and protective effects of Schinus terbenthifolius ethanolic extract against CCl4 -induced acute hepatotoxicity in rats. Materials and Methods: S. terbenthifolius extract was orally administered in a dose of 350 mg dried extract/kg b.wt. before and after intoxication with CCl4 for curative and protective experiments, respectively. A group of hepatotoxicity indicative enzymes, oxidant-antioxidant capacity, DNA oxidation, and apoptosis markers were measured. Results: CCl4 increased liver enzyme leakage, oxidative stress, hepatic apoptosis, DNA oxidation, and inflammatory markers. Administration of S. terebinthifolius, either before or after CCl4 intoxication, significantly decreased elevated serum liver enzymes and reinstated the antioxidant capacity. Interestingly, S. terebinthifolius extract inhibited hepatocyte apoptosis as revealed by approximately 20 times down-regulation in caspase-3 expression when compared to CCl4 untreated group. On the other hand, there was neither protective nor curative effect of S. terebinthifolius against DNA damage caused by CCl4. Conclusion: The present study suggests that S. terebinthifolius extract could be a substantially promising hepatoprotective agent against CCl4 toxic effects and may be against other hepatotoxic chemical or drugs.

  19. Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada.

    PubMed

    Miller, David H; Tietge, Joseph E; McMaster, Mark E; Munkittrick, Kelly R; Xia, Xiangsheng; Griesmer, David A; Ankley, Gerald T

    2015-07-01

    Recovery of fish and wildlife populations after stressor mitigation serves as a basis for evaluating remediation success. Unfortunately, effectively monitoring population status on a routine basis can be difficult and costly. In the present study, the authors describe a framework that can be applied in conjunction with field monitoring efforts (e.g., through effects-based monitoring programs) to link chemically induced alterations in molecular and biochemical endpoints to adverse outcomes in whole organisms and populations. The approach employs a simple density-dependent logistic matrix model linked to adverse outcome pathways (AOPs) for reproductive effects in fish. Application of this framework requires a life table for the organism of interest, a measure of carrying capacity for the population of interest, and estimation of the effect of stressors on vital rates of organisms within the study population. The authors demonstrate the framework using linked AOPs and population models parameterized with long-term monitoring data for white sucker (Catostomus commersoni) collected from a study site at Jackfish Bay, Lake Superior, Canada. Individual responses of fish exposed to pulp mill effluent were used to demonstrate the framework's capability to project alterations in population status, both in terms of ongoing impact and subsequent recovery after stressor mitigation associated with process changes at the mill. The general approach demonstrated at the Jackfish Bay site can be applied to characterize population statuses of other species at a variety of impacted sites and can account for effects of multiple stressors (both chemical and nonchemical) and dynamics within complex landscapes (i.e., meta-populations including emigration and immigration processes). Environ Toxicol Chem 2015;34:1623-1633. © 2015 SETAC. PMID:25943079

  20. Toxicology and safety of anti-oxidant of bamboo leaves. Part 1: Acute and subchronic toxicity studies on anti-oxidant of bamboo leaves

    Microsoft Academic Search

    Baiyi Lu; Xiaoqin Wu; Xiaowei Tie; Yu Zhang; Ying Zhang

    2005-01-01

    The anti-oxidant of bamboo leaves (AOB) has recently been certificated as a novel kind of natural anti-oxidant by the Ministry of Health of the People’s Republic of China, and has been used in various food systems. Here, AOB was subjected to a series of acute and subchronic toxicological tests to evaluate its safety. It was examined to evaluate acute oral

  1. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Subchronic Toxicity of Sulfur Mustard (HD) In Rats Final Report

    SciTech Connect

    Sasser, L. B.; Miller, R. A.; Kalkwarf, D, R.; Buschbom, R. L.; Cushing, J. A.

    1989-06-30

    Occupational health standards have not been established for sulfur mustard [bis(2- chlorethyl)-sulfide], a strong alkylating agent with known mutagenic properties. Seventytwo Sprague-Dawley rats of each sex, 6-7 weeks old, were divided into six groups (12/group/ sex) and gavaged with either 0, 0.003 , 0.01 , 0.03 , 0.1 or 0.3 mg/kg of sulfur mustard in sesame oil 5 days/week for 13 weeks. No dose-related mortality was observed. A significant decrease (P ( 0.05) in body weight was observed in both sexes of rats only in the 0.3 mg/kg group. Hematological evaluations and clinical chemistry measurements found no consistent treatment-related effects at the doses studied. The only treatment-related lesion associated with gavage exposure upon histopathologic evaluation was epithelial hyperplasia of the forestomach of both sexes at 0.3 mg/kg and males at 0.1 mg/kg. The hyperplastic change was minimal and characterized by cellular disorganization of the basilar layer, an apparent increase in mitotic activity of the basilar epithelial cells, and thickening of the epithelial layer due to the apparent increase in cellularity. The estimated NOEL for HD in this 90-day study is 0.1 mg/kg/day when administered orally.

  2. Toxicological study of injuries of rat’s hippocampus after lead poisoning by synchrotron microradiography and elemental mapping

    NASA Astrophysics Data System (ADS)

    Liang, Feng; Zhang, Guilin; Xiao, Xianghui; Cai, Zhonghou; Lai, Barry; Hwu, Yeukuang; Yan, Chonghuai; Xu, Jian; Li, Yulan; Tan, Mingguang; Zhang, Chuanfu; Li, Yan

    2010-09-01

    The hippocampus, a major component of the brain, is one of the target nervous organs in lead poisoning. In this work, a rat's hippocampal injury caused by lead was studied. The lead concentrations in blood, bone and hippocampus collected from rats subject to lead poisoning were quantified by Inductively Coupled Plasma Mass Spectrometry while morphological information and elemental distributions in the hippocampus were obtained with synchrotron radiation X-ray phase contrast imaging and synchrotron radiation micro-beam X-ray fluorescence, respectively. For comparison, identical characterization of the specimens from the rats in the control group was done in parallel. Results show that the ratios between the lead content in the treated group and that in the control group of the hippocampus, bone, and blood are about 2.66, 236, and 39.6, respectively. Analysis also revealed that some health elements such as S, K, Cl and P increase in the regions with high lead content in the treated hippocampus. Morphological differences between the normal and lead-exposed hippocampus specimens in some local areas were observed. Explicitly, the structure of the lead-exposed hippocampus was tortuous and irregular, and the density of the neurons in the Dentate Gyrus was significantly lower than that from the control group. The study shows that the synchrotron radiation methods are very powerful for investigating structural injury caused by heavy metals in the nervous system.

  3. Designed Synthesis of CeO2 Nanorods and Nanowires for Studying Toxicological Effects of High Aspect Ratio Nanomaterials

    PubMed Central

    Ji, Zhaoxia; Wang, Xiang; Zhang, Haiyuan; Lin, Sijie; Meng, Huan; Sun, Bingbing; George, Saji; Xia, Tian; Nel, André E.; Zink, Jeffrey I.

    2012-01-01

    While it has been shown that high aspect ratio nanomaterials like carbon nanotubes and TiO2 nanowires can induce toxicity by acting as fiber-like substances that damage the lysosome, it is not clear what the critical lengths and aspect ratios are that induce this type of toxicity. To answer this question, we synthesized a series of cerium oxide (CeO2) nanorods and nanowires with precisely controlled lengths and aspect ratios. Both phosphate and chloride ions were shown to play critical roles in obtaining these high aspect ratio nanostructures. High resolution TEM analysis shows that single crystalline CeO2 nanorods/nanowires were formed along the [211] direction by an “oriented attachment” mechanism, followed by Ostwald ripening. The successful creation of a comprehensive CeO2 nanorod/nanowire combinatorial library allows, for the first time, the systematic study of the effect of aspect ratio on lysosomal damage, cytoxicity and IL-1? production by the human myeloid cell line (THP-1). This in vitro toxicity study demonstrated that at lengths ?200 nm and aspect ratios ? 22, CeO2 nanorods induced progressive cytotoxicity and pro-inflammatory effects. The relatively low “critical” length and aspect ratio were associated with small nanorod/nanowire diameters (6–10 nm), which facilitates the formation of stacking bundles due to strong van der Waals and dipole-dipole attractions. Our results suggest that both length and diameter components of aspect ratio should be considered when addressing the cytotoxic effects of long aspect ratio materials. PMID:22564147

  4. Postmortem diagnosis and toxicological validation of illicit substance use

    PubMed Central

    Lehrmann, E; Afanador, ZR; Deep-Soboslay, A; Gallegos, G; Darwin, WD; Lowe, RH; Barnes, AJ; Huestis, MA; Cadet, JL; Herman, MM; Hyde, TM; Kleinman, JE; Freed, WJ

    2008-01-01

    The present study examines the diagnostic challenges of identifying ante-mortem illicit substance use in human postmortem cases. Substance use, assessed by clinical case history reviews, structured next-of-kin interviews, by general toxicology of blood, urine, and/or brain, and by scalp hair testing, identified 33 cocaine, 29 cannabis, 10 phencyclidine and 9 opioid cases. Case history identified 42% cocaine, 76% cannabis, 10% phencyclidine, and 33% opioid cases. Next-of-kin interviews identified almost twice as many cocaine and cannabis cases as Medical Examiner (ME) case histories, and were crucial in establishing a detailed lifetime substance use history. Toxicology identified 91% cocaine, 68% cannabis, 80% phencyclidine, and 100% opioid cases, with hair testing increasing detection for all drug classes. A cocaine or cannabis use history was corroborated by general toxicology with 50% and 32% sensitivity, respectively, and with 82% and 64% sensitivity by hair testing. Hair testing corroborated a positive general toxicology for cocaine and cannabis with 91% and 100% sensitivity, respectively. Case history corroborated hair toxicology with 38% sensitivity for cocaine and 79% sensitivity for cannabis, suggesting that both case history and general toxicology underestimated cocaine use. Identifying ante-mortem substance use in human postmortem cases are key considerations in case diagnosis and for characterization of disorder-specific changes in neurobiology. The sensitivity and specificity of substance use assessments increased when ME case history was supplemented with structured next-of-kin interviews to establish a detailed lifetime substance use history, while comprehensive toxicology, and hair testing in particular, increased detection of recent illicit substance use. PMID:18201295

  5. A toxicological study of inhalable particulates in an industrial region of Lanzhou City, northwestern China: Results from plasmid scission assay

    NASA Astrophysics Data System (ADS)

    Xiao, Zhenghui; Shao, Longyi; Zhang, Ning; Wang, Jing; Chuang, Hsiao-Chi; Deng, Zhenzhen; Wang, Zhen; BéruBé, Kelly

    2014-09-01

    The city of Lanzhou in northwestern China experiences serious air pollution episodes in the form of PM10 that is characterized by having high levels of heavy metals. The Xigu District represents the industrial core area of Lanzhou City and is denoted by having the largest petrochemical bases in western China. This study investigates heavy metal compositions and oxidative potential of airborne PM10 (particulate matter with aerodynamic diameter of 10 ?m or less) collected in Xigu District in the summer and winter of 2010. An in vitro plasmid scission assay (PSA) was employed to study the oxidative potential of airborne PM10 and inductively coupled plasma-mass spectrometry (ICP-MS) was used to examine heavy metal compositions. Transmission electron microscopy coupled with energy-dispersive X-ray spectrometry (TEM/EDX) was used to investigate elemental compositions and mixing states of PM10. The average mass concentrations of PM10 collected in Xigu District were generally higher than the national standard for daily PM10 (150 ?g/m3). Cr, Zn, Pb and Mn were the most abundant metals in the intact whole particles of PM10. Zn, Mn and As was the most abundant metal in the water-soluble fraction, while Cr, Pb, and V existed primarily in insoluble forms. TD20 values (i.e. toxic dosage of PM10 causing 20% of plasmid DNA damage) varied considerably in both winter and summer (from 19 ?g/mL to >1000 ?g/mL) but were typically higher in summer, suggesting that the winter PM10 exhibited greater bioreactivity. In addition, the PM10 collected during a dust storm episode had a highest TD20 value and thus the least oxidative damage to supercoiled plasmid DNA, while the particles collected on a hazy day had a lowest TD20 value and thus the highest oxidative damage to supercoiled plasmid DNA. The particles collected on the first day after snow fall and on a day of cold air intrusion exhibited minor oxidative potential (i.e. caused limited DNA damage). The water-soluble Zn, Mn, As, and Cu displayed a significant negative correlation with TD20 values, suggesting that these heavy metals were responsible for the increase of oxidative potential. The high mass concentration of PM10 and resulting high oxidative potential in Xigu District may be due to the constant low wind speed and high relative humidity, particularly in winter. Finally, TEM analysis suggested that the oxidative potential of PM10 may be associated with its degree of internal mixing, whereby the heterogeneous assortment of soot, mineral and metals created a highly reactive moiety.

  6. [Toxicological studies on dibekacin for intravenous injection use. I. Subacute toxicity in rats and rabbits (author's transl)].

    PubMed

    Koeda, T; Odaki, M; Sasaki, H; Yokota, M; Niizato, T; Watanabe, H; Kawaoto, H; Hirano, F; Kumagai, K; Ishiwatari, N; Suzuki, H; Watanuki, T

    1980-05-01

    Dibekacin sulfate (DKB) dissolved in physiological saline J.P. was administered to rats intraperitoneally and rabbits intravenously for subacute 35-day toxicity test. The results were as follows: I. Wistar-strain rats (1) All the animals of both male and female died in the group with 500 mg/kg. (2) In general conditions stretching physical positions, decrease in spontaneous movements, decrease in respiration rates, unsteady steps of walking and muscular relaxation developed in the groups of high doses of either sex. The effects through the administration of this drug were also noted on the progress of body weights and food intakes in the groups of high doses. (3) In the hematological and histopathological studies, degenerative and reparative changes of tubular epithelia were evidently noted in the groups which were administered more than 100 mg/kg of DKB in both male and female. No pathological findings were noted in administration groups less than 20 mg/kg. (4) Microscopically, slight inflammatory changes were noted in the bladder of the male groups of high doses and the direct stimulative effects on the peritoneum due to intraperitoneal administration were noted but slightly in the serous membrane of the liver, spleen and the gastrointestinal tracts. (5) Judging from the above-mentioned results, "the maximal non toxic dose" through the intraperitoneal administration to rats of this drug was assumed 20 mg/kg in either sex. II. Albino rabbits (1) Neither remarkable change in the general conditions nor death was noted in each administration group. (2) The increase in the mean body weight in each group was almost similar to the control value. They consumed the amounts of food given. (3) The specific abnormal finding was not noted in the hematology and biochemical tests of serum or urine. (4) Since no change was noted on ERG in each rabbits, we estimate there is no effect to the visual organs. (5) In histopathological study, several changes revealed in some organs through the macroscopic findings, organ weights and microscopic findings but they were no more the serious changes attributable to administration. (6) We estimate "the maximal non effective dose" in this test was 10 mg/kg. PMID:7431659

  7. Unsuitability of the northern bobwhite as a model species for the assessment of reproductive behavior in toxicological studies.

    PubMed

    Quinn, Michael J; McFarland, Craig A; Johnson, Mark S

    2009-01-01

    The northern bobwhite (Colinus virginianus) is used in numerous wildlife toxicity studies, however no published reports could be located that mention the measurement of reproductive behavior in this species. Changes in reproductive behavior can be potentially more sensitive to environmental contaminant exposures and less resilient than more traditional physiological responses. Male bobwhite copulatory behaviors were measured similarly to those that are well established for use in Japanese quail (Coturnix japonica). Time to initiate mating, time to achieve a successful copulation, the number of mating attempts, and the number of successful copulations were recorded daily for four consecutive days over a period of 3 min for each male/female pair of birds per day. When females were introduced to male cages, males were more occupied with shows of aggression towards neighboring males than attempts to mate with the female sharing their space. Only one male successfully mated with a female over the entire 4 days of the test. Future attempts at assessing reproductive behavior in this species may be more successful if birds are separated from the rest of the group when paired. The Japanese quail seems to be a more appropriate species for overall reproductive tests due to: willingness of males to copulate in the presence of other males, consistent egg laying ability, and the short time required for embryonic development and reproductive maturity. PMID:19778231

  8. Cationic surfactants in the form of nanoparticles and micelles elicit different human neutrophil responses: a toxicological study.

    PubMed

    Hwang, Tsong-Long; Sung, Calvin T; Aljuffali, Ibrahim A; Chang, Yuan-Ting; Fang, Jia-You

    2014-02-01

    Cationic surfactants are an ingredient commonly incorporated into nanoparticles for clinical practicability; however, the toxicity of cationic surfactants in nanoparticles is not fully elucidated. We aimed to evaluate the inflammatory responses of cationic nanobubbles and micelles in human neutrophils. Soyaethyl morpholinium ethosulfate (SME) and hexadecyltrimethyl-ammonium bromide (CTAB) are the two cationic surfactants employed in this study. The zeta potential of CTAB nanobubbles was 80 mV, which was the highest among all formulations. Nanobubbles, without cationic surfactants, showed no cytotoxic effects on neutrophils in terms of inflammatory responses. Cationic nanobubbles caused a concentration-dependent cytotoxicity of degranulation (elastase release) and membrane damage (release of lactate dehydrogenase, LDH). Among all nanoparticles and micelles, CTAB-containing nanosystems showed the greatest inflammatory responses. A CTAB nanobubble diluent (1/150) increased the LDH release 80-fold. Propidium iodide staining and scanning electron microscopy (SEM) verified cell death and morphological change of neutrophils treated by CTAB nanobubbles. SME, in a micelle form, strengthened the inflammatory response more than SME-loaded nanobubbles. Membrane interaction and subsequent Ca(2+) influx were the mechanisms that triggered inflammation. The information obtained from this work is beneficial in designing nanoparticulate formulations for balancing clinical activity and toxicity. PMID:24246197

  9. Selective exposure and analysis of the sheep tracheal lobe as a model for toxicological studies of respirable particles

    SciTech Connect

    Begin, R.; Masse, S.; Rola-Pleszczynski, M.; Drapeau, G.; Dalle, D.

    1985-04-01

    A conscious sheep model, recently developed to study sequentially the bronchoalveolar milieu, was further refined to use in the rapid in vivo assessment of the biological effects of respirable particles. In this model, the anatomically isolated tracheal lobe was selectively exposed to either 100 ml phosphate buffered saline (PBS) (control group of 12 sheep), 100 mg of 0.1-..mu..m latex beads in 100 ml PBS (latex group of 12 sheep), or 100 mg of UICC Canadian chrysotile fibers in 100 ml PBS (asbestos group of 12 sheep). Bronchoalveolar lavages (BAL) of the tracheal lobe were obtained prior to exposure and at Days 1, 8, 15, 21, 29, 45, and 60 after exposure. Whole-lung detailed pulmonary function tests (PFT) were performed at the same times and the histopathology of the lobe was examined in six sheep in each group at Days 29 and 60. In the latex group, there was no significant change in PFT, the BAL analyses documented early transient increase in cellularity (macrophages and neutrophils at Day 1) and only macrophages after; lung histology documented an early macrophagic alveolitis which decreased to less than 10% of the initial inflammatory reaction at Day 60, without other distortion of the lung and airway architecture. In the asbestos sheep, the only change in whole-lung PFT was a 10-torr fall in arterial O/sub 2/ pressure. BAL analyses documented persistent increases in macrophages, neutrophils, and lactate dehydrogenase as well as increasing ..gamma..-globulins. Lung histology revealed a macrophagic and neutrophilic peribronchiolar alveolitis, early fibrosis, and severe distortion of the small airways, lesions comparable to those of early asbestosis in sheep or humans.

  10. 76 FR 68461 - Meeting of the National Toxicology Program (NTP) Board of Scientific Counselors

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-04

    ...toxicology, pharmacology, pathology, biochemistry, epidemiology, risk assessment, carcinogenesis, mutagenesis, molecular biology, behavioral toxicology, neurotoxicology, immunotoxicology, reproductive toxicology or teratology, and...

  11. Contamination of vineyard soils with fungicides: A review of environmental and toxicological aspects

    Microsoft Academic Search

    Michael Komárek; Eva ?adková; Vladislav Chrastný; François Bordas; Jean-Claude Bollinger

    2010-01-01

    The contamination of agricultural soils with inorganic (Cu-based) and organic pesticides (including their residues) presents a major environmental and toxicological concern. This review summarizes available studies published on the contamination of vineyard soils throughout the world with Cu-based and synthetic organic fungicides. It focuses on the behavior of these contaminants in vineyard soils and the associated environmental and toxicological risks.

  12. Toxicological effects of malachite green

    Microsoft Academic Search

    Shivaji Srivastava; Ranjana Sinha; D. Roy

    2004-01-01

    This review summarises the wide range of toxicological effects of malachite green (MG), a triarylmethane dye on various fish species and certain mammals. MG is widely used in aquaculture as a parasiticide and in food, health, textile and other industries for one or the other purposes. It controls fungal attacks, protozoan infections and some other diseases caused by helminths on

  13. CAROLINA CENTER FOR COMPUTATIONAL TOXICOLOGY

    EPA Science Inventory

    The Center will advance the field of computational toxicology through the development of new methods and tools, as well as through collaborative efforts. In each Project, new computer-based models will be developed and published that represent the state-of-the-art. The tools p...

  14. A short history of the toxicology of inhaled particles

    PubMed Central

    2012-01-01

    Particle toxicology arose in order to understand the mechanisms of adverse effects of 3 major particle types that had historically exerted the greatest toll of ill-health—quartz, coal and asbestos. By the middle of the last century rat inhalation studies had been carried out and the pathology documented, but true mechanistic particle toxicology did not really take off until the 1970s when cell culture techniques became available. By the 1980s glass fibres were a major focus of interest and attempts to develop a structure-toxicity paradigm centred on biopersistence. In the 1990s environmental particles dominated the particle toxicology agenda and the cardiovascular system emerged as a target for inhaled particles, raising new challenges for particle toxicologists. We are currently in the era of nanotoxicology where a large and diverse range of new nanoparticles types are under scrutiny. PMID:22559156

  15. Applications of Emerging Technologies in Toxicology and Safety Assessment

    Microsoft Academic Search

    Vincent L. Reynolds

    2005-01-01

    Standardized protocols for repeat-dose toxicity studies have many advantages, including experimental redundancy (i.e., the use of more than a single experimental approach in the assessment of a given organ or tissue) and evaluation of numerous tissues to ensure detection of adverse effects, as well as the ability to develop robust historical control databases. However, traditional toxicology study designs may not

  16. Imaging technologies for preclinical models of bone and joint disorders

    PubMed Central

    2011-01-01

    Preclinical models for musculoskeletal disorders are critical for understanding the pathogenesis of bone and joint disorders in humans and the development of effective therapies. The assessment of these models primarily relies on morphological analysis which remains time consuming and costly, requiring large numbers of animals to be tested through different stages of the disease. The implementation of preclinical imaging represents a keystone in the refinement of animal models allowing longitudinal studies and enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time. Our aim is to highlight examples that demonstrate the advantages and limitations of different imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging. All of which are in current use in preclinical skeletal research. MRI can provide high resolution of soft tissue structures, but imaging requires comparatively long acquisition times; hence, animals require long-term anaesthesia. CT is extensively used in bone and joint disorders providing excellent spatial resolution and good contrast for bone imaging. Despite its excellent structural assessment of mineralized structures, CT does not provide in vivo functional information of ongoing biological processes. Nuclear medicine is a very promising tool for investigating functional and molecular processes in vivo with new tracers becoming available as biomarkers. The combined use of imaging modalities also holds significant potential for the assessment of disease pathogenesis in animal models of musculoskeletal disorders, minimising the use of conventional invasive methods and animal redundancy. PMID:22214535

  17. Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities.

    PubMed

    Valerio, Luis G; Cross, Kevin P

    2012-05-01

    Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure-activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity. PMID:22426359

  18. Toxicological Effects of Fullerenes on Caenorhabditis elegans

    NASA Astrophysics Data System (ADS)

    Schomaker, Justin; Snook, Renee; Howell, Carina

    2014-03-01

    The nematode species Caenorhabditis elegans is a useful genetic model organism due to its simplicity and the substantial molecular, genetic, and developmental knowledge about the species. In this study, this species was used to test the toxicological effects of C60 fullerene nanoparticles. In previous studies using rats, a solution of C60 fullerenes in olive oil proved to extend the life of the subjects. The purpose of this experiment was to subject C. elegans to varying concentrations of C60 fullerenes and observe their toxicological effects. Initial findings indicate a link between fullerene exposure and enlargement of the vulva as well as the formation of a small nodule at the base of the tail in some individuals. While the fullerenes are not lethally toxic in C. elegans, results will be presented that pertain to changes in life span and progeny of the nematodes exposed to varying concentrations of fullerenes as well as the mechanisms of toxicity. High magnification imaging via SEM and/or AFM will be used to characterize the fullerene nanoparticles. Testing the toxicity of fullerenes in a wide variety of organisms will lead to a more complete understanding of the effects of fullerenes on living organisms to ultimately understand their effects in humans. This work was supported by National Science Foundation grants DUE-1058829, DMR-0923047, DUE-0806660 and Lock Haven FPDC grants.

  19. The Role of Grape Seed Extract in the Treatment of Chemo/Radiotherapy Induced Toxicity: A Systematic Review of Preclinical Studies.

    PubMed

    Olaku, Oluwadamilola O; Ojukwu, Mary O; Zia, Farah Z; White, Jeffrey D

    2015-07-01

    Grapes are one of the most consumed fruits in the world and are rich in polyphenols. Grape seed proanthocyanidins (GSP) have demonstrated chemopreventive and/or chemotherapeutic effects in various cancer cell cultures and animal models. The clinical efficacy of chemotherapy is often limited by its adverse effects. Several studies show that reactive oxygen species mediate the cardiotoxicity and neurotoxicity induced by various cancer chemotherapeutic agents. This implies that concomitant administration of antioxidants may prevent these adverse effects. The review was carried out in accordance with the PRISMA guidelines. An electronic search strategy in Medline and Embase databases was conducted. Of the 41 studies reviewed, 27 studied GSP while the remainder (14) studied grape seed or skin extracts (GSE). All the studies were published in English, except 2 in Chinese. A significant percentage (34%) of the studies we reviewed assessed the effect of GSE or GSP on cardiotoxicity induced by chemotherapy. Doxorubicin was the most common chemotherapeutic drug studied followed by cisplatin. Research studies that assessed the effect of GSE or GSP on radiation treatment accounted for 22% of the articles reviewed. GSE/GSP ameliorates some of the cytotoxic effects on normal cells/tissues induced by chemo/radiotherapy. PMID:25880972

  20. Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)- N-(2-methyl-1 H-pyrrolo[2,3- b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor

    Microsoft Academic Search

    Réjean Ruel; Carl Thibeault; Alexandre L’Heureux; Alain Martel; Zhen-Wei Cai; Donna Wei; Ligang Qian; Joel C. Barrish; Arvind Mathur; Celia D’Arienzo; John T. Hunt; Amrita Kamath; Punit Marathe; Yueping Zhang; George Derbin; Barri Wautlet; Steven Mortillo; Robert Jeyaseelan; Benjamin Henley; Ravindra Tejwani; Rajeev S. Bhide; George L. Trainor; Joseph Fargnoli; Louis J. Lombardo

    2008-01-01

    We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure–activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.

  1. Toxicology of acid rain: are we overlooking the obvious

    Microsoft Academic Search

    1986-01-01

    Although the potential toxicological problems caused by increased aqueous concentrations of inorganic substances merit extensive study, an area of even greater importance has not received proper consideration. Specifically the author refers to the predictable changes in the toxicity of many lipophilic organic compounds concomitant with changes in hydrogen ion concentration. Of the many lipophilic organic compounds - whether they are

  2. Toxicology and carcinogenesis studies of nitrofurantoin (CAS No. 67-20-9) in F344/n rats and B6C3F1 mice (feed studies). Technical report

    SciTech Connect

    French, J.E.

    1989-09-01

    Two-year toxicology and carcinogenesis studies were conducted by administering diets containing 0, 600, or 1,300 ppm nitrofurantoin to groups of 50 female rats for 103 weeks. Groups of 50 male rats and 50 mice of each sex were fed diets containing 0, 1,300 or 2,500 ppm for 103 weeks. Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of nitrofurantoin for male F344/N rats as shown by increased incidences of uncommon kidney tubular cell neoplasms. Uncommon osteosarcomas of the bone and neoplasms of the subcutaneous tissue were observed in dosed male rats. Incidences of interstitial cell adenomas of the testis and neoplasms of the preputial gland were decreased in the 2,500-ppm group of male rats. There was no evidence of carcinogenic activity of nitrofurantoin for female F344/N rats fed diets containing 600 ppm or 1,300 ppm for 2 years. Female rats may have been able to tolerate higher doses. There was no evidence of carcinogenic activity of nitrofurantoin for male B6C3F(1) mice fed diets containing 1,300 ppm or 2,500 ppm for 2 years. There was clear evidence of carcinogenic activity of nitrofurantoin for female B6C3F(1) mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary.

  3. Development of a sensitive LC-MS/MS method for the determination of bilobalide in rat plasma with special consideration of ex vivo bilobalide stability: application to a preclinical pharmacokinetic study.

    PubMed

    Wang, Jie; Ouyang, Jingping; Liu, Youping; Jia, Xian; You, Song; He, Xin; Di, Xin

    2014-07-01

    The ex vivo instability of bilobalide containing three ?-lactone rings has been paid less attention by researchers who developed bioanalytical methods for bilobalide. In the present study, a sensitive LC-MS/MS method for the determination of bilobalide in rat plasma was developed with special consideration of ex vivo bilobalide stability. Several important factors affecting the stability of bilobalide in sampling and handling procedures were investigated. To prevent the ex vivo degradation of bilobalide, EDTA instead of heparin was used as an anticoagulant as well as an esterase inhibitor for blood collection and the separation of plasma was performed at 4 °C. 20 ?L of plasma sample was acidified with 0.1 M hydrochloric acid, and then extracted with ethyl ether-methylene chloride (2:1, v/v). The extract was chromatographed on a Thermo Hypersil GOLD (100 mm × 2.1 mm, 5 ?m) column using acetonitrile-10mM ammonium acetate-formic acid (90:10:0.4, v/v/v) as the mobile phase. The analyte and the internal standard (ginkgolide B) were detected by selected reaction monitoring mode via negative electrospray ionization. The method was fully validated and proved to be linear over a concentration range of 5.0-5000 ng/mL. The intra- and inter-day precisions were less than 5.2% and the accuracy was within 92.5-101%. The extraction recoveries ranged from 80.7% to 86.7%. The proposed method was successfully applied to a preclinical pharmacokinetic study of bilobalide in rats after intragastric administration of a single dose of bilobalide at 7, 14 and 28 mg/kg. PMID:24704454

  4. Bone cement with reduced proportion of monomer in total hip arthroplasty: Preclinical evaluation and randomized study of 47 cases with 5 years' follow-up

    Microsoft Academic Search

    Bo Nivbrant; Johan Kärrholm; Stefan Röhrl; Helén Hassander; Bengt Wesslén

    2001-01-01

    Bone cement with reduced amount of monomer and low curing temperature may improve implant fixation due to reduced toxicity. We analyzed the mechanical, chemical and thermal properties of such a cement (Cemex Rx) using Palacos R as control. The in vivo performance of the 2 cements was also evaluated in a prospective randomized study of 47 hips, where either of

  5. ACToR A Aggregated Computational Toxicology Resource

    EPA Science Inventory

    We are developing the ACToR system (Aggregated Computational Toxicology Resource) to serve as a repository for a variety of types of chemical, biological and toxicological data that can be used for predictive modeling of chemical toxicology....

  6. ACToR A Aggregated Computational Toxicology Resource (S)

    EPA Science Inventory

    We are developing the ACToR system (Aggregated Computational Toxicology Resource) to serve as a repository for a variety of types of chemical, biological and toxicological data that can be used for predictive modeling of chemical toxicology....

  7. Toxicological evaluation of dry ice expanded tobacco.

    PubMed

    Theophilus, Eugenia H; Poindexter, Dale B; Meckley, Daniel R; Bombick, Betsy R; Borgerding, Michael F; Higuchi, Mark A; Ayres, Paul H; Morton, Michael J; Mosberg, Arnold T; Swauger, James E

    2003-11-30

    A tiered testing strategy has been developed to evaluate the potential of tobacco processes, ingredients, or technological developments to change the biological activity resulting from burning tobacco. The strategy is based on comparative chemical and biological testing. Dry ice expanded tobacco (DIET) is an example of a common tobacco expansion process currently used in the manufacture of cigarettes to increase tobacco filling capacity. As part of the toxicological evaluation of DIET, test cigarettes containing DIET were compared with control cigarettes containing tobacco expanded with a traditional expansion agent (Freon-11, also known as trichlorofluoromethane). Testing included mainstream cigarette smoke chemistry studies, genotoxicity studies (Ames and sister chromatid exchange, SCE), a 13-week inhalation study in Sprague-Dawley rats, and a 30-week dermal tumor promotion study in SENCAR mice. Cigarettes containing DIET or Freon-11 expanded tobacco were similar in biological activity. PMID:14581163

  8. 3D laser optoacoustic ultrasonic imaging system for preclinical research

    NASA Astrophysics Data System (ADS)

    Ermilov, Sergey A.; Conjusteau, André; Hernandez, Travis; Su, Richard; Nadvoretskiy, Vyacheslav; Tsyboulski, Dmitri; Anis, Fatima; Anastasio, Mark A.; Oraevsky, Alexander A.

    2013-03-01

    In this work, we introduce a novel three-dimensional imaging system for in vivo high-resolution anatomical and functional whole-body visualization of small animal models developed for preclinical or other type of biomedical research. The system (LOUIS-3DM) combines a multi-wavelength optoacoustic and ultrawide-band laser ultrasound tomographies to obtain coregistered maps of tissue optical absorption and acoustic properties, displayed within the skin outline of the studied animal. The most promising applications of the LOUIS-3DM include 3D angiography, cancer research, and longitudinal studies of biological distribution of optoacoustic contrast agents (carbon nanotubes, metal plasmonic nanoparticles, etc.).

  9. Murine toxicology and pharmacokinetics evaluation of Retinoic Acid Metabolism Blocking Agent (RAMBA), VN/12-1

    PubMed Central

    Godbole, Abhijit M.; Purushottamachar, Puranik; Martin, Marlena S.; Njar, Vincent C. O.

    2012-01-01

    Purpose Novel retinoic acid metabolism blocking agent (RAMBA), VN/12-1, is a highly potent anti-cancer agent which induces autophagy. Its combination with autophagy inhibitor chloroquine (CHL) has been shown to synergistically enhance apoptosis in breast cancer cells. The purpose of this study was to determine the toxicity and pharmacokinetic profile of VN/12-1 and its combination with CHL. Methods Preliminary toxicology of VN/12-1 was determined using female SCID mice (n=4 for each group). ATRA was used for comparison. We selected four different doses of VN/12-1 and ATRA. Two of the doses were low and less frequent (2.5 and 5 mg/kg twice a week) and the remaining doses were high and more frequent (10 and 20 mg/kg every day). The dose of CHL was 50 mg/kg twice a week. For pharmacokinetic (PK) study, 20 mg/kg of VN/12-1 was injected subcutaneously (s.c.) into the mice and their plasma was collected at various intervals (n=2) and analyzed by HPLC. Results The lower and less frequent doses of VN/12-1 and ATRA were found to be least toxic. However, high and more frequent doses of these compounds were toxic to the mice. PK results showed that VN/12-1 has a half-life of 6 hours. The area under the curve (AUC) for VN/12-1 was 83.78 hr*?g/ml. Conclusions VN/12-1 and ATRA are non-toxic when used as 5 mg/kg twice a week as single agents or in combination with CHL. The favorable PK properties of VN/12-1 can potentially be used for its further advanced pre-clinical and clinical development. PMID:22580781

  10. Noninvasive Multimodality Imaging of the Tumor Microenvironment: Registered Dynamic Magnetic Resonance Imaging and Positron Emission Tomography Studies of a Preclinical Tumor Model of Tumor Hypoxia12

    PubMed Central

    Cho, HyungJoon; Ackerstaff, Ellen; Carlin, Sean; Lupu, Mihaela E; Wang, Ya; Rizwan, Asif; O'Donoghue, Joseph; Ling, C Clifton; Humm, John L; Zanzonico, Pat B; Koutcher, Jason A

    2009-01-01

    In vivo knowledge of the spatial distribution of viable, necrotic, and hypoxic areas can provide prognostic information about the risk of developing metastases and regional radiation sensitivity and may be used potentially for localized dose escalation in radiation treatment. In this study, multimodality in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging using stereotactic fiduciary markers in the Dunning R3327-AT prostate tumor were performed, focusing on the relationship between dynamic contrast-enhanced (DCE) MRI using Magnevist (Gd-DTPA) and dynamic 18F-fluoromisonidazole (18F-Fmiso) PET. The noninvasive measurements were verified using tumor tissue sections stained for hematoxylin/eosin and pimonidazole. To further validate the relationship between 18F-Fmiso and pimonidazole uptake, 18F digital autoradiography was performed on a selected tumor and compared with the corresponding pimonidazole-stained slices. The comparison of Akep values (kep = rate constant of movement of Gd-DTPA between the interstitial space and plasma and A = amplitude in the two-compartment model (Hoffmann U, Brix G, Knopp MV, Hess T and Lorenz WJ (1995). Magn Reson Med 33, 506–514) derived from DCE-MRI studies and from early 18F-Fmiso uptake PET studies showed that tumor vasculature is a major determinant of early 18F-Fmiso uptake. A negative correlation between the spatial map of Akep and the slope map of late (last 1 hour of the dynamic PET scan) 18F-Fmiso uptake was observed. The relationships between DCE-MRI and hematoxylin/eosin slices and between 18F-Fmiso PET and pimonidazole slices confirm the validity of MRI/PET measurements to image the tumor microenvironment and to identify regions of tumor necrosis, hypoxia, and well-perfused tissue. PMID:19242606

  11. Noninvasive multimodality imaging of the tumor microenvironment: registered dynamic magnetic resonance imaging and positron emission tomography studies of a preclinical tumor model of tumor hypoxia.

    PubMed

    Cho, HyungJoon; Ackerstaff, Ellen; Carlin, Sean; Lupu, Mihaela E; Wang, Ya; Rizwan, Asif; O'Donoghue, Joseph; Ling, C Clifton; Humm, John L; Zanzonico, Pat B; Koutcher, Jason A

    2009-03-01

    In vivo knowledge of the spatial distribution of viable, necrotic, and hypoxic areas can provide prognostic information about the risk of developing metastases and regional radiation sensitivity and may be used potentially for localized dose escalation in radiation treatment. In this study, multimodality in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging using stereotactic fiduciary markers in the Dunning R3327-AT prostate tumor were performed, focusing on the relationship between dynamic contrast-enhanced (DCE) MRI using Magnevist (Gd-DTPA) and dynamic (18)F-fluoromisonidazole ((18)F-Fmiso) PET. The noninvasive measurements were verified using tumor tissue sections stained for hematoxylin/eosin and pimonidazole. To further validate the relationship between (18)F-Fmiso and pimonidazole uptake, (18)F digital autoradiography was performed on a selected tumor and compared with the corresponding pimonidazole-stained slices. The comparison of Akep values (kep = rate constant of movement of Gd-DTPA between the interstitial space and plasma and A = amplitude in the two-compartment model (Hoffmann U, Brix G, Knopp MV, Hess T and Lorenz WJ (1995). Magn Reson Med 33, 506-514) derived from DCE-MRI studies and from early (18)F-Fmiso uptake PET studies showed that tumor vasculature is a major determinant of early (18)F-Fmiso uptake. A negative correlation between the spatial map of Akep and the slope map of late (last 1 hour of the dynamic PET scan) (18)F-Fmiso uptake was observed. The relationships between DCE-MRI and hematoxylin/eosin slices and between (18)F-Fmiso PET and pimonidazole slices confirm the validity of MRI/PET measurements to image the tumor microenvironment and to identify regions of tumor necrosis, hypoxia, and well-perfused tissue. PMID:19242606

  12. Preclinical Evaluation of the Novel, Orally Bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Spontaneous Canine Cancer: Results of a Phase I Study

    PubMed Central

    London, Cheryl A.; Bernabe, Luis Feo; Barnard, Sandra; Kisseberth, William C.; Borgatti, Antonella; Henson, Mike; Wilson, Heather; Jensen, Kiersten; Ito, Daisuke; Modiano, Jaime F.; Bear, Misty D.; Pennell, Michael L.; Saint-Martin, Jean-Richard; McCauley, Dilara; Kauffman, Michael; Shacham, Sharon

    2014-01-01

    Background The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. Methods and Findings Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2–42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n?=?2) and stable disease (SD, n?=?7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35–256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35–354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. Conclusions This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer. PMID:24503695

  13. Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [ 18F]FPS

    Microsoft Academic Search

    Rikki N Waterhouse; Michael G Stabin; John G Page

    2003-01-01

    [18F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([18F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [18F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [18F]FPS

  14. Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.

    PubMed

    Hau, Peter; Jachimczak, Piotr; Schlingensiepen, Reimar; Schulmeyer, Frank; Jauch, Tanya; Steinbrecher, Andreas; Brawanski, Alexander; Proescholdt, Martin; Schlaier, Jürgen; Buchroithner, Johanna; Pichler, Josef; Wurm, Gabriele; Mehdorn, Maximilian; Strege, Rainer; Schuierer, Gerhard; Villarrubia, Victoria; Fellner, Franz; Jansen, Olav; Straube, Thorsten; Nohria, Virinder; Goldbrunner, Michael; Kunst, Mechthild; Schmaus, Susanne; Stauder, Gerhard; Bogdahn, Ulrich; Schlingensiepen, Karl-Hermann

    2007-01-01

    Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors. PMID:17638524

  15. Student perception about efficacy of preclinical fixed prosthodontic training to facilitate smooth transition to clinical context

    PubMed Central

    Haralur, Satheesh B.; Al-Malki, Abdullah Edrees

    2014-01-01

    Background: Studies indicate that the initial transition period between preclinical and clinical phases are the most stressful. The students have experienced the difficulty in performing clinical procedures due to the vast difference in the clinical and preclinical setup. It is better to identify the particular skill found poorly correlated, enabling educators to address the concerns. We sought the opinion and suggestion from the beneficiary student on fixed prosthodontics steps difficult to practice in clinical setup at the initial stage, their suggestion to overcome these shortcomings was also sought. Aims: To determine the fixed prosthodontics skills difficult to perform in a transition period due to poor correlation between preclinical and clinical training from our focus group study on the student's perception, and their suggestion regarding alternative methods to improve the preclinical training. Materials and Methods: Focus groups in the study were the students involved in clinical practice of fixed partial denture procedure. A well-constructed Questionnaire, designed to evaluate the difficult clinical steps in a transitional period and suggestion to improve the existing preclinical training was distributed to all focus group students. The response to the questionnaire was based on the five-point Likert scale. Statistical Analysis Used: Medians, frequencies were used to assess their perception on preclinical training and suggestion. Results: A total of 97 students participated in the study, 88% response received during the survey. The clinical steps student felt difficult during a transition period from preclinical to clinical phase were positional variations of teeth (52.6%-63.9%), fluid control (48.5-67.1%), shade selection procedure (29.9%-50.5%), subgingival cervical finish line preparation (38.1-51.5%), and gingival retraction procedure. The students felt that the inclusion of problem-based learning, preclinical patient exposure, and better simulation will alleviate the stress during the transition period. Conclusions: This study highlighted the tooth preparation steps found difficult to practice in a transition period between preclinical and clinical phases. This study also obtained suggestions from the students for innovative upgradation of the course curricula. PMID:25077166

  16. Feasibility and optimal dosage of indocyanine green fluorescence for sentinel lymph node detection using robotic single-site instrumentation: preclinical study.

    PubMed

    Levinson, Kimberly L; Mahdi, Haider; Escobar, Pedro F

    2013-01-01

    The present study was performed to determine the optimal dosage of indocyanine green (ICG) to accurately differentiate the sentinel node from surrounding tissue and then to test this dosage using novel single-port robotic instrumentation. The study was performed in healthy female pigs. After induction of anesthesia, all pigs underwent exploratory laparotomy, dissection of the bladder, and colpotomy to reveal the cervical os. With use of a 21-gauge needle, 0.5 mL normal saline solution was injected at the 3- and 9-o'clock positions as control. Four concentrations of ICG were constituted for doses of 1000, 500, 250, and 175 ?g per 0.5 mL. ICG was then injected at the 3- and 9-o'clock positions on the cervix. The SPY camera was used to track ICG into the sentinel nodes and to quantify the intensity of light emitted. SPY technology uses an intensity scale of 1 to 256; this scale was used to determine the difference in intensity between the sentinel node and surrounding tissues. The optimal dosage was tested using single-port robotic instrumentation with the same injection techniques. A sentinel node was identified at all doses except 175 ?g, at which ICG stayed in the cervix and vasculature only. For both the 500- and 250-?g doses, the sentinel node was identified before reaching maximum intensity. At maximum intensity, the difference between the surrounding tissue and the node was 207 (251 vs 44) for the 500-?g dose and 159 (251 vs 92) for the 250-?g dose. Sentinel lymph node (SLN) biopsy was successfully performed using single-port robotic technology with both the 250- and 500-?g doses. For SLN detection, the dose of ICG is related to the ability to differentiate the sentinel node from the surrounding tissue. An ICG dose of 250 to 500 ?g enables identification of a SLN with more distinction from the surrounding tissues, and this procedure is feasible using single-port robotics instrumentation. PMID:24034538

  17. Differential responses to JNJ-37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague-Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics.

    PubMed

    de Waal, Eric J; Desmidt, Maria; Korte, Sven; Niehoff, Marc; Chase, Kevan; Arrowsmith, Wayne; Lampo, Ann

    2014-09-01

    JNJ-37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague-Dawley rats. The maximum duration of treatment was 9 and 6?months, respectively. Interspecies differences were noted in the response to JNJ-37822681 in terms of extrapyramidal (EPS)-like clinical signs and prolactin-mediated tissue changes in the mammary gland. Monkeys showed severe EPS-like clinical signs such as abnormal posture, abnormal eye movements and hallucination-like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ-37822681-induced EPS-like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin-related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ-37822681. The monkey toxicology studies did not provide an exposure-based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ-37822681-associated adverse events in humans than the Sprague-Dawley rat. PMID:24105799

  18. Preclinical Pharmacokinetic Studies of the Tritium Labelled D-Enantiomeric Peptide D3 Developed for the Treatment of Alzheimer´s Disease

    PubMed Central

    Jiang, Nan; Leithold, Leonie H. E.; Post, Julia; Ziehm, Tamar; Mauler, Jörg; Gremer, Lothar; Cremer, Markus; Schartmann, Elena; Shah, N. Jon; Kutzsche, Janine; Langen, Karl-Josef; Breitkreutz, Jörg; Willbold, Dieter; Willuweit, Antje

    2015-01-01

    Targeting toxic amyloid beta (A?) oligomers is currently a very attractive drug development strategy for treatment of Alzheimer´s disease. Using mirror-image phage display against A?1-42, we have previously identified the fully D-enantiomeric peptide D3, which is able to eliminate A? oligomers and has proven therapeutic potential in transgenic Alzheimer´s disease animal models. However, there is little information on the pharmacokinetic behaviour of D-enantiomeric peptides in general. Therefore, we conducted experiments with the tritium labelled D-peptide D3 (3H-D3) in mice with different administration routes to study its distribution in liver, kidney, brain, plasma and gastrointestinal tract, as well as its bioavailability by i.p. and p.o. administration. In addition, we investigated the metabolic stability in liver microsomes, mouse plasma, brain, liver and kidney homogenates, and estimated the plasma protein binding. Based on its high stability and long biological half-life, our pharmacokinetic results support the therapeutic potential of D-peptides in general, with D3 being a new promising drug candidate for Alzheimer´s disease treatment. PMID:26046986

  19. Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain--a primate study.

    PubMed

    Hynynen, Kullervo; McDannold, Nathan; Clement, Greg; Jolesz, Ferenc A; Zadicario, Eyal; Killiany, Ron; Moore, Tara; Rosen, Douglas

    2006-08-01

    MRI-guided and monitored focused ultrasound thermal surgery of brain through intact skull was tested in three rhesus monkeys. The aim of this study was to determine the amount of skull heating in an animal model with a head shape similar to that of a human. The ultrasound beam was generated by a 512 channel phased array system (Exablate 3000, InSightec, Haifa, Israel) that was integrated within a 1.5-T MR-scanner. The skin was pre-cooled by degassed temperature controlled water circulating between the array surface and the skin. Skull surface temperature was measured with invasive thermocouple probes. The results showed that by applying surface cooling the skin and skull surface can be protected, and that the brain surface temperature becomes the limiting factor. The MRI thermometry was shown to be useful in detecting the tissue temperature distribution next to the bone, and it should be used to monitor the brain surface temperature. The acoustic intensity values during the 20 s sonications were adequate for thermal ablation in the human brain provided that surface cooling is used. PMID:16716552

  20. Determination of pterostilbene in rat plasma by a simple HPLC-UV method and its application in pre-clinical pharmacokinetic study.

    PubMed

    Lin, Hai-Shu; Yue, Bing-De; Ho, Paul C

    2009-12-01

    A simple HPLC-UV method was developed and validated for the quantification of pterostilbene (3,5-dimethoxy-4'-hydroxy-trans-stilbene), a pharmacologically active phytoalexin in rat plasma. The assay was carried out by measuring the UV absorbance at 320 nm. Pterostilbene and the internal standard, 3,5,4'-trimethoxy-trans-stilbene eluted at 5.7 and 9.2 min, respectively. The calibration curve (20-2000 ng/mL) was linear (R(2)> 0.997). The lower limits of detection and of quantification were 6.7 and 20 ng/mL, respectively. The intra- and inter-day precisions in terms of RSD were all lower than 6%. The analytical recovery ranged from 95.5 +/- 3.7 to 103.2 +/- 0.7% while the absolute recovery ranged from 101.9 +/- 1.1 to 104.9 +/- 4.4%. This simple HPLC method was subsequently applied in a pharmacokinetic study carried out in Sprague-Dawley rats. The terminal elimination half-life and clearance of pterostilbene were 96.6 +/- 23.7 min and 37.0 +/- 2.5 mL/min/kg, respectively, while its absolute oral bioavailability was 12.5 +/- 4.7%. Pterostilbene appeared to have better pharmacokinetic characteristics than its natural occurring analog, resveratrol. PMID:19488981

  1. Preclinical Studies of Amixicile, a Systemic Therapeutic Developed for Treatment of Clostridium difficile Infections That Also Shows Efficacy against Helicobacter pylori

    PubMed Central

    Bruce, Alexandra M.; Olekhnovich, Igor; Warren, Cirle A.; Burgess, Stacey L.; Hontecillas, Raquel; Viladomiu, Monica; Bassaganya-Riera, Josep; Guerrant, Richard L.; Macdonald, Timothy L.

    2014-01-01

    Amixicile shows efficacy in the treatment of Clostridium difficile infections (CDI) in a mouse model, with no recurrence of CDI. Since amixicile selectively inhibits the action of a B vitamin (thiamine pyrophosphate) cofactor of pyruvate:ferredoxin oxidoreductase (PFOR), it may both escape mutation-based drug resistance and spare beneficial probiotic gut bacteria that do not express this enzyme. Amixicile is a water-soluble derivative of nitazoxanide (NTZ), an antiparasitic therapeutic that also shows efficacy against CDI in humans. In comparative studies, amixicile showed no toxicity to hepatocytes at 200 ?M (NTZ was toxic above 10 ?M); was not metabolized by human, dog, or rat liver microsomes; showed equivalence or superiority to NTZ in cytochrome P450 assays; and did not activate efflux pumps (breast cancer resistance protein, P glycoprotein). A maximum dose (300 mg/kg) of amixicile given by the oral or intraperitoneal route was well tolerated by mice and rats. Plasma exposure (rats) based on the area under the plasma concentration-time curve was 79.3 h · ?g/ml (30 mg/kg dose) to 328 h · ?g/ml (100 mg/kg dose), the maximum concentration of the drug in serum was 20 ?g/ml, the time to the maximum concentration of the drug in serum was 0.5 to 1 h, and the half-life was 5.6 h. Amixicile did not concentrate in mouse feces or adversely affect gut populations of Bacteroides species, Firmicutes, segmented filamentous bacteria, or Lactobacillus species. Systemic bioavailability was demonstrated through eradication of Helicobacter pylori in a mouse infection model. In summary, the efficacy of amixicile in treating CDI and other infections, together with low toxicity, an absence of mutation-based drug resistance, and excellent drug metabolism and pharmacokinetic metrics, suggests a potential for broad application in the treatment of infections caused by PFOR-expressing microbial pathogens in addition to CDI. PMID:24890599

  2. Hands-On Defibrillation Has the Potential to Improve the Quality of Cardiopulmonary Resuscitation and Is Safe for Rescuers—A Preclinical Study

    PubMed Central

    Neumann, Tobias; Gruenewald, Matthias; Lauenstein, Christoph; Drews, Tobias; Iden, Timo; Meybohm, Patrick

    2012-01-01

    Background Recently, it has been demonstrated that rescuers could safely provide a low, static downward force in direct contact with patients during elective cardioversion. The purpose of our experimental study was to investigate whether shock delivery during uninterrupted chest compressions may have an impact on cardiopulmonary resuscitation (CPR) quality and can be safely performed in a realistic animal model of CPR. Methods and Results Twenty anesthetized swine were subjected to 7 minutes of ventricular fibrillation followed by CPR according to the 2010 American Heart Association Guidelines. Pregelled self-adhesive defibrillation electrodes were attached onto the torso in the ventrodorsal direction and connected to a biphasic defibrillator. Animals were randomized either to (1) hands-on defibrillation, where rescuers wore 2 pairs of polyethylene gloves and shocks were delivered during ongoing chest compressions, or (2) hands-off defibrillation, where hands were taken off during defibrillation. CPR was successful in 9 out of 10 animals in the hands-on group (versus 8 out of 10 animals in the hands-off group; not significant). In the hands-on group, chest compressions were interrupted for 0.8% [0.6%; 1.4%] of the total CPR time (versus 8.2% [4.2%; 9.0%]; P=0.0003), and coronary perfusion pressure was earlier restored to its pre-interruption level (P=0.0205). Also, rescuers neither sensed any kind of electric stimulus nor did Holter ECG reveal any serious cardiac arrhythmia. Conclusions Hands-on defibrillation may improve CPR quality and could be safely performed during uninterrupted chest compressions in our standardized porcine model. PMID:23316286

  3. Identification and characterization of psoralen and isopsoralen as potent CYP1A2 reversible and time-dependent inhibitors in human and rat preclinical studies.

    PubMed

    Zhuang, Xiao-Mei; Zhong, Yu-Huan; Xiao, Wei-Bin; Li, Hua; Lu, Chuang

    2013-11-01

    Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC(50), k(inact), and K(I) values were 10.4 ± 1.4 ?M, 0.060 ± 0.002 min(-1), and 1.13 ± 0.12 ?M for PRN, and 7.1 ± 0.6 ?M, 0.10 ± 0.01 min(-1), and 1.95 ± 0.31 ?M for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC(50) values of 0.26 ± 0.01 ?M and 0.22 ± 0.03 ?M for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with kinact and KI values of 0.050 ± 0.002 min(-1) and 0.40 ± 0.06 ?M, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71- and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24- and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN. PMID:23975028

  4. The Toxicology Education Summit: Building the Future of Toxicology Through Education

    PubMed Central

    Barchowsky, Aaron; Buckley, Lorrene A.; Carlson, Gary P.; Fitsanakis, Vanessa A.; Ford, Sue M.; Genter, Mary Beth; Germolec, Dori R.; Leavens, Teresa L.; Lehman-McKeeman, Lois D.; Safe, Stephen H.; Sulentic, Courtney E. W.; Eidemiller, Betty J.

    2012-01-01

    Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the “Total Toxicologist”; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives. PMID:22461448

  5. Preclinical study of the systemic toxicity and pharmacokinetics of 5-iodo-2-deoxypyrimidinone-2'-deoxyribose as a radiosensitizing prodrug in two, non-rodent animal species: implications for phase I study design.

    PubMed

    Kinsella, T J; Schupp, J E; Davis, T W; Berry, S E; Hwang, H S; Warren, K; Balis, F; Barnett, J; Sands, H

    2000-09-01

    We have demonstrated previously an improved therapeutic index for oral 5-iodo-2-deoxypyrimidinone-2'-deoxyribose (IPdR) compared with oral and continuous infusion of 5-iodo-2'-deoxyuridine (IUdR) as a radiosensitizing agent using three different human tumor xenografts in athymic mice. IPdR is a prodrug that is efficiently converted to IUdR by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for > or =1 h after p.o. IPdR. Athymic mice tolerated oral IPdR at up to 1500 mg/kg/day given four times per day for 6-14 days without significant systemic toxicities. In anticipation of an investigational new drug application for the first clinical Phase I and pharmacology study of oral IPdR in humans, we studied the drug pharmacokinetics and host toxicities in two non-rodent, animal species. For the IPdR systemic toxicity and toxicology study, twenty-four male or female ferrets were randomly assigned to four IPdR dosage groups receiving 0, 15, 150, and 1500 mg/kg/day by oral gavage x 14 days prior to sacrifice on study day 15. All ferrets survived the 14-day treatment. Ferrets receiving 1500 mg/kg/day showed observable systemic toxicities with diarrhea, emesis, weight loss, and decreased motor activity beginning at days 5-8 of the 14-day schedule. Overall, both male and female ferrets receiving IPdR at 1500 mg/kg/day experienced significant weight loss (9 and 19%, respectively) compared with controls after the 14-day treatment. No weight loss or other systemic toxicities were observed in other IPdR dosage groups. Grossly, no anatomical lesions were noted at complete necropsy, although liver weights were increased in both male and female ferrets in the two higher IPdR dosage groups. Histologically, IPdR-treated animals showed dose-dependent microscopic changes in liver consisting of minimal to moderate cytoplasmic vacuolation of hepatocytes, which either occurred in the periportal area (high dosage group) or diffusely throughout the liver (lower dosage groups). Female ferrets in the highest IPdR dose group also showed decreased kidney and uterus weights at autopsy without any associated histological changes. No histological changes were found in central nervous system tissues. No significant abnormalities in blood cell counts, liver function tests, kidney function tests, or urinalysis were noted. Hepatic aldehyde oxidase activity was decreased to approximately 50 and 30% of control ferrets in the two higher IPdR dosage groups, respectively, after the 14-day treatment period. The % IUdR-DNA incorporation in ferret bone marrow at the completion of IPdR treatment was < or =0.05% in the two lower dosage groups and approximately 2% in the 1500 mg/kg/day dosage group. The % IUdR-DNA in normal liver was < or =0.05% in all IPdR dosage groups. In a pharmacokinetic study in four Rhesus monkeys, we determined the plasma concentrations of IPdR after a single i.v. bolus of 50 mg/kg over 20 min. Using a two-compartment model to fit the plasma pharmacokinetic data, we found that IPdR was cleared in these non-human primates in a biexponential manner with an initial rapid distributive phase (mean T1/2alpha = 6.5 min), followed by an elimination phase with a mean T1/2 of 63 min. The mean maximum plasma concentration of IPdR was 124+/-43 microM with a mean total body clearance of 1.75+/-0.95 l/h/kg. IPdR was below detection (<0.5 microM) in the cerebrospinal fluid. We conclude that there are dose-limiting systemic toxicities to a 14-day schedule of p.o. IPdR at 1500 mg/kg/day in ferrets that were not found previously in athymic mice. However, no significant hematological, biochemical, or histopathological changes were found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent in ferret liver, suggesting partial enzyme saturation by this IPdR schedule. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance is similar to our published data in athymic mice. These data are being applied PMID:10999760

  6. Electronic cigarettes in the USA: a summary of available toxicology data and suggestions for the future

    PubMed Central

    Orr, Michael S

    2014-01-01

    Objective To review the available evidence evaluating the toxicological profiles of electronic cigarettes (e-cigarettes) in order to understand the potential impact of e-cigarettes on individual users and the public health. Methods Systematic literature searches were conducted between October 2012 and October 2013 using five electronic databases. Search terms such as ‘e-cigarettes’ and ‘electronic delivery devices’ were used to identify the toxicology information for e-cigarettes. Results As of October 2013, the scientific literature contains very limited information regarding the toxicity of e-cigarettes commercially available in the USA. While some preliminary toxicology data suggests that e-cigarette users are exposed to lower levels of toxicants relative to cigarette smokers, the data available is extremely limited at this time. At present, there is insufficient toxicological data available to perform thorough risk assessment analyses for e-cigarettes; few toxicology studies evaluating e-cigarettes have been conducted to date, and standard toxicological testing paradigms have not been developed for comparing disparate types of tobacco products such as e-cigarettes and traditional cigarettes. Conclusions Overall, the limited toxicology data on e-cigarettes in the public domain is insufficient to allow a thorough toxicological evaluation of this new type of tobacco product. In the future, the acquisition of scientific datasets that are derived from scientifically robust standard testing paradigms, include comprehensive chemical characterisation of the aerosol, provide information on users’ toxicant exposure levels, and from studies replicated by independent researchers will improve the scientific community's ability to perform robust toxicological evaluations of e-cigarettes. PMID:24732158

  7. 76 FR 10906 - Proposed Substances To Be Evaluated for Set 25 Toxicological Profiles

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-28

    ...OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [ATSDR-269...Toxicological Profiles AGENCY: Agency for Toxic Substances and Disease Registry (ATSDR...and studies on the health effects of toxic substances'' under CERCLA Section...

  8. Physicochemical comparison of commercially available metal oxide nanoparticles: implications for engineered nanoparticle toxicology and risk assessment

    EPA Science Inventory

    Accurate and affordable physicochemical characterization of commercial engineered nanomaterials is required for toxicology studies to ultimately determine nanomaterial: hazard identification; dose to response metric(s); and mechanism(s) of injury. A minimal physical and chemica...

  9. Intestinal structure and function related to toxicology.

    PubMed Central

    Crane, R K

    1979-01-01

    The study of toxic effects on small intestinal function is complicated by the integration of the activity of the small intestine with the activities of other regions of the GI tract. Also, the barrier and portal functions of the intestine are not as clearly defined as sometimes assumed. The intestinal surface functions as a barrier to the ingress of large quantities of large water soluble molecules. Lipidic substances enter the body quite readily as do small water-soluble molecules. The small intestinal surface is more a portal than a barrier, with its portal functions divided between nonspecific diffusional entry, which depends on physical properties and electric charge, and entry by specific membrane transport, which depends upon chemical structure. The implications of these properties of the small intestine for toxicological studies are stressed. PMID:540622

  10. The inhalation toxicology of p-aramid fibrils.

    PubMed

    Donaldson, Ken

    2009-01-01

    The pandemic of lung disease caused by asbestos has cast suspicion on any industrial fibrous material that can become airborne in respirable form in workplaces, such that the respirable fibres might be inhaled. Fibre toxicology arose as a sub-specialty of particle toxicology to address the specialised nature of fibre effects and has evolved substantially in the last 25 years. It has yielded valuable information on the dosimetry, structure-activity relationships, and mechanism involved in toxicological effects of a range of fibrous materials, including asbestos, other naturally occurring fibrous materials, and synthetic vitreous fibres. A robust structure/activity paradigm has emerged from this research that highlights fibre length, thinness, and biopersistence as major factors in determining the pathogenicity of a fibre. p-Aramid is a manufactured fibre composed of synthetic polyamide (poly paraphenylene terephthalamide) manufactured on a commercial scale since 1970 by polymerisation and spinning steps. It is used as an advanced composite and in fabrics, body armour, friction materials, etc. Respirable fibrils of p-aramid can be released from the fibres during working and can become airborne. A considerable body of research has been carried out into the hazard posed by inhaled p-aramid fibrils, and this review considers this body of literature and summarises the state-of-the-science in the toxicology of p-aramid fibrils in the light of the existing overarching fibre toxicology paradigm. The peer-reviewed studies demonstrate that p-aramid fibrils can be long and thin but that the fibrils are not biopersistent. Residence in the milieu of the lungs leads to fibre shortening, allowing efficient and complete phagocytosis and effective clearance. Subsequently the p-aramid hazard is low, and this is confirmed in animal studies. The mechanism of shortening of p-aramid fibrils is not well-understood, but may involve the action of macrophages on the fibrils following phagocytosis. PMID:19545198

  11. TOXICOLOGY OF COMPLEX MIXTURES OF INDOOR AIR

    EPA Science Inventory

    This review focuses on strategies for assessing the toxicology of indoor air pollutant mixtures. hese strategies are illustrated by reviewing the current problems and approaches to the toxicology of indoor air pollutants from three indoor source categories which make a major cont...

  12. Proceedings of aquatic toxicology and hazard assessment

    Microsoft Academic Search

    Cowgill

    1989-01-01

    This book contains the proceeding of Aquatic toxicology and hazard assessment. During the past twelve year, the aquatic toxicology group (Subcommittee E47.01) of ASTM has sponsored an annual symposium for the major purpose of bring together aquatic specialists from industry, government, and academe. The end result of these gatherings has been a debate on the merits of test development, animal

  13. From alternative methods to a new toxicology

    Microsoft Academic Search

    Thomas Hartung

    2011-01-01

    Mechanistic toxicology has evolved by relying, to a large extent, on methodologies that substitute or complement traditional animal tests. The biotechnology and informatics revolutions of the last decades have made such technologies broadly available and useful, but regulatory toxicology has been slow to embrace these new approaches. Major validation efforts, however, have delivered the evidence that new approaches do not

  14. Preclinical Efficacy Testing in Middle-Aged Rats: Nicotinamide, a Novel Neuroprotectant, Demonstrates Diminished Preclinical Efficacy after Controlled Cortical Impact

    PubMed Central

    Swan, Alicia A.; Chandrashekar, Rupa; Beare, Jason

    2011-01-01

    Abstract Age is a consistent predictor of poor outcome following traumatic brain injury (TBI). Although the elderly population has one of the highest rates of TBI-related hospitalization and death, few preclinical studies have attempted to model and treat TBI in the aged population. Recent studies have indicated that nicotinamide (NAM), a soluble B-group vitamin, improved functional recovery in experimental models of TBI in young animals. The purpose of the present study was to examine the preclinical efficacy of NAM in middle-aged rats. Groups of middle-aged (14-month-old) rats were assigned to NAM (500?mg/kg or 50?mg/kg) or saline alone (1?mL/kg) treatment conditions, and received unilateral cortical contusion injuries (CCI) and injections at 1?h and 24?h following injury. The animals were tested on a variety of tasks to assess vestibulomotor (tapered beam) and cognitive performance (reference and working memory in the Morris water maze), and were evaluated for lesion size, blood–brain barrier compromise, astrocytic activation, and edema formation. In summary, the preclinical efficacy of NAM as a treatment following CCI in middle-aged rats differs from that previously documented in younger rats; while treatment with 50?mg/kg NAM appeared to have no effect, the 500-mg/kg dose worsened performance in middle-aged animals. Histological indicators demonstrated more nuanced group differences, indicating that NAM may positively impact some of the cellular cascades following injury, but were not substantial enough to improve functional recovery. These findings emphasize the need to examine potential treatments for TBI utilizing non-standard populations, and may explain why so many treatments have failed in clinical trials. PMID:21083416

  15. Environmental toxicology and risk assessment

    SciTech Connect

    Landis, W.G. (ed.) (Western Washington Univ., Bellingham, WA (United States). Huxley College of Environmental Studies); Hughes, J.S. (ed.) (Malcolm Pirnie, Inc., Chapel Hill, NC (United States)); Lewis, M.A. (ed.) (Environmental Protection Agency, Gulf Breeze, FL (United States))

    1993-01-01

    This symposium was held April 14--16, 1991 in Atlantic City, New Jersey. The purpose of this conference was to provide a forum for exchange of state-of-the-art information on environmental toxicology. A major theme in this volume is on ecological risk assessment. Topics focus on the following: ecological risk assessment under TSCA; evaluating ecological impacts at the population and community levels; biomarkers; marine toxicity and test methods; and methods development. Individual papers have been processed separately for inclusion in the appropriate data bases.

  16. [Neurodevelopmental theories of schizophrenia--preclinical studies].

    PubMed

    Lehner, Ma?gorzata; Taracha, Ewa; Wis?owska, Aleksandra; Zienowicz, Ma?gorzata; Maciejak, Piotr; Skórzewska, Anna; P?a?nik, Adam

    2003-01-01

    Schizophrenia is a complex disorder of unknown origin, characterised by abnormalities in the realms of perception, thinking and the experience of emotions that onset is restricted to young adulthood. Many techniques that range from neuropathology to neuroimaging identified subtle brain abnormalities particularly in frontal, temporal cortex, hippocampus, basal ganglia and cerebellum. Neurodevelopmental models of schizophrenia test hypotheses that this disease is caused by a defect in cerebral development which results in altered neural connectivity, brain neurochemistry and aberrant behaviour observed in adult life. Recent evidence indicates that neonatal hippocampal damage may affect prefrontal neuronal integrity. The developmental lesion model appears to have predictive validity because treatment with antipsychotic drugs normalises some abnormal behaviour changes. Therefore it will be a useful paradigm in the work on new therapies and in providing new insights about pathophysiology and etiology of schizophrenia. PMID:14560492

  17. Preclinical molecular imaging using PET and MRI.

    PubMed

    Wolf, Gunter; Abolmaali, Nasreddin

    2013-01-01

    Molecular imaging fundamentally changes the way we look at cancer. Imaging paradigms are now shifting away from classical morphological measures towards the assessment of functional, metabolic, cellular, and molecular information in vivo. Interdisciplinary driven developments of imaging methodology and probe molecules utilizing animal models of human cancers have enhanced our ability to non-invasively characterize neoplastic tissue and follow anti-cancer treatments. Preclinical molecular imaging offers a whole palette of excellent methodology to choose from. We will focus on positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques, since they provide excellent and complementary molecular imaging capabilities and bear high potential for clinical translation. Prerequisites and consequences of using animal models as surrogates of human cancers in preclinical molecular imaging are outlined. We present physical principles, values and limitations of PET and MRI as molecular imaging modalities and comment on their high potential to non-invasively assess information on hypoxia, angiogenesis, apoptosis, gene expression, metabolism, and cell trafficking in preclinical cancer research. PMID:23179885

  18. Mapping preclinical compensation in Parkinson's disease: an imaging genomics approach.

    PubMed

    van Nuenen, Bart F L; van Eimeren, Thilo; van der Vegt, Joyce P M; Buhmann, Carsten; Klein, Christine; Bloem, Bastiaan R; Siebner, Hartwig R

    2009-01-01

    Mutations in the Parkin (PARK2) and PINK1 gene (PARK 6) can cause recessively inherited Parkinson's disease (PD). The presence of a single Parkin or PINK1 mutation is associated with a dopaminergic nigrostriatal dysfunction and conveys an increased risk to develop PD throughout lifetime. Therefore neuroimaging of non-manifesting individuals with a mutant Parkin or PINK1 allele opens up a window for the investigation of preclinical and very early phases of PD in vivo. Here we review how functional magnetic resonance imaging (fMRI) can be used to identify compensatory mechanisms that help to prevent development of overt disease. In two separate experiments, Parkin mutation carriers displayed stronger activation of rostral supplementary motor area (SMA) and right dorsal premotor cortex (PMd) during a simple motor sequence task and anterior cingulate motor area and left rostral PMd during internal movement selection as opposed to externally cued movements. The additional recruitment of the rostral SMA and right rostral PMd during the finger sequence task was also observed in a separate group of nonmanifesting mutation carriers with a single heterozygous PINK1 mutation. Because mutation carriers were not impaired at performing the task, the additional recruitment of motor cortical areas indicates a compensatory mechanism that effectively counteracts the nigrostriatal dysfunction. These first results warrant further studies that use these imaging genomics approach to tap into preclinical compensation of PD. Extensions of this line of research involve fMRI paradigms probing nonmotor brain functions. Additionally, the same fMRI paradigms should be applied to nonmanifesting mutation carriers in genes linked to autosomal dominant PD. This will help to determine how "generically" the human brain compensates for a preclinical dopaminergic dysfunction. PMID:19877238

  19. 75 FR 64311 - National Toxicology Program (NTP); Office of Liaison, Policy and Review Meeting of the NTP Board...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-19

    ...toxicology, pharmacology, pathology, biochemistry, epidemiology, risk assessment, carcinogenesis, mutagenesis, molecular biology, behavioral toxicology, neurotoxicology, immunotoxicology, reproductive toxicology or teratology, and...

  20. 75 FR 12244 - National Toxicology Program (NTP); Office of Liaison, Policy and Review; Meeting of the NTP Board...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-15

    ...toxicology, pharmacology, pathology, biochemistry, epidemiology, risk assessment, carcinogenesis, mutagenesis, molecular biology, behavioral toxicology, neurotoxicology, immunotoxicology, reproductive toxicology or teratology, and...

  1. Pest toxicology: the primary mechanisms of pesticide action.

    PubMed

    Casida, John E

    2009-04-01

    Pesticides are used to control pests before they harm us or our crops. They are selective toxicants in the form and manner used. Pesticides must be effective without human or crop injury. They must also be safe relative to human and environmental toxicology. The study of how the pesticide works on the pest is referred to here as pest toxicology. About 700 pesticides, including insecticides, herbicides, and fungicides, act on perhaps 95 biochemical targets in pest insects, weeds, and destructive fungi. Current insecticides act primarily on four nerve targets, i.e., acetylcholinesterase, the voltage-gated chloride channel, the acetylcholine receptor, and the gamma-aminobutyric acid receptor, systems which are present in animals but not plants. Herbicides act mostly on plant specific pathways by blocking photosynthesis, carotenoid synthesis, or aromatic and branched chain amino acid synthesis essential in plants but not mammals. Many fungicides block ergosterol (the fungal sterol) or tubulin biosynthesis or cytochrome c reductase, while others disrupt basic cellular functions. A major limiting factor in the continuing use of almost all pesticides is the selection of strains not only resistant to the selecting or pressuring compounds but also cross-resistant to other pesticides acting at the same target. One approach to reinstating control is to shift from compounds with the resistant target site or mode of action to another set which have a sensitive target. This type of pesticide management led to the formation of Resistance Action Committees for insecticides, herbicides, and fungicides with very knowledgable experts to define resistance groups, which are in fact listings of primary target sites in pest toxicology. Continued success in pest and pesticide management requires an understanding of comparative biochemistry and molecular toxicology considering pests, people, and crops. Defining and applying the principles of pest toxicology are critical to food production and human health. PMID:19284791

  2. NTP technical report on the toxicology and carcinogenesis studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in female Harlan Sprague-Dawley rats (Gavage Studies).

    PubMed

    2006-04-01

    DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized, they accumulate in body tissue, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. TCDD is not manufactured commercially other than for scientific research purposes. The main sources of TCDD releases into the environment are from combustion and incineration; metal smelting, refining, and processing; chemical manufacturing and processing; biological and photochemical processes; and existing reservoir sources that reflect past releases. TCDD (dioxin) was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report, only the TCDD results are presented and discussed. TCDD was included because it is the reference compound for the dioxin TEF methodology. Female Harlan Sprague-Dawley rats were administered TCDD (at least 98% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. 2-YEAR STUDY: Groups of 81 or 82 female rats were administered 3, 10, 22, 46, or 100 ng TCDD/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. A stop-exposure group of 50 female rats was administered 100 ng/kg TCDD in corn oil:acetone (99:1) by gavage for 30 weeks and then just the vehicle for the remainder of the study. Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of 100 ng/kg core study and stop-exposure groups were less than those of the vehicle control group after week 13 of the study. Mean body weights of 46 ng/kg rats were less than those of the vehicle controls during year 2 of the study, and those of 22 ng/kg rats were less than those of the

  3. Peripapillary Retinal Nerve Fiber Layer Changes in Preclinical Diabetic Retinopathy: A Meta-Analysis

    PubMed Central

    Chen, Xiaofei; Nie, Chuang; Gong, Yan; Zhang, Ying; Jin, Xin; Wei, Shihui; Zhang, Maonian

    2015-01-01

    Background Diabetic retinopathy is a microvascular neurodegenerative disorder in diabetic patients. Peripapillary retinal nerve fiber layer changes have been described in patients with preclinical diabetic retinopathy, but study results have been inconsistent. Objective To assess changes in peripapillary retinal nerve fiber layer thickness in diabetic patients with preclinical diabetic retinopathy. Methods A literature search was conducted through PubMed, EMBASE, Web of Science and Cochrane Library. Case-control studies on RNFL thickness in preclinical diabetic retinopathy patients and healthy controls were retrieved. A meta-analysis of weighted mean difference and a sensitivity analysis were performed using RevMan 5.2 software. Results Thirteen case-control studies containing 668 diabetic patients and 556 healthy controls were selected. Peripapillary RNFL thickness was significantly reduced in patients with preclinical diabetic retinopathy compared to healthy controls in studies applying Optical Coherence Tomography (-2.88?m, 95%CI: -4.44 to -1.32, P = 0.0003) and in studies applying Scanning Laser Polarimeter (-4.21?m, 95%CI: -6.45 to -1.97, P = 0.0002). Reduction of RNFL thickness was significant in the superior quadrant (-3.79?m, 95%CI: -7.08 to -0.50, P = 0.02), the inferior quadrant (-2.99?m, 95%CI: -5.44 to -0.54, P = 0.02) and the nasal quadrant (-2.88?m, 95%CI: -4.93 to -0.82, P = 0.006), but was not significant in the temporal quadrant (-1.22?m, 95%CI: -3.21 to 0.76, P = 0.23), in diabetic patients. Conclusion Peripapillary RNFL thickness was significantly decreased in preclinical diabetic retinopathy patients compared to healthy control. Neurodegenerative changes due to preclinical diabetic retinopathy need more attention. PMID:25965421

  4. Functional Toxicogenomics: Mechanism-Centered Toxicology

    PubMed Central

    North, Matthew; Vulpe, Chris D.

    2010-01-01

    Traditional toxicity testing using animal models is slow, low capacity, expensive and assesses a limited number of endpoints. Such approaches are inadequate to deal with the increasingly large number of compounds found in the environment for which there are no toxicity data. Mechanism-centered high-throughput testing represents an alternative approach to meet this pressing need but is limited by our current understanding of toxicity pathways. Functional toxicogenomics, the global study of the biological function of genes on the modulation of the toxic effect of a compound, can play an important role in identifying the essential cellular components and pathways involved in toxicity response. The combination of the identification of fundamental toxicity pathways and mechanism-centered targeted assays represents an integrated approach to advance molecular toxicology to meet the challenges of toxicity testing in the 21st century. PMID:21614174

  5. The bioactivity and toxicological actions of carvacrol.

    PubMed

    Suntres, Zacharias E; Coccimiglio, John; Alipour, Misagh

    2015-01-01

    Carvacrol is a monoterpenic phenol produced by an abundant number of aromatic plants, including thyme and oregano. Presently, carvacrol is used in low concentrations as a food flavoring ingredient and preservative, as well as a fragrance ingredient in cosmetic formulations. In recent years, considerable research has been undertaken in an effort to establish the biological actions of carvacrol for its potential use in clinical applications. Results from in vitro and in vivo studies show that carvacrol possess a variety of biological and pharmacological properties including antioxidant, antibacterial, antifungal, anticancer, anti-inflammatory, hepatoprotective, spasmolytic, and vasorelaxant. The focus of this review is to evaluate the existing knowledge regarding the biological, pharmacological, and toxicological effects of carvacrol. PMID:24915411

  6. PHARMACOKINETICS AND METABOLISM OF A SELECTIVE ANDROGEN RECEPTOR MODULATOR IN RATS: IMPLICATION OF MOLECULAR PROPERTIES AND INTENSIVE METABOLIC PROFILE TO INVESTIGATE IDEAL PHARMACOKINETIC CHARACTERISTICS OF A PROPANAMIDE IN PRECLINICAL STUDY

    PubMed Central

    Wu, Di; Wu, Zengru; Yang, Jun; Nair, Vipin A.; Miller, Duane D.; Dalton, James T.

    2007-01-01

    S-1 [3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide] is one member of a series of potent selective androgen receptor modulators (SARMs) that are being explored and developed for androgen-dependent diseases. Recent studies showed that S-1 holds great promise as a novel therapeutic agent for benign hyperplasia [W. Gao, J. D. Kearbey, V. A. Nair, K. Chung, A. F. Parlow, D. D. Miller, and J. T. Dalton (2004) Endocrinology 145:5420–5428]. We examined the pharmacokinetics and metabolism of S-1 in rats as a component of our preclinical development of this compound and continued interest in structure-activation relationships for SARM action. Forty male Sprague-Dawley rats were randomly assigned to treatment groups and received either an i.v. or a p.o. dose of S-1 at a dose level of 0.1, 1, 10, or 30 mg/kg. S-1 demonstrated a low clearance (range, 3.6–5.2 ml/min/kg), a moderate volume of distribution (range, 1460–1560 ml/kg), and a terminal half-life ranging from 3.6 to 5.2 h after i.v. doses. The oral bioavailability of S-1 ranged from 55% to 60%. Forty phase I and phase II metabolites of S-1 were identified in the urine and feces of male Sprague-Dawley rats dosed at 50 mg/kg via the i.v. route. The two major urinary metabolites of S-1 were a carboxylic acid and a sulfate-conjugate of 4-nitro-3-trifluoromethylphenylamine. Phase I metabolites arising from A-ring nitro reduction to an aromatic amine and B-ring hydroxylation were also identified in the urinary and fecal samples of rats. Furthermore, a variety of phase II metabolites through sulfation, glucuronidation, and methylation were also found. These studies demonstrate that S-1 is rapidly absorbed, slowly cleared, moderately distributed, and extensively metabolized in rats. PMID:16381665

  7. A pre-clinical pharmacokinetic study in rats of three naturally occurring iridoid glycosides, Picroside-I, II and III, using a validated simultaneous HPLC-MS/MS assay.

    PubMed

    Zhu, Jianwei; Xue, Bingyang; Ma, Bo; Zhang, Qi; Liu, Ming; Liu, Lei; Yao, Di; Qi, Huanhuan; Wang, Yonglu; Ying, Hanjie; Wu, Zimei

    2015-07-01

    A selective and sensitive high-performance liquid chromatography-electro-spray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed for the simultaneous quantitative determination of Picroside-I, II, and III in rat plasma and tissue homogenate to aid the pre-clinical studies. The chromatographic separation was performed on a Hypersil GOLD AQ C18 column using a gradient elution program with a mobile phase consisting of 2mM ammonium acetate and acetonitrile. The detection was achieved using a triple quadrupole tandem MS in negative ionization multiple reaction monitoring (MRM) mode. One-step protein precipitation was selected for plasma and tissue sample preparation while liquid-liquid extraction failed to achieve satisfactory recoveries. The calibration curves of all three analytes in either plasma or tissue homogenate showed good linearity over the concentration range of 0.5-500ng/mL with a limit of quantitation at 0.5ng/mL. Both the intra- and inter-day accuracy and precision were within ±10%. The extraction recoveries were >70%, and the relative matrix effect ranged from 80.4% to 107.4% in all the biological samples. All the analytes were stable in matrices for at least 24h at room temperature, or 21 days in frozen. Three freeze/thaw cycles did not cause degradation. The method was successfully applied for quantification of the three iridoid glycosides in the collected plasma and various tissues following intravenous administration in rats. Picroside-I, II, and III were all eliminated rapidly with large volume of distribution. Among the three glycosides, Picroside-II showed the highest liver uptake, and only Picroside-I and II were found to get across the blood brain barrier (BBB). These results were consistent with their hepatoprotective or neuroprotective effects reported clinically. With the aid of the efficient and reliable simultaneous LC-ESI-MS/MS assay this pharmacokinetic study provided insights into their therapeutic targets of these three iridoid glycosides as well as valuable experimental basis for an expansion of their clinical indications. PMID:25984965

  8. Evolution of toxicology information systems

    SciTech Connect

    Wassom, J.S.; Lu, P.Y. [Oak Ridge National Laboratory, TN (United States)

    1990-12-31

    Society today is faced with new health risk situations that have been brought about by recent scientific and technical advances. Federal and state governments are required to assess the many potential health risks to exposed populations from the products (chemicals) and by-products (pollutants) of these advances. Because a sound analysis of any potential health risk should be based on the use of relevant information, it behooves those individuals responsible for making the risk assessments to know where to obtain needed information. This paper reviews the origins of toxicology information systems and explores the specialized information center concept that was proposed in 1963 as a means of providing ready access to scientific and technical information. As a means of illustrating this concept, the operation of one specialized information center (the Environmental Mutagen Information Center at Oak Ridge National Laboratory) will be discussed. Insights into how toxicological information resources came into being, their design and makeup, will be of value to those seeking to acquire information for risk assessment purposes. 7 refs., 1 fig., 4 tabs.

  9. Toxicological Assessment of Noxious Inhalants

    PubMed Central

    Kleinsasser, N. H.; Sassen, A. W.; Wallner, B. W.; Staudenmaier, R.; Harréus, U. A.; Richter, E.

    2004-01-01

    In the past centuries mankind has been exposed to various forms of air pollution not only at his occupational but also in his social environment. He mainly gets exposed with these pollutants through the respiratory organs and partially absorbs them into the body. Many of these airborne substances can be harmful for humans and some of them may account for tumorigenic effects. The following essay describes the main features of toxicological assessment of inhalative environmental and workplace xenobiotics. The essay also explains relevant characteristics and limit values of noxious compounds and gases and depicts modern testing methods. To this end, emphasis is given on methods characterizing the different stages of tumorigenic processes. Various test systems have been developed which can be used in vivo, ex vivo or in vitro. They are to a great part based on the evidence of changes in DNA or particular genes of cells. Among others they have highlighted the impact of interindividual variability on enzymatic activation of xenobiotics and on susceptibility of the host to tumor diseases. Unfortunately, for many inhalative environmental noxious agents no sufficient risk profiles have been developed. The completion of these profiles should be the goal of toxicological assessment in order to allow reasonable socioeconomic or individual-based risk reduction. PMID:22073045

  10. The Role of Toxicology in the Pharmacy Curriculum

    ERIC Educational Resources Information Center

    Autian, John; Wood, George

    1976-01-01

    The past history of toxicology courses, recent trends, departments or divisions of toxicology, undergraduate and graduate courses, and residency programs are described. The emphasis of clinical toxicology in the University of Tennessee program is discussed, along with the school's Drug and Toxicology Information Center. (LBH)

  11. Is high pulse pressure a marker of preclinical cardiovascular disease?

    PubMed

    de Simone, Giovanni; Roman, Mary J; Alderman, Michael H; Galderisi, Maurizio; de Divitiis, Oreste; Devereux, Richard B

    2005-04-01

    This study tests the hypothesis that high brachial pulse pressure might constitute preclinical cardiovascular disease, rather than a risk factor. We studied 1250 subjects (472 nonobese normotensive [<135/80 mm Hg] and 778 untreated hypertensive). Central pulse pressure was estimated from brachial pulse pressure and age and divided by stroke volume (PP/SV). Brachial pulse pressure was considered high when >63 mm Hg, and peripheral resistance high when >90th percentile of normal distribution. Among hypertensive subjects, 34% had high resistance; among them, 33% had high brachial pulse pressure, as opposed to 147 of 516 patients (28.5%) with normal resistance (P=not significant). After adjusting for age, sex, race, body mass index, heart rate, and center, left ventricular (LV) internal dimension and mass were lower with high resistance, and higher when brachial pulse pressure was high. PP/SV was 36% higher with high resistance than with normal resistance, and higher when brachial pulse pressure was high (all P<0.0001). Factorial analysis demonstrated that associations of high brachial pulse pressure with both higher PP/SV and LV mass were independent of other pressure components. Thus, because of these associations, our hypothesis is that in hypertension, pulse pressure may be considered as a marker of preclinical cardiovascular disease, similar to LV mass and PP/SV, rather than a cardiovascular risk factor. PMID:15767471

  12. [Pyrethroid resistance in human lice (Anoplura, Pediculidae): toxicological and molecular genetic methods].

    PubMed

    Lopatina, Iu V; Eremina, O Iu; Karan', L S

    2015-01-01

    The paper gives the data obtained in toxicological experiments versus analysis by a real-time polymerase chain reaction assay in permethrin-resistant human lice (VSSC1 gene kdr mutations leading to the amino acid replacements T9171 and L920F have been found). It is shown that the results of toxicological experiments may be indirectly indicative of the genetic composition of a study sample of lice. PMID:25850312

  13. The Substance Abuse Subtle Screening Inventory Minimizes the Need for Toxicology Screening of Prenatal Patients

    Microsoft Academic Search

    Terrence J Horrigan; Nick Piazza

    1999-01-01

    Multiple authors have reported attempts to effectively address the discovery of substance abuse in pregnancy using various mechanisms to encourage positive self-reports and urine toxicology to augment identification. In this study, we evaluated 1,251 patients with (a) self-report, (b) the Substance Abuse Subtle Screening Inventory (SASSI), and (c) urine toxicology screening to determine which modality or combination would yield the

  14. The Impact of Interactive, Computerized Educational Modules on Preclinical Medical Education

    ERIC Educational Resources Information Center

    Bryner, Benjamin S.; Saddawi-Konefka, Daniel; Gest, Thomas R.

    2008-01-01

    Interactive computerized modules have been linked to improved retention of material in clinical medicine. This study examined the effects of a new series of interactive learning modules for preclinical medical education, specifically in the areas of quiz performance, perceived difficulty of concepts, study time, and perceived stress level. We…

  15. Toxicity of Bothrops sp snake venoms from Ecuador and preclinical assessment of the neutralizing efficacy of a polyspecific antivenom from Costa Rica.

    PubMed

    Laines, Johana; Segura, Álvaro; Villalta, Mauren; Herrera, María; Vargas, Mariángela; Alvarez, Gladys; Gutiérrez, José María; León, Guillermo

    2014-09-01

    The toxicological profile of the venoms of the snakes Bothrops asper and Bothrops atrox from Ecuador was investigated, together with the venom of a population of B. asper formerly classified as 'Bothrops xanthogrammus'. The three venoms exerted lethal, hemorrhagic, myotoxic, coagulant and defibrinogenating effects, in agreement with the characteristic toxicological profile of Bothrops sp venoms. A polyspecific antivenom (bothropic-crotalic-lachesic) manufactured in Costa Rica was assessed for its preclinical efficacy against the toxic activities of these Ecuadorian venoms. Antivenom was effective in the neutralization of the five activities tested in the three venoms. These observations are in agreement with previous reports on the extensive cross-reactivity and paraspecific neutralization of antivenoms manufactured in Latin America against the venoms of Bothrops sp snakes. PMID:24950051

  16. Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic.

    PubMed

    Kester, Mark; Bassler, Jocelyn; Fox, Todd E; Carter, Carly J; Davidson, Jeff A; Parette, Mylisa R

    2015-06-01

    Despite the therapeutic potential of sphingolipids, the ability to develop this class of compounds as active pharmaceutical ingredients has been hampered by issues of solubility and delivery. Beyond these technical hurdles, significant challenges in completing the necessary preclinical studies to support regulatory review are necessary for commercialization. This review seeks to identify the obstacles and potential solutions in the translation of a novel liposomal technology from the academic bench to investigational new drug (IND) stage by discussing the preclinical development of the Ceramide NanoLiposome (CNL), which is currently being developed as an anticancer drug for the initial indication of hepatocellular carcinoma (HCC). PMID:25838296

  17. Inhalation reproductive toxicology studies: Sperm morphology study of n-hexane in B6C3F1 mice: Final report

    SciTech Connect

    Mast, T.J.; Hackett, P.L.; Decker, J.R.; Westerberg, R.B.; Sasser, L.B.; McClanahan, B.J.; Rommereim, R.L.; Evanoff, J.J.

    1988-08-01

    The straight-chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent routinely used in industrial environments. Although myelinated nerve tissue is the primary target organ of hexane, the testes have also been identified as being sensitive to hexacarbon exposure. The objective of this study was to evaluate the epididymal sperm morphology of male B6D3F1 mice 5 weeks after exposure to 0, 200, 1000, or 5000 ppM n-hexane, 20 h/day for 5 consecutive days. Two concurrent positive control groups of animals were injected intraperitoneally with either 200 or 250 mg/kg ethyl methanesulfonate, a known mutagen, once each day for 5 consecutive days. The mice were weighed just prior to the first day of exposure and at weekly intervals until sacrifice. During the fifth post-exposure week the animals were killed and examined for gross lesions of the reproductive tract and suspensions of the epididymal sperm were prepared for morphological evaluations. The appearance and behavior of the mice were unremarkable throughout the experiment and there were no deaths. No evidence of lesions in any organ was noted at sacrifice. Mean body weights of male mice exposed to n-hexane were not significantly different from those for the 0-ppM animals at any time during the study. Analyses of the sperm morphology data obtained 5 weeks post-exposure (the only time point examined) indicated that exposure of male mice to relatively high concentrations of n-hexane vapor for 5 days produced no significant effects on the morphology of sperm relative to that of the 0-ppM control group. 24 refs., 2 figs., 7 tabs.

  18. Flexible peritoneal windows for quantitative fluorescence and bioluminescence preclinical imaging.

    PubMed

    Souris, Jeffrey S; Hickson, Jonathan A; Msezane, Lambda; Rinker-Schaeffer, Carrie W; Chen, Chin-Tu

    2013-01-01

    At present, there is considerable interest in the use of in vivo fluorescence and bioluminescence imaging to track the onset and progression of pathologic processes in preclinical models of human disease. Optical quantitation of such phenomena, however, is often problematic, frequently complicated by the overlying tissue's scattering and absorption of light, as well as the presence of endogenous cutaneous and subcutaneous fluorophores. To partially circumvent this information loss, we report here the development of flexible, surgically implanted, transparent windows that enhance quantitative in vivo fluorescence and bioluminescence imaging of optical reporters. These windows are metal and glass free and thus compatible with computed tomography, magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography; they also permit visualization of much larger areas with fewer impediments to animal locomotion and grooming than those previously described. To evaluate their utility in preclinical imaging, we surgically implanted these windows in the abdominal walls of female athymic nude mice and subsequently inoculated each animal with 1 × 10(4) to 1 × 10(6) bioluminescent human ovarian cancer cells (SKOV3ip.1-luc). Longitudinal imaging studies of fenestrated animals revealed up to 48-fold gains in imaging sensitivity relative to nonfenestrated animals, with relatively few complications, allowing wide-field in vivo visualization of nascent metastatic ovarian cancer colonization. PMID:23348789

  19. Artificial Neural Network Analysis in Preclinical Breast Cancer

    PubMed Central

    Motalleb, Gholamreza

    2014-01-01

    Objective: In this study, artificial neural network (ANN) analysis of virotherapy in preclinical breast cancer was investigated. Materials and Methods: In this research article, a multilayer feed-forward neural network trained with an error back-propagation algorithm was incorporated in order to develop a predictive model. The input parameters of the model were virus dose, week and tamoxifen citrate, while tumor weight was included in the output parameter. Two different training algorithms, namely quick propagation (QP) and Levenberg-Marquardt (LM), were used to train ANN. Results: The results showed that the LM algorithm, with 3-9-1 arrangement is more efficient compared to QP. Using LM algorithm, the coefficient of determination (R2) between the actual and predicted values was determined as 0.897118 for all data. Conclusion: It can be concluded that this ANN model may provide good ability to predict the biometry information of tumor in preclinical breast cancer virotherapy. The results showed that the LM algorithm employed by Neural Power software gave the better performance compared with the QP and virus dose, and it is more important factor compared to tamoxifen and time (week). PMID:24381857

  20. Common questions in veterinary toxicology.

    PubMed

    Bates, N; Rawson-Harris, P; Edwards, N

    2015-05-01

    Toxicology is a vast subject. Animals are exposed to numerous drugs, household products, plants, chemicals, pesticides and venomous animals. In addition to the individual toxicity of the various potential poisons, there is also the question of individual response and, more importantly, of species differences in toxicity. This review serves to address some of the common questions asked when dealing with animals with possible poisoning, providing evidence where available. The role of emetics, activated charcoal and lipid infusion in the management of poisoning in animals, the toxic dose of chocolate, grapes and dried fruit in dogs, the use of antidotes in paracetamol poisoning, timing of antidotal therapy in ethylene glycol toxicosis and whether lilies are toxic to dogs are discussed. PMID:25728477

  1. Statistical designs in combination toxicology: a matter of choice.

    PubMed

    Schoen, E D

    1996-01-01

    Combination toxicological studies with statistically designed experiments do not often elaborate on the qualities of the design. Therefore, it may seem that the design used is the only one to meet the objectives of the study. This article demonstrates, on the contrary, that there are often several possibilities. Three recent toxicological experiments, featuring economy of experimentation, robustness against inhomogeneity of experimental material and increasing precision of results, respectively are used for illustration. The alternatives differ statistically in the number of distinct effects for which information can be obtained or in the safeguards to counter both inhomogeneity of material and incorrect models. Practically they differ in complexity of experimental conduct. It is concluded that the choice between the alternatives is a result of balancing practical complexity of the design against informational gain. Continuous co-operation between toxicologists and statisticians is needed to strike the balance again and again. PMID:9119316

  2. NTP Toxicology and Carcinogenesis Studies of Rhodamine 6G (C.I. Basic Red 1) (CAS No. 989-38-8) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    PubMed

    1989-09-01

    NTP Toxicology and Carcinogenesis studies of rhodamine 6G were conducted because of potential human exposure related to its use as a dye for natural and synthetic fibers and as a research chemical. These studies were conducted by administering rhodamine 6G (greater than 95% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies (0, 310, 620, 1,250, 2,500, or 5,000 ppm), all five male and five female rats that received 5,000 ppm and 1/5 male rats that received 2,500 ppm died before the end of the studies; all mice lived to the end of the study. The final mean body weights of rats that received 2,500 ppm were lower than the initial weights. The final mean body weights of mice that received 2,500 or 5,000 ppm were 8% or 18% lower than that of controls for males and 2% or 8% lower for females. In the 13-week studies, all rats lived to the end of the studies (dietary concentrations of 0 or 120-2,000 ppm). The final mean body weights of rats that received 500, 1,000 or 2,000 ppm were 12%, 13%, or 32% lower than that of controls for males and 4%, 8%, or 20% lower for females. Feed consumption by rats that received 2,000 ppm was somewhat lower than that by controls. Bone marrow atrophy was observed at increased incidences and severity in dosed rats. In the 13-week study (0 or 500-8,000 ppm), 1/10 male mice that received the highest concentration died before the end of the studies. The final mean body weights of mice that received 8,000 ppm were lower than the initial mean body weights. The final mean body weights of male mice that received 4,000 ppm and of female mice that received 2,000 or 4,000 ppm were 13%-19% lower than those of controls. Feed consumption was not related to dose. Minimal-to-moderate cytoplasmic vacuolization of hepatocytes was seen in 8/10 male mice that received 8,000 ppm. Based on these results, dietary concentrations selected for the 2-year studies were 0, 120, or 250 ppm rhodamine 6G for rats, 0, 1,000, or 2,000 ppm for male mice, and 0, 500, 1,000 ppm for female mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were similar to those of controls throughout the studies. The average daily feed consumption by dosed rats was within 5% that by controls for all dosed groups. The average amount of rhodamine 6G consumed per day was approximately 5 mg/kg for low dose rats and 10 or 12 mg/kg for high dose male or female rats. Mean body weights of high dose male and dosed female mice were generally 5%-14% lower than those of controls. The average daily feed consumption by dosed mice was within 5% that by controls for all dosed groups. The average amount of rhodamine 6G consumed per day was approximately 210 or 440 mg/kg for low dose or high dose male mice and 125 or 250 mg/kg for low dose or high dose female mice. No significant differences in survival were observed between any groups of rats or mice (male rats: control, 22/50; low dose, 21/50; high dose, 27/50; female rats: 29/50; 30/50; 30/50; male mice: 36/50; 32/50; 38/50; female mice: 39/50; 35/50; 36/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No chemically related nonneoplastic lesions in male or female rats and no chemically related neoplastic or nonneoplastic lesions in male or female mice were observed in these studies. The incidences of keratoacanthomas of the skin was increased in high dose male rats (control, 1/50; low dose, 2/50; high dose, 8/50). The historical incidence of keratoacanthomas in untreated control male F344/N rats is 31/1,936 (1.6%; range, 0/50-7/49). Both fur and skin of rats in the dosed groups apparently were exposed to feed dust containing rhodamine 6G; the intensity of staining was proportional to the concentration of rhodamine 6G in feed. Because of the variable background incidence of keratoacanthomas in F344/N rats, the incidee

  3. Learning Style Preferences of Preclinical Medical Students in Oman

    PubMed Central

    Panambur, Sabitha; Nambiar, Vinod; Heming, Thomas

    2014-01-01

    Objective: Our study sought to assess the learning preferences of students studying in the preclinical years of the medical degree program at Oman Medical College, Sohar.?Methods: In this descriptive, cross-sectional study, we administered a learning style questionnaire (VARK model) to 140 students to assess their preferred mode of learning, specifically the sensory modality by which they prefer to take in information.?Results: Over one third (35%) of the respondents expressed their preference for a single mode of learning, either visual (8%), auditory (9%), read/write (9%), or kinesthetic (9%). The remaining students preferred learning using a combination of either two (14%), three (19%), or four (32%) sensory modalities.?Conclusion: The results of our study provide us with useful information to develop appropriate learning approaches to reach all types of learners at the college. PMID:25584167

  4. Aspects of matrix effects in applications of liquid chromatography-mass spectrometry to forensic and clinical toxicology--a review.

    PubMed

    Peters, Frank T; Remane, Daniela

    2012-06-01

    In the last decade, liquid chromatography coupled to (tandem) mass spectrometry (LC-MS(-MS)) has become a versatile technique with many routine applications in clinical and forensic toxicology. However, it is well-known that ionization in LC-MS(-MS) is prone to so-called matrix effects, i.e., alteration in response due to the presence of co-eluting compounds that may increase (ion enhancement) or reduce (ion suppression) ionization of the analyte. Since the first reports on such matrix effects, numerous papers have been published on this matter and the subject has been reviewed several times. However, none of the existing reviews has specifically addressed aspects of matrix effects of particular interest and relevance to clinical and forensic toxicology, for example matrix effects in methods for multi-analyte or systematic toxicological analysis or matrix effects in (alternative) matrices almost exclusively analyzed in clinical and forensic toxicology, for example meconium, hair, oral fluid, or decomposed samples in postmortem toxicology. This review article will therefore focus on these issues, critically discussing experiments and results of matrix effects in LC-MS(-MS) applications in clinical and forensic toxicology. Moreover, it provides guidance on performance of studies on matrix effects in LC-MS(-MS) procedures in systematic toxicological analysis and postmortem toxicology. PMID:22549818

  5. Relationships between admissions requirements and pre-clinical and clinical performance in a distributed veterinary curriculum.

    PubMed

    Fuentealba, Carmen; Hecker, Kent G; Nelson, Phil D; Tegzes, John H; Waldhalm, Stephen J

    2011-01-01

    The purpose of this study was twofold: first, to assess the relationships between knowledge-based admission requirements and pre-clinical and clinical performance in a distributed model of veterinary education that uses problem-based learning as the main instruction method in the first two years of the curriculum; second, to compare pre-clinical and clinical performance with performance on the Program for the Assessment of Veterinary Education Equivalence (PAVE) exam. Admissions data including overall GPA, prerequisite GPA, Graduate Record Examination (GRE) score on the Analytical, Analytical Writing, Quantitative, and Verbal sections), veterinary school performance data (GPA for pre-clinical and clinical years), and performance PAVE (taken at the end of second year) were analyzed for two classes (N = 155, 85.8% women and 14.2% men). Overall GPA, prerequisite GPA, and GRE Quantitative and Analytical scores were the best predictors for pre-clinical (years 1 and 2) performance (R = 0.49, 23.5% of the variance), GRE Analytical score was the best predictor for year 3 (pre-clinical and clinical) performance (R = 0.25, 6.3% of the variance), GRE Quantitative score was the best predictor for PAVE performance (R = 0.27, 7.5% of the variance), and GRE Analytical score was the best predictor for clinical performance (year 4; R = 0.21, 4.4% of the variance). PAVE scores correlated with GRE Quantitative scores (r = 0.27, p <.01) and veterinary school performance, with higher correlations in the pre-clinical years (rs = 0.67-0.36, p < .01), providing evidence of convergent validity for the PAVE exam. PMID:21805935

  6. Toxicological evaluation of propane expanded tobacco.

    PubMed

    Theophilus, Eugenia H; Bombick, Betsy R; Meckley, Daniel R; Higuchi, Mark A; Borgerding, Michael F; Morton, Michael J; Mosberg, Arnold T; Swauger, James E

    2003-12-01

    A tiered testing strategy has been developed to evaluate the potential for tobacco processes, ingredients, and other technological developments to increase or decrease the biological activity resulting from burning tobacco. The strategy is based on comparative chemical and biological testing. Propane expanded tobacco is an example of a processed tobacco used in the modern manufacture of cigarettes. Test cigarettes containing propane expanded tobacco were compared to control cigarettes containing tobacco expanded with a traditional expansion agent (Freon-11). The toxicological evaluation included chemistry studies using mainstream cigarette smoke (determination of selected constituent yields), in vitro studies using cigarette smoke condensate (Ames study in Salmonella typhimurium and sister chromatid exchange study in Chinese hamster ovary cells) and in vivo studies (13-week inhalation study of mainstream cigarette smoke in Sprague-Dawley rats and 30-week dermal tumor promotion study of cigarette smoke condensate in SENCAR mice). Although statistically significant differences in several smoke constituents were observed, most constituents from cigarettes containing 100% propane expanded tobacco were within market survey ranges. Furthermore, biological tests indicated that the cigarettes containing propane or Freon-11 expanded tobacco were not significantly different. PMID:14563402

  7. IRIS Toxicological Review of Pentachlorophenol (2010 Final)

    EPA Science Inventory

    The final Toxicological Review of Pentachlorophenol provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to pentachlorophenol. Pentachlorophenol is a wood preservative used to prevent decay from fungal organ...

  8. Space Toxicology: Human Health during Space Operations

    NASA Technical Reports Server (NTRS)

    Khan-Mayberry, Noreen; James, John T.; Tyl, ROchelle; Lam, Chiu-Wing

    2010-01-01

    Space Toxicology is a unique and targeted discipline for spaceflight, space habitation and occupation of celestial bodies including planets, moons and asteroids. Astronaut explorers face distinctive health challenges and limited resources for rescue and medical care during space operation. A central goal of space toxicology is to protect the health of the astronaut by assessing potential chemical exposures during spaceflight and setting safe limits that will protect the astronaut against chemical exposures, in a physiologically altered state. In order to maintain sustained occupation in space on the International Space Station (ISS), toxicological risks must be assessed and managed within the context of isolation continuous exposures, reuse of air and water, limited rescue options, and the need to use highly toxic compounds for propulsion. As we begin to explore other celestial bodies in situ toxicological risks, such as inhalation of reactive mineral dusts, must also be managed.

  9. IRIS TOXICOLOGICAL REVIEW OF ACROLEIN (2003 Final)

    EPA Science Inventory

    EPA is announcing the release of the final report, Toxicological Review of Acrolein: in support of the Integrated Risk Information System (IRIS) . The updated Summary for Acrolein and accompanying Quickview have also been added to the IRIS Database....

  10. IRIS Toxicological Review of Hexachloroethane (2011 Final)

    EPA Science Inventory

    EPA is announcing the release of the final report Toxicological Review of Hexachloroethane: in support of the Integrated Risk Information System (IRIS). The updated Summary for Acrylamide and accompanying Quickview have also been added to the IRIS database. ...

  11. Reproductive Toxicology: From Science to Public Policy

    EPA Science Inventory

    Male reproductive toxicology research substantially influences policies that protect men's health. US policy directs regulatory agencies to ensure environmental protection for vulnerable groups, including boys and men where factors like age- and sex-specific sensitivities are app...

  12. COMPUTATIONAL TOXICOLOGY: FRAMEWORK, PARTNERSHIPS, AND PROGRAM DEVELOPMENT

    EPA Science Inventory

    Computational toxicology is a new research initiative being developed within the Office of Research and Development (ORD) of the US Environmental Protection Agency (EPA). Operationally, it is defined as the application of mathematical and computer models together with molecular c...

  13. DTP | Toxicology and Pharmacology Branch (TPB)

    Cancer.gov

    Donzanti, B., P. Tosca, M. Placke, A. Singer, J. Roth, J. Driscoll, J. Kelley and J. Tomaszewski, 1993. Comparative Cardiotoxicity of Dideoxynucleosides in Sprague-Dawley and Fischer 344 Rats. Annual Meeting of the Society of Toxicology, New Orleans, Louisiana.

  14. Pathophysiological Progression Model for Selected Toxicological Endpoints

    EPA Science Inventory

    The existing continuum paradigms are effective models to organize toxicological data associated with endpoints used in human health assessments. A compendium of endpoints characterized along a pathophysiological continuum would serve to: weigh the relative importance of effects o...

  15. IRIS TOXICOLOGICAL REVIEW OF PHOSGENE (2006 Final)

    EPA Science Inventory

    EPA is announcing the release of the final report, Toxicological Review of Phosgene: in support of the Integrated Risk Information System (IRIS) . The updated Summary for Phosgene and accompanying Quickview have also been added to the IRIS Database. ...

  16. Multimodality imaging of hypoxia in preclinical settings

    PubMed Central

    Mason, Ralph P.; Zhao, Dawen; Pacheco-Torres, Jesús; Cui, Weina; Kodibagkar, Vikram D.; Gulaka, Praveen K.; Hao, Guiyang; Thorpe, Philip; Hahn, Eric W.; Peschke, Peter

    2011-01-01

    Hypoxia has long been recognized to influence solid tumor response to therapy. Increasingly, hypoxia has also been implicated in tumor aggressiveness, including growth, development and metastatic potential. Thus, there is a fundamental, as well as a clinical interest, in assessing in situ tumor hypoxia. This review will examine diverse approaches focusing on the pre-clinical setting, particularly, in rodents. The strategies are inevitably a compromise in terms of sensitivity, precision, temporal and spatial resolution, as well as cost, feasibility, ease and robustness of implementation. We will review capabilities of multiple modalities and examine what makes them particularly suitable for investigating specific aspects of tumor pathophysiology. Current approaches range from nuclear imaging to magnetic resonance and optical, with varying degrees of invasiveness and ability to examine spatial heterogeneity, as well as dynamic response to interventions. Ideally, measurements would be non-invasive, exploiting endogenous reporters to reveal quantitatively local oxygen tension dynamics. A primary focus of this review is magnetic resonance imaging (MRI) based techniques, such as 19F MRI oximetry, which reveals not only hypoxia in vivo, but more significantly, spatial distribution of pO2 quantitatively, with a precision relevant to radiobiology. It should be noted that pre-clinical methods may have very different criteria for acceptance, as compared with potential investigations for prognostic radiology or predictive biomarkers suitable for use in patients. PMID:20639813

  17. Toward a new toxicology - evolution or revolution?

    PubMed

    Hartung, Thomas

    2008-12-01

    This essay summarises the author's thoughts on the current paradigm change in toxicology. The driving factors and mechanisms of this change, and obstacles to it, are discussed. Current developments are discussed on the basis of some key assumptions in Thomas Kuhn's famous book, The Structure of Scientific Revolutions. The author's personal view is that there is clear evidence that revolutionary changes in regulatory toxicology are emerging. PMID:19154090

  18. Chemical Risk Assessment in Toxicological Perspective

    Microsoft Academic Search

    Helmut Greim

    \\u000a The discipline of toxicology is concerned with the health risks of human exposure to chemicals. According to the Paracelsus’\\u000a paradigm toxicology is charged with describing the adverse effects of chemicals in a qualitative sense, and with evaluating\\u000a them quantitatively by determining how much of a chemical is required to produce a substance specific. Taken together the\\u000a intrinsic properties of an

  19. Stability of Repeated Student Evaluations of Teaching in the Second Preclinical Year of a Medical Curriculum

    ERIC Educational Resources Information Center

    Krantz-Girod, Catherine; Bonvin, Raphael; Lanares, Jacques; Cueanot, Seagoleine; Feihl, Francois; Bosman, Fred; Waeber, Bernard

    2004-01-01

    The second preclinical year of the medical curriculum at the Medical Faculty of the University of Lausanne in Switzerland includes nine multidisciplinary organ-system-oriented modules consisting of lectures and problem-based-learning tutorials. This study reports the experience accumulated with the evaluation of lectures during the academic years…

  20. Improved Prediction, for Medical Students with Low MCATS, of Indices of Preclinical Performance.

    ERIC Educational Resources Information Center

    Bridgham, Robert G.

    The purpose of this study was to explore the value of variables beyond undergraduate grades and admission test scores in predicting success in the preclinical curriculum of the College of Human Medicine of Michigan State University (East Lansing). Subjects included about 93 students with relatively low scores on the Medical College Admissions Test…

  1. The rationale for and pre-clinical results of chondroitinase ABC in chemonucleolysis

    Microsoft Academic Search

    Mark D Brown

    2001-01-01

    This report details the results of three enzymes, chymopapain, collagenase and chondroitinase ABC (CABC), for chemonucleolysis of the spine intervertebral disc. The deleterious effects of chymopapain and collagenase have led to pre-clinical trials of chondroitinase ABC. Animal studies of chondroitinase ABC are promising with respect to less severe side effects and tissue damage than what has been observed with chymopapain

  2. The distribution of structural neuropathology in pre-clinical Huntington's disease

    Microsoft Academic Search

    M. J. Thieben; A. J. Duggins; C. D. Good; L. Gomes; N. Mahant; F. Richards; E. McCusker; R. S. J. Frackowiak

    2002-01-01

    Summary Putative neuroprotective agents in Huntington's disease may have particular application before brain pathology becomes manifest clinically. If these agents were to be tested in clinical trials, a reliable marker of the burden and rate of progression of pathological change in the pre-clinical group would be needed. The present study investigates whether the Huntington's disease genotype is associated with regional

  3. The automated bioaerosol exposure system: Preclinical platform development and a respiratory dosimetry application with nonhuman primates

    Microsoft Academic Search

    Justin M. Hartings; Chad J. Roy

    2004-01-01

    Introduction: Well-characterized inhalation exposure systems are critical for preclinical testing and pathogenesis studies. The automated bioaerosol exposure system (ABES) provides a microprocessor-driven inhalation platform that provides exquisite data acquisition and control over all aspects of inhalation exposures. Because this represents a new technology, the development and characteristics of the ABES are thoroughly discussed. In addition to control over homeostatic and

  4. Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): V. A 13-week toxicity study of tripeptides-containing casein hydrolysate in male and female rats.

    PubMed

    Mizuno, Seiichi; Mennear, John H; Matsuura, Keiichi; Bernard, Bruce K

    2005-01-01

    The objective of this multiple-dose toxicity study was to assess the toxicological potential of two tripeptides, L-valyl-L-prolyl-L-proline (VPP) and L-isoleucyl-L-prolyl-L-proline (IPP), when administered once daily for 91 consecutive days to rats. The test article, powdered casein hydrolysate (CH) known to contain 0.6% VPP plus IPP, was prepared using Aspergillus oryzae protease. Prior to administration to the rats by oral gavage, the test article was suspended in sterile water. Groups of 12 male and 12 female Charles River rats were administered once daily doses of 0, 40, 200, or 1000 mg of CH (0, 0.2, 1.2, or 6 mg VPP plus IPP/kg body weight [BW]). Antemortem evaluative parameters included gross observations of behavior and clinical signs; food consumption and body weight gains; ophthalmologic examinations; clinical pathology (hematology, clinical chemistry); and urinalysis. Postmortem parameters included determination of absolute and relative (to fasting body weight) organ weights and histopathological evaluation of approximately 50 organs and tissues from each animal. All rats survived until the scheduled termination of the study and no treatment-related clinical signs were observed. Food consumption was unaffected by administration of CH. All animals gained weight and there were no statistical differences between groups with respect to weight gains. There were no meaningful changes in hematological or coagulation parameters. Mid- and high-dose males (but not females) had slightly (< 2%) increased mean serum chloride concentrations, but because the difference was so small and it was observed in only one sex, the authors considered its association with CH administration to be doubtful. Urinalysis revealed the occasional presence of crystals, leukocytes, and epithelial cells in animals from all experimental groups. Similarly, ophthalmic changes (lenticular clouding) were observed in both control and dosed animals. Mean relative (to body weight) kidney weight was decreased by 8% in low-dose males and mean relative uterus weight was elevated 46% in low-dose females. Absolute organ weights were not affected. Only naturally occurring microscopic changes were observed in all groups and none could be attributed to CH administration. It was concluded that, under the conditions of these experiments, the maximally tolerated dose (MTD) and the no-observable-effect level (NOEL) for powdered CH administered once daily for 13 weeks was greater than 1000 mg/kg BW/day or greater than 6 mg of VPP plus IPP/kg BW/day. There was no evidence of target organ toxicity associated with administration of the tripeptides. This corresponds to an margin of safety (MOS) of 60 based upon current thinking regarding incorporation in food. PMID:16419578

  5. Hair: a complementary source of bioanalytical information in forensic toxicology.

    PubMed

    Barroso, Mário; Gallardo, Eugenia; Vieira, Duarte Nuno; López-Rivadulla, Manuel; Queiroz, João António

    2011-01-01

    Hair has been used for years in the assessment and documentation of human exposure to drugs, as it presents characteristics that make it extremely valuable for this purpose, namely the fact that sample collection is performed in a noninvasive manner, under close supervision, the possibility of collecting a specimen reflecting a similar timeline in the case of claims or suspicion of a leak in the chain of custody, and the increased window of detection for the drugs. For these reasons, testing for drugs in hair provides unique and useful information in several fields of toxicology, from which the most prominent is the possibility of studying individual drug use histories by means of segmental analysis. This paper will review the unique role of hair as a complementary sample in documenting human exposure to drugs in the fields of clinical and forensic toxicology and workplace drug testing. PMID:21175368

  6. NTP Toxicology and Carcinogenesis Studies of Barium Chloride Dihydrate (CAS No. 10326-27-9) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).

    PubMed

    1994-01-01

    Barium chloride dihydrate, a white crystalline granule or powder, is used in pigments, aluminum refining, leather tanning and coloring, the manufacture of magnesium metal, ceramics, glass, and paper products, as a pesticide, and in medicine as a cardiac stimulant. Toxicology and carcinogenicity studies were conducted by administering barium chloride dihydrate (99% pure) in drinking water to F344/N rats and B6C3F1 mice for 15 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse lymphoma cells. 15-DAY STUDY IN RATS: Groups of five males and five females received barium chloride dihydrate in the drinking water at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm for 15 days, corresponding to average daily doses of 10, 15, 35, 60, or 110 mg barium/kg body weight to males and females. No chemical-related deaths, differences in final mean body weights, or clinical findings of toxicity were observed. Water consumption by male and female rats exposed to 2,000 ppm was slightly less (S16%) than controls during week 2. There were no significant differences in absolute or relative organ weights between exposed and control rats. No biologically significant differences in hematology, clinical chemistry, or neurobehavioral parameters occurred in rats. 15-DAY STUDY IN MICE: Groups of five males and five females received barium chloride dihydrate in the drinking water at concentrations of 0, 40, 80,173, 346, or 692 ppm for 15 days, corresponding to average daily doses of 5,10, 20, 40, or 70 mg barium/kg body weight to males and 5, 10, 15, 40, or 85 mg barium/kg body weight to females. No chemical-related deaths, differences in mean body weights or in water consumption, or clinical findings of toxicity were observed in mice. The relative liver weight of males receiving 692 ppm was significantly greater than that of the controls. The absolute and relative liver weights of females that received 692 ppm were significantly greater than those of the controls. No histopathologic evidence of toxicity was observed in mice. 13-WEEK STUDY IN RATS: Groups of 10 males and 10 females received barium chloride dihydrate in the drinking water at concentrations of 0, 125, 500, 1,000, 2,000, or 4,000 ppm for 13 weeks, corresponding to average daily doses of 10, 30, 65, 110, or 200 mg barium/kg body weight to males and 10, 35, 65, 115, or 180 mg barium/kg body weight to females. Three males and one female in the 4,000 ppm groups died during the last week of the study. The final mean body weights of male and female rats receiving 4,000 ppm were significantly lower (13% and 8%) than those of the controls. Water consumption by male and female rats in the 4,000 ppm groups was approximately 30% lower than that by the controls. No clearly chemical-related clinical findings of toxicity or neurobehavioral or cardiovascular effects were noted. Serum phosphorus levels in 2,000 and 4,000 ppm male and female rats were significantly higher than those in controls, but there were no biologically significant differences in hematology parameters or in serum sodium, potassium, or calcium levels. Renal tubule dilatation in the outer stripe of the outer medulla and cortex occurred in male and female rats receiving 4,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 males and 10 females received barium chloride dihydrate in the drinking water at concentrations of 0, 125, 500, 1,000, 2,000, or 4,000 ppm for 13 weeks, corresponding to average daily doses of 15, 55, 100, 205, or 450 mg barium/kg body weight to males and 15, 60, 110, 200, or 495 mg barium/kg body weight to females. Six males and seven females that received 4,000 ppm and one male that received 125 ppm died during the study. Final mean body weights of male and female mice receiving 4,000 ppm were significantly lower (>30%) than those of controls. Water consumption by male mice in the 4,000 ppm group was 18% lower than that by the controls; water consumption by other exposed groups of male and female mice was similar to th

  7. Distinguishing between Exploratory and Confirmatory Preclinical Research Will Improve Translation

    PubMed Central

    Kimmelman, Jonathan; Mogil, Jeffrey S.; Dirnagl, Ulrich

    2014-01-01

    Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode. PMID:24844265

  8. Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

    PubMed Central

    Kellar, Amelia; Egan, Cay; Morris, Don

    2015-01-01

    Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer. PMID:26064932

  9. NTP toxicology and carcinogenesis studies of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage Studies).

    PubMed

    2006-01-01

    DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in adipose tissue resulting in chronic lifetime human exposure. Since human exposure to DLCs always occurs as a complex mixture, the Toxic Equivalency Factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD that is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation, because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally-related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 3,3',4,4',5-Pentachlorobiphenyl (PCB 126) was produced commercially before 1977 for the electric industry as a dielectric insulating fluid for transformers and capacitors. Manufacture and use of the chemical was stopped because of increased PCB residues in the environment, but it continues to be released into the environment through the use and disposal of products containing PCBs, as by-products during the manufacture of certain organic chemicals, and during combustion of some waste materials. Bioaccumulation of PCB 126 results in persistent levels in animal and human tissues and the biological responses to PCB 126 are similar to those of TCDD, a known human carcinogen. PCB 126 was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. PCB 126 was included since this is the most potent coplanar PCB that has dioxin-like activities. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report only the results of the PCB 126 study are presented and discussed. Female Harlan Sprague-Dawley rats were administered PCB 126 (99% pure) in corn oil with acetone by gavage for 14, 31, or 53 weeks or 2 years. 2-YEAR STUDY: Groups of 81 female rats were administered 30, 100, 175, 300, 550, or 1,000 ng PCB 126/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 104 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. A group of 28 rats received 10 ng/kg for up to 53 weeks only. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. A stop-exposure group of 50 female rats was administered 1,000 ng/kg PCB 126 in corn oil:acetone (99:1) by gavage for 30 weeks then the vehicle for the remainder of the study. Mean body weights of 30 and 100 ng/kg rats were similar to those of the vehicle controls during most of the study, mean body weights of 175 and 300 ng/kg rats were less than those of the

  10. DSSTOX NATIONAL TOXICOLOGY PROGRAM BIOASSAY ON-LINE DATABASE STRUCTURE-INDEX LOCATOR FILE: SDF FILE AND DOCUMENTATION

    EPA Science Inventory

    NTPBSI: National Toxicology Program Bioassay On-line Database Structure-Index Locator File. Database contains the results collected on approxiately 300 toxicity studies from shorter duration test and from genetic toxicity studies, both in vitro and in vivo tests....

  11. NTP Toxicology and Carcinogenesis Studies of Diglycidyl Resorcinol Ether (Technical Grade) (CAS No. 101-90-6) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1986-10-01

    Diglycidyl resorcinol ether (DGRE), a pale, yellow, translucent, amorphous solid at room temperature, is used as a liquid spray epoxy resin, as a diluent in the production of other epoxy resins used in electrical, tooling, adhesive, and laminating applications, and as a curing agent for polysulfide rubber. Approximately 3,000 workers are exposed to DGRE. The quantity of DGRE produced in the United States is not known. Toxicology and carcinogenesis studies of technical grade diglycidyl resorcinol ether (81% pure) were conducted by administering the chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 25 or 50 mg/kg and to groups of 50 male and female B6C3F1 mice at doses of 50 or 100 mg/kg. A supplemental study of similar design in male and female rats (0 or 12 mg/kg) was started approximately 12 months later because of high mortality in the 50 mg/kg dose groups. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Throughout most of the primary study, mean body weights of high dose male and female rats and female mice were lower than those of the corresponding vehicle controls. In the supplemental study, body weights of both sexes of the dosed rats were unaffected by administration of DGRE. Survival of dosed rats of each sex in the primary study was dose related and was shorter (P<0.001) than that of the vehicle controls. No high dose male rats and only 1/50 high dose female rats lived to the end of the study. Bronchopneumonia was the most frequent cause of early death among the rats and may have resulted from the animals' aspiration of corn oil containing diglycidyl resorcinol ether. Survival of the dosed male rats in the supplemental study was reduced (P<0.005) when compared to controls. There was no significant difference in survival between dosed and control female rats in the supplemental study. Survival of dosed and control mice was comparable but poorer in females, with 20/50 (40%) of the controls, 13/50 (26%) of the low dose, and 10/50 (20%) of the high dose groups alive at the end of 2 years. These early deaths were due to suppurative and necrotizing inflammation of the reproductive tract, possibly caused by a Klebsiella sp. infection. The incidences of rats and mice with hyperkeratosis and hyperplasia of the forestomach were compound related. For rats and mice of each sex, incidences of animals with squamous cell papillomas, squamous cell carcinomas, or both occurred with statistically significant positive trends and the incidences observed in other organs in dosed groups relative to the controls. An audit of the experimental data was conducted for the 2-year studies of diglycidyl resorcinol ether. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, technical grade diglycidyl resorcinol ether caused hyperkeratosis and hyperplasia of the forestomach in rats and mice. DGRE was carcinogenic for male and female F344/N rats and for male and female B6C3F1 mice, causing both benign and malignant neoplasms of the forestomach. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive Synonym: DGRE PMID:12748690

  12. Assessment of the knowledge and attitudes regarding HIV/AIDS among pre-clinical medical students in Israel

    PubMed Central

    2014-01-01

    Background Today’s medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. Methods A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. Results The study’s response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students’ attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students’ attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students’ attitudes were observed during the pre-clinical years of medical school. Conclusion The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students’ attitudes are unaffected by their progression through medical school. Therefore, medical schools in Israel should modify their curricula to include teaching methods aimed at improving HIV-related attitudes and adherence to medical professionalism. PMID:24650351

  13. Toxicologic Pathology, 33:441448, 2005 Copyright C by the Society of Toxicologic Pathology

    E-print Network

    Bortolotti, Gary R.

    Toxicologic Pathology, 33:441­448, 2005 Copyright C by the Society of Toxicologic Pathology ISSN: 0192-6233 print / 1533-1601 online DOI: 10.1080/01926230590953097 Skeletal Pathology in White Storks of Veterinary Pathology, 2 Department of Biology, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada 3

  14. Data governance in predictive toxicology: A review

    PubMed Central

    2011-01-01

    Background Due to recent advances in data storage and sharing for further data processing in predictive toxicology, there is an increasing need for flexible data representations, secure and consistent data curation and automated data quality checking. Toxicity prediction involves multidisciplinary data. There are hundreds of collections of chemical, biological and toxicological data that are widely dispersed, mostly in the open literature, professional research bodies and commercial companies. In order to better manage and make full use of such large amount of toxicity data, there is a trend to develop functionalities aiming towards data governance in predictive toxicology to formalise a set of processes to guarantee high data quality and better data management. In this paper, data quality mainly refers in a data storage sense (e.g. accuracy, completeness and integrity) and not in a toxicological sense (e.g. the quality of experimental results). Results This paper reviews seven widely used predictive toxicology data sources and applications, with a particular focus on their data governance aspects, including: data accuracy, data completeness, data integrity, metadata and its management, data availability and data authorisation. This review reveals the current problems (e.g. lack of systematic and standard measures of data quality) and desirable needs (e.g. better management and further use of captured metadata and the development of flexible multi-level user access authorisation schemas) of predictive toxicology data sources development. The analytical results will help to address a significant gap in toxicology data quality assessment and lead to the development of novel frameworks for predictive toxicology data and model governance. Conclusions While the discussed public data sources are well developed, there nevertheless remain some gaps in the development of a data governance framework to support predictive toxicology. In this paper, data governance is identified as the new challenge in predictive toxicology, and a good use of it may provide a promising framework for developing high quality and easy accessible toxicity data repositories. This paper also identifies important research directions that require further investigation in this area. PMID:21752279

  15. Male golden hamster in male reproductive toxicology testing: Assessment of protective activity of selenium in acute cadmium intoxication

    SciTech Connect

    Wiodarczyk, B.; Biernacki, B.; Minta, M.; Juszkiewicz, T.; Kozaczynski, W. [National Veterinary Research Institute, Pulawy (Poland)

    1995-06-01

    The golden hamster has a short history as a laboratory animal. In spite of this, it has been extensively used as a subject for biomedical research. The hamster has also been utilized in toxicological evaluations, especially in teratology studies. Results of these investigations reveal that laboratory hamsters are very sensitive to many chemical compounds, including: drugs, food additives, industrial chemicals, heavy metals, and other environmental contaminants. The animals most frequently used in toxicological investigations are rats and mice. This is also true in male reproductive toxicology. Apparent differences in species sensitivity to chemical compounds suggest a need to examine a new species in this field of toxicology. A good example of chemical specific differences in species sensitivity is the testicular toxicity of 1,2-dibromo-3-chloropropane (DBCP), which was a testicular toxicant in humans and in rats, but it was not effective, even at relatively high dose levels, in the mouse. From our own vast experience in using hamsters in toxicological studies, we decided to use this laboratory animal in male reproductive toxicology screening tests. The purpose of this study was to determine the suitability of golden hamsters as an experimental animal species for male reproductive toxicology testing. To this effect we have chosen selenium and cadmium as test agents as they were well known for their spectacular effect on the male reproductive system. 13 refs., 1 tab.

  16. Toxicological evaluation of clay minerals and derived nanocomposites: a review.

    PubMed

    Maisanaba, Sara; Pichardo, Silvia; Puerto, María; Gutiérrez-Praena, Daniel; Cameán, Ana M; Jos, Angeles

    2015-04-01

    Clays and clay minerals are widely used in many facets of our society. This review addresses the main clays of each phyllosilicate groups, namely, kaolinite, montmorillonite (Mt) and sepiolite, placing special emphasis on Mt and kaolinite, which are the clays that are more frequently used in food packaging, one of the applications that are currently exhibiting higher development. The improvements in the composite materials obtained from clays and polymeric matrices are remarkable and well known, but the potential toxicological effects of unmodified or modified clay minerals and derived nanocomposites are currently being investigated with increased interest. In this sense, this work focused on a review of the published reports related to the analysis of the toxicological profile of commercial and novel modified clays and derived nanocomposites. An exhaustive review of the main in vitro and in vivo toxicological studies, antimicrobial activity assessments, and the human and environmental impacts of clays and derived nanocomposites was performed. From the analysis of the scientific literature different conclusions can be derived. Thus, in vitro studies suggest that clays in general induce cytotoxicity (with dependence on the clay, concentration, experimental system, etc.) with different underlying mechanisms such as necrosis/apoptosis, oxidative stress or genotoxicity. However, most of in vivo experiments performed in rodents showed no clear evidences of systemic toxicity even at doses of 5000mg/kg. Regarding to humans, pulmonary exposure is the most frequent, and although clays are usually mixed with other minerals, they have been reported to induce pneumoconiosis per se. Oral exposure is also common both intentionally and unintentionally. Although they do not show a high toxicity through this pathway, toxic effects could be induced due to the increased or reduced exposure to mineral elements. Finally, there are few studies about the effects of clay minerals on wildlife, with laboratory trials showing contradictory outcomes. Clay minerals have different applications in the environment, thus with a strict control of the concentrations used, they can provide beneficial uses. Despite the extensive number of reports available, there is also a need of systematic in vitro-in vivo extrapolation studies, with still scarce information on toxicity biomarkers such as inmunomodulatory effects or alteration of the genetic expression. In conclusion, a case by case toxicological evaluation is required taking into account that different clays have their own toxicological profiles, their modification can change this profile, and the potential increase of the human/environmental exposure to clay minerals due to their novel applications. PMID:25732897

  17. Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities*

    SciTech Connect

    Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov [Science and Research Staff, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993–0002 (United States); Cross, Kevin P. [Leadscope, Inc., 1393 Dublin Road, Columbus, OH, 43215–1084 (United States)] [Leadscope, Inc., 1393 Dublin Road, Columbus, OH, 43215–1084 (United States)

    2012-05-01

    Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure–activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity. -- Highlights: ? We characterize a new in silico model to predict mutagenicity of drug impurities. ? The model predicts Salmonella mutagenicity and will be useful for safety assessment. ? We examine toxicity fingerprints and toxicophores of this Ames assay model. ? We compare these attributes to those found in drug impurities known to FDA/CDER. ? We validate the model and find it has a desired predictive performance.

  18. Interregional compensatory mechanisms of motor functioning in progressing preclinical neurodegeneration

    PubMed Central

    Scheller, Elisa; Abdulkadir, Ahmed; Peter, Jessica; Tabrizi, Sarah J.; Frackowiak, Richard S.J.; Klöppel, Stefan

    2013-01-01

    Understanding brain reserve in preclinical stages of neurodegenerative disorders allows determination of which brain regions contribute to normal functioning despite accelerated neuronal loss. Besides the recruitment of additional regions, a reorganisation and shift of relevance between normally engaged regions are a suggested key mechanism. Thus, network analysis methods seem critical for investigation of changes in directed causal interactions between such candidate brain regions. To identify core compensatory regions, fifteen preclinical patients carrying the genetic mutation leading to Huntington's disease and twelve controls underwent fMRI scanning. They accomplished an auditory paced finger sequence tapping task, which challenged cognitive as well as executive aspects of motor functioning by varying speed and complexity of movements. To investigate causal interactions among brain regions a single Dynamic Causal Model (DCM) was constructed and fitted to the data from each subject. The DCM parameters were analysed using statistical methods to assess group differences in connectivity, and the relationship between connectivity patterns and predicted years to clinical onset was assessed in gene carriers. In preclinical patients, we found indications for neural reserve mechanisms predominantly driven by bilateral dorsal premotor cortex, which increasingly activated superior parietal cortices the closer individuals were to estimated clinical onset. This compensatory mechanism was restricted to complex movements characterised by high cognitive demand. Additionally, we identified task-induced connectivity changes in both groups of subjects towards pre- and caudal supplementary motor areas, which were linked to either faster or more complex task conditions. Interestingly, coupling of dorsal premotor cortex and supplementary motor area was more negative in controls compared to gene mutation carriers. Furthermore, changes in the connectivity pattern of gene carriers allowed prediction of the years to estimated disease onset in individuals. Our study characterises the connectivity pattern of core cortical regions maintaining motor function in relation to varying task demand. We identified connections of bilateral dorsal premotor cortex as critical for compensation as well as task-dependent recruitment of pre- and caudal supplementary motor area. The latter finding nicely mirrors a previously published general linear model-based analysis of the same data. Such knowledge about disease specific inter-regional effective connectivity may help identify foci for interventions based on transcranial magnetic stimulation designed to stimulate functioning and also to predict their impact on other regions in motor-associated networks. PMID:23501047

  19. Fucoidan as a Marine Anticancer Agent in Preclinical Development

    PubMed Central

    Kwak, Jong-Young

    2014-01-01

    Fucoidan is a fucose-containing sulfated polysaccharide derived from brown seaweeds, crude extracts of which are commercially available as nutritional supplements. Recent studies have demonstrated antiproliferative, antiangiogenic, and anticancer properties of fucoidan in vitro. Accordingly, the anticancer effects of fucoidan have been shown to vary depending on its structure, while it can target multiple receptors or signaling molecules in various cell types, including tumor cells and immune cells. Low toxicity and the in vitro effects of fucoidan mentioned above make it a suitable agent for cancer prevention or treatment. However, preclinical development of natural marine products requires in vivo examination of purified compounds in animal tumor models. This review discusses the effects of systemic and local administration of fucoidan on tumor growth, angiogenesis, and immune reaction and whether in vivo and in vitro results are likely applicable to the development of fucoidan as a marine anticancer drug. PMID:24477286

  20. Image Informatics for Clinical and Preclinical Biomedical Analysis

    SciTech Connect

    Tobin Jr, Kenneth William [ORNL; Chaum, Edward [ORNL; Gregor, Jens [ORNL; Karnowski, Thomas Paul [ORNL; Wall, Jonathan [ORNL; Price, Jeffery R [ORNL

    2008-01-01

    Biomedical informatics refers to the study of the application of computational and statistical algorithms, data structures, and methods to improve communication, understanding and management of biomedical information. Our objective through this chapter is to describe and demonstrate our research in the use of biomedical image databases - in both preclinical and clinical settings - to classify, predict, research, diagnose, and otherwise learn from the informational content encapsulated in historical image repositories. This will be accomplished by detailing our approach of describing image content in a Bayesian probabilistic framework to achieve learning from retrieved populations of similar images. We will use specific examples from two biomedical applications to describe anatomic segmentation, statistical feature generation and indexing, efficient retrieval architectures, and predictive results.

  1. Ferulic acid: pharmacological and toxicological aspects.

    PubMed

    Mancuso, Cesare; Santangelo, Rosaria

    2014-03-01

    Ferulic acid (FA) belongs to the family of phenolic acids and is very abundant in fruits and vegetables. Over the past years, several studies have shown that FA acts as a potent antioxidant by scavenging free radicals and enhancing the cell stress response through the up-regulation of cytoprotective systems, e.g. heme oxygenase-1, heat shock protein 70, extracellular signal-regulated kinase 1/2 and the proto-oncogene Akt. Furthermore, FA was shown to inhibit the expression and/or activity of cytotoxic enzymes, including inducible nitric oxide synthase, caspases and cyclooxygenase-2. Based on this evidence, FA has been proposed as a potential treatment for many disorders including Alzheimer's disease, cancer, cardiovascular diseases, diabetes mellitus and skin disease. However, despite the great abundance of preclinical research, only a few studies were carried out in humans, the majority of which used foods containing FA, and therefore the clinical efficacy of this mode of administration needs to be further documented. New efforts and resources are needed in clinical research for the complete evaluation of FA therapeutic potential in chronic diseases. PMID:24373826

  2. Organic N-chloramines: chemistry and toxicology.

    PubMed Central

    Scully, F E; Bempong, M A

    1982-01-01

    The stability of aqueous solutions of organic N-chloramines, suspected of contaminating chlorinated water, has been studied. Two factors influence the decomposition of solutions of N-chloropiperidine and N-chlorodiethylamine: a spontaneous decomposition and photodecomposition. Since solutions of these compounds are relatively long-lived, a need for an analytical method for their identification is discussed. A new method is described which involves reaction of organic N-chloramines with arenesulfinic acid salts. The method gives high yields of stable arenesulfonamides. Several toxicological studies of N-chloropiperidine are described. The compound is mutagenic by Ames assay in Salmonella typhimurium strain TA 100 and does not require metabolic activation as indicated in a total body fluids analysis using C57BL/J6 mice. N-Chloropiperidine was subjected to a modified in vitro cell transformation assay using diploid fibroblast cells from Syrian hamster fetuses. A maximum number of foci of 4 per dish was observed at a seeding of 5 X 10(3) cells/60 mm dish. Under similar conditions, MNNG-induced foci ranged from 4 to 7 per dish. PMID:7151751